S (+) Etodolac and Paracetamol Tablets (200mg + 325mg)

Each uncoated tablet contains:

S (+) Etodolac 200 mg

Paracetamol IP 325 mg

Excipients q.s

Tablet

200 mg of S (+) Etodolac and 325 mg of Paracetamol

4.1 Therapeutic indication

For the symptomatic treatment of acute pain and inflammation in patients with osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

4.2 Posology and method of administration

Adults: One tablet two times daily orally.

Paediatric population: Not recommended.

Method of administration: For oral administration.

To be taken preferably with or after food. Swallow the tablet whole with a glass of water.

4.3 Contraindications

• Patients with known hypersensitivity to S (+) Etodolac and/or Paracetamol.
• Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
• Patients with severe hepatocellular insufficiency
• Setolac®-P Tablets should not be used in patients with active or history of recurrent peptic ulceration or a history of peptic ulcer disease (with two or more distinct episodes of proven ulceration or bleeding).
• During the last trimester of pregnancy.
• Patients with hepatic failure, active liver disease and renal failure.
• Setolac®-P tablet is not recommended for pediatric use.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

The use of Setolac®-P Tablets with concomitant NSAIDs including cyclooxygenase-2-selective inhibitors should be avoided.

Cardiovascular and Cerebrovascular Effects

COX-2 selective and non-selective NSAIDs have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV events in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. NSAIDs, including Etodolac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Fluid retention and edema have been observed in some patients taking NSAIDs. Setolac®-P tablets should be used with caution in patients with fluid retention or heart failure.

Pre-existing Asthma

Patients with asthma may have Aspirin-sensitive asthma. Since cross reactivity, including bronchospasm, between Aspirin and other NSAIDs has been reported in such Aspirin-sensitive patients, Setolac®-P tablets should not be administered to patients with this form of Aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. No information is available from controlled clinical studies regarding the use of S (+) Etodolac extended-release tablets in patients with advanced renal disease. Therefore, treatment with Setolac®-P tablets is not recommended in these patients with advanced renal disease.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including S (+) Etodolac. Owing to the presence of Paracetamol, Setolac®-P tablets should be used with caution in patients with hepatocellular insufficiency or non-cirrhotic alcoholic liver disease. Impairment