Zosa HP Kit Tablets

Combipack of Clarithromycin Tablets IP, Esomeprazole Tablets IP and Amoxicillin Tablets USP

Each strip contains :

A. Clarithromycin Tablets IP 2 Tablets

Each film coated tablet contains :

Clarithromycin IP 500 mg

Excipients q.s.

Colour : Titanium Dioxide IP

B. Esomeprazole Tablets IP 2 Tablets

Each enteric coated tablet contains :

Esomeprazole Magnesium Trihydrate IP

equivalent to Esomeprazole 40 mg

Excipients q.s

Colours : Red Oxide of Iron & Titanium Dioxide IP

C. Amoxicillin Tablets USP 2 Tablets

Each film coated tablet contains:

Amoxycillin Trihydrate IP

equivalent to Amoxycillin 750 mg

Excipients q.s

Colours : Sunset Yellow FCF & Titanium Dioxide IP

Film Coated Tablet, Clarithromycin 500 mg and Amoxycillin 750 mg Enteric Coated Tablet, Esomeprazole 40 mg

4.1 Therapeutic indication

For healing of duodenal ulcer associated with Helicobacter pylori and eradication of Helicobacter pylori in patients with active or healed peptic ulcer.

4.2 Posology and method of administration

Posology

The combipack contains two tablets of Clarithromycin (500 mg), two tablets of Esomeprazole (40 mg) and two tablets of Amoxicillin (750 mg). One pack is for 1 day of treatment. From this specially designed pack, one tablet of Clarithromycin, one tablet of Esomeprazole, and one tablet of Amoxicillin are to be taken in the morning and similarly one each in the evening. The duration of therapy recommended is for 7 days or as directed by the Physician.

Renal and hepatic impairment

Caution should be exercised while administering the combipack of Clarithromycin, Esomeprazole and Amoxicillin to patients with renal and hepatic impairment.

Method of administration

For oral administration only

4.3 Contraindications

• Contraindicated in patients with known severe hypersensitivity to any component of the formulation.

• Patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointes.

• Concomitant administration of Clarithromycin and Colchicine is contraindicated in patients with renal or hepatic impairment.

• Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (Lovastatin or Simvastatin), due to the increase risk of myopathy, including rhabdomyolysis.

• Patients with hypokalaemia (risk of prolongation of QT-time).

• In patients who suffer from severe hepatic failure in combination with renal impairment.

• Concomitant Administration with any of the following drugs is contraindicated : Cisapride, Pimozide, Astemizole, Terfenadine and Ergotamine or Dihydroergotamine. There have been post marketing reports of drug interactions when Clarithromycin and/or Erythromycin are co-administered with Cisapride, Pimozide, Astemizole or Terfenadine, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes), most likely due to inhibition of metabolism of these drugs by erythromycin and Clarithromycin. Fatalities have been reported.

• Should not be used concomitantly with Nelfinavir.

• History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

4.4 Special warnings and precautions for use

Embryo-fetal toxicity

Clarithromycin, a component of ZOSA HP KIT, has demonstrated adverse effects on pregnancy outcomes and/or embryo-fetal development in monkeys, rats, mice, and rabbits at doses that produced plasma concentrations 2 to 17 times the serum concentrations achieved in humans at the maximum recommended human dose. Based on findings in animal studies, ZOSA HP KIT is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If ZOSA HP KIT is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus.

Severe cutaneous adverse reactions

There have been post marketing reports of colchicine toxicity, some fatal, with concomitant use of Clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Monitor patients for clinical symptoms of colchicine toxicity

Myasthenia gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome have been reported in patients receiving Clarithromycin therapy. Monitor patients for symptoms.

Clostridioides difficile-associated diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of Clarithromycin and Amoxicillin, 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. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. 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.

Acute tubulointerstitial nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs, a component of ZOSA HP KIT. TIN may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue ZOSA HP KIT and evaluate patients with suspected acute TIN.

Cutaneous and systemic lupus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. 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. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus(SLE) isless commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving ZOSA HP KIT, discontinue the drug and refer the patient to the appropriate specialist for evaluation.

Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Development of bacterial superinfections

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy with ZOSA HP KIT due to the Clarithromycin and Amoxicillin components. If superinfections occur, ZOSA HP KIT should be discontinued and appropriate therapy instituted.

Mononucleosis and Ampicillin

A high percentage of patients with mononucleosis who receive ampicillin develop an erythematosus skin rash. Thus, administration of ampicillin-class antibiotics is not recommended in patients with mononucleosis.

Development of drug resistant bacteria

Prescribing ZOSA HP KIT (Clarithromycin or Amoxicillin component) 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.

4.5 Drug interaction

Colchicine

Concurrent use of Colchicine and ZOSA HP KIT may increase plasma Colchicine concentrations. Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). The Clarithromycin component of ZOSA HP KIT is known to inhibit CYP3A and Pgp. When Clarithromycin and Colchicine are administered together, inhibition of Pgp and/or CYP3A by Clarithromycin may lead to increased plasma exposure to colchicine. Monitor patients for clinical symptoms of colchicine toxicity.

Ergotamine / Dihydroergotamine

Ergotamine / Dihydroergotamine plasma concentrations may increase when administered concomitantly with ZOSA HP KIT. Post-marketing reports indicate that co-administration of Clarithromycin with Ergotamine or Dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of Clarithromycin with ergotamine or Dihydroergotamine is contraindicated.

Pimozide

The co-administration of Pimozide and ZOSA HP KIT may increase the Pimozide plasma concentrations due to an interaction with the Clarithromycin component of ZOSA HP KIT. Post-marketing reports indicate that coadministration of Clarithromycin with Pimozide has been associated with cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes). Two sudden deaths have been reported when Clarithromycin was added to ongoing Pimozide therapy. Pimozide is metabolized partly by CYP3A4. When Clarithromycin and Pimozide are administered together, inhibition of CYP3A4 by Clarithromycin may lead to increased plasma exposure to Pimozide. ZOSA HP KIT is contraindicated in patients receiving Pimozide.

Antiarrhythmics

Concurrent use of antiarrhythmic drugs and ZOSA HP KIT may potentiate the antiarrhythmic effects due to an interaction with the Clarithromycin component of ZOSA HP KIT. There have been post-marketing reports of torsades de pointes occurring with concurrent use of Clarithromycin and Quinidine or Disopyramide. Elevated digoxin serum concentrations in patients receiving Clarithromycin and Digoxin concomitantly have also been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitor electrocardiograms for QTc prolongation during coadministration of ZOSA HP KIT with antiarrhythmic drugs. Serum concentrations of antiarrhythmics, including Digoxin, should also be monitored.

Anticoagulants

The simultaneous administration of anticoagulants and ZOSA HP KIT may alter the anticoagulant effects of Warfarin and other oral anticoagulants due to an interaction with the components of ZOSA HP KIT. Monitor prothrombin time and INR in patients receiving ZOSA HP KIT and oral anticoagulants simultaneously. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, and Warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Spontaneous reports in the post-marketing period suggest that concomitant administration of Clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.

Antiretroviral drugs

Concurrent use of antiretroviral agents and ZOSA HP KIT may alter the antiretroviral effects due to interactions with the components of ZOSA HP KIT. Concomitant use of Atazanavir or Nelfinavir is not recommended unless the benefits of taking Atazanavir or nelfinavir with ZOSA HP KIT outweigh the risks. Co-administration of Atazanavir or Nelfinavir with proton pump inhibitors is expected to substantially decrease Atazanavir or nelfinavir plasma concentrations and thereby reduce the therapeutic effect of either of these drugs. Dose reduction of Saquinavir should be considered when co-administered with ZOSA HP KIT.

Cilostazol

Concomitant administration of ZOSA HP KIT and Cilostazol may increase systemic exposure of Cilostazol. Therefore, a dose reduction of Cilostazol by 50% should be considered when concomitantly administered with ZOSA HP KIT.

Tacrolimus

Concomitant administration of ZOSA HP KIT and Tacrolimus may increase the serum concentrations of Tacrolimus due to an interaction with the omeprazole component of ZOSA HP KIT. Frequent monitoring of whole blood trough concentrations of Tacrolimus is recommended when concomitantly administered with ZOSA HP KIT.

