For the treatment of chronic obstructive pulmonary disease, bronchial asthma and bronchitis.
4.2 Posology and method of administration
Adults
The usually recommended dose of acebrophylline for adults is one Brophyle Capsules twice daily. Acebrophylline capsules are not recommended for use in children (who may find difficulty in swallowing capsules).
In elderly patients dosage may be adjusted if required.
4.3 Contraindications
Hypersensitivity to ambroxol, acebrophylline, theophylline or any other xanthine derivative
Patients suffering from acute myocardial infarction
Patients with hypotension, hemodynamic instability, and arrhythmias
Patients with renal disease or liver disorder
4.4 Special warnings and precautions for use
Careful monitoring is recommended for patients with congestive heart failure, chronic alcoholism, hepatic dysfunction, or viral infections. Caution should be exercised in patients with cardiac arrhythmias, other cardiovascular diseases, hyperthyroidism or hypertension, gastric and duodenal ulceration or convulsive disorders. Patients with hepatic and renal insufficiency should take it with caution.
4.5 Drugs interactions
The following reduce clearance and a reduced dosage may therefore be necessary to avoid side-effects: allopurinol, cimetidine, ciprofloxacin, corticosteroids, diltiazem, erythromycin, frusemide, isoprenaline, oral contraceptives, thiabendazole and verapamil, doxycycline, amoxicillin etc.
Xanthines can potentiate hypokalaemia resulting from beta2-agonist therapy, steroids, diuretics and hypoxia. Particular caution is advised in severe asthma. It is recommended that serum potassium levels are monitored in such situations.
No clinically relevant unfavourable interactions with other medications have been reported.
4.6 Use in special populations
Pregnancy
Acebrophylline is not recommended in pregnancy as well as during parturition.
Lactation
The safety of acebrophylline is not established during lactation period. Hence the use of acebrophylline is not advisable in lactating mothers.
4.7 Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed.
4.8 Undesirable effects
Transient nausea and dizziness may occur on taking this drug, but these effects are reversible. On cessation of therapy, these symptoms tend to disappear.
The commonly reported adverse effects with acebrophylline include abdominal discomfort, stomach/abdominal distension, vomiting, abdominal pain, diarrhea, constipation, heart burn, loss of appetite, esophageal bleeding, rashes, urticaria, itching, drowsiness, difficulty in breathing, leukocytosis, and nasal inflammation. If chills and fevers occur, the drug should be immediately discontinued.
Other rarely reported adverse events include headache, occasional numbness including numbness in arm, insomnia, tachycardia, fatigue, hypertension, albuminuria, glycosuria, hypotension and occasionally hyperglycemia.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
Nausea, vomiting (which is often severe), epigastric pain and haematemesis. Pancreatitis if abdominal pain persists. Restlessness, hypertonia, exaggerated limb reflexes and convulsions. Tachycardia is common.
Symptomatic treatment should be provided.
5.0 Pharmacological properties
5.1 Mechanism of Action
Acebrophylline is a compound which has been found to act as a bronchodilating, mucoregulating and anti-inflammatory drug due to its components theophylline-7-acetate and ambroxol.
Theophylline-7-acetate, as with other xanthinic derivatives, has a bronchodilator effect due to inhibition of the intracellular phosphodiesterases, followed by an increase of adenosine monophosphate cyclic levels, which promote the relaxation of bronchial muscles.
Ambroxol modifies the mucous gel phase of secretions by decreasing the viscosity and increasing the serous gel phase. It increases the mucociliary clearance by stimulating cilia motility.
5.2 Pharmacodynamic properties
Acebrophylline inhibits phospholipase A2 and phosphatidylcholine leading to lesser production of the powerful pro-inflammatory substances like leukotrienes and tumor necrosis factor. By inhibiting the synthesis and release of these inflammatory mediators, acebrophylline reduces inflammation, a key factor in airway obstruction, especially in chronic forms.
5.3 Pharmacokinetic properties
In healthy volunteers, given 200 mg oral acebrophylline, the two components of the molecule ambroxol and theophylline-7 acetic acid are released in the stomach and absorbed in the intestine, reaching optimal concentrations of ambroxol within 2 hours and of theophylline-7 acetic acid after 1 hour. The plasma half-life varies from 4 to 9 hours after oral administration. The drug is metabolized in the liver and eliminated renally.
6.0 Nonclinical properties
6.1 Animal Toxicology or Pharmacology
Negative interference has been reported between theophylline and erythromycin and in animal’s simultaneous administration of theophylline together with erythromycin estolate at doses that alone are non-toxic enhanced the toxicity of the former, as indicated by the drastic drop in the LD50, i.e. the dose causing the death of half the animals. In similar experimental conditions, acebrophylline was not affected by simultaneous use of erythromycin, and not only was there no reduction in the LD50 but in some cases it was actually higher, indicating the safety of the two components as regards their potential tolerability in patients.
7.0 Description
Acebrophylline, an airway mucoregulator and anti-inflammatory agent is a combination product of ambroxol and theophylline 7 acetic acid.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable
8.2 Shelf-life
Refer on pack
8.3 Packaging information
8.4 Storage and handing instructions
Store below 30°C. Protect from light & moisture.
9.0 Patient counselling information
You have been prescribed Acebrophylline for prevention and treatment of asthma and chronic obstructive pulmonary disease (COPD).
It should be taken at the same time each day, preferably in the evening after food.
It does not work right away and should not be used to relieve sudden breathing problems. Always keep a fast-acting (rescue) inhaler with you.
Your doctor may take regular blood test to monitor potassium level and the level of this medicine in your body.
Notify your doctor if you have ever been diagnosed with kidney, liver or heart disease, or if you have a smoking history. Your dose may need to be adjusted.
Do not discontinue use without consulting your doctor, even if you feel better.
12.0 Date of revision
18.05.2022
About Leaflet
Please read this leaflet carefully before you start using this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
What is in this leaflet
What Brophyle is and what it is used for
What you need to know before you use Brophyle
How to use Brophyle
Possible side effects
How to store Brophyle
Contents of the pack and other information
1. What Brophyle is and what it is used for
Brophyle Capsules contain the active substance acebrophylline, which is used to treat chronic obstructive pulmonary disease (COPD), bronchial asthma, and bronchitis. It helps to relax the muscles in the airways and reduces inflammation, making it easier to breathe.
2. What you need to know before you take Brophyle
Do not take Brophyle Capsules if you:
Are allergic to acebrophylline, ambroxol, theophylline, or any other xanthine derivative.
Have had a recent heart attack.
Suffer from low blood pressure, unstable blood circulation, or irregular heartbeats.
Have severe kidney or liver disease.
Warnings and precautions:
Inform your doctor if you have heart failure, chronic alcoholism, liver dysfunction, or viral infections.
Use with caution if you have heart arrhythmias, cardiovascular diseases, hyperthyroidism, hypertension, stomach ulcers, or convulsive disorders.
Patients with liver or kidney insufficiency should use this medicine with caution.
Other medicines and Brophyle Capsules:
Allopurinol, cimetidine, ciprofloxacin, corticosteroids, diltiazem, erythromycin, frusemide, isoprenaline, oral contraceptives, thiabendazole, and verapamil: These medicines can reduce the clearance of acebrophylline, potentially increasing the risk of side effects. Your doctor may need to adjust your dose.
Doxycycline and amoxicillin: These antibiotics can interact with acebrophylline, requiring careful monitoring.
Beta2-agonists, steroids, diuretics, and hypoxia: Xanthines like acebrophylline can potentiate hypokalaemia (low potassium levels) caused by these treatments. Monitoring of serum potassium levels is recommended, especially in severe asthma. No clinically relevant unfavourable interactions with other medications have been reported, but always inform your doctor about all the medicines you are taking.
Pregnancy and breastfeeding:
Brophyle Capsules are not recommended during pregnancy or breastfeeding.
Driving and using machines:
No studies have been conducted on the effects of Brophyle Capsules on the ability to drive or use machines. Use caution until you know how the medicine affects you.
Important Precautions
You have been prescribed Acebrophylline for prevention and treatment of asthma and chronic obstructive pulmonary disease (COPD).
It should be taken at the same time each day, preferably in the evening after food.
It does not work right away and should not be used to relieve sudden breathing problems. Always keep a fast-acting (rescue) inhaler with you.
Your doctor may take regular blood test to monitor potassium level and the level of this medicine in your body. Notify your doctor if you have ever been diagnosed with kidney, liver or heart disease, or if you have a smoking history. Your dose may need to be adjusted. Do not discontinue use without consulting your doctor, even if you feel better.
3. How to take Brophyle
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.
Adults:
The usual dose is one capsule twice daily, preferably in the evening after food.
Elderly:
Dosage may need to be adjusted.
Children:
Not recommended for children who may have difficulty swallowing capsules.
If you use more Brophyle than you should
Tell your doctor if you accidentally use more than you were told.
If you forget to use Brophyle
If you forget to take at the right time, use it as soon as you remember, then carry on as before. Do not take a double dose to make up for a forgotten dose.
If you stop using Brophyle
Do not stop your treatment even if you feel better unless told to do so by your doctor. If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly: Website: www.zuventus.com in and click the tab “Drug Safety Reporting” located on the top end of the home page. Website link: https://www.zuventus.com/drug-safety-reporting. By reporting side effects, you can help provide more information on the safety of this medicine. You can also report the side effect with the help of your treating physician.
5. How to store Brophyle
Keep this medicine out of the sight and reach of children.
Store below 30°C. Protect from light & moisture.
Do not use this medicine after the expiry date which is stated on the label and carton after EXP.
The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
C-Tri XP Injection to be administered by deep intramuscular (I.M.) injection, slow intravenous (I.V.) injection, or as a slow I.V. infusion, after reconstitution with sterile water for injection (SWFI).
Dosage Recommendations in Adults
Usual Recommended Dose : 1.125 g to 2.25 g of C-Tri XP Injection (1 g / 2 g ceftriaxone + 125 mg / 250 mg tazobactam) per day given once a day or in two equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. Tazobactam can be given up to 2 grams per day.
For Uncomplicated Gonococcal Infections : A single dose of 562.5 mg of C-Tri XP Injection (500 mg ceftriaxone + 62.5 mg tazobactam) to be administered by I.M. route. For Preoperative Use (Surgical Prophylaxis) : A single dose of 1.125 g of C-Tri XP Injection (1g ceftriaxone + 125 mg tazobactam) to be administered I.V. 30 minutes to 2 hours before surgery. The usual duration of therapy is 4 to 14 days. In complicated infections, longer therapy may be required.
Or, as prescribed by the physician.
Dosage in Adult Patients with Renal Impairment and Hepatic Dysfunction.
In patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 gram daily. Tazobactam should be used with care in patients with renal impairment or in hemodialysis patients. The I.V. dose and administration interval should be adjusted to the degree of renal function impairment.
Dosage Recommendations in Pediatric Patients
For children with bodyweight above 50 kg or age over 12 years, the usual adult dosage should be administered. Although, ceftriaxone can be administered in neonates and infants, the safety and efficacy of this combination product (ceftriaxone + tazobactam injection) has not been established in children below 2 years of age. Thus, C-Tri XP Injection is recommended only in children above 2 years of age.
Following doses in children are expressed in terms of ceftriaxone content of the formulation. Usual Recommended Dosage : 50 to 75 mg/kg/day, given in divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 2 grams. In children, tazobactam can be given up to 12.5 mg/kg body weight per dose.
Treatment of Meningitis : The initial therapeutic dose should be 100 mg/kg body weight. Thereafter, daily dose of 100 mg/kg may be administered once a day or in equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. The usual duration of therapy is 7 to 14 days depending on the type and severity of infection. Or, as prescribed by the physician.
Pharmaceutical Precautions
Ceftriaxone-containing injection should not be mixed with other drugs in infusion bottle since compatibility has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Directions for reconstitution and dilution for use
Intramuscular injection : Contents of one vial should be dissolved in 0.45 ml of Sterile Water for Injections IP for C-Tri XP-KID 125 mg of injection, 0.9 ml of Sterile Water for Injections IP for C-Tri XP-250 mg injection, 1.8 ml of Sterile Water for Injections IP for C-Tri XP-500 mg injection and 3.6 ml of Sterile Water for Injections IP for C-Tri XP-1 g injection. The solution should be administered by deep intramuscular injection. Doses greater than 1 g (of Ceftriaxaone) should be divided and injected at more than one site.
Intravenous injection : Contents of one vial should be dissolved in 1.2 ml of Sterile Water for Injections IP for C-Tri XP-KID 125 mg of injection, 2.4 ml of Sterile Water for Injections IP for C-Tri XP-250 mg injection, 4.8 ml of Sterile Water for Injections IP for C-Tri XP-500 mg injection and 9.6 ml of Sterile Water for Injections IP for C-Tri XP-1 g injection. The solution should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.
Incompatibility / Interaction with Calcium-Containing Products
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line.
Ceftriaxone with tazobactam must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition.
4.3 Contraindications
In patients with known hypersensitivity to ceftriaxone,cephalosporin class of antibiotics, or to tazobactam or to any component of the formulation.
In hyperbilirubinemic neonates/preterm newborns : Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.
Premature neonates : Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
In neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium.
Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated.
4.4 Special warnings and precautions
Test Dose
Before therapy with ceftriaxone and tazobactam injection is instituted, a test dose is recommended to ascertain possibility of hypersensitivity to ingredients of injection. Serious acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other emergency measures.
Hypersensitivity
Before initiation of therapy, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.
Clostridium Difficile-Associated Diarrhea (CDAD)
CDAD has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Hemolytic Anemia
An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class of antibacterial drugs including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.
Development of Drug-Resistant Bacteria
Prescribing ceftriaxone in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of ceftriaxone may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Pancreatitis
Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, and total parenteral nutrition). A cofactor role of ceftriaxone-related biliary precipitation cannot be ruled out.
Urolithiasis and Post-Renal Acute Renal Failure
Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of appropriate management. Ensure adequate hydration in patients receiving ceftriaxone. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings.
Gallbladder Pseudolithiasis
Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings.
Effect on Prothrombin Time
Alterations in prothrombin times have occurred in patients treated with ceftriaxone. Monitor prothrombin time during ceftriaxone treatment in patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.
Altered Laboratory Tests
Positive direct Coombs' test and galactosemia test, false-positive test for urinary glucose and elevated lactate dehydrogenase (LDH).
4.5 Drug interactions
Ceftriaxone
Amsacrine, Vancomycin, Fluconazole, and Aminoglycosides : Ceftriaxone is incompatible with these drugs.
Oral Contraceptives : Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment.
Chloramphenicol : Caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.
Vitamin K Antagonist : Concomitant use of ceftriaxone with vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone.
Tazobactam
Probenecid : When probenecid administered concomitantly with tazobactam, it prolongs the half-life of tazobactam by 71%. This is because probenecid inhibits tubular renal secretion of tazobactam. Probenecid should not be co-administered with tazobactam unless the benefit outweighs the risk.
4.6 Use in special populations
Pregnancy
Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, C-Tri XP Injection should be used during pregnancy only if clearly needed.
Lactation
Low quantities of both ceftriaxone and tazobactam are excreted in human milk. Therefore, caution should be exercised when C-Tri XP Injection is administered to a nursing woman. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.
Pediatric patients
Safety and effectiveness of ceftriaxone has been established in pediatric patients. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Thus, ceftriaxone-containing preparations should not be administered to hyperbilirubinemic children. Safety and efficacy of C-Tri XP Injection has not been established in children below 2 years of age.
Geriatric patients
Dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 grams per day provided there is no severe renal and hepatic impairment.
4.7 Effects on the ability to drive and use machines
During treatment with ceftriaxone and tazobactam combination, undesirable effects such as dizziness, headache, and convulsions may occur, which may influence the ability to drive and
use machines. If affected by such events, patients should not drive or operate machinery.
4.8 Undesirable effects
Ceftriaxone-containing preparations are generally well tolerated. In clinical trials, the following adverse reactions were observed (related to ceftriaxone therapy or of uncertain etiology).
Local Reactions : Injection site pain, induration, tenderness, phlebitis, warmth, tightness. Hypersensitivity : Rash, pruritus, fever or chills.
Infections and Infestations : Genital fungal infection.
Hematologic : Eosinophilia, thrombocytosis, leukopenia. Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
Blood and Lymphatic Disorders : Granulocytopenia, coagulopathy.
Other rarely observed adverse reactions (< 0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
In the case of overdose nausea, vomiting, and diarrhea can occur. There is no specific antidote. Treatment should be supportive and symptomatic according the patient's clinical presentation.
5.0 Pharmacological properties
5.1 Mechanism of action
Ceftriaxone
Ceftriaxone is a third generation cephalosporin class of beta-lactam antibiotic. Ceftriaxone inhibits bacterial cell wall synthesis and produces bactericidal effect. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gramnegative and Gram-positive bacteria.
Tazobactam
Beta-lactamases are the enzymes produced by certain bacteria to develop resistant to antibiotics. Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins. Tazobactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance.
Rationale of the combination
Ceftriaxone is a third generation semi-synthetic parenteral cephalosporin that has excellent activity against variety of gram -ve organisms and some gram +ve organisms like Streptococcus pneumoniae, Staphylococcus aureus, H.influenzae, Neisseria meningitides and members of Enterobacteriaceae. Ceftriaxone is indicated in number of community and hospital acquired infections caused by the susceptible organisms both in adults and in children including neonates.
Tazobactam is penicillanic acid sulfone derivative with beta-lactamase inhibitory properties, having good affinity for a variety of both plasmid mediated and chromosomal beta lactamases produced by gram +ve and gram –ve bacteria which are originally sensitive to Ceftriaxone. Therefore, it enhances the activity of penicillins and cephalosporins against many resistant strains of bacteria. It is regarded as more potent than other β-lactamase inhibitors (like sulbactam).
Clinical role of Ceftriaxone can be compromised due to increasing proportion of extended spectrum β-lactamase (ESBL) producing bacteria which exhibit resistance to Ceftriaxone. To treat such infections Ceftriaxone can be combined with a beta lactamases inhibitor of better efficacy like Tazobactam. The combination of Ceftriaxone and Tazobactam will be effective not only against the beta lactamase producing organisms but also against the originally Ceftriaxone-susceptible bacteria.
5.2 Pharmacodynamic properties
The combination of ceftriaxone and tazobactam is active against wide variety of beta-lactamase producing gram-positive and gram-negative bacteria. In addition, it demonstrates synergistic activity (reduction in MICs of combination therapy versus ceftriaxone alone) in a variety of organisms which are sensitive to ceftriaxone.
C-Tri XP Injection has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections :
Bacteroides fragilis, Clostridium species, Peptostreptococcus species
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftriaxone. However, the efficacy of ceftriaxone in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.
Gram-negative Bacteria
Citrobacter diversus, Citrobacter freundii, Providencia species (including Providencia rettgeri), Salmonella species (including Salmonella typhi), Shigella species
Absorption : Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 gram is about 81 mg/l and is reached in 2 to 3 hours after administration. The area under the plasma concentrationtime curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.
After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone (Cmax) levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. An 8 to 15 % increase in Cmax is seen on repeated administration; steady state is reached in most cases within 48 to 72 hours depending on the route of administration.
Distribution : The volume of distribution of ceftriaxone is 7 to 12 litre. Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l. Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l).
Metabolism : Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora.
Elimination : Plasma clearance of total ceftriaxone (bound and unbound) is 10 to 22 ml/min. Renal clearance is 5 to 12 ml/min. 50 to 60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40 to 50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.
Tazobactam
Peak plasma concentration is attained immediately after completion of an I.V. infusion. Plasma protein binding of tazobactam is approximately 23%. Tazobactam is widely distributed in tissues and body fluids including intestinal mucosa, gall bladder, lung and bile.
Approximately 20% of a dose of tazobactam is metabolized to a single metabolite that has been found to be microbiologically inactive. Tazobactam is eliminated by the kidney via glomerular filtration and tubular secretion. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the dose appearing as unchanged drug and the remainder of the dose appearing as the metabolite. In healthy subjects, plasma elimination half-life of tazobactam range from 0.7 to 1.2 hours following single or multiple doses.
6.0 Nonclinical properties
6.1 Animal Toxicology or Pharmacology
Ceftriaxone
LD50 values after administration of ceftriaxone by intravenous route were in mice 1840 mg/kg, in rat 2240 mg/kg, and in rabbit 240 mg/kg. LD50 value reported after administration of ceftriaxone by oral route in mice and rats was >10,000 mg/kg. In a 2-week intravenous administration study, groups of eight male Füllinsdorf rats were administered 0, 25 or 60 mg/kg/day of ceftriaxone. Body weight gain was slightly depressed by 9.2 and 20.1% in the 25 and 60 mg/kg/day groups respectively. The average weight of the thyroid glands was increased in the treated groups by 11 to 14% in comparison to the control animals. A 50% reduction in plasma bilirubin in the treated rats was reported along with a decrease in the number of leucocytes. 11 Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies. Carcinogenicity studies on ceftriaxone were not conducted. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 g/day.
Tazobactam
In an embryo-fetal study in rats, tazobactam administered at doses up 3000 mg/kg/day (approximately 19 times the recommended human dose based on body surface area comparison) did not produce maternal toxicity, or fetal toxicity or teratogenicity. Reproductive toxicity : In males, tazobactam had no effect on epididymal and testes weight or mating and fertility indexes. In females, tazobactam did not produce changes in the female estrus cycle length, days in cohabitation, mating index, fertility index, fetal body weight, or fetal gender ratio. In female rats that underwent caesarean section, the number of surviving offspring was reduced to a non-significant degree with the high-dose (640 mg/kg/day) of tazobactam. In high-dose females that were allowed to proceed to delivery without caesarean section, the number of implantations was significantly decreased, and this finding was accompanied by a significant increase in the number of still births and a non-significant decrease in the number of surviving offspring compared to control values. Tazobactam was shown to be negative for mutagenicity or clastogenesis in an Ames assay, a chromosomal aberration assay, and an in vivo micronucleus assay.
7.0 Description
C-Tri XP is a combination of Ceftriaxone, a semi - synthetic third generation broad spectrum cephalosporin antibiotic along with a β- lactamase inhibitor Tazobactam. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.
Ceftriaxone
Ceftriaxone is a beta-lactam, third-generation cephalosporin antibiotic with bactericidal activity.
Molecular Weight : 554.6g/mol.
Molecular Formula : C18H18N8O7S3.
Chemical Name : (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino acetyl]amino]- 3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Tazobactam
Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Tazobactam is a β-lactamase inhibitor given in combination with β-lactam antibiotics to inhibit β-lactamase, an enzyme produced by bacteria that destroys antibiotic activity.
Molecular Weight : 322.28g/mol.
Molecular Formula : C10H11N4NaO5S.
Chemical Name : Sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4- thia-1- azabicyclo[3.2.0] heptane-2-carboxylate-4,4-dioxide.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
8.2 Shelf-life
Refer to the pack.
8.3 Packaging information
C-Tri XP KID 125 mg : A vial of 140.625 mg with SWFI IP 5 ml.
C-Tri XP 250 mg : A vial of 281.25 mg with SWFI IP 5 ml.
C-Tri XP 500 mg : A vial of 562.5 mg with SWFI IP 5 ml.
C-Tri XP 1 g : A vial of 1.125 g with SWFI IP 10 ml.
8.4 Storage and handling instructions
Store below 30°C. Protect from light & moisture.
Keep out of reach of children. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.
9.0 Patient counselling information
Instruct patient to store medication as advised and not to expose the vial to moisture or direct light.
The medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of therapy and increase the likelihood that bacteria will develop antimicrobial resistance.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools even as late as two months after the last dose of the antibiotic. If this occurs, instruct patients to contact their physician immediately.
Instruct patient not to freeze the reconstituted solution and use it immediately after the preparation. Unused portion of solution, if any, should be discarded.
C-Tri XP Injection to be administered by deep intramuscular (I.M.) injection, slow intravenous (I.V.) injection, or as a slow I.V. infusion, after reconstitution with sterile water for injection (SWFI).
Dosage Recommendations in Adults
Usual Recommended Dose : 1.125 g to 2.25 g of C-Tri XP Injection (1 g / 2 g ceftriaxone + 125 mg / 250 mg tazobactam) per day given once a day or in two equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. Tazobactam can be given up to 2 grams per day.
For Uncomplicated Gonococcal Infections : A single dose of 562.5 mg of C-Tri XP Injection (500 mg ceftriaxone + 62.5 mg tazobactam) to be administered by I.M. route. For Preoperative Use (Surgical Prophylaxis) : A single dose of 1.125 g of C-Tri XP Injection (1g ceftriaxone + 125 mg tazobactam) to be administered I.V. 30 minutes to 2 hours before surgery. The usual duration of therapy is 4 to 14 days. In complicated infections, longer therapy may be required.
Or, as prescribed by the physician.
Dosage in Adult Patients with Renal Impairment and Hepatic Dysfunction.
In patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 gram daily. Tazobactam should be used with care in patients with renal impairment or in hemodialysis patients. The I.V. dose and administration interval should be adjusted to the degree of renal function impairment.
Dosage Recommendations in Pediatric Patients
For children with bodyweight above 50 kg or age over 12 years, the usual adult dosage should be administered. Although, ceftriaxone can be administered in neonates and infants, the safety and efficacy of this combination product (ceftriaxone + tazobactam injection) has not been established in children below 2 years of age. Thus, C-Tri XP Injection is recommended only in children above 2 years of age.
Following doses in children are expressed in terms of ceftriaxone content of the formulation. Usual Recommended Dosage : 50 to 75 mg/kg/day, given in divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 2 grams. In children, tazobactam can be given up to 12.5 mg/kg body weight per dose.
Treatment of Meningitis : The initial therapeutic dose should be 100 mg/kg body weight. Thereafter, daily dose of 100 mg/kg may be administered once a day or in equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. The usual duration of therapy is 7 to 14 days depending on the type and severity of infection. Or, as prescribed by the physician.
Pharmaceutical Precautions
Ceftriaxone-containing injection should not be mixed with other drugs in infusion bottle since compatibility has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Directions for reconstitution and dilution for use
Intramuscular injection : Contents of one vial should be dissolved in 0.45 ml of Sterile Water for Injections IP for C-Tri XP-KID 125 mg of injection, 0.9 ml of Sterile Water for Injections IP for C-Tri XP-250 mg injection, 1.8 ml of Sterile Water for Injections IP for C-Tri XP-500 mg injection and 3.6 ml of Sterile Water for Injections IP for C-Tri XP-1 g injection. The solution should be administered by deep intramuscular injection. Doses greater than 1 g (of Ceftriaxaone) should be divided and injected at more than one site.
Intravenous injection : Contents of one vial should be dissolved in 1.2 ml of Sterile Water for Injections IP for C-Tri XP-KID 125 mg of injection, 2.4 ml of Sterile Water for Injections IP for C-Tri XP-250 mg injection, 4.8 ml of Sterile Water for Injections IP for C-Tri XP-500 mg injection and 9.6 ml of Sterile Water for Injections IP for C-Tri XP-1 g injection. The solution should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.
Incompatibility / Interaction with Calcium-Containing Products
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line.
Ceftriaxone with tazobactam must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition.
4.3 Contraindications
In patients with known hypersensitivity to ceftriaxone,cephalosporin class of antibiotics, or to tazobactam or to any component of the formulation.
In hyperbilirubinemic neonates/preterm newborns : Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.
Premature neonates : Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
In neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium.
Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated.
4.4 Special warnings and precautions
Test Dose
Before therapy with ceftriaxone and tazobactam injection is instituted, a test dose is recommended to ascertain possibility of hypersensitivity to ingredients of injection. Serious acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other emergency measures.
Hypersensitivity
Before initiation of therapy, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.
Clostridium Difficile-Associated Diarrhea (CDAD)
CDAD has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Hemolytic Anemia
An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class of antibacterial drugs including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.
Development of Drug-Resistant Bacteria
Prescribing ceftriaxone in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of ceftriaxone may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Pancreatitis
Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, and total parenteral nutrition). A cofactor role of ceftriaxone-related biliary precipitation cannot be ruled out.
Urolithiasis and Post-Renal Acute Renal Failure
Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of appropriate management. Ensure adequate hydration in patients receiving ceftriaxone. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings.
Gallbladder Pseudolithiasis
Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings.
Effect on Prothrombin Time
Alterations in prothrombin times have occurred in patients treated with ceftriaxone. Monitor prothrombin time during ceftriaxone treatment in patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.
Altered Laboratory Tests
Positive direct Coombs' test and galactosemia test, false-positive test for urinary glucose and elevated lactate dehydrogenase (LDH).
4.5 Drug interactions
Ceftriaxone
Amsacrine, Vancomycin, Fluconazole, and Aminoglycosides : Ceftriaxone is incompatible with these drugs.
Oral Contraceptives : Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment.
Chloramphenicol : Caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.
Vitamin K Antagonist : Concomitant use of ceftriaxone with vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone.
Tazobactam
Probenecid : When probenecid administered concomitantly with tazobactam, it prolongs the half-life of tazobactam by 71%. This is because probenecid inhibits tubular renal secretion of tazobactam. Probenecid should not be co-administered with tazobactam unless the benefit outweighs the risk.
4.6 Use in special populations
Pregnancy
Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, C-Tri XP Injection should be used during pregnancy only if clearly needed.
Lactation
Low quantities of both ceftriaxone and tazobactam are excreted in human milk. Therefore, caution should be exercised when C-Tri XP Injection is administered to a nursing woman. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.
Pediatric patients
Safety and effectiveness of ceftriaxone has been established in pediatric patients. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Thus, ceftriaxone-containing preparations should not be administered to hyperbilirubinemic children. Safety and efficacy of C-Tri XP Injection has not been established in children below 2 years of age.
Geriatric patients
Dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 grams per day provided there is no severe renal and hepatic impairment.
4.7 Effects on the ability to drive and use machines
During treatment with ceftriaxone and tazobactam combination, undesirable effects such as dizziness, headache, and convulsions may occur, which may influence the ability to drive and
use machines. If affected by such events, patients should not drive or operate machinery.
4.8 Undesirable effects
Ceftriaxone-containing preparations are generally well tolerated. In clinical trials, the following adverse reactions were observed (related to ceftriaxone therapy or of uncertain etiology).
Local Reactions : Injection site pain, induration, tenderness, phlebitis, warmth, tightness. Hypersensitivity : Rash, pruritus, fever or chills.
Infections and Infestations : Genital fungal infection.
Hematologic : Eosinophilia, thrombocytosis, leukopenia. Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
Blood and Lymphatic Disorders : Granulocytopenia, coagulopathy.
Other rarely observed adverse reactions (< 0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
In the case of overdose nausea, vomiting, and diarrhea can occur. There is no specific antidote. Treatment should be supportive and symptomatic according the patient's clinical presentation.
5.0 Pharmacological properties
5.1 Mechanism of action
Ceftriaxone
Ceftriaxone is a third generation cephalosporin class of beta-lactam antibiotic. Ceftriaxone inhibits bacterial cell wall synthesis and produces bactericidal effect. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gramnegative and Gram-positive bacteria.
Tazobactam
Beta-lactamases are the enzymes produced by certain bacteria to develop resistant to antibiotics. Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins. Tazobactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance.
Rationale of the combination
Ceftriaxone is a third generation semi-synthetic parenteral cephalosporin that has excellent activity against variety of gram -ve organisms and some gram +ve organisms like Streptococcus pneumoniae, Staphylococcus aureus, H.influenzae, Neisseria meningitides and members of Enterobacteriaceae. Ceftriaxone is indicated in number of community and hospital acquired infections caused by the susceptible organisms both in adults and in children including neonates.
Tazobactam is penicillanic acid sulfone derivative with beta-lactamase inhibitory properties, having good affinity for a variety of both plasmid mediated and chromosomal beta lactamases produced by gram +ve and gram –ve bacteria which are originally sensitive to Ceftriaxone. Therefore, it enhances the activity of penicillins and cephalosporins against many resistant strains of bacteria. It is regarded as more potent than other β-lactamase inhibitors (like sulbactam).
Clinical role of Ceftriaxone can be compromised due to increasing proportion of extended spectrum β-lactamase (ESBL) producing bacteria which exhibit resistance to Ceftriaxone. To treat such infections Ceftriaxone can be combined with a beta lactamases inhibitor of better efficacy like Tazobactam. The combination of Ceftriaxone and Tazobactam will be effective not only against the beta lactamase producing organisms but also against the originally Ceftriaxone-susceptible bacteria.
5.2 Pharmacodynamic properties
The combination of ceftriaxone and tazobactam is active against wide variety of beta-lactamase producing gram-positive and gram-negative bacteria. In addition, it demonstrates synergistic activity (reduction in MICs of combination therapy versus ceftriaxone alone) in a variety of organisms which are sensitive to ceftriaxone.
C-Tri XP Injection has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections :
Bacteroides fragilis, Clostridium species, Peptostreptococcus species
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftriaxone. However, the efficacy of ceftriaxone in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.
Gram-negative Bacteria
Citrobacter diversus, Citrobacter freundii, Providencia species (including Providencia rettgeri), Salmonella species (including Salmonella typhi), Shigella species
Absorption : Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 gram is about 81 mg/l and is reached in 2 to 3 hours after administration. The area under the plasma concentrationtime curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.
After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone (Cmax) levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. An 8 to 15 % increase in Cmax is seen on repeated administration; steady state is reached in most cases within 48 to 72 hours depending on the route of administration.
Distribution : The volume of distribution of ceftriaxone is 7 to 12 litre. Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l. Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l).
Metabolism : Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora.
Elimination : Plasma clearance of total ceftriaxone (bound and unbound) is 10 to 22 ml/min. Renal clearance is 5 to 12 ml/min. 50 to 60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40 to 50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.
Tazobactam
Peak plasma concentration is attained immediately after completion of an I.V. infusion. Plasma protein binding of tazobactam is approximately 23%. Tazobactam is widely distributed in tissues and body fluids including intestinal mucosa, gall bladder, lung and bile.
Approximately 20% of a dose of tazobactam is metabolized to a single metabolite that has been found to be microbiologically inactive. Tazobactam is eliminated by the kidney via glomerular filtration and tubular secretion. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the dose appearing as unchanged drug and the remainder of the dose appearing as the metabolite. In healthy subjects, plasma elimination half-life of tazobactam range from 0.7 to 1.2 hours following single or multiple doses.
6.0 Nonclinical properties
6.1 Animal Toxicology or Pharmacology
Ceftriaxone
LD50 values after administration of ceftriaxone by intravenous route were in mice 1840 mg/kg, in rat 2240 mg/kg, and in rabbit 240 mg/kg. LD50 value reported after administration of ceftriaxone by oral route in mice and rats was >10,000 mg/kg. In a 2-week intravenous administration study, groups of eight male Füllinsdorf rats were administered 0, 25 or 60 mg/kg/day of ceftriaxone. Body weight gain was slightly depressed by 9.2 and 20.1% in the 25 and 60 mg/kg/day groups respectively. The average weight of the thyroid glands was increased in the treated groups by 11 to 14% in comparison to the control animals. A 50% reduction in plasma bilirubin in the treated rats was reported along with a decrease in the number of leucocytes. 11 Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies. Carcinogenicity studies on ceftriaxone were not conducted. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 g/day.
Tazobactam
In an embryo-fetal study in rats, tazobactam administered at doses up 3000 mg/kg/day (approximately 19 times the recommended human dose based on body surface area comparison) did not produce maternal toxicity, or fetal toxicity or teratogenicity. Reproductive toxicity : In males, tazobactam had no effect on epididymal and testes weight or mating and fertility indexes. In females, tazobactam did not produce changes in the female estrus cycle length, days in cohabitation, mating index, fertility index, fetal body weight, or fetal gender ratio. In female rats that underwent caesarean section, the number of surviving offspring was reduced to a non-significant degree with the high-dose (640 mg/kg/day) of tazobactam. In high-dose females that were allowed to proceed to delivery without caesarean section, the number of implantations was significantly decreased, and this finding was accompanied by a significant increase in the number of still births and a non-significant decrease in the number of surviving offspring compared to control values. Tazobactam was shown to be negative for mutagenicity or clastogenesis in an Ames assay, a chromosomal aberration assay, and an in vivo micronucleus assay.
7.0 Description
C-Tri XP is a combination of Ceftriaxone, a semi - synthetic third generation broad spectrum cephalosporin antibiotic along with a β- lactamase inhibitor Tazobactam. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.
Ceftriaxone
Ceftriaxone is a beta-lactam, third-generation cephalosporin antibiotic with bactericidal activity.
Molecular Weight : 554.6g/mol.
Molecular Formula : C18H18N8O7S3.
Chemical Name : (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino acetyl]amino]- 3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Tazobactam
Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Tazobactam is a β-lactamase inhibitor given in combination with β-lactam antibiotics to inhibit β-lactamase, an enzyme produced by bacteria that destroys antibiotic activity.