Theophylline

ZOSA HP KIT use in patients who are receiving Theophylline may be associated with an increase of serum Theophylline concentrations due to an interaction with the Clarithromycin component of ZOSA HP KIT. Monitoring of serum Theophylline concentrations should be considered for patients receiving high doses of Theophylline or with baseline concentrations in the upper therapeutic range.

Carbamazepine

The simultaneous administration of Carbamazepine and ZOSA HP KIT may alter the effect of carbamazepine due to an interaction with the Clarithromycin component of ZOSA HP KIT. Concomitant administration of single doses of Clarithromycin and Carbamazepine has been shown to result in increased plasma concentrations of Carbamazepine. Blood level monitoring of carbamazepine should be considered when administered concomitantly with ZOSA HP KIT.

Sildenafil

The systemic exposure of Sildenafil may increase when it is administered concomitantly with ZOSA HP KIT due to an interaction with the Clarithromycin component of ZOSA HP KIT; consider a reduction in sildenafil dosage.

HMG-CoA reductase inhibitors (Statins)

Concurrent use of HMG-CoA reductase inhibitors (statins) and ZOSA HP KIT may alter the effect of HMG-CoA due to an interaction with the Clarithromycin component of ZOSA HP KIT. As with other macrolides, Clarithromycin has been reported to increase concentrations of statins (e.g., Lovastatin and Simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Triazolobenzodiazepines (e.g. Triazolam and Alprazolam) and related Benzodiazepines (e.g. Midazolam)

The effect of Triazolobenzodiazepines / related Benzodiazepines may be altered when administered concomitantly with ZOSA HP KIT due to an interaction with the Clarithromycin component. There have been post-marketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of Clarithromycin and Triazolam.

Probenecid

Probenecid decreases the renal tubular secretion of Amoxicillin. Concurrent use of ZOSA HP KIT and probenecid may result in increased and prolonged blood concentrations of the Amoxicillin component of ZOSA HP KIT.

Drugs for which gastric ph can affect bioavailability

Patients may need to be monitored when digoxin is taken concomitantly with ZOSA HP KIT. Use with caution in transplant patients receiving Mycophenolate Mofetil.

Drug-laboratory test interactions

High urine concentrations of Ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using glucose tests based on the Benedict's copper reduction reaction that determines the amount of reducing substances like glucose in urine. Since this effect may also occur with Amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of Ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estradiol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with Amoxicillin.

4.6 Use in special population

Pregnancy

Use of ZOSA HP KIT during pregnancy may cause fetal harm. ZOSA HP KIT is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If ZOSA HP KIT is used during pregnancy, or if pregnancy occurs while taking ZOSA HP KIT, the patient should be apprised of the potential hazard to the fetus.

Breast-feeding

The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Esomeprazole or Clarithromycin or Amoxicillin and any potential adverse effects on the breast-fed child from Clarithromycin or from the underlying maternal condition.

Pediatric population

The safety and effectiveness of this combipack in pediatric patients infected with H. pylori have 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. However, undesirable effects may occur (e.g. allergic reactions, dizziness, confusion, vertigo, blurred vision (rarely), and or convulsions), which may influence the ability to drive and use machines.

4.8 Undesirable effects

The most frequent and common adverse reactions are abdominal pain, diarrhea, nausea, vomiting dysgeusia, acute kidney injury, headache. These adverse reactions are consistent with the known safety profile of macrolide antibiotics. There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without pre-existing mycobacterial infections.

Blood and lymphatic system disorders

Thrombocytopenia, Agranulocytosis, Pancytopenia.

Cardiac disorders

Torsades de pointes, Ventricular tachycardia, Ventricular arrhythmia.

Ear and labyrinth disorders

Deafness was reported chiefly in elderly women and was usually reversible, Blurred vision.

Gastrointestinal disorders

Pancreatitis acute, tongue discoloration, stomatitis, microscopic colitis was reported and was usually reversible with professional cleaning upon discontinuation of the drug. There have been reports of Clarithromycin tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different Clarithromycin formulation (e.g. suspension) or another antibacterial drug.

Hepatobiliary disorders

Hepatic failure, Jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with Clarithromycin.

Immune system

disorders Anaphylactic reaction.

Infections and infestations

Pseudomembranous colitis, GI candidiasis, Clostridium difficile associated diarrhea, Hypomagnesemia, Gynecomastia, Interstitial nephritis, Bronchospasm, Mucocutaneous candidiasis

Investigations

Prothrombin time prolonged, WBC count decreased, INR increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and nutrition disorders

Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin, muscular weakness, Myalgia, Bone fracture.

Musculoskeletal and connective tissue disorders

Myopathy and rhabdomyolysis were reported and in some of the reports, Clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol, Muscular weakness, myalgia, bone fracture.

Nervous system disorders

Convulsion, Ageusia, Parosmia, Anosmia, Paresthesia, Hepatic encephalopathy, Taste disturbance.

Psychiatric disorders

Psychotic disorder, Confusional state, Depersonalization, Disorientation, Hallucination, Abnormal behavior, Abnormal dreams, Aggression, Agitation, Depression.

Renal and urinary disorders

Nephritis interstitial, Renal failure.

Skin and subcutaneous tissue disorders

Stevens-Johnson syndrome, Toxic epidermal necrolysis, Drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, Acne, Alopecia, Erythema multiforme, hyperhidrosis, Photosensitivity, Stevens-Johnson syndrome, Toxic epidermal necrolysis (some fatal).

Reproductive system and breast

Gynaecomastia.

Respiratory, thoracic and mediastinal

Bronchospasm.

Vascular disorders

Hemorrhage. There have been reports of colchicine toxicity with concomitant use of Clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients.

Haemic and lymphatic systems

Anaemia, including haemolytic anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leucopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Central nervous system

Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported rarely.

Miscellaneous

Tooth discolouration (brown, yellow, or grey staining) has been rarely reported. Most reports occurred in pediatric patients. Discolouration was reduced or eliminated with brushing or dental cleaning in most cases.

Changes in laboratory values

Changes in laboratory values with possible clinical significance were as follows : Hepatic : Elevated SGPT (ALT) < 1%; SGOT (AST) < 1%; GGT < 1%; alkaline phosphatase < 1%; LDH < 1%; total bilirubin < 1%. Hematologic : Decreased WBC < 1%; elevated prothrombin time, 1%. Renal : Elevated BUN, 4%; elevated serum creatinine < 1%. Note : GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.

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 Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is very limited experience to date with deliberate overdose. No specific antidote is known. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilized.

5.1 Mechanism of action

Esomeprazole belongs to a class of antisecretory compounds, the substituted Benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral Sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, Esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Clarithromycin exerts its antibacterial activity by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis. Amoxicillin acts through the inhibition of biosynthesis of cell wall mucopeptide.

5.2 Pharmacodynamic properties

Clarithromycin

Pharmacotherapeutic Group : Antibacterial for systemic use, macrolide. Clarithromycin is a semisynthetic derivative of erythromycin A. Clarithromycin is active in-vitro against a variety of aerobic and anaerobic Gram-positive and Gram-negative bacteria as well as most Mycobacterium avium complex (MAC) bacteria. Additionally, the 14-OH-Clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH-Clarithromycin is twice as active against Hemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH-metabolite is 4 to 7 times less active than Clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown. Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Hemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter spp.

Esomeprazole

Pharmacotherapeutic group : Drugs for acid-related disorders, proton pump inhibitor. Esomeprazole is a proton-pump inhibitor (PPI) that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral Sulfenamide. By acting specifically on the proton pump, Esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion. Mechanism of action : Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.

Amoxicillin

Pharmacotherapeutic group : Penicillins with extended spectrum. Amoxicillin is semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bactericidal peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of Amoxicillin alone does not include organisms which produce these enzymes.

5.2 Pharmacokinetic properties

Clarithromycin

Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose (on a body surface area basis). Lymphoid depletion occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose (on a body surface area basis).