Molecular Weight : 322.28g/mol.
Molecular Formula : C10H11N4NaO5S.
Chemical Name : Sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4- thia-1- azabicyclo[3.2.0] heptane-2-carboxylate-4,4-dioxide.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
8.2 Shelf-life
Refer to the pack.
8.3 Packaging information
C-Tri XP KID 125 mg : A vial of 140.625 mg with SWFI IP 5 ml.
C-Tri XP 250 mg : A vial of 281.25 mg with SWFI IP 5 ml.
C-Tri XP 500 mg : A vial of 562.5 mg with SWFI IP 5 ml.
C-Tri XP 1 g : A vial of 1.125 g with SWFI IP 10 ml.
8.4 Storage and handling instructions
Store below 30°C. Protect from light & moisture.
Keep out of reach of children. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.
9.0 Patient counselling information
Instruct patient to store medication as advised and not to expose the vial to moisture or direct light.
The medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of therapy and increase the likelihood that bacteria will develop antimicrobial resistance.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools even as late as two months after the last dose of the antibiotic. If this occurs, instruct patients to contact their physician immediately.
Instruct patient not to freeze the reconstituted solution and use it immediately after the preparation. Unused portion of solution, if any, should be discarded.
For the treatment of diarrhea of mixed infection in adult patients only.
4.2 Posology and method of administration
Dose of Ofloxacin is 15 mg/kg/day and that of Metronidazole is 30 mg/kg/day in two divided doses. Therefore, New Normet suspension containing 100 mg of Ofloxacin and 200 mg of Metronidazole in each 5 ml is an appropriate combination.
Dosage: As advised by the physician.
Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involves the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended. Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage.
Pediatric Use
Safety and effectiveness in pediatric patients and adolescents below the age of 18 years have not been established. Ofloxacin causes arthropathy (arthrosis) and osteochondrosis in juvenile animals of several species.
Safety and effectiveness of metronidazole in pediatric patients have not been established, except for the treatment of amebiasis.
4.3 Contraindications
Patients hypersensitivity to any fluoroquinolone antibacterials.
Patients having history of epilepsy or tendon disorders or CNS disorder with a lowered seizure threshold should be avoided giving ofloxacin formulation.
Ofloxacin shall not be prescribed to Adolescent, pregnant or breastfeeding women, since animal experiments do not entirely exclude the risk of damage to the growth-plate cartilage.
In patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they more prone to haemolytic reactions when treated with quinolone antibacterial agents.
Ofloxacin is not the drug of first choice in pneumonia, caused by Streptococcus pneumoniae or Chlamydia pneumonia, Methicillin resistant S. aureus. Ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to ofloxacin.
Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
In patients with trichomoniasis, metronidazole is contraindicated during the first trimester of pregnancy.
Use of metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks.
Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole.
4.4 Special warnings and precautions for use
Ofloxacin
Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitisand Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects:
Fluoroquinolones, including ofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. Discontinue ofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
Tendinopathy and Tendon Rupture: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. Discontinue ofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Peripheral Neuropathy: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ofloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients. Discontinue ooxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ofloxacin, in patients who have previously experienced peripheral neuropathy.
Central Nervous System Effects: Psychiatric Adverse Reactions: Fluoroquinolones, including ooxacin, have been associated with an increased risk of psychiatric adverse reactions, including toxic psychoses or hallucinations; agitation; delirium, confusion, disorientation, or disturbances in attention; nervousness or restlessness, memory impairment. If these reactions occur in patients receiving ofloxacin, the drug should be discontinued and appropriate measures instituted.
Central Nervous System Adverse Reactions: Fluoroquinolones have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), lightheadedness, or tremors.The effects of ofloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, ofloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. Exacerbation of Myasthenia Gravis: Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid ofloxcain in patients with known history of myasthenia gravis. The safety and efficacy of ofloxacin in pediatric patients and adolescents (under the age of 18 years), pregnant women, and lactating women have not been established.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones, including ofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. This drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous incluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and
some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
interstitial nephritis; acute renal insufficiency or failure;
hepatitis; jaundice; acute hepatic necrosis or failure;
anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice or any other sign of hypersensitivity and supportive measures instituted.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ofloxacin tablets, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
General:
Prescribing ofloxacin tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Adequate hydration of patients receiving ofloxacin should be maintained to prevent the formation of a highly concentrated urine.
Administer ofloxacin with caution in the presence of renal or hepatic insufficiency/impairment. In patients with known or suspected renal or hepatic insufficiency/impairment, careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of ofloxacin may be reduced. In patients with impaired renal function (creatinine clearance ≤ 50 mg/mL), alteration of the dosage regimen is necessary.
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs.
As with other quinolones, ofloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction).
A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide) or with insulin and fluoroquinolone antimicrobial agents have been reported resulting in a potentiation of the hypoglycemic action of these drugs, sometimes resulting in coma or death. The mechanism for this interaction is not known. If a hypoglycemic reaction occurs in a patient being treated with ofloxacin, discontinue ofloxacin immediately and consult a physician. As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.
Torsades de pointes
Some quinolones, including ofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving quinolones, including ofloxacin. Ofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.
Metronidazole
Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Metronidazole for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions, such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures).
Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.
Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued.
Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking metronidazole.
Cases of severe bullous skin reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalised exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SJS, TEN or AGEP are present, Metronidazole treatment must be immediately discontinued.
Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Metronidazole should therefore, be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.
Psychotic Reaction with Disulfiram
Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks.
Interaction with Alcohol
Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headache, flushing, throbbing headache, rapid heartbeat, palpitation, sweating, thirst, chest pain, lightheadness, blurred vision, dizziness and difficulty in breathing. Rarely more severe reactions may include abnormal heart rhythm, heart attack, heart failure, unconsciousness, convulsions and even death. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole.
Central and Peripheral Nervous System Effects
Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.
Hepatic Impairment
Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of metronidazole is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events.
Renal Impairment
Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended.
Fungal Superinfections
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent.
Use in Patients with Blood Dyscrasias
Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.
Drug-Resistant Bacteria and Parasites
Prescribing metronidazole in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.
4.5 Drugs interactions
Ofloxacin
Antacids, Sucralfate, Metal Cations, Multivitamins
Quinolones form chelates with alkaline earth and transition metal cations. Administration of quinolones with antacids containing calcium, magnesium, or aluminum, with sucralfate, with divalent or trivalent cations such as iron, or with multivitamins containing zinc or with didanosine, may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the twohour period after ofloxacin administration.
Caffeine
Interactions between ofloxacin and caffeine have not been detected.
Cimetidine
Cimetidine has demonstrated interference with the elimination of some quinolones. This interference has resulted in significant increases in half-life and AUC of some quinolones. The potential for interaction between ofloxacin and cimetidine has not been studied.
Cyclosporine
Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with some other quinolones. The potential for interaction between ofloxacin and cyclosporine has not been studied.
Drugs Metabolized by Cytochrome P450 Enzymes
Most quinolone antimicrobial drugs inhibit cytochrome P450 enzyme activity. This may result in a prolonged half-life for some drugs that are also metabolized by this system (e.g., cyclosporine, theophylline/methylxanthines, warfarin) when co-administered with quinolones. The extent of this inhibition varies among different quinolones.
Non-Steroidal Anti-Inflammatory Drugs
The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures.
Probenecid
The concomitant use of probenecid with certain other quinolones has been reported to affect renal tubular secretion. The effect of probenecid on the elimination of ofloxacin has not been studied.
Theophylline
Steady-state theophylline levels may increase when ofloxacin and theophylline are administered concurrently. As with other quinolones, concomitant administration of ofloxacin may prolong the half life of theophylline, elevate serum theophylline levels, and increase the risk of theophylline-related adverse reactions. Theophylline levels should be closely monitored and theophylline dosage adjustments made, if appropriate, when ofloxacin is co-administered. Adverse reactions (including seizures) may occur with or without an elevation in the serum theophylline level.
Warfarin
Some quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Therefore, if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored.
Since disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concurrently with quinolones and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly.
Interaction with Laboratory or Diagnostic Testing
Some quinolones, including ofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.
Metronidazole
Disulfiram
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.
Alcoholic Beverages
Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy.
Warfarin and other Oral Anticoagulants
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.
Lithium
In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.
Busulfan
Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.
Drugs that Inhibit CYP450 Enzymes
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.
Drugs that Induce CYP450 Enzymes
The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.
Drug/Laboratory Test Interactions
Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
4.6 Use in special populations
Pregnancy
There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justies the potential risk to the foetus.
There are no adequate and well controlled studies of Metronidazole in pregnant women. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the foetus due to metronidazole.
Nursing Mothers
Because of the potential for serious adverse reactions from ooxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.
4.7 Effects on ability to drive and use machines
Since there have been occasional reports of drowsiness/somnolence, impairment of skills, dizziness/vertigo and visual disturbances, which may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery); patients should advised not to drive or operate machinery if these symptoms occur. These effects may be enhanced by alcohol.
4.8 Undesirable effects
Ofloxacin
In clinical trials, the following events were considered likely to be drug-related in patients receiving multiple doses of ofloxacin: nausea, insomnia, headache, dizziness, diarrhea, vomiting, rash, pruritus, external genital pruritus in women, vaginitis, dysgeusia.
In clinical trials, the most frequently reported adverse events, regardless of relationship to drug, were: nausea, headache, insomnia, external genital pruritus in women, dizziness, vaginitis, diarrhea, vomiting.
In clinical trials, the following events, regardless of relationship to drug, occurred in 1 to 3% of patients: abdominal pain and cramps, chest pain, decreased appetite, dry mouth, dysgeusia, fatigue, fatulence, gastrointestinal distress, nervousness, pharyngitis, pruritus, fever, rash, sleep disorders, somnolence, trunk pain, vaginal discharge, visual disturbances, and constipation.
Additional events, occurring in clinical trials at a rate of less than 1%, regardless of relationship to drug, were :
The following laboratory abnormalities appeared in ≥1% of patients receiving multiple doses of ofloxacin. It is not known whether these abnormalities were caused by the drug or the underlying conditions being treated.
In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with other quinolones. The relationship of the drugs to these events is not presently established.
Metronidazole
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
Symptoms-The most important signs to be expected following acute overdose are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures increases in QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions.
Management-In the case of overdose steps to remove any unabsorbed ofloxacin e.g. gastric lavage, administration of adsorbants and sodium sulphate, if possible during the first 30 minutes, are recommended; antacids are recommended for protection of the gastric mucosa. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. No specific antidote exists. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.
5.0 Pharmacological properties
5.1 Mechanism of Action
Ofloxacin inhibits bacterial DNA replication by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV. The nitro group of metronidazole acts as electron acceptor and is thus reduced to a chemically reactive drug form. This produces biochemical lesions in the cells, thus causing death. The major site of action is believed to be DNA, where it causes loss of the helical structure and inhibits synthesis.
5.2 Pharmacodynamic properties
Ofloxacin
Therapeutic doses of ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system. According to DIN 58 940, the following limits apply for ofloxacin:
Range of acquired bacterial resistance to ooxacin is as follows:
Normally susceptible
Aerobic Gram-positive micro-organisms: S. aureus - methicillin-sensitive (0.3-12.6%), S. pyogenes (2-5%) Aerobic Gram-negative micro-organisms: Acinetobacter spp (0.3-7.3%), Citrobacter spp. (3-15%), Enterobacter spp. (2-13%), E. coli (1-8%), H. influenzae (1%), Klebsiella spp. (1-10%), Moraxella spp. (0-0.2%), Morganella morganii (0- 6.9%), N. gonorrhoeae (25%) Proteus spp. (1-15%), Serratia marcescens (2-2.4%)
Others: Chlamydia spp, L. pneumophila
Intermediately susceptible
Aerobic Gram-positive micro-organisms: S. pneumoniae (70%), Providentia (17.1%)
Aerobic Gram-negative micro-organisms: E. faecalis (50%), P. aeruginosa (20-30%), Serratia spp. (20-40%)
Metronidazole
A potential for development of resistance exists against metronidazole. Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair.
Gram-negative anaerobes: Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Fusobacterium species.
Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
Gram-negative anaerobes: Bacteroides fragilis group (B. caccae, B. uniformis), Prevotella species (P. bivia, P. buccae, P. disiens)
5.3 Pharmacokinetic properties
6.0 Nonclinical properties
6.1 Animal toxicology or pharmacology
Ofloxacin
Preclinical effects in conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, reproductive studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Joint toxicity was observed at exposure in the human therapeutic range in juvenile rats and dogs. Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.
Mutagenicity studies showed no evidence for mutagenicity of ofloxacin. However, like some other quinolones Ofloxacin is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of ofloxacin is comparable with that of other gyrase inhibitors. Preclinical data from conventional genotoxicity studies reveal no special hazard to humans, carcinogen potential has not been investigated.
Reproduction toxicity
Ofloxacin has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Ooxacin crosses the placenta and levels reached in the amniotic fluid are about 30% of the maximal concentrations measured in maternal serum.
Metronidazole
Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans. Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while others studies were negative.
7.0 Description
Ofloxacin is a synthetic broad-spectrum second-generation fluoroquinolone antibacterial agent. Metronidazole Benzoate is the benzoate ester of metronidazole, a synthetic nitroimidazole derivative with antiprotozoal and antibacterial activities.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable
8.2 Shelf-life
Refer on the pack.
8.3 Packaging information
Diof : A bottle of 60 ml.
Diof-DS : A bottle of 60 ml.
8.4 Storage and handling instructions
Store below 25°C. Protect from light. Do not freeze.
Keep out of reach of children.
Shake well before use.
9.0 Patient counselling information
Your medicine contains Ofloxacin and Metronidazole which belong to a group of medicines called antibacterials.
Do not take this medicine, if you are allergic to ofloxacin or metronidazole.
Signs of an allergic reaction include a rash, itching or shortness of breath.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
If you have any further questions, ask your doctor or pharmacist.
Collagen (Type I, II, V, X), Mucopolysaccharides, Chondroitin Sulfate & Hyaluronic Acid Capsules
2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
3.0 DOSAGE FORM AND STRENGTH
Capsule
4.0 CLINICAL PARTICULARS
4.1 Therapeutic indication
Stimulates joint health recovery and flexibility.
4.2 Posology and method of administration
2 capsules once or twice daily on empty stomach or as directed by a Healthcare Professional.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in the formulation.
4.4 Special warnings and precautions for use
Chondroitin sulfate may increase the anticoagulant activities of Warfarin. Don't take chondroitin if you are taking warfarin. Precaution: This Product is consumed by adults only and not recommended for pregnant women, lactating mothers and children below 5 years of age. Supportive therapy for cartilage and joint health.
4.5 Drugs interactions
No known drug-drug interaction
4.6 Use in special populations
Pregnancy & Lactation, usage in pediatrics
Precaution: This product is consumed by adults only and not recommended for pregnant women, lactating mothers and children below 5 years of age. Safety and efficacy in children has not been established.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effects
Tendofirm is a nutritional supplement and it is generally regarded as safe for oral consumption in adults.
In clinical studies, hydrolyzed Collagen produced no skin irritation, sensitization, or indication of phototoxicity
4.9 Overdose
No cases of overdose have been reported.
5.0 PHARMACOLOGICAL PROPERTIES
5.1 Mechanism of Action
Tendofirm offers a multifaceted approach to the management of degenerative joint diseases, hypothesized to provide benefits like rebuilding, strengthening of cartilage, strengthening of tendons, fortification of ligaments and improved viscosity of synovial fluid.
5.2 Pharmacodynamic properties
Collagen is composed of amino acids responsible for the growth, repair and maintenance of various tissues. Collagen is a major component in forming ligaments, tendons, muscles and cartilage. As one increase in age, it is difficult to manufacture sufficient amounts of collagen, this may lead to arthritis and age related joint pain. Collagen promotes structural recovery from injurious strains of the muscle, tendons, ligaments and cartilage. Collagen is required to mend and restore connective tissue aiding muscle strengthening and better joint mobility. Hyaluronic acid increases viscosity of synovial fluid. Chondroitin Sulphate provides tensile strength of cartilage, tendons and ligaments. Mucopolysaccharides also known as Glycosaminoglycans (GAGs)— primarily function to support the most important structural proteins: collagen and elastin. Glycosaminoglycans are used in the body as a lubricant for joints, for supporting connective tissues such as cartilage and tendons, and may even help assist with weight loss. Recent research shows that GAGs don’t lubricate joints as originally thought, but instead reduce cartilage deterioration and inflammation. GAGs also work as the “building blocks” of new joint cartilage, which makes them extra beneficial for managing osteoarthritis or degenerative joint disease.
5.3 Pharmacokinetic properties
In experimental studies, it has been demonstrated that orally administered collagen hydrolysate is thoroughly absorbed by the intestines and circulated in the blood stream, reaching a maximal plasma concentration in 6 h, at which point < 10% of collagen hydrolysate remains in the gastrointestinal tract. These studies also revealed that collagen hydrolysate is not completely broken down by the digestive system, but that a variety of collagen fragments, including up to 10% high molecular form collagen fragments that range from 1 to ≈10 kD, are absorbed following oral administration of collagen hydrolysate, with some individual variability. In experiments with radiolabelled collagen hydrolysate, it has been shown that a significant amount of collagen hydrolysate-derived peptides reach cartilage tissue within 12 h after administration ( p < 0.05 compared with control animals). Hyaluronic acid (HA) is a component that is particularly abundant in the synovial fluid. HA is not absorbed into the body as a high-molecular-weight polymer after ingestion. A test using intestinal epithelia model cells (Caco-2 cells) revealed that HA with a MW exceeding 1 × 105 is rarely absorbed. On the contrary, the amount of HA absorbed by Caco-2 cells increases as the MW of HA decreases to 7 × 104, 2×104, or 5×103. Kurihara et al. reported that HA is decomposed into 2–6-membered polysaccharides by enteric bacteria, and these polysaccharides are partially absorbed into the body by the small intestine. Following the decomposition of HA by enteric bacteria to a low MW form, free polysaccharides are known to migrate into the joints and other tissues. Lactobacillus and Bifidobacterium have been reported as examples of enteric bacteria that play a critical role in HA absorption. The approximate half-life of chondroitin sulfate and its derivative metabolites is 15 hours. Chondroitin sulfate is excreted in the urine as intact polymers and as partial degradation products. Mucopolysaccharides may help reduce collagen breakdown in the body, and protect cartilage inside joints as well. It may also work to reduce inflammation in the body, which is one of the primary causes of joint pain and cartilage breakdown in individuals living with osteoarthritis. It also works as the “building blocks” of new joint cartilage, which makes them extra beneficial for managing osteoarthritis or degenerative joint disease.