Esomeprazole

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows : Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.

Amoxicillin

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. Carcinogenicity studies have not been conducted with Amoxicillin.

Helicobacter pylori (H. pylori) is probably the most common bacterial infection, with a worldwide revalence of approximately 50%. H. pylori is implicated in the etiology of gastritis and peptic ulcers in humans. Newer triple therapies, including proton-pump inhibitors (PPIs) such as Esomeprazole, Amoxicillin, and Clarithromycin, serve as a shorter, simpler and effective drug regimen for the eradication of H. pylori.

Clarithromycin is a semi-synthetic macrolide antimicrobial for oral use. Chemically, it is 6-0methylerythromycin. The molecular formula is C H NO , and the molecular weight is 747.96 38 69 13 gm/mol.

The structural formula is :

Esomeprazole is bis(5-methoxy-2sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S-and R-isomers. (Initial U.S. approval of Esomeprazole Magnesium : 2001). Its molecular formula is (C₁₇ H₁₈ N ₃O ₃S) Mg x 3  H₂ O with molecular weight of 767.2 gm/mol as a trihydrate and 713.1 gm/mol on an anhydrous 2 basis.

The structural formula is :

Amoxicillin is one of the most commonly used antibiotics in the primary care setting. It is an amino-penicillin, created by adding an extra amino group to penicillin to battle antibiotic resistance.

The chemical name of Amoxicillin is (2S,5R,6R)-6--3,3-dimethyl-7-oxo-4-thia-1-azabicyclo heptane-2-carboxylic acid

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

Alu strip containing 2 Tablets of Clarithromycin Tablets IP, 2 Tablets of Esomeprazole Tablets IP and 2 Tablets of Amoxicillin Tablets USP.

8.4 Storage and handing instructions

Store at room temperature, protected from light and moisture.

Keep out of reach of children.

Tablet should be swallowed whole and not to be chewed or crushed.

Read this entire 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.

What is Clarithromycin, Esomeprazole and Amoxicillin Tablets and it is used for ?

Clarithromycin, Esomeprazole and Amoxicillin Tablets is a combination pack, which contains three different medicines. When taken together in the right doses, they will kill the bacteria in your stomach called Helicobacter pylori and let your peptic ulcer heal. Depending on the position of the ulcer it is called a gastric or duodenal ulcer. A gastric ulcer occurs in the stomach. A duodenal ulcer occurs in the duodenum which is the tube leading out from the stomach.

Most people who have a peptic ulcer also have a bacterium called Helicobacter pylori in their stomach. If the bacteria are killed it is unlikely that your ulcer will come back. Clarithromycin, Esomeprazole and Amoxicillin Tablets contains Esomeprazole, Amoxicillin and Clarithromycin. Amoxicillin and Clarithromycin are both types of antibiotic.

Before you take Clarithromycin, Esomeprazole and Amoxicillin Tablets When you must not take it

Do not take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you have an allergy to :

• Any medicines containing Esomeprazole, Amoxicillin or Clarithromycin.

• Any ingredients listed at the end of the leaflet.

• Any other similar medicines such as proton pump inhibitors, penicillins, cephalosporins or macrolide antibiotics

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you are taking any of the following medicines :

• Ergotamine

• Cisapride

• Pimozide

• Dihydroergotamine

• Astemizole

• Terfenadine

• Cilostazol

• Atazanavir

• Colchicine

• Simvastatin

• Lovastatin

• Ticagrelor

• Ranolazine

• Colchicine

• Oral midazolam

• Domperidone

Please check with your doctor or pharmacist if you are taking any of these medicines. These medicines will be affected by the medicines in Clarithromycin, Esomeprazole and Amoxicillin Tablets and it is more likely you will get side effects. Do not take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you have a history of heart conditions such as QT prolongation or ventricular cardiac arrhythmia. Do not take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you have low potassium levels. Do not take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you have both liver and kidney problems. Clarithromycin, Esomeprazole and Amoxicillin Tablets is not recommended for use in children. There is no information about the use of Clarithromycin, Esomeprazole and Amoxicillin Tablets in children. Do not take this medicine after the use by (expiry) date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal. If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

You must tell your doctor if you have :

• Problems with your blood.