6.0 NONCLINICAL PROPERTIES
6.1 Animal Toxicology or Pharmacology
No known animal toxicology data
7.0 DESCRIPTION
The product Tendofirm is a blend of collagen type I, type II type V and type X; Hyaluronic acid, chondroitin sulphate and mucopolysaccharides.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable
8.2 Shelf-life
Best Before Twenty-Four Months (24) From The Date of Manufacture.
8.3 Packaging information
Net Quantity: 1 x 15 N Capsules
8.4 Storage and handing instructions
Store in a dry, well-ventilated place at a temperature not exceeding 30°C. Protect from light & moisture. Keep out of reach of children.
9.0 Patient Counselling Information
It is NUTRACEUTICAL product.
Not for medicinal use
This product is not intended to diagnose, treat, cure or prevent any disease. Not to exceed the stated recommended daily dose. Precaution: This Product is consumed by adults only and not recommended for pregnant women, lactating mothers and children below 5 years of age. Supportive therapy for cartilage and joint health.
12.0 Date of revision
04.07.2024
About leaflet
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What TENDOFIRM® is and what it is used for
2. What you need to know before you take TENDOFIRM®
3. How to take TENDOFIRM®
4. Possible side effects
5. How to store TENDOFIRM®
6. Contents of the pack and other information
1. What TENDOFIRM® is and what it is used for
TENDOFIRM® contains collagen, chondroitin sulfate, hyaluronic acid, mucopolysaccharides. It is a nutritional supplement obtained from sternum (breast bone) of birds and the shell membrane of the eggs. It is a blend of various products which are helpful in maintaining good health of joints, cartilages and joint cavities and it also helps in relieving pain and swelling of various joints. It also helps in speedy recovery of the joints and reforms the damaged cartilage and joint fluids to its normal state. Tendofirm provides 4 important types of collagen which serve as building blocks of the cartilages of joints. Chondroitin sulfate, hyaluronic acid and mucopolysaccharides present in the combination protects the cartilage from degradation and wear and tear. While lysozyme, ovotransferrin and sialic acid act as anti-inflammatory agents and helps to relieve joint pain and swelling. TENDOFIRM® provides significant pain and symptom relief. It also causes improvement in walking distance in patients with osteoarthritis. Overall, it helps in reducing pain and stiffness of joints and improves joint mobility.
2. What you need to know before you take TENDOFIRM®.
Do not take TENDOFIRM® if:
You are allergic to the active substance or to any of the excipients in the formulation. Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of the lips, face, throat and tongue.
Do not take this medicine if the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking TENDOFIRM®.
Warnings and precautions
Talk to your doctor or pharmacist before taking TENDOFIRM® if: Chondroitin sulfate may increase the anticoagulant activities of Warfarin. Don't take chondroitin if you are taking warfarin. Precaution: This Product is consumed by adults only and not recommended for pregnant women, lactating mothers and children below 5 years of age.
Other medicines and TENDOFIRM®
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines you buy without a prescription, including herbal medicines. This is because TENDOFIRM® can affect the way some other medicines work. Also, some medicines can affect the way TENDOFIRM® works. Till date no drug-drug interactions are reported.
Pregnancy and breast-feeding
Precaution: This product is consumed by adults only and not recommended for pregnant women, lactating mothers and children below 5 years of age. Safety and efficacy in children has not been established.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. No effect anticipated.
3. How to take TENDOFIRM®.
The recommended dose for Adults, Elderly: It is a nutritional supplement available in the form of hard gelatin capsules. Two capsules once or twice daily, should be consumed orally on empty stomach with a glass of drinking water or it should be used as directed by healthcare professional.
If you take more TENDOFIRM® than you should
If you have too much of this medicine, talk to your doctor straight away.
If you forget to take TENDOFIRM®
If you forget to take a dose, take it as soon as you remember it. However, if it is nearly time for the next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose.
If you stop taking TENDOFIRM®
Do not stop taking this medicine without talking to your doctor. You should not stop taking TENDOFIRM® just because you feel better. This is because the condition may come back or get worse again. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Tendofirm is a nutritional supplement and it is generally regarded as safe for oral consumption in adults. However, like all medicines, this medicine can cause side effects, although not everybody gets them. Tell your doctor straight away or go to the nearest hospital casualty department if you notice any of the following serious side effects – you may need urgent medical treatment:
You have an allergic reaction. The signs may include: a rash, joint pain, swallowing or breathing problems, swelling of your lips, face, throat or tongue.
In clinical studies, hydrolyzed Collagen produced no skin irritation, sensitization, or indication of phototoxicity
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly: Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top of the home page. https://www.zuventus.co.in/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.
5. How to store TENDOFIRM®
Store in a dry, well-ventilated place at a temperature not exceeding 30°C. Protect from light & moisture. Keep out of reach of children.
6. Contents of the pack and other information
Packaging information
Net Quantity: 1 x 15 N Capsules
Marketing Authorisation Holder
Zuventus Healthcare Limited
Zuventus House Plot No. Y2, CTS No: 358/A2,
near Nahur Railway Station,off Raycon IT Park Road,
Approved colours used in hard gelatin capsule shells.
3.0 Dosage form and strength
Capsule
Rabeprazole 20 mg and Levosulpiride 75 mg
4.0 Clinical particulars
4.1 Therapeutic Indication
For the treatment of Gastroesophageal Reflux Disease (GERD)
4.2 Posology and method of administration
Adults
One capsule per day on an empty stomach or as directed by Physician
Paediatric Use
Rabeprazole are not recommended for use in children due to a lack of data on safety and efficacy.
Method of administration
Capsule should be swallowed whole & not to be opened, chewed or crushed.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients
Pregnancy and Breast feeding
Elderly people
Children less than 14 years of age
Parkinson disease
Severe renal or hepatic insufficiency
History of epilepsy
Porphyrias
Breast cancer
Alcohol intoxication
Certain tumors like phaeochromocytoma and pituitary prolactinoma
Hypokalemia
4.4 Special warnings and precautions for use
Rabeprazole
Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded. Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
A risk of cross-hypersensitivity reactions with other proton pump inhibitor (PPI) or substituted benzimidazoles cannot be excluded.
Rabeprazole is not recommended for use in children due to a lack of data on safety and efficacy.
There have been post marketing reports of blood dyscrasias (thrombocytopenia and neutropenia). In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
Hepatic enzyme abnormalities have been seen in clinical trials and have also been reported since market authorisation. In the majority of cases where an alternative aetiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.
No evidence of significant drug related safety problems was seen in a study of patients with mild to moderate hepatic impairment versus normal age and sex matched controls. However because there are no clinical data on the use of rabeprazole in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole is first initiated in such patients.
Co-administration of atazanavir with rabeprazole is not recommended
Treatment with PPIs, including rabeprazole, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile
Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with PPIs like rabeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
PPIs, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that PPIs may increase the overall risk of fracture by 10–40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.
Concomitant use of rabeprazole with methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.
Influence on vitamin B12 absorption
Rabeprazole sodium, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or a- chlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.
Subacute cutaneous lupus erythematosus (SCLE)
PPIs are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Rabeprazole. SCLE after previous treatment with a PPI may increase the risk of SCLE with other PPIs.
Interference with laboratory tests
Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Rabeprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of PPI treatment.
Levosulpiride
Caution should be exercised in patients with history of neuroendocrine tumor, epilepsy, manic states, abnormally-high levels of prolactin in the blood, painful, lumpy breasts, heart disease, any allergy, during pregnancy and breastfeeding.
4.5 Drugs interactions
Rabeprazole
Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur. Co-administration of rabeprazole sodium with ketoconazole or itraconazole may result in a significant decrease in antifungal plasma levels. Therefore, individual patients may need to be monitored to determine if a dosage adjustment is necessary when ketoconazole or itraconazole are taken concomitantly with rabeprazole.
In clinical trials, antacids were used concomitantly with the administration of rabeprazole and, in a specific drug-drug interaction study, no interaction with liquid antacids was observed.
Co-administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) to healthy volunteers resulted in a substantial reduction in atazanavir exposure. The absorption of atazanavir is pH dependent. Although not studied, similar results are expected with other proton pump inhibitors. Therefore, PPIs, including rabeprazole, should not be co-administered with atazanavir
Methotrexate
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.
Levosulpiride
Antacids and Sucralfate: They can decrease the absorption of the drug from the intestine. So, these medicines should not be taken along with levosulpiride. There should be a minimum 2 hour time lag between the two medicines.
Alcohol: there is increased chance of sedation.
Smoking: increased metabolism of the drug may require higher dose.
Antihypertensive medications: concomitant use may enhance the hypotensive effect seen with the drug.
Anticholinergics: increased incidence of anticholinergic side effects.
Levo dopa: It may oppose the antipsychotic action of the drug, conversely levosulpiride can cause decrease the efficacy of levo-dopa in the management of Parkinsonism.
Arrhythmia especially prolonged QT interval with the concurrent use of
Atomoxetine
Antiarrhythmics
Terfenadine
Chloroquine, quinine
Cisapride
Drugs causing hypokalemia (corticosteroids, laxatives, diuretics like furosemide)
Use in special populations
Pregnancy
Rabifast XL is not recommended in human pregnancy.
Breast-feeding
It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in lactating women have been performed. Rabeprazole sodium is however excreted in rat mammary secretions. Therefore, Rabifast XL must not be used during breast feeding.
4.6 Effects on ability to drive and use machines
Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that Rabeprazole would cause an impairment of driving performance or compromise the ability to use machinery. Do not drive a car or operate machinery while Levosulpiride may cause dizziness or drowsiness.
4.8 Undesirable effects
Rabeprazole
The most commonly reported adverse drug reactions, during controlled clinical trials with rabeprazole were headache, diarrhoea, abdominal pain, asthenia, flatulence, rash and dry mouth. The majority of adverse events experienced during clinical studies were mild or moderate in severity, and transient in nature.
The following adverse events have been reported from clinical trial and post-marketed experience.
Frequencies are defined as: common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)
1. Includes facial swelling, hypotension and dyspnoea
2. Erythema, bullous reactions and hypersensitivity reactions have usually resolved after discontinuation of therapy.
3. Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. In treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole is first initiated in such patients
4. See Special warnings and precautions for use
Levosulpiride
The following side effects can occur with the use of this drug;
Acute muscular dystonia characterized by abnormal movements (twitching, tremor etc.) of hands, leg, tongue and facial muscles.
Sedation or drowsiness (because of decrease in sensory inputs to reticular activating system)
Increase in plasma prolactin levels manifested by breast enlargement, production of milk and stopping of menstrual periods. This can be taken care of with the use of lower dose of this drug.
Neuroleptic malignant syndrome (characterized by hyperpyrexia, muscle rigidity, increased myoglobin and creatine kinase; the last two suggestive of muscle damage.
Akathisia (uncontrollable desire to move about without any anxiety).
Tardive dyskinesia, it occurs late in the therapy and its features include involuntary rhythmical movements of face, mouth and jaw. The reason for tardive dyskinesia is synthesis of newer DA receptors which are supersensitive to even a small amount of DA. This causes a decrease in cholinergic activity in the striatum followed by decrease in GABA release. This decreased in inhibitory GABA is responsible for increased involuntary motor activity.
Postural hypotension (because of autonomic blockade), tolerance develops to this effect after some time.
Weight gain.
Elevated liver transaminases.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top end of the home page.
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
Rabeprazole
Experience to date with deliberate or accidental overdose is limited. The maximum established exposure has not exceeded 60 mg twice daily, or 160 mg once daily. Effects are generally minimal, representative of the known adverse event profile and reversible without further medical intervention. No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.
5.0 Pharmacological properties
5.1 Mechanism of Action
Rabeprazole sodium belongs to the class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme (the acid or proton pump). The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
Levosulpride is an atypical antipsychotic agent that blocks the presynaptic dopaminergic D2 receptors.
5.2 Pharmacodynamic properties
Rabeprazole
As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of the parietal cells. Rabeprazole is converted to the active sulphenamide form through protonation and it subsequently reacts with the available cysteines on the proton pump. Systemic effects of rabeprazole sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabeprazole sodium, given in oral doses of 20 mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.
Levosulpiride
Like its parent compound, levosulpiride shows antagonism at D3 and D2 receptors present pre-synaptically as well as post-synaptically in the rat striatum or nucleus accumbens. The preferential binding of the presynaptic dopamine receptors decreases the synthesis and release of dopamine at low doses whereas it causes postsynaptic D2 receptor antagonism at higher dose. This receptor profile of the drug along with its limbic selectivity explains its effectiveness in the management of both positive and negative symptoms of schizophrenia.
5.3 Pharmacokinetic properties
Rabeprazole
Absorption: Rabeprazole, an enteric-coated (gastro-resistant) formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the capsule leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52 % due in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 ml/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.
Distribution: Rabeprazole is approximately 97 % bound to human plasma proteins.
Biotransformation and elimination: Rabeprazole sodium, as is the case with other members of the proton pump inhibitor (PPI) class of compounds, is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolising system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma concentrations rabeprazole neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive of in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin. In humans the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.
Following a single 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90 % of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.
Renal dysfunction
In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance ≤ 5ml/min/1.73 m2), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the Cmax in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during haemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.
Hepatic dysfunction
Following a single 20 mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2-3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20 mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.
Older people
Elimination of rabeprazole was somewhat decreased in older people. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and t½ increased by approximately 30% as compared to young healthy volunteers. However, there was no evidence of rabeprazole accumulation.
CYP2C19 polymorphism
Following a 20 mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers, had AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolisers whilst Cmax had increased by only 40%.
Levosulpiride
The parent drug is given in a dose of 400-1800 mg orally daily although a much lower dose is effective for producing antidepressant effect (about 50-300 mg). The plasma t1/2 of the drug is about 6-8 hours. The drug is chiefly excreted through the renal route.
6.0 Nonclinical properties
6.1 Animal Toxicology or Pharmacology
Rabeprazole
Non-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data. Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.
7.0 Description
Rabifast XL is a combination of Rabeprazole sodium and Levosulpiride.
Rabeprazole sodium is a proton pump inhibitor. It is a substituted benzimidazole that inhibits gastric acid secretion.
Levosulpiride is the levo enantiomer of sulpiride. It is a substituted benzamide which is meant to be used for several indications: depression, psychosis, somatoform disorders, emesis and dyspepsia. It is physically present as a white crystalline powder.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable
8.2 Shelf-life
Refer to the pack
8.3 Packaging information
10 Blister Strips of capsules each
8.4 Storage and handing instructions
Store protected from light and moisture at a temperature not exceeding 300 C.
Keep out of reach of children.
Capsule should be swallowed whole & not to be opened, chewed or crushed.
9.0 Patient Counselling Information
Advice patient Not to take the medicine if the patient is
When stimulation of the gastric motility could be harmful e.g. in patients with gastro-intestinal haemorrhage, mechanical obstruction or perforation.
In patients with moderate or severe hepatic impairment oIn patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure
Co-administration with QT-prolonging drugs, at the exception of apomorphine
Co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects
Acute Interstitial Nephritis Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute interstitial nephritis
Clostridium difficile-Associated Diarrhea Advise the patient or caregiver to immediately call the patient’s healthcare provider if they experience diarrhea that does not improve
Bone Fracture Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient’s healthcare provider
Cutaneous and Systemic Lupus Erythematosus Advise the patient or caregiver to immediately call the patient’s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus.
Cyanocobalamin (Vitamin B-12) Deficiency Advise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient’s healthcare provider if they have been receiving rabeprazole sodium delayed-release tablets for longer than 3 years
Hypomagnesemia Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia to the patient’s healthcare provider, if they have been receiving rabeprazole sodium delayed-release tablets for at least 3 months
Drug Interactions Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products, warfarin, digoxin or high-dose methotrexate, Diltiazem, Pregabalin, Sucralfate, Tramadol, Aluminium Hydroxide/Magnesium Hydroxide, Ipratropium
Interaction with Alcohol: Consumption of alcohol while taking this medicine can cause CNS depression characterized by confusion, lack of focus, anxiety, drowsiness etc.
Avoid or limit the uptake of alcohol while taking this medicine as the risk of adverse effects are increasingly high. Contact your doctor if an excess of drowsiness is experienced.
Administration: Capsule should be swallowed whole & not to be opened, chewed or crushed. Do not take this medicine, if you are allergic to Rabeprazole or Levosulpiride
Signs of an allergic reaction include a rash, itching or shortness of breath.
Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.
Advice patients If they have any further questions, ask doctor or pharmacist.
12.0 Date of revision
07/2024
About leaflet
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor, pharmacist or nurse.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1.What RABIFAST XL is and what it is used for
2.What you need to know before you take RABIFAST XL
3.How to take RABIFAST XL
4.Possible side effects
5.How to store RABIFAST XL
6.Contents of the pack and other information
1. WHAT RABIFAST XL IS AND WHAT IT IS USED FOR
The active ingredients of RABIFAST XL capsule are Rabeprazole and Levosulpiride.
Rabeprazole belongs to a group of medicines called Proton Pump Inhibitors (PPIs). It acts by reducing the amount of acid made by the stomach.
Levosulpiride belongs to the class of antipsychotic medicines. However, it is primarily used for its gut motility properties i.e., to improve food movement and treats disorders of the stomach and intestines. This medicine works by inhibiting the action of certain specific neurotransmitters in the brain and specific regions of the stomach and the intestine.
RABIFAST XL capsules are used to treat:
gastro-esophageal reflux disease (GERD). GERD is commonly referred to as inflammation of the gullet caused by acid and associated with heartburn. Heartburn is a burning feeling rising from the stomach or lower chest up towards the neck.
2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE RABIFAST XL
Do not use RABIFAST XL if you
are allergic (hypersensitive) to rabeprazole sodium, Levosulpiride or any of the other ingredients
are pregnant or think that you are pregnant
are breast-feeding
If you have epilepsy
If you have mood disorder that can make you feel excited (manic states or in the manic phase of manic-depressive psychosis)
If you have high blood pressure which is suspected to be due to pheochromocytoma
If you have breast cancer
Warnings and precautions
Talk to your doctor before taking RABIFAST XL, especially if you
are allergic to other proton pump inhibitors or “substituted benzimidazoles”.
have a stomach tumour.
have or have had any liver problems.
are taking a medicine called atazanavir (used to treat HIV).
have reduced body stores or risk factors for reduced vitamin B12 and receive long term treatment with rabeprazole sodium. As with all acid reducing agents, rabeprazole sodium may lead to a reduced absorption of vitamin B12.
are due to have a specific blood test (Chromogranin A).
have ever had a skin reaction after treatment with a medicine similar to Rabeprazole that reduces stomach acid.
If you have presence of gastrointestinal bleeding, mechanical obstructions or perforations.
If you suffer from dementia (loss of memory or other mental abilities), or if you have ever had a stroke or “mini” stroke.
If you suffer from cardiovascular diseases (diseases of the heart and circulation) or if you have a family history of an abnormal heart rhythm tracing (ECG) that shows a problem called QT prolongation.
If you suffer from blood clots or someone else in your family has a history of blood clots, as antipsychotics have been associated with formation of blood clots.
If you are in treatment with other neuroleptics because of the risk of developing a complex symptoms disorder (such as fever, severe muscle stiffness, severe movement difficulties (akinesia), excessive sweating, rapid heartbeat, impaired pressure or loss of consciousness) potentially fatal, called Neuroleptic Malignant Syndrome, that has been reported with use of this medicines (in general in the course of treatment with antipsychotic drugs). In this case, stop taking RABIFAST XL and contact your doctor immediately
If you get a rash on your skin, especially in areas exposed to the sun, tell your doctor as soon as you can, as you may need to stop your treatment with RABIFAST XL. Remember to also mention any other ill-effects like pain in your joints.
If you are not sure if any of the above applies to you, consult your doctor or pharmacist before taking RABIFAST XL capsule.
Your doctor may perform or have performed an additional investigation called an endoscopy in order to diagnose your condition and/or exclude malignant disease. The possibility of stomach and oesophageal tumours should be excluded before the treatment is started.
If you take RABIFAST XL capsule on a long-term basis (longer than one year) your doctor will probably monitor you regularly. You should report any new or different symptoms whenever you see your doctor.
Taking a proton pump inhibitor like RABIFAST XL capsule, especially over a period of more than one year, may slightly increase your risk of fracture of the hip, wrist or spine. Tell your doctor if you have osteoporosis or if you are taking corticosteroids (which can increase the risk of osteoporosis).
Talk to your doctor straight away if you experience severe (watery or bloody) or persistent diarrhoea with symptoms such as fever, abdominal pain or tenderness, as rabeprazole has been associated with a small increase in infectious diarrhoea. Some abnormal blood and liver enzyme values have been reported during treatment with RABIFAST XL capsule. Usually, the values become normal when the treatment is discontinued.
If you are not sure if any of the above applies to you, consult your doctor or pharmacist before taking RABIFAST XL capsule.
Children and adolescents
RABIFAST XL capsule are not recommended for use in children
Other medicines and RABIFAST XL
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is especially important in case you are taking any of the following medicines:
Rabeprazole
atazanavir (used to treat HIV); Rabeprazole may lower the amount of this type of medicine in your blood and they should not be used together
ketoconazole or itraconazole (used to treat infections caused by a fungus). Rabeprazole may lower the amount of this type of medicine in your blood. Your doctor may need to adjust your dose
methotrexate (a chemotherapy medicine used in high doses to treat cancer) – if you are taking a high dose of methotrexate, your doctor may temporarily stop your Rabeprazole treatment.
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Rabeprazole.
Levosulpiride
Medicines that prolong the QT interval (an abnormal heart rhythm).
Medicines that cause electrolyte disturbances (an abnormality in the concentration of electrolytes in the body).
Other medicines that act on the Nervous Central System.
RABIFAST XL with alcohol
You should avoid simultaneous intake of alcohol
Pregnancy and breast-feeding
Do not use RABIFAST XL capsule if you are pregnant or think you may be pregnant.
Do not use RABIFAST XL capsule if you are breastfeeding or planning to breast-feed.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
RABIFAST XL may have an influence on the ability to drive and use machines.
Patients under treatment may experience numbness, dizziness or involuntary movements (dyskinesia); therefore, they should be advised to avoid driving or operating machines.
3. HOW TO USE RABIFAST XL
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
Taking this medicine
Only remove a capsule from the blister strip when it is time to take your medicine.
Swallow your capsule whole with a drink of water.
Do not chew or crush the capsule.
Your doctor will tell you how many capsule to take and how long to take them for. When RABIFAST XL capsule are taken once daily, it should be taken in the morning before breakfast.
If you are taking this medicine for a long time, your doctor will want to monitor you.
The recommended dose is: Once capsule once daily in adults
Use in children
RABIFAST XL capsules are not recommended for use in children.
If you take more RABIFAST XL than you should
If you have taken more RABIFAST XL capsules than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you.
If you forget to take RABIFAST XL
If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue as usual
If you forget to take your medicine for more than 5 days, talk to your doctor before taking any more medicine
Do not take a double dose (two doses at the same time) to make up for a forgotten dose.
If you stop taking RABIFAST XL
It is important that you do not stop taking the medicine until told to do so by your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects are usually mild and improve without you having to stop taking this medicine.
Rabeprazole
If you notice any of the following serious side effects, stop taking RABIFAST XL capsule and contact a doctor immediately, you may need urgent medical treatment:
Allergic reactions – the signs may include: sudden swelling of your face, difficulty breathing or low blood pressure which may cause fainting or collapse.
Frequent infections, such as a sore throat or high temperature (fever), or ulcers in your mouth or throat. Bruising or bleeding easily.
These side effects are rare (affect fewer than 1 in 1,000 people).
Sudden onset of severe rash or blistering or peeling skin. This may be associated with a high fever and joint pains (erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN))
These side effects are very rare (affect fewer than 1 in 10,000 people).
Other possible side effects:
Common side effects (may affect up to 1 in 10 people):
cough, sore throat (inflammation of the pharynx), runny nose.
effects on your stomach or gut such as stomach pain, diarrhoea, wind (flatulence), feeling sick (nausea), being sick (vomiting) or constipation
aches, back pain, non-specific pain.
weakness or loss of strength, flu-like symptoms.
difficulty sleeping.
headache, dizziness.
infection.
benign polyps in the stomach. Uncommon side effects (may affect up to 1 in 100 people):
feeling nervous or drowsy.
sleepiness.
chest infection (bronchitis).
painful and blocked sinuses (sinusitis).
indigestion, dry mouth, belching.
rash, skin redness (erythema).
muscle pains, joint pains, leg cramps.
bladder infection (urinary tract infection).
chest pain, chills, fever.
muscle, leg or joint pain.
change in how your liver is working (which is measured by blood tests).
fracture of the hip, wrist or spine.
Rare side effects (may affect up to 1 in 1,000 people):
blood problems such as reduced number of white cells or platelets. This can cause weakness, bruising or make infections more likely.
changes in white blood cells (show in blood tests) which may result in frequent infection.
allergic reactions including facial swelling, low blood pressure and breathing difficulties.
loss of appetite (anorexia).
depression.
visual disturbance.
upset stomach or stomach pain, sore mouth, taste disturbance.
inflammation of the liver, jaundice (yellowing of the skin or eyes).
itchy rash, sweating, skin blisters.
kidney inflammation (interstitial nephritis).
increased weight.
Not known (frequency cannot be estimated from the available data):
low levels of sodium in the blood which can cause tiredness and confusion, muscle twitching, fits and coma. confusion.
swelling of the feet and ankles.
enlarged breasts in men.
Patients who have previously had liver problems may very rarely get encephalopathy (a brain disease).
rash, possibly with pain in the joints.
inflammation of the gut (leading to diarrhoea).
If you are on Rabeprazole for more than three months it is possible that the levels of magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, and increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of magnesium. Do not be concerned by this list of side effects. You may not get any of them.
Levosulpiride
Major & minor side effects of Levosulpiride
Drowsiness
Breast tenderness
Irregular menstrual periods
Gynecomastia
Constipation
Abdominal pain and cramps
Weight gain
Sleeplessness
Unusual tiredness and weakness
Increased salivation
Decrease in libido
Fever
Excessive sweating
Change in heart rate
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly:
Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top end of the home page.
By reporting side effects, you can help provide more information on the safety of this medicine.
You can also report the side effect with the help of your treating physician.
5. HOW TO STORE RABIFAST XL
Store protected from light and moisture at a temperature not exceeding 30°C.
Keep out of reach of children.
Capsule should be swallowed whole & not to be opened, chewed or crushed.
Do not use this medicine after the expiry date which is stated on the blister and the carton after “EXP”. The expiry date refers to the last day of that month.
6. CONTENTS OF THE PACK AND OTHER INFORMATION
What RABIFAST XL contains
Rabifast XL
Each hard gelatin capsule contains:
Rabeprazole Sodium IP……………………. 20 mg
(as Gastro-resistant pellets)
Colour: Red Oxide of Iron Levosulpiride………………………………. 75 mg
(as Prolonged release pellets)
Colour: Lake of Sunset Yellow
Approved colours used in hard gelatin capsule shells.
For the treatment of gastritic & deodenal ulcer, gastroesophagal reflux disease (GERD) as an alternative to oral therapy in patients who are unable to take oral proton pump inhibitor.
4.2 Posology and method of administration
The intravenous administration is recommended only in cases where the oral administration is not indicated. As soon as an oral therapy is possible, the intravenous therapy should be discontinued.
Recommended dose is intravenous administration of the content of one vial (20 mg Rabeprazole) once daily.
Parenteral routes of administration other than intravenous are not recommended.
Injection: The content of the vial needs to be reconstituted with 5 ml Sterile Water for Injections IP, which should be given slowly over 5 - 15 min.
Infusion: For intravenous infusion the reconstituted solution should be further diluted and administered as short-term infusion over 15 - 30 min.
Compatibility with various I.V. fluids: Rabeprazole I.V. is compatible with Sterile Water for Injections IP and 0.9% Sodium Chloride Injection IP. No other solvent or infusion fluid must be used for administration of Rabeprazole I.V. injection.
Reconstitution: To reconstitute add 5 ml of Sterile Water for Injections IP to make a solution. After preparation, the reconstituted solution must be used within 4 hours and the unused portion discarded. As with all parenteral admixtures, the reconstituted or further diluted solution should be examined for change in colour, precipitation, haziness or leakage. The unused portion should be discarded. pH of the reconstituted solution: Between 11.2-12.5.
4.3 Contraindications
Rabeprazole is contraindicated in patients with known hypersensitivity to Rabeprazole, substituted benzimidazoles or to any component of the formulation
4.4 Special warnings and precautions for use
Presence of gastric malignancy: Symptomatic response to therapy with Rabeprazole does not preclude the presence of gastric malignancy.
Renal impairment: No dose adjustment is necessary in patients with renal impairment.
Hepatic impairment: No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Due to the lack of clinical data on Rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.
4.5 Drug interactions
Drugs metabolized by CPY450: Studies in healthy subjects have shown that Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing).
Warfarin: There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including Rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Cyclosporine: In vitro incubations employing human liver microsomes indicated that Rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 μM, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of Rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.
Compounds dependent on gastric pH for absorption: Co-administration of Rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with Rabeprazole. Concomitant use of atazanavir and proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
4.6 Use in special populations
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Breast-feeding
Since many drugs are excreted in milk, caution should be exercised when Rabeprazole is administered to a nursing mother.
Pediatric use
The safety and effectiveness of Rabeprazole in pediatric patients has not been established.
Geriatric use
No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
4.7 Effects on the ability to drive and use machines
Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that Rabifast would cause an impairment of driving performance or compromise the ability to use machinery. If however, alertness is impaired due to somnolence, it is recommended that driving and operating complex machinery be avoided.
4.8 Undesirable effects
Worldwide, over 2900 patients have been treated with oral Rabeprazole in Phase II-III clinical trials involving various dosages and durations of treatment.
The most commonly reported adverse reactions observed in patients included pain, pharyngitis, flatulence, infection, and constipation. Other adverse reactions observed include headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia. Proton Pump Inhibitors associated with acute kidney injury.
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to:medico@zuventus.com
Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top end of the home page.
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
There has been no experience with large overdoses of Rabeprazole.
No specific antidote for Rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
5.0 PHARMACOLOGICAL PROPERTIES
5.1 Mechanism of Action
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine-2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+/K+-ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, Rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.
5.2 Pharmacodynamic properties
In gastric parietal cells, Rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, Rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds.
The anti-secretory effect begins within one hour after oral administration of 20 mg Rabeprazole. The median inhibitory effect of Rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose.
5.3 Pharmacokinetic properties
The plasma concentration time profile of Rabeprazole after intravenous administration of a single 20 mg dose is biphasic, with a terminal half-life of 1.02 ± 0.63 hrs. Peak plasma concentration of 1646.07 ± 461.27 ng/mL is obtained within 0.14 ± 0.08 hrs of administration. Intravenous infusion of 20 mg Rabeprazole over five minutes results in a four-fold increase in peak concentration and a more rapid elimination as compared to the same oral dose. The AUC0-t and AUC0-∞ are 1297.70 ± 357.07 and 1289.83 ± 356.52 ng*h/mL, respectively. The total body clearance of Rabeprazole is 282.93 ± 98.01 mL/min.
Rabeprazole is extensively metabolized. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites are not observed to have significant antisecretory activity. In vitro studies have demonstrated that Rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl Rabeprazole. The thioether metabolite is formed non-enzymatically by reduction of Rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations; therefore, they are referred to as poor metabolizers of the drug.
6.0 Nonclinical Properties
6.1 Animal Toxicology or Pharmacology
Non-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.
7.0 Description
RABIFAST-IV contains Rabeprazole, a substituted benzimidazole that inhibits gastric acid secretion.
Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:
Injection Site Reactions
Potential for Exacerbation of Zinc Deficiency
Acute Tubulointerstitial Nephritis
Clostridium difficile-Associated Diarrhea
Bone Fracture
Severe Cutaneous Adverse Reactions
Cutaneous and Systemic Lupus Erythematosus
Hepatic Effects
Hypomagnesemia and Mineral Metabolism
Drug Interactions
Instruct patients to inform their healthcare provider of any other medications they are currently taking, including rilpivirine-containing products and high dose methotrexate.
Pregnancy
Advise a pregnant woman of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.
If you have any further questions, ask your doctor or pharmacist.
Bacillus subtilis (HU58*) 2 Billion CFU / 5 ml & Bacillus coagulans (SC208Ψ) 1 Billion CFU / 5 ml
2.0 Qualitative and quantitative composition
Per 5 ml mini bottle contains:
Bacillus subtilis (HU58*) 2 Billion CFU
Bacillus coagulans (SC208Ψ) 1 Billion CFU
HU58* is a trademark of Synergia Life Sciences Pvt. Ltd.
Original Research of Royal Holloway, University of London.
ΨSC208 is a trademark of Synergia Life Sciences Pvt. Ltd
3.0 Dosage form and strength
Oral suspension
Bacillus subtilis (HU58*) 2 Billion CFU / 5 ml & Bacillus coagulans (SC208Ψ) 1 Billion CFU / 5 ml
4.0 Clinical particulars
4.1 Therapeutic Indication
Helps in the restoration of intestinal flora altered during diarrhoea, constipation and course of antibiotic therapy.
4.2 Posology and method of administration
One - Two serving sizes daily
4.3 Contraindications
Ascertained hypersensitivity towards the components of the product
4.4 Special warnings and precautions for use
Shake well before use.
Not to exceed the recommended daily usage.
To be given under medical advice by a recognized medical doctor or dietician or nutritionist for children 2 to 5 year.
This product is not intended to mitigate, treat, cure or prevent any disease.
This product is not to be used as a substitute for a varied diet.
This medicine is for oral use only. Do not inject or administer in any other way
4.5 Drugs interactions
There are no known medicinal interactions subsequent to the concomitant administration of other drugs
4.6 Use in special populations
Pregnancy and lactation
Pregnant or lactating women or anyone with a medical condition should consult with a healthcare professional before consuming this product
4.7 Effects on ability to drive and use machines
The drug does not interfere with the ability to drive or use machinery.
4.8 Undesirable effects
During post marketing experience, hypersensitivity reactions, including rash urticaria and angioedema have been reported. Bacteremia, septicemia or sepsis in immunocompromised patients or those hospitalized due to a serious illness.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
Up to the present time no clinical manifestations of overdose have been reported. However, in case of accidental overdose, contact a healthcare professional.
5.0 Pharmacological properties
5.1 Pharmacodynamic Properties
Bacillus subtilis and Bacillus coagulans help to re-establish the gut microbalance or help to prevent the imbalance of intestinal microbial flora due to various causes including diarrhea, constipation and antibiotic use. Bacillus coagulans helps in improving gut health and enhancing immune system by producing lactic acid. Bacillus coagulans also helps in digestion of lactose, fructose and proteins.
5.2 Mechanism of Action
Spores of Bacillus subtilis & Bacillus coagulans pass the acid barrier of the gastric juices intact and reach the intestinal tract where they are transformed to metabolically active vegetative cells. These spores are also resistant to many chemical and physical agents. Once converted to vegetative cells, these spores help to alter the intestinal micoflora, help to restore the normal flora and thereby helps to correct the microflora imbalance. They also help improving immunity.
6.0 Nonclinical properties
6.1 Animal Toxicology or Pharmacology
No known animal toxicology data
7.0 Description
The preparation consists of spores of Bacillus subtilis & Bacillus coagulans which are normal non-pathogenic inhabitants of the intestine.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
None
8.2 Shelf-life
Refer the pack
Viability at the end of shelf life: 3 billion CFU per 5 ml.
8.3 Packaging information
Net quantity: 30ml
6 mini bottles of 5 ml each
8.4 Storage and handing instructions
Store at a temperature below 30°C, protect from direct sunlight
Product is required to be stored out of reach of children.
Consume immediately after opening.
Do not use if cap / seal broken of the bottle.
9.0 Patient Counselling Information
ProDiof help to maintain a healthy intestinal microflora and supports healthy digestion.
They help to restore the equilibrium of the intestinal flora altered during diarrhea, constipation and during the course of antibiotic therapy.
Tell patients that after the mini bottle has been opened, the preparation should be consumed within a very short period of time to avoid deterioration of the suspension.
Tell the patients if they get any side effects, talk to the doctor. This includes any possible side effects not listed in this leaflet. Advice patients if they have any further questions, ask the doctor or pharmacist.
12.0 Date of revision of text
04-07-2024
About Leaflet
Read all of this leaflet carefully before your child starts taking this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for your child. Do not pass it on to others. It may harm them, even if their signs of illness are the same as your child’s.
If your child gets any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
What is in this leaflet?
1.What ProDiof® liquid is and what it is used for?
2.What you need to know before you take ProDiof® Liquid?