• Problems with your liver or kidneys.

• Any heart conditions, such as QT prolongation or ventricular cardiac arrhythmia.

• You have glandular fever.

• Myasthenia gravis, a condition in which the muscles become weak and tire easily.

• Been diagnosed with osteoporosis.

• Low Potassium, low Magnesium or any other electrolyte imbalances.

• If you have ever had a skin reaction after treatment with a medicine similar to Esomeprazole that reduces stomach acid.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant or plan to be pregnant, are breast-feeding or plan to breastfeed

It is not known if it is safe for you to take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you are pregnant. The medicines in Clarithromycin, Esomeprazole and Amoxicillin Tablets may affect the developing baby. Your baby can take in all the medicines in Clarithromycin, Esomeprazole and Amoxicillin Tablets from breast milk if you are breast-feeding. Clarithromycin, Esomeprazole and Amoxicillin Tablets is not recommended when breast-feeding. Your doctor can discuss with you the risks and benefits of using Clarithromycin, Esomeprazole and Amoxicillin Tablets if you are pregnant or breast-feeding. If you have not told your doctor about any of the above, tell them before you start taking Clarithromycin, Esomeprazole and Amoxicillin Tablets.

Taking other medicines

Do not take Clarithromycin, Esomeprazole and Amoxicillin Tablets if you are taking the following medicines :

• Ergotamine or Dihydroergotamine - medicines used to treat migraine headaches.

• Astemizole or Terfenadine – medicines used to treat hayfever and allergies

. • Atazanavir - a medicine used to treat Human Immunodeficiency Virus (HIV).

• Cilostazol - a medicine used to treat intermittent claudication.

• Colchicine - a medicine used to treat gout.

• Lovastatin or simvastatin – medicines used to treat high cholesterol.

• Ticagrelor - a medicine used to treat blood clots.

• Oral midazolam - a medicine used for surgical sedation.

• Domperidone - a medicine used for nausea.

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines and Clarithromycin, Esomeprazole and Amoxicillin Tablets may interfere with each other

These include :

• Diazepam, Triazolam or Alprazolam - medicines used as sedatives or to treat anxiety

• Ketoconazole, Itraconazole, Voriconazole or Fluconazole - medicines used to treat fungal infections

• Warfarin and Clopidogrel - medicines used to prevent blood clots.

• Allopurinol or probenecid - medicines used to treat gout.

• Phenytoin, Sodium valproate or Carbamazepine - medicines used to treat seizures.

• Atorvastatin or Rosuvastatin - medicines used to treat high cholesterol.

• Theophylline - a medicine used to treat asthma.

• Zidovudine, Saquinavir, Efavirenz, Etravirine, Nevirapine, Nelfinavir or Ritonavir - medicines used to treat HIV.

• Insulin, Repaglinide, Nateglinide, Pioglitazone or Rosiglitazone - medicines used to treat diabetes.

• Digoxin, Quinidine or Disopyramide - medicines used to treat heart conditions.

• Citalopram, Fluoxetine, Clomipramine and Imipramine - medicines used to treat depression.

• St John's wort - a herbal remedy used to treat mood disorders.

• Rifabutin, Rifapentine, Rifampicin or Erythromycin - medicines used to treat bacterial infections.

• Sildenafil, Tadalafil or Vardenafil - medicines used to treat impotence.

• Tolterodine - a medicine used to treat incontinence.

• Verapamil, Amlodipine or Diltiazem - medicines used to treat high blood pressure and some heart conditions. • Methylprednisolone - a corticosteroid.

• Vinblastine - a medicine used to treat cancer.

• Oral contraceptives or birth control pills.

Talk to your doctor about the need for an additional method of contraception while on Clarithromycin, Esomeprazole and Amoxicillin Tablets

• Tacrolimus or Ciclosporin - medicines used to prevent organ transplant rejection or to treat certain problems with the immune system.

• Methotrexate - a medicine used to treat arthritis and some types of cancer.

• Erlotinib or related medicines used to treat cancer.