3.How to take ProDiof® Liquid?
4.Possible side effects
5.How to store ProDiof® Liquid?
6.Contents of the pack and other information
1. What ProDiof liquid is and what it is used for?
ProDiof Liquid is probiotic health supplement containing good bacteria Bacillus subtilis (HU58) 2 Billion CFU per 5 ml and Bacillus coagulans (SC208Ψ)1 Billion CFU per 5 ml.
Probiotics assist to restore the intestinal microbial flora, altered during the use of antibiotics. Supportive supplement during antibiotic use
1. Assist in protecting the gut of children during microbial imbalance from side effects such as diarrhoea and abdominal discomfort
2. Assist in restoring alterations of intestinal flora and bacterial flora
3. Assist in the natural balance of bacterial flora, balancing the presence of good and bad bacteria and thus targeting the root of intestinal disorders
4. Support gut health when normal intestinal flora has been disrupted.
ProDiof liquid is used to treat alterations of the intestinal bacterial flora that occur during diarrhea, constipation or as a result of therapies involving antibiotics or chemotherapy. It helps correct the consequent dysvitaminosis, which is an imbalance in the production and assimilation of vitamins.
2. What you need to know before you take ProDiof Liquid?
Do not take ProDiof if you are allergic to any of its ingredients listed in section 6.
Warnings and Precautions:
Do not exceed the recommended daily dose
This product is not intended to treat, cure, or prevent any disease
During antibiotic therapy, the product should be administered in the interval between one dose of antibiotic and the next
Do not use as a substitute for a varied diet
This medicinal product is for oral use only
Do not inject or administer in any other way
Pregnancy and Breastfeeding:
Consult your doctor before taking ProDiof liquid if you are pregnant or breastfeeding. There are no relevant data available on the use of ProDiof liquid in pregnant and breastfeeding women.
Children:
Consult a healthcare professional before giving to children aged 2-5 years
Other medicines and ProDiof Liquid:
ProDiof has no known interactions with other medicines. This means that it can generally be taken alongside other medications without any issues. However, it's always important to be cautious and consult your healthcare provider if you are taking any other medications.
Driving and using machines
ProDiof has no influence on the ability to drive and use machines.
3. How to take ProDiof Liquid?
Take 1-2 servings daily, as directed by your healthcare professional
Use is recommended for short periods of time till the symptoms subsides.
Instructions:
Shake well before use
For oral use only
ProDiof should be consumed shortly after opening to avoid deterioration
If you take more ProDiof liquid than you should:
No overdose has been reported; however, it is advisable to go to the nearest casualty department or contact your doctor immediately. Take the carton with you.
If you forget to take ProDiof Liquid:
Do not take a double dose to make up for a forgotten dose, take your usual dose at the usual time.
If you stop taking ProDiof Liquid:
Before stopping any supplement, including ProDiof, it’s a good idea to talk to your healthcare provider.
If you have any further questions on the use of this supplement, ask your doctor or pharmacist.
4. Possible side-effects
Some people may experience allergic reactions such as rash, hives, or swelling
In rare cases, especially in immunocompromised individuals or those with serious illnesses, it may cause severe infections like bacteremia or sepsis
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
You can also report side effects directly:
Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top end of the home page.
Pantoprazole Gastro-resistant and Domperidone Prolonged-release Capsules IP [40 mg + 30 mg]
2.0 Qualitative and quantitative composition
Each hard gelatin capsule contains :
Pantoprazole Sodium IP
equivalent to Pantoprazole 40 mg
(As Gastro-resistant pellets)
Colour : Indigo Carmine
Domperidone IP 30 mg
(As Prolonged-release pellets)
Colour : Lake of Sunset Yellow
Approved colours used in the capsule shell.
3.0 Pharmaceutical form and strength
Capsule, Pantoprazole (40 mg) and Domperidone (30 mg).
4.0 Clinical particulars
4.1 Therapeutic indications
For the treatment gastro-esophageal reflux disease (GERD) not responding adequately to Pantoprazole alone.
4.2 Posology and method of administration
1 Capsule to be administered once daily.
Pansa DSR capsules should be administered on empty stomach, preferably in the morning or at least 1 hour prior to meal. The capsules should be swallowed whole with water and not to be opened, chewed or crushed.
Pediatric patients
Pansa DSR Capsules are not recommended for use in children.
4.3 Contraindications
Patients with known hypersensitivity to Pantoprazole or to any substituted Benzimidazole derivative or to Domperidone or to any component of the formulation.
In patients receiving Rilpivirine-containing products.
In patients with gastrointestinal hemorrhage, mechanical obstruction or perforation (i.e. when stimulation of the gastric motility could be harmful).
In patients with moderate or severe hepatic impairment.
In patients who have known existing prolongation of cardiac conduction intervals, particularly QTc.
Patients with significant electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia) or underlying cardiac disease such as congestive heart failure (CHF).
Co-administration with QT-prolonging drugs.
Co-administration with potent CYP3A4 inhibitors.
4.4 Special warnings and precautions for use
Pantoprazole
Presence of gastric malignancy
In adults, symptomatic response to therapy with Pantoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a Pantoprazole.
Acute interstitial nephritis
Acute interstitial nephritis has been observed in patients taking Pantoprazole. Acute interstitial nephritis may occur at any point during Pantoprazole therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Pantoprazole if acute interstitial nephritis develops.
Clostridium difficile-associated diarrhea (CDAD)
Published observational studies suggest that Pantoprazole therapy may be associated with an increased risk of CDAD, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
Risk of bone fractures
Proton pump inhibitors (PPIs), especially if used in high doses and over long durations (> 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognized risk factors. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of Vitamin D and Calcium.
Cutaneous and systemic lupus erythematosus
Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including Pantoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. The occurrence of CLE with previous PPI treatment may increase the risk of CLE with other PPIs. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. The majority of patients presented with rash. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and Pantoprazole therapy should be stopped immediately. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks.
Cyanocobalamin (Vitamin B12) deficiency
Generally, daily treatment with any acid-suppressing medication over a long period of time (e.g. longer than 3 years) may lead to malabsorption of Vitamin B12 caused by hypo- or achlorhydria. Rare reports of Cyanocobalamin deficiency occurring with acidsuppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with Cyanocobalamin deficiency are observed.
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g. diuretics), monitoring of magnesium levels prior to initiation of PPI treatment and periodically thereafter should be considered.
Domperidone
Cardiovascular effects
Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors.
Epidemiological studies showed that Domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30 mg and patients concurrently taking QT-prolongation drugs or CYP3A4 inhibitors.
Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with underlying cardiac diseases such as congestive heart failure (CHF) due to increased risk of ventricular arrhythmia. Electrolyte disturbances or bradycardia are known to be conditions increasing the proarrythmic risk. Treatment with Domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should consult their physician. Patients should be advised to promptly report any cardiac symptoms.
Use with Apomorphine
Domperidone is contraindicated with QT prolonging drugs including Apomorphine, unless the benefit of the co-administration with Apomorphine outweighs the risks.
Use in infants and children
Although neurological side effects are rare, the risk of neurological side effects are higher in young children since metabolic
functions and the blood-brain barrier are not fully developed in the first months of life. Overdosing may cause extrapyramidal
symptoms in children, but other causes should be taken into consideration.
4.5 Interaction with other medicinal products and other forms of interaction
Pantoprazole
Antiretroviral drugs
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Decreased exposure of some antiretroviral drugs (e.g. Rilpivirine, Atazanavir and Nelfinavir) when used concomitantly with Pantoprazole may reduce antiviral effect and promote the development of drug resistance. Concomitant use of Rilpivirine containing products with Pantoprazole is contraindicated. Also, concomitant use of nelfinavir with Pantoprazole should be avoided.
Increased exposure of other antiretroviral drugs (e.g. Saquinavir) when used concomitantly with Pantoprazole may increase toxicity
There are other antiretroviral drugs which do not result in clinically relevant interactions with Pantoprazole.
Coumarin anticoagulants / Warfarin
There has been post-marketing reports of increased international normalized ratio (INR) and prothrombin time in patients receiving PPIs, including Pantoprazole and Warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Monitor INR and prothrombin time and adjust the dose of Warfarin if needed, to maintain the target INR range.
Clopidogrel
Concomitant administration of Pantoprazole and Clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of Clopidogrel or Clopidogrel-induced platelet inhibition. No dose adjustment of Clopidogrel is necessary when administered with an approved dose of Pantoprazole.
Methotrexate
Literature suggests that concomitant use of PPIs with Methotrexate (primarily at high dose) may elevate and prolong serum levels of Methotrexate and/or its metabolite, possibly leading to Methotrexate toxicities. A temporary withdrawal of Pantoprazole therapy may be considered in some patients receiving high-dose of Methotrexate.
Drugs for which gastric pH can affect bioavailability (iron salts, Erlotinib, Dasatinib, Nilotinib, Mycophenolate Mofetil, and Ketoconazole)
Pantoprazole causes long-lasting inhibition of gastric acid secretion. Therefore, Pantoprazole may reduce absorption of other drugs where gastric pH is an important determinant of their bioavailability.
Mycophenolate Mofetil (MMF)
Co-administration of Pantoprazole Sodium in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, Mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving Pantoprazole therapy and MMF. Use Pantoprazole with caution in transplant patients receiving MMF.
Drug / laboratory tests interactions
False positive urine tests for THC
There have been reports of false positive urine screening tests for Tetrahydrocannabinol (THC) in patients receiving PPIs, including Pantoprazole. An alternative confirmatory method should be considered to verify positive results.
Increased Chromogranin A (CgA) level
Increase in CgA may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pantoprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of Pantoprazole treatment.
Domperidone
The main metabolic pathway of Domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of Domperidone. There is increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.
Concomitant use of the following drugs is contraindicated.
A. QTc-prolonging medicinal products
Anti-arrhythmic class IA (e.g. Disopyramide, Hydroquinidine, Quinidine).
Anti-arrhythmic class III (e.g. Amiodarone, Dofetilide, Dronedarone, Ibutilide, Sotalol).
Certain antipsychotics (e.g. Haloperidol, Pimozide, Sertindole). • Certain antidepressants (e.g. Citalopram, Escitalopram).
Certain antibiotics (e.g. Erythromycin, Levofloxacin, Moxifloxacin, Spiramycin).
Certain antifungal agents (e.g. Pentamidine).
Certain antimalarial agents (e.g. Halofantrine, Lumefantrine).
Certain gastrointestinal medicines (e.g. Cisapride, Dolasetron, Prucalopride).
Certain antihistaminic (e.g. Mequitazine, Mizolastine).
Certain medicines used in cancer (e.g. Toremifene, Vandetanib, Vincamine).
Other medicines (e.g. Bepridil, Diphemanil, Methadone).
B. Potent CYP3A4 inhibitors (regardless of their QT prolonging effects)
Protease inhibitors.
Systemic azole antifungals.
Some macrolides (e.g. Erythromycin, Clarithromycin and Telithromycin).
Concomitant use of the following drugs is not recommended.
Moderate CYP3A4 inhibitors (e.g. Diltiazem, Verapamil and some macrolides).
Concomitant use of the following drugs requires caution.
Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation : Azithromycin and Roxithromycin.
Ketoconazole / Erythromycin and QTc prolongation
Separate in vivo pharmacokinetic / pharmacodynamic interaction studies with oral Ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of Domperidone's CYP3A4 mediated first pass metabolism by these drugs (as both of these drugs significantly inhibit CYP3A4 enzyme). Both the Cmax and AUC of Domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies, concomitant use of Domperidone and Ketoconazole or Erythromycin resulted in increase in QTc, over the observation period.
4.6 Use in special populations
Pregnancy
Pansa DSR capsule should be used during pregnancy only if the potential benefit justifies the possible risk to the fetus.
Breast-feeding
Pansa DSR capsules should not be used during breast feeding. Accordingly, a decision should be made whether to discontinue nursing or to discontinue / abstain from therapy, taking into account the benefit of the drug to the mother.
4.7 Effects on ability to drive and use machines
Both, Pantoprazole and Domperidone have no or negligible influence on the ability to drive and use machines. However, adverse reactions such as dizziness and visual disturbances may occasionally occur in patients on PPIs drug therapy. If affected, patients should not drive or use machines.
4.8 Undesirable effects
Pantoprazole
Clinical trials experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in clinical practice. Common adverse reactions reported with Pantoprazole therapy in clinical trials with frequency > 2% include : Headache, diarrhoea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. Additional adverse reactions reported in clinical trials with a frequency of ≤ 2% include : Body as a whole :
Acute kidney injury as an adverse drug reaction reported with the use of proton pump inhibitors. The following adverse reactions have been identified during post-approval use of Pantoprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General disorders and administration conditions : Asthenia, fatigue, malaise
Hematologic : Pancytopenia, agranulocytosis
Hepatobiliary disorders : Hepatocellular damage leading to jaundice and hepatic failure
Immune system disorders : Anaphylaxis (including anaphylactic shock), SLE
Infections and infestations : Clostridium difficile-associated diarrhea
Investigations : Weight changes
Metabolism and nutritional disorders : Hyponatremia, hypomagnesemia
Musculoskeletal disorders : Rhabdomyolysis, bone fracture
Renal and urinary disorders : Interstitial nephritis
Skin and subcutaneous tissue disorders : Severe dermatologic reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), angioedema (Quincke’s edema) and CLE
Domperidone
Central nervous system : As the pituitary gland is outside the blood-brain barrier, Domperidone may cause an increase in prolactin levels. In rare cases this hyperprolactinaemia may lead to neuro-endocrinological side effects such as galactorrhoea, gynaecomastia and amenorrhoea.
Extrapyramidal side effects are very rare in neonates and infants, and exceptional in adults. These side effects reverse spontaneously and completely as soon as the treatment is stopped. Other central nervous system-related effects of convulsion, agitation and somnolence also are very rare and primarily reported in infants and children.
General disorders
Uncommon : Asthenia.
Immune system disorder
Not known : Anaphylactic reactions including anaphylactic shock and angioedema
Psychiatric disorders
Uncommon : Anxiety, loss of libido;
Not known : Agitation, nervousness
Nervous system disorders
Uncommon : Somnolence, headache;
Not known : Extrapyramidal disorder, convulsions
Eye disorders Not known : Oculogyric crisis Cardiac disorders
Not known : Ventricular arrhythmias, QTc prolongation, Torsade de Pointes, sudden cardiac death. Gastrointestinal disorders
Common : Dry mouth;
Uncommon : Diarrhea Skin and subcutaneous tissue disorders
Uncommon : Rash, pruritus;
Not known : Urticaria, angioedema Reproductive system and breast disorders
Uncommon : Breast pain, breast tenderness, galactorrhoea;
Not known : Gynaecomastia, amenorrhoea
Renal and urinary disorders
Not known : Urinary retention Investigations
Not known : Abnormal liver function test, increased blood prolactin
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
Symptoms
Symptoms of overdose are agitation, altered consciousness, convulsions, disorientation, somnolence, and extrapyramidal reactions.
Treatment
There is no specific antidote, but in the event of overdose, gastric lavage as well as the administration of activated charcoal, may be useful. Close medical supervision and supportive therapy is recommended. Anticholinergic, Antiparkinson drugs may be helpful in controlling the extrapyramidal reactions.
5.0 Pharmacological properties
5.1 Mechanism of action
Pantoprazole
Pantoprazole is a proton pump inhibitor (PPI) class of anti-secretory agent. Pantoprazole is a lipophilic weak base that crosses the parietal cell membrane and enters the acidic parietal cell canaliculus where it becomes protonated, producing the active metabolite sulfenamide. Sulfenamide forms an irreversible covalent bond with two sites of the H+/K+-ATPase enzyme located on the gastric parietal cell. Thus, Pantoprazole suppress the final step in gastric acid (Hydrochloric Acid - HCl) production by covalently binding to the H+/K+-ATPase enzyme (also called as proton pump) system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the H+/K+-ATPase results in duration of anti-secretory effect that persists longer than 24 hours.
Domperidone
Domperidone is a dopamine receptor (D2) antagonist. Domperidone act predominantly on peripheral dopamine receptors and produces anti-emetic and gastro-kinetic effects. Domperidone does not readily cross the blood-brain barrier (BBB). Thus, in Domperidone users, especially in adults, extrapyramidal side effects are very rare (unlike metoclopramide). Anti-emetic effect of Domperidone is due to a combination of peripheral (gastro-kinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone (CTZ), which lies outside the BBB in the area postrema. Oral Domperidone also increases lower esophageal sphincter (LES) pressure, thus, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.
5.2 Pharmacodynamic properties
With a single oral dose of 20 to 80 mg of Pantoprazole, a dose-dependent decrease in gastric acid secretion occurs. Following the initial oral dose of 40 mg Pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once-a-day dosing for 7 days, the mean inhibition was increased to 85%. Acid secretion had returned to normal within a week after the last dose of Pantoprazole; there was no evidence of rebound hypersecretion.
Pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since Pantoprazole binds to the enzyme distal to the receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (Acetylcholine, histamine and gastrin). The fasting gastrin values increase under Pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases.
Domperidone
Prokinetic effect : The prokinetic (gastro-kinetic) properties of Domperidone are related to its peripheral dopamine receptor blocking action.
Antiemetic effect : Domperidone produces antiemetic effect by blocking dopamine receptors (D2) peripherally. Inhibition of peripheral D2 receptor signaling prevents or relieves various GI symptoms, such as nausea and vomiting, and also relieves reflux and other symptoms associated with upper GI disorders.
5.3 Pharmacokinetic properties
Pantoprazole
Absorption
Like other PPIs, Pantoprazole is an acid-labile drug and therefore, administered orally in the form of gastro-resistant pellets. Absorption of Pantoprazole, therefore, begins in the intestine only after the pellets leave the stomach. After administration of a single or multiple oral doses of Pantoprazole 40 mg, the peak plasma concentration of Pantoprazole was achieved in approximately 2.5 hours, and Cmax was 2.5 mcg/ml. Peak serum concentration (Cmax) and area under the serum concentration time curve (AUC) increases in a dose-dependent manner (with dose range from 10 to 80 mg). Pantoprazole does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. Pantoprazole undergoes little first-pass metabolism, resulting in an absolute bioavailability of approximately 77%.
Effect of antacid / food
Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of Pantoprazole with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of Pantoprazole absorption (AUC) are not altered. Thus, Pantoprazole may be taken without regard to timing of meals.
Distribution
The apparent volume of distribution of Pantoprazole is approximately 11 to 23.6 liters, distributing mainly in extracellular fluid.
The plasma protein binding of Pantoprazole is about 98%, primarily to albumin.
Metabolism
Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the Pantoprazole metabolites have significant pharmacologic activity.
Excretion
Renal elimination represents the major route of excretion (about 80 %) for the metabolites of Pantoprazole, the rest is excreted with the faeces. There is no renal excretion of unchanged Pantoprazole. The main metabolite in both the serum and urine is desmethyl Pantoprazole which is conjugated with Sulphate. Following oral administration, the serum concentration of Pantoprazole declines biexponentially, with a terminal elimination half-life of approximately one hour.
Domperidone
Pharmacokinetics of Domperidone in sustained release formulation is not available. Conventional formulation of Domperidone (i.e. immediate release) has following pharmacokinetic properties :
Absorption
Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1 hour after dosing. The Cmax and AUC values of Domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. The low absolute bioavailability of oral Domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut and liver.
Distribution
Oral Domperidone does not appear to accumulate or induce its own metabolism. The peak plasma concentration (Cmax) of 18 ng/ml to 21 ng/ml occurs 1.5 hours (Tmax) after the oral dose. Domperidone is 91 to 93% bound to plasma proteins. Distribution studies with Domperidone have shown wide tissue distribution, but low brain concentration.
Metabolism
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of Domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in Domperidone aromatic hydroxylation.
Excretion
After oral dose, Domperidone is excreted mainly by renal (31%) and biliary (66%) routes. The proportion of the drug excreted unchanged is small (10% of fecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7 to 9 hours in healthy subjects, but is prolonged in patients with severe renal insufficiency.
6.0 Nonclinical properties
6.1 Animal toxicology or pharmacology
Pantoprazole
Carcinogenesis
In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with Pantoprazole doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50 kg person dosed with 40 mg/day. In the gastric fundus, treatment with 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment with 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with Pantoprazole treatment included an adenocarcinoma of the duodenum with 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus with 200 mg/kg/day. In the liver, treatment with 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment with 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats. In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day of Pantoprazole, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment with 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment with 5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia. A 26-week p53 +/-transgenic mouse carcinogenicity study was not positive.
Domperidone
Safety margins in in vitro proarrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 9- up to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitized for torsade de 13 pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4 ng/ml, which are 3-fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered 3 times a day). At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits. Development abnormalities observed in rats at a high exposure. Risk of carcinogenicity, mutagenicity or sensitisation cannot be excluded.
7.0 Description
Each capsule of Pansa DSR contains 40 mg of Pantoprazole (in a gastro-resistant form) and 30 mg of Domperidone (in a prolonged release form) for oral administration in adults.
Pantoprazole
Pantoprazole Sodium is the Sodium salt form of Pantoprazole. Pantoprazole is a substituted Benzimidazole, proton pump inhibitor (PPI) class of anti-secretory agents which suppressesgastric acid production.
Molecular weight : 405.40 g/mol
Molecular formula : C16H14F2N3NaO4S
Chemical name : Sodium; 5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2- yl) methylsulfinyl] benzimidazol-1-ide Domperidone Domperidone is a dopamine receptor antagonist drug with antiemetic and gastrokinetic properties. Domperidone is white or almost white powder which is slightly soluble in water. Molecular weight : 425.90 g/mol Molecular formula : C22H24ClN5O2 Chemical name : 6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one.
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable
8.2 Shelf-life
Refer on the pack.
8.3 Packaging information
Alu-Alu blister strip of 10 capsules.
8.4 Storage and handling instructions
Store protected from moisture at a temperature not exceeding 25°C.
Keep out of reach of children.
9.0 Patient counseling information
Instruct patients to take Pansa DSR Capsule exactly as prescribed by doctor. Do not change the dose or stop therapy without consulting to your doctor.
Instruct patients to swallow Pansa DSR Capsule as a whole with water and not to open, chew or crush the capsules.
If you miss a dose, take it as soon as possible. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 capsules per doses at the same time to make up for the missed dose.
Pregnant women can use this medicine only if essential and in consultation with their doctor.
Advise nursing mothers to avoid use of this medicine during lactation or not to breastfeed their infants while on drug therapy.
This medicine is not recommended for use in children.
Instruct patients not to share this medication with other people even though symptoms are similar. It may harm them.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Pansa DSR Capsules and certain other medicines can interact with each other causing serious side effects.
12.0 Date of issue
04 July 2024
About Leaflet
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor, pharmacist or nurse.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
What is in this leaflet
1.What PANSA DSR is and what it is used for
2. What you need to know before you take PANSA DSR
3. How to take PANSA DSR
4. Possible side effects
5. How to store PANSA DSR
6. Contents of the pack and other information
1. What PANSA DSR is and what it is used for
Pansa DSR Capsule is a combination of two medicines: Domperidone and Pantoprazole. Domperidone is a prokinetic which works on the upper digestive tract to increase the movement of the stomach and intestines, allowing the food to move more easily through the stomach. Pantoprazole is a proton pump inhibitor (PPI) which works by reducing the amount of acid in the stomach which helps in the relief of acid-related indigestion and heartburn
PANSA DSR is used for the treatment of Gastroesophageal reflux disease (occurs when stomach acid repeatedly flows back into the tube connecting your mouth and stomach that is esophagus)
2. What you need to know before you take PANSA DSR
Do not take PANSA DSR if you are
If you are allergic to pantoprazole, domperidone or to any of the other ingredients listed in the formulation
If you are allergic to medicines containing other proton pump inhibitors.
You have black, tarry bowel motions (stools) or notice blood in your bowel motions. This could be a sign of bleeding in the stomach or intestines
You have a blockage or tear in your intestines
You have a tumour of the pituitary gland called a prolactinoma.
have a disorder known as phenylketonuria (a metabolic disorder) orodispersible tablets should not be used as they contain aspartamine
if you have a moderate or severe liver disease
if your ECG (electrocardiogram) shows a heart problem called "prolonged QT corrected interval"
if you have or had a problem where your heart cannot pump the blood round your body as well as it should (condition called heart failure).
if you have a problem that gives you a low level of potassium or magnesium, or a high level of potassium in your blood.
Do not take PANSA DSR tablets if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking PANSA DSR tablet. Do this even if they have applied in the past.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PANSA DSR
If you have severe liver problems. Please tell your doctor if you ever had problems with your liver in the past. He will check your liver enzymes more frequently, especially when you are taking Pantoprazole as a long-term treatment. In the case of a rise of liver enzymes the treatment should be stopped.
If you have reduced body stores or risk factors for reduced vitamin B12 and receive long-term treatment with pantoprazole. As with all acid reducing agents, pantoprazole may lead to a reduced absorption of vitamin B12.
If you are taking HIV protease inhibitors such as atazanavir (for the treatment of HIV-infection) at the same time as pantoprazole, ask your doctor for specific advice.
Taking a proton pump inhibitor like pantoprazole, especially over a period of more than one year, may slightly increase your risk of fracture in the hip, wrist or spine. Tell your doctor if you have osteoporosis or if you are taking corticosteroids (which can increase the risk of osteoporosis).
If you are on Pantoprazole for more than three months it is possible that the levels of magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of magnesium.
If you have ever had a skin reaction after treatment with a medicine similar to Pantoprazole that reduces stomach acid.
If you get a rash on your skin, especially in areas exposed to the sun tell your doctor as soon as you can, as you may need to stop your treatment with Pantoprazole. Remember to also mention any other ill-effects like pain in your joints.
if you are due to have a specific blood test (Chromogranin A).
if you suffer from liver problems (liver function impairment or failure)
if you suffer from kidney problems (kidney function impairment or failure).
It is advisable to ask your doctor for advice in case of prolonged treatment as you may need to take a lower dose or take this medicine less often, and your doctor may want to examine you regularly. Domperidone may be associated with an increased risk of heart rhythm disorder and cardiac arrest. This risk may be more likely in those over 60 years old or taking doses higher than 30mg per day. The risk also increases when domperidone is given together with some drugs. Tell your doctor or pharmacist if you are taking drugs to treat infection (fungal infections or bacterial infection) and/or if you have heart problems or AIDS/HIV. Domperidone should be used at the lowest effective dose. While taking domperidone, contact your doctor if you experience heart rhythm disorders such as palpitations, trouble breathing, loss of consciousness. Treatment with domperidone should be stopped.
Adolescents weighing less than 35 kg and children
PANSA DSR should not be given to adolescents 12 years of age and older weighing less than 35 kg, or in any children less than 12 years of age, as it is not effective in these age groups.
Tell your doctor immediately, before or after taking this medicine, if you notice any of the following
An unintentional loss of weight
Vomiting, particularly if repeated
Vomiting blood; this may appear as dark coffee grounds in your vomit
You notice blood in your stools; which may be black or tarry in appearance
Difficulty in swallowing or pain when swallowing
You look pale and feel weak (anaemia)
Chest pain, Stomach pain, severe and/or persistent diarrhoea, because this medicine
has been associated with a small increase in infectious diarrhoea.
Your doctor may decide that you need some tests to rule out malignant disease because pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. If you take Pantoprazole on a long-term basis (longer than 1 year) your doctor will probably keep you under regular surveillance. You should report any new and exceptional symptoms and circumstances whenever you see your doctor.
Other medicines and PANSA DSR
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This is because Pantoprazole may influence the effectiveness of other medicines, so tell your doctor if you are taking:
Medicines such as ketoconazole, itraconazole and posaconazole (used to treat fungal infections) or erlotinib (used for certain types of cancer) because Pantoprazole may stop these and other medicines from working properly.
Warfarin and phenprocoumon, which affect the thickening, or thinning of the blood. You may need further checks.
Medicines used to treat HIV-infection, such as atazanavir.
Methotrexate (used to treat rheumatoid arthritis, psoriasis, and cancer) – if you are taking methotrexate your doctor may temporarily stop your Pantoprazole treatment because pantoprazole can increase levels of methotrexate in the blood.
Fluvoxamine (used to treat depression and other psychiatric diseases) – if you are taking fluvoxamine your doctor may reduce the dose.
Rifampicin (used to treat infections).
St John’s wort (Hypericum perforatum) (used to treat mild depression).
Do not take Domperidone tablet if you are taking medicine to treat:
fungal infections such as azole antifungals, specifically oral ketoconazole, fluconazole or voriconazole
bacterial infections, specifically erythromycin, clarithromycin, telithromycin,moxifloxacin, pentamidine (these are antibiotics)
heart problems or high blood pressure (e.g., amiodarone, dronedarone, quinidine, disopyramide, dofetilide, sotalol, diltiazem, verapamil)
certain other medicines (e.g., bepridil, diphemanil, methadone)
Before you use Domperidone tablet and apomorphine, your doctor will ensure that you tolerate both medicines when used simultaneously. Ask your doctor or specialist for a personalised advice. Tell your doctor or pharmacist if you are taking drugs to treat infection, heart problems or AIDS/HIV. It is important to ask your doctor or pharmacist if Domperidone tablet is safe for you when you are taking any other medicines, including medicines obtained without prescription.
Pregnancy
Pantoprazole: There are no adequate and well-controlled studies in pregnant women.
Domperidone: There are limited post-marketing data of its use in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose.
Because animal reproduction studies are not always predictive of human response, PANSA DSR tablet should be used during pregnancy only if clearly needed.
Lactation
There is insufficient data on the excretion of pantoprazole in human milk but excretion into human milk has been reported.
Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants.
A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from PANSA DSR therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women.
Driving and using machines
PANSA DSR has no or negligible influence on the ability to drive and use machines. If you experience side effects like dizziness or disturbed vision, you should not drive or operate machines.
3. How to take PANSA DSR
One capsule daily. The capsule should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.
Pediatric
PANSA DSR tablets are not recommended in children below 12 years of age.
Hepatic impairment
No dosage adjustment is needed in patients with mild to severe hepatic impairment. In patients with severe liver impairment, the liver enzymes should be monitored regularly during treatment with pantoprazole, particularly on long-term use.
In the case of a rise of the liver enzymes, the treatment should be discontinued. Doses higher than 40 mg/day have not been studied in patients with hepatic impairment
Renal impairment
In subjects with renal insufficiency (creatinine clearance<30 ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours. Since very little unchanged drug (approx. 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency of PANSA DSR should be reduced to once or twice daily depending on severity of the impairment.
If you take more PANSA DSR than you should
Consult your doctor or pharmacist. There are no known symptoms of overdose.
If you forget to take PANSA DSR
Do not take a double dose to make up for a forgotten dose. Take your next, normal dose at the usual time.
If you stop taking PANSA DSR
Do not stop taking these tablets without first talking to your doctor or pharmacist.
4. Possible Side Effects
Pantoprazole
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any of the following side effects, stop taking these tablets and tell your doctor immediately, or contact the casualty department at your nearest hospital:
Serious allergic reactions (frequency rare: may affect up to 1 in 1,000 people): swelling of the tongue and/or throat, difficulty in swallowing, hives (nettle rash), difficulties in breathing, allergic facial swelling (Quincke’s oedema / angioedema), severe dizziness with very fast heartbeat and heavy sweating.
Serious skin conditions (frequency not known: frequency cannot be estimated from the available data): blistering of the skin and rapid deterioration of your general condition, erosion (including slight bleeding) of eyes, nose, mouth/lips or genitals (Stevens-Johnson-Syndrome, Lyell-Syndrome, Erythema multiforme), and sensitivity to light.
Other serious conditions (frequency not known: frequency cannot be estimated from the available data): yellowing of the skin or whites of the eyes (severe damage to liver cells, jaundice) or fever, rash, and enlarged kidneys sometimes with painful urination, and lower back pain (serious inflammation of the kidneys), possibly leading to kidney failure.
Other side effects are:
Common (may affect up to 1 in 10 people) Benign polyps in the stomach.
Uncommon (may affect up to 1 in 100 people) Headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind); constipation; dry mouth; abdominal pain and discomfort; skin rash, exanthema, eruption; itching; feeling weak, exhausted or generally unwell; sleep disorders; fracture in the hip, wrist or spine.
Rare (may affect up to 1 in 1,000 people) Distortion or complete lack of the sense of taste; disturbances in vision such as blurred vision; hives; pain in the joints; muscle pains; weight changes; raised body temperature; high fever; swelling of the extremities (peripheral oedema); allergic reactions; depression; breast enlargement in males.
Very Rare (may affect up to 1 in 10,000 people) Disorientation.
Not known (frequency cannot be estimated from the available data) Hallucination, confusion (especially in patients with a history of these symptoms); decreased sodium level in blood, decreased magnesium level in blood, feeling of tingling, prickling, pins and needles, burning sensation or numbness, rash, possibly with pain in the joints, inflammation in the large bowel, that causes persistent watery diarrhoea.
Side effects identified through blood tests:
Uncommon (may affect up to 1 in 100 people) an increase in liver enzymes.
Rare (may affect up to 1 in 1,000 people) an increase in bilirubin; increased fat levels in blood; sharp drop in circulating granular white blood cells, associated with high fever.
Very Rare (may affect up to 1 in 10,000 people) a reduction in the number of blood platelets, which may cause you to bleed or bruise more than normal; a reduction in the number of white blood cells, which may lead to more frequent infections; coexisting abnormal reduction in the number of red and white blood cells, as well as platelets.
Domperidone
Uncommon (may affect up to 1 in 100 people): Involuntary movements of the face or arms and legs, excessive trembling, excessive muscle stiffness or muscle spasm
Not known (frequency cannot be estimated from the available data):
Seizures
a type of reaction that may occur soon after administration and is recognised by skin rash, itching, shortness of breath, and/or a swollen face.
a severe hypersensitivity reaction that may occur soon after administration that is characterised by hives, itching, flushing, fainting, and difficulty breathing among other possible symptoms.
disorders of the cardiovascular system: heart rhythm disorders (rapid or irregular heart beat) have been reported; if this happens, you should stop the treatment immediately.
Domperidone may be associated with an increased risk of heart rhythm disorder and cardiac arrest. This risk may be more likely in those over 60 years old or taking doses higher than 30 mg per day. Domperidone should be used at the lowest effective dose. Stop treatment with Domperidone and contact your doctor immediately if you experience any of the unwanted events described above.
Other unwanted effects that have been observed with Domperidone are listed below:
Common (may affect up to 1 in 10 people): Dry mouth
Uncommon (may affect up to 1 in 100 people): anxiety, agitation, nervousness, loss of interest in sex or diminished interest in sex, headache, sleepiness, diarrhoea, rash, itchiness, hives, Painful or tender breasts, milk discharge from breasts, a general feeling of weakness, feeling dizzy
Not known (frequency cannot be estimated from the available data): Upward movement of the eyes, stopped menstrual periods in women, enlarged breasts in men, inability to urinate, changes in certain laboratory test results, restless legs syndrome (uncomfortable feeling, with an irresistible urge to move your legs, and sometimes arms and other parts of your body).
Some patients who have used Domperidone for conditions and dosages requiring medical oversight have experienced the following unwanted effects: Restlessness; swollen or enlarged breasts, unusual discharge from breasts, irregular menstrual periods in women, difficulty breastfeeding, depression, hypersensitivity.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly: Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top of the home page.
By reporting side effects, you can help provide more information on the safety of this medicine.
You can also report the side effect with the help of your treating physician.
5. How to store PANSA DSR
Store protected from light & moisture at a temperature not exceeding 30°C.
Keep out of reach of children.
Do not use the tablets after the expiry date is stated on the label. Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
6. Contents of the pack and other information
What Zosa Junior gastro-resistant granules for oral suspension contains
Colours : Yellow Oxide of Iron & Titanium Dioxide IP
3.0 Dosage form and strength
Tablets
4.0 Clinical particulars
4.1 Therapeutic indication
For the treatment of GERD not responding to pantoprazole.
4.2 Posology and method of administration
One tablet to be taken 1-3 times a day. The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.
4.3 Contraindications
known hypersensitivity to the active substance pantoprazole, domperidone or to substituted benzimidazoles or to any excipients listed in formulation.
in patients with moderate or severe hepatic impairment
renal impairment
in patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.
co-administration with QT-prolonging drugs, at the exception of apomorphine
co-administration with potent CY3A4 inhibitors (regardless of their QT prolonging effects) when stimulation of gastric motility could be harmful : gastro-intestinal haemorrhage, mechanical obstruction or perforation.
4.4 Special warnings and precautions for use
In patients with severe liver impairment the liver enzymes should be monitored regularly during treatment with pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes the treatment should be discontinued.
The use of pantoprazole as a preventive of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued NSAID treatment and have an increased risk to develop gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (>65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.