• phenobarbitone - a medicine used to treat epilepsy.

• Tetracycline and aminoglycoside antibiotics - medicines used to treat certain infections.

• Atypical antipsychotics - medicines used to treat psychiatric conditions, such as schizophrenia and bipolar disorder (e.g. quetiapine).

• Ibrutinib - a medicine used to treat cancer.

These medicines may affect Clarithromycin, Esomeprazole and Amoxicillin Tablets or may affect how well it works. You may need different amounts of your medicines or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

If you have not told your doctor about any of these things, tell them before you take any Clarithromycin, Esomeprazole and Amoxicillin Tablets.

How to take Clarithromycin, Esomeprazole and Amoxicillin Tablets ?

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure

Posology

The combipack contains two tablets of Clarithromycin (500 mg), two tablets of Esomeprazole (40 mg), and two tablets of Amoxicillin (750 mg). One pack is for 1 day of treatment. From this specially designed pack, one tablet of Clarithromycin, one tablet of Esomeprazole, and one tablet of Amoxicillin are to be taken in the morning and similarly one each in the evening. The duration of therapy recommended is for 7 days or as directed by the Physician.

Renal and hepatic impairment

Caution should be exercised while administering the combipack of Clarithromycin, Esomeprazole and Amoxicillin to patients with renal and hepatic impairment.

Method of administration

For oral administration only.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you notice any of the serious side effects, stop taking this medicine and contact a doctor immediately. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Clarithromycin, Esomeprazole and Amoxicillin Tablets. Clarithromycin, Esomeprazole and Amoxicillin Tablets helps most people with peptic ulcer and Helicobacter pylori infection, but it may have unwanted side effects in a few people.

Tell your doctor if you notice any of the following and they worry you :

• Diarrhoea, nausea or vomiting

• Headache

• Dizziness

• Constipation

• Loss of appetite

• Stomach pain (e.g. cramps)

• Wind

• Dryness of the mouth or other body cavities

• Soreness of mouth or tongue

• "Pins and needles"

• Metallic taste or other change in taste or smell

• Chills

• Fatigue

• Excessive burping

These side effects are usually mild.

Tell your doctor immediately or go to emergency room at your nearest hospital if you notice the following :

• Muscle pain or weakness

• Increase in breast size (males)

• Fever

• Changes in sleep patterns

• Mood changes, hallucinations, confusion or depression

• Change in sexual function • Blurred vision, hearing disturbances

• Hair loss

• Bleeding or bruising more easily than normal

• Signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers

• Skin rash

• Blood in urine

• Tremor

• Convulsions or fits

• Overgrowth of yeast infections (thrush)

• Fainting, irregular heart heat

• Yellowing of the eyes or skin

These may be serious side effects. You may need urgent medical attention. If any of the following happen, stop taking Clarithromycin, Esomeprazole and Amoxicillin Tablets and tell your doctor immediately or go to emergency room at your nearest hospital :

• Shortness of breath, wheezing or difficulty breathing.

• Swelling of the face, lips, tongue or other parts of the body.

• Chest pain.

• Severe skin reaction which may include rash, itching, redness, blistering or peeling of the skin

• Severe upper stomach pain, with nausea and vomiting.

• Signs of liver inflammation including yellowing of the skin or eyes, feeling generally unwell, nausea, vomiting, loss of appetite.

• Skin reaction, especially in sun-exposed areas, with joint pain.

• Severe stomach or abdominal cramps, watery and severe diarrhoea, which may also be bloody (this may occur several weeks after you stop taking Clarithromycin, Esomeprazole and Amoxicillin Tablets).

Do not take any medicine to stop the diarrhoea unless advised by your doctor. These are very serious side effects. If you have them, you may have had a serious reaction to one of the medicines in Clarithromycin, Esomeprazole and Amoxicillin Tablets. You may need urgent medical attention or hospitalization. Tell your doctor if you notice anything else that is making you feel unwell. Some people may get other side effects while taking Clarithromycin, Esomeprazole and Amoxicillin Tablets. Do not be alarmed by this list of possible side effects. You may not experience any of them.

16 January 2023