Symptomatic response to pantoprazole may mask the symptoms of gastric malignancy and may delay diagnosis. In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded. Further investigation is to be considered if symptoms persist despite adequate treatment.
Pantoprazole may reduce the absorption of vitamin B12 due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.
In long-term treatment with pantoprazole, especially when exceeding 1 year, patients should be kept under regular surveillance.
Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinalinfections caused by bacteria such as Salmonella and Campylobacter or C. difficile.
For patients expected to be on prolonged pantoprazole treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically thereafter.
PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
PPIs are associated with very infrequent cases of Subacute Cutaneous Lupus Erythematosus (SCLE). If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping pantoprazole.
Increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, pantoprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.
The risk of neurological side effects with domperidone is higher in young children. Overdosing may cause extra-pyramidal symptoms, but other causes should be taken into consideration.
Domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. Contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patient with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia.
4.5 Drugs interactions
Pantoprazole
Medicinal products with pH-dependent absorption pharmacokinetics
Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with the absorption of other medicinal products where gastric pH is an important determinant of oral availability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicinal products such as erlotinib
HIV protease inhibitors
Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their bioavailability.
If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended. A pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.
Coumarin anticoagulants (phenprocoumon or warfarin)
Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.
Methotrexate
Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered. Other interactions studies
Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.
Interaction studies with medicinal products also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.
An interaction of pantoprazole with other medicinal products or compounds, which are metabolized using the same enzyme system, cannot be excluded.
Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption of digoxin.
There were no interactions with concomitantly administered antacids.
Interaction studies have also been performed by concomitantly administering pantoprazole with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.
Medicinal products that inhibit or induce CYP2C19
Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with hepatic impairment.
Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John´s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.
Domperidone
The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.
Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions. Concomitant use of the following substances is contraindicated
QTc-prolonging medicinal products
anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)
anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
certain antipsychotics (e.g., haloperidol, pimozide, sertindole)
certain antidepressants (e.g., citalopram, escitalopram)
certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)
certain antifungal agents (e.g., pentamidine)
certain antimalarial agents (in particular halofantrine, lumefantrine)
certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)
certain antihistaminics (e.g., mequitazine, mizolastine)
certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)
certain other medicines (e.g., bepridil, diphemanil, methadone)
apomorphine, unless the benefit of the co-administration outweighs the risks, and only if the recommended precautions for co-administration are strictly fulfilled.
Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e :
protease inhibitors
systemic azole antifungals
some macrolides (erythromycin, clarithromycin and telithromycin)
Concomitant use of the following substances is not recommended
Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides.
Concomitant use of the following substances requires caution in use
Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation : azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).
The above list of substances is representative and not exhaustive.
Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs
With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10mg four times daily and oral erythromycin 500mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while Ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.
4.6 Use in special populations
Pregnancy
Pantoprazole : There are no adequate and well-controlled studies in pregnant women. Domperidone : There are limited post-marketing data of its use in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. Because animal reproduction studies are not always predictive of human response, Pansa D tablet should be used during pregnancy only if clearly needed.
Lactation
There is insufficient data on the excretion of pantoprazole in human milk but excretion into human milk has been reported. Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants.
A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from Pansa D therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women.
Pediatric
Pansa D tablets are not recommended in children below 12 years of age.
Hepatic impairment
A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment. Domperidone is contraindicated in moderate or severe hepatic impairment. Hence, a Pansa D tablet is contraindicated in patients with moderate or severe hepatic impairment.
Renal impairment
In subjects with renal insufficiency (creatinine clearance<30 ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours. Since very little unchanged drug (approx. 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency of Pansa D should be reduced to once or twice daily depending on severity of the impairment.
4.7 Effects on ability to drive and use machines
Pansa D tablet has no or negligible influence on the ability to drive and use machines. Adverse drug reactions such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.
4.8 Undesirable effects
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
Systemic exposure with up to pantoprazole 240 mg administered intravenously over 2 minutes, were well tolerated. As pantoprazole is extensively protein bound, it is not readily dialysable. Symptoms of overdosage with domperidone may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions. In the event of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal may be useful. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Close medical supervision and supportive therapy is recommended. Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.
5.0 Pharmacological properties
5.1 Mechanism of Action
Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the (H+,K+)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours. Domperidone binds to dopamine receptor D2 (D2R) expressed by peripheral neurons; this inhibits dopamine binding and D2R-mediated signaling. Inhibition of peripheral D2R signaling prevents or relieves various gastrointestinal (GI) symptoms, such as nausea and vomiting, and may help relief reflux and symptoms of a variety of other upper GI disorders.
5.2 Pharmacodynamicproperties
Pantoprazole
The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments have not been observed in humans. During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also Chromogranin A (CgA) increases due to decreased gastric acidity.
Domperidone
Domperidone does not readily cross the blood brain barrier. In domperidone users, especially in adults, extra pyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Studies have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion. When domperidone was administered in healthy subjects at up to 80 mg/day (i.e., more than twice the maximum recommended dosing) in QT study performed in accordance with ICH-E14 guidelines, no clinically relevant QTc effects were observed.
5.3 Pharmacokinetic properties
6.0 Nonclinical properties
No known animal toxicology data
7.0 Description
8.0 Pharmaceutical particulars
8.1 Incompatibilities
None
8.2 Shelf-life
24 Months.
8.3 Packaging information
A blister strip of 10 tablets.
8.4 Storage and handing instructions
Store protected from light & moisture at a temperature not exceeding 30°C.
Keep out of reach of children.
9.0 Patient Counselling Information
Ask the patient to report any adverse events.
Not to exceed the stated recommended daily dose.
12.0 Date of revision
14.05.2021
About Leaflet
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor, pharmacist or nurse.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
What is in this leaflet
1. What Pansa D is and what it is used for
2. What you need to know before you take Pansa D
3. How to take Pansa D
4. Possible side effects
5. How to store Pansa D
6. Contents of the pack and other information
1. What Pansa D is and what it is used for
Pansa D is the combination of Pantoprazole & Domperidone. Pantoprazole is a selective “proton pump inhibitor”, a medicine which reduces the amount of acid produced in your stomach. It is used for treating acid-related diseases of the stomach and intestine. Domperidone as the active ingredient, which belongs to a group of medicines called 'dopamine antagonists'.
Pansa D is used for the treatment of GERD not responding to pantoprazole.
2. What you need to know before you take Pansa D
Do not take Pansa D if you are
If you are allergic to pantoprazole, domperidone or to any of the other ingredients listed in the formulation
If you are allergic to medicines containing other proton pump inhibitors.
You have black, tarry bowel motions (stools) or notice blood in your bowel motions.
This could be a sign of bleeding in the stomach or intestines You have a blockage or tear in your intestines You have a tumour of the pituitary gland called a prolactinoma. have a disorder known as phenylketonuria (a metabolic disorder) orodispersible tablets should not be used as they contain aspartamine
if you have a moderate or severe liver disease
if your ECG (electrocardiogram) shows a heart problem called "prolonged QT corrected interval"
if you have or had a problem where your heart cannot pump the blood round your body as well as it should (condition called heart failure).
if you have a problem that gives you a low level of potassium or magnesium, or a high level of potassium in your blood.
Do not take Pansa D tablets if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Pansa D tablet. Do this even if they have applied in the past.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Pansa D
If you have severe liver problems. Please tell your doctor if you ever had problems with your liver in the past. He will check your liver enzymes more frequently, especially when you are taking Pantoprazole as a long-term treatment. In the case of a rise of liver enzymes the treatment should be stopped.
If you have reduced body stores or risk factors for reduced vitamin B12 and receive long-term treatment with pantoprazole. As with all acid reducing agents, pantoprazole may lead to a reduced absorption of vitamin B12.
If you are taking HIV protease inhibitors such as atazanavir (for the treatment of HIV-infection) at the same time as pantoprazole, ask your doctor for specific advice.
Taking a proton pump inhibitor like pantoprazole, especially over a period of more than one year, may slightly increase your risk of fracture in the hip, wrist or spine. Tell your doctor if you have osteoporosis or if you are taking corticosteroids (which can increase the risk of osteoporosis).
If you are on Pantoprazole for more than three months it is possible that the levels of magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of magnesium.
If you have ever had a skin reaction after treatment with a medicine similar to Pantoprazole that reduces stomach acid.
If you get a rash on your skin, especially in areas exposed to the sun tell your doctor as soon as you can, as you may need to stop your treatment with Pantoprazole. Remember to also mention any other ill-effects like pain in your joints.
if you are due to have a specific blood test (Chromogranin A).
if you suffer from liver problems (liver function impairment or failure)
if you suffer from kidney problems (kidney function impairment or failure).
It is advisable to ask your doctor for advice in case of prolonged treatment as you may need to take a lower dose or take this medicine less often, and your doctor may want to examine you regularly. Domperidone may be associated with an increased risk of heart rhythm disorder and cardiac arrest. This risk may be more likely in those over 60 years old or taking doses higher than 30mg per day. The risk also increases when domperidone is given together with some drugs. Tell your doctor or pharmacist if you are taking drugs to treat infection (fungal infections or bacterial infection) and/or if you have heart problems or AIDS/HIV. Domperidone should be used at the lowest effective dose. While taking domperidone, contact your doctor if you experience heart rhythm disorders such as palpitations, trouble breathing, loss of consciousness. Treatment with domperidone should be stopped.
Adolescents weighing less than 35 kg and children
Pansa D should not be given to adolescents 12 years of age and older weighing less than 35 kg, or in any children less than 12 years of age, as it is not effective in these age groups.
Tell your doctor immediately, before or after taking this medicine, if you notice any of the following
An unintentional loss of weight
Vomiting, particularly if repeated
Vomiting blood; this may appear as dark coffee grounds in your vomit
You notice blood in your stools; which may be black or tarry in appearance Difficulty in swallowing
or pain when swallowing You look pale and feel weak (anaemia) Chest pain,
Stomach pain, severe and/or persistent diarrhoea, because
this medicine has been associated with a small increase in infectious diarrhoea.
Your doctor may decide that you need some tests to rule out malignant disease because pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. If you take Pantoprazole on a long-term basis (longer than 1 year) your doctor will probably keep you under regular surveillance. You should report any new and exceptional symptoms and circumstances whenever you see your doctor.
Other medicines and Pansa D
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. This is because Pantoprazole may influence the effectiveness of other medicines, so tell your doctor if you are taking:
Medicines such as ketoconazole, itraconazole and posaconazole (used to treat fungal infections) or erlotinib (used for certain types of cancer) because Pantoprazole may stop these and other medicines from working properly.
Warfarin and phenprocoumon, which affect the thickening, or thinning of the blood. You may need further checks.
Medicines used to treat HIV-infection, such as atazanavir.
Methotrexate (used to treat rheumatoid arthritis, psoriasis, and cancer) – if you are taking methotrexate your doctor may temporarily stop your Pantoprazole treatment because pantoprazole can increase levels of methotrexate in the blood.
Fluvoxamine (used to treat depression and other psychiatric diseases) – if you are taking fluvoxamine your doctor may reduce the dose.
Rifampicin (used to treat infections).
St John’s wort (Hypericum perforatum) (used to treat mild depression).
Do not take Domperidone tablet if you are taking medicine to treat:
fungal infections such as azole antifungals, specifically oral ketoconazole, fluconazole or voriconazole
bacterial infections, specifically erythromycin, clarithromycin, telithromycin,moxifloxacin, pentamidine (these are antibiotics)
heart problems or high blood pressure (e.g., amiodarone, dronedarone, quinidine, disopyramide, dofetilide, sotalol, diltiazem, verapamil)
certain other medicines (e.g., bepridil, diphemanil, methadone)
Before you use Domperidone tablet and apomorphine, your doctor will ensure that you tolerate both medicines when used simultaneously. Ask your doctor or specialist for a personalised advice. Tell your doctor or pharmacist if you are taking drugs to treat infection, heart problems or AIDS/HIV. It is important to ask your doctor or pharmacist if Domperidone tablet is safe for you when you are taking any other medicines, including medicines obtained without prescription.
Pregnancy
Pantoprazole: There are no adequate and well-controlled studies in pregnant women.
Domperidone: There are limited post-marketing data of its use in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose.
Because animal reproduction studies are not always predictive of human response, Pansa D tablet should be used during pregnancy only if clearly needed.
Lactation
There is insufficient data on the excretion of pantoprazole in human milk but excretion into human milk has been reported.
Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants.
A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from Pansa D therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women.
Driving and using machines
Pansa D has no or negligible influence on the ability to drive and use machines. If you experience side effects like dizziness or disturbed vision, you should not drive or operate machines.
3. How to take Pansa D
One tablet to be taken 1-3 times a day. The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.
Pediatric
Pansa D tablets are not recommended in children below 12 years of age.
Hepatic impairment
A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment.
Domperidone is contraindicated in moderate or severe hepatic impairment.
Hence, a Pansa D tablet is contraindicated in patients with moderate or severe hepatic impairment.
Renal impairment
In subjects with renal insufficiency (creatinine clearance<30 ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours. Since very little unchanged drug (approx. 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency of Pansa D should be reduced to once or twice daily depending on severity of the impairment.
If you take more Pansa D than you should
Consult your doctor or pharmacist. There are no known symptoms of overdose.
If you forget to take Pansa D
Do not take a double dose to make up for a forgotten dose. Take your next, normal dose at the usual time.
If you stop taking Pansa D
Do not stop taking these tablets without first talking to your doctor or pharmacist.
4. Possible Side Effects
Pantoprazole
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any of the following side effects, stop taking these tablets and tell your doctor immediately, or contact the casualty department at your nearest hospital:
Serious allergic reactions (frequency rare: may affect up to 1 in 1,000 people): swelling of the tongue and/or throat, difficulty in swallowing, hives (nettle rash), difficulties in breathing, allergic facial swelling (Quincke’s oedema / angioedema), severe dizziness with very fast heartbeat and heavy sweating.
Serious skin conditions (frequency not known: frequency cannot be estimated from the available data): blistering of the skin and rapid deterioration of your general condition, erosion (including slight bleeding) of eyes, nose, mouth/lips or genitals (Stevens-Johnson-Syndrome, Lyell-Syndrome, Erythema multiforme), and sensitivity to light.
Other serious conditions (frequency not known: frequency cannot be estimated from the available data): yellowing of the skin or whites of the eyes (severe damage to liver cells, jaundice) or fever, rash, and enlarged kidneys sometimes with painful urination, and lower back pain (serious inflammation of the kidneys), possibly leading to kidney failure.
Other side effects are:
Common (may affect up to 1 in 10 people) Benign polyps in the stomach.
Uncommon (may affect up to 1 in 100 people) Headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind); constipation; dry mouth; abdominal pain and discomfort; skin rash, exanthema, eruption; itching; feeling weak, exhausted or generally unwell; sleep disorders; fracture in the hip, wrist or spine.
Rare (may affect up to 1 in 1,000 people) Distortion or complete lack of the sense of taste; disturbances in vision such as blurred vision; hives; pain in the joints; muscle pains; weight changes; raised body temperature; high fever; swelling of the extremities (peripheral oedema); allergic reactions; depression; breast enlargement in males.
Very Rare (may affect up to 1 in 10,000 people) Disorientation.
Not known (frequency cannot be estimated from the available data) Hallucination, confusion (especially in patients with a history of these symptoms); decreased sodium level in blood, decreased magnesium level in blood, feeling of tingling, prickling, pins and needles, burning sensation or numbness, rash, possibly with pain in the joints, inflammation in the large bowel, that causes persistent watery diarrhoea.
Side effects identified through blood tests:
Uncommon (may affect up to 1 in 100 people) an increase in liver enzymes.
Rare (may affect up to 1 in 1,000 people) an increase in bilirubin; increased fat levels in blood; sharp drop in circulating granular white blood cells, associated with high fever.
Very Rare (may affect up to 1 in 10,000 people) a reduction in the number of blood platelets, which may cause you to bleed or bruise more than normal; a reduction in the number of white blood cells, which may lead to more frequent infections; coexisting abnormal reduction in the number of red and white blood cells, as well as platelets.
Domperidone
Uncommon (may affect up to 1 in 100 people): Involuntary movements of the face or arms and legs, excessive trembling, excessive muscle stiffness or muscle spasm
Not known (frequency cannot be estimated from the available data):
Seizures
a type of reaction that may occur soon after administration and is recognised by skin rash, itching, shortness of breath, and/or a swollen face.
a severe hypersensitivity reaction that may occur soon after administration that is characterised by hives, itching, flushing, fainting, and difficulty breathing among other possible symptoms.
disorders of the cardiovascular system: heart rhythm disorders (rapid or irregular heart beat) have been reported; if this happens, you should stop the treatment immediately.
Domperidone may be associated with an increased risk of heart rhythm disorder and cardiac arrest. This risk may be more likely in those over 60 years old or taking doses higher than 30 mg per day. Domperidone should be used at the lowest effective dose. Stop treatment with Domperidone and contact your doctor immediately if you experience any of the unwanted events described above.
Other unwanted effects that have been observed with Domperidone are listed below:
Common (may affect up to 1 in 10 people): Dry mouth
Uncommon (may affect up to 1 in 100 people): anxiety, agitation, nervousness, loss of interest in sex or diminished interest in sex, headache, sleepiness, diarrhoea, rash, itchiness, hives, Painful or tender breasts, milk discharge from breasts, a general feeling of weakness, feeling dizzy
Not known (frequency cannot be estimated from the available data): Upward movement of the eyes, stopped menstrual periods in women, enlarged breasts in men, inability to urinate, changes in certain laboratory test results, restless legs syndrome (uncomfortable feeling, with an irresistible urge to move your legs, and sometimes arms and other parts of your body).
Some patients who have used Domperidone for conditions and dosages requiring medical oversight have experienced the following unwanted effects: Restlessness; swollen or enlarged breasts, unusual discharge from breasts, irregular menstrual periods in women, difficulty breastfeeding, depression, hypersensitivity.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly: Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top right end of the home page.
By reporting side effects, you can help provide more information on the safety of this medicine.
You can also report the side effect with the help of your treating physician.
5. How to store Pansa D
Store protected from light & moisture at a temperature not exceeding 30°C.
Keep out of reach of children.
Do not use the tablets after the expiry date is stated on the label. Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
6. Contents of the pack and other information
Each gastro-resistant tablet contains -
Pantoprazole Sodium IP equivalent to Pantoprazole 20 mg
Domperidone Maleate IP equivalent to Domperidone 10 mg
Excipients q.s.
Colours : Yellow Oxide of Iron and Titanium Dioxide IP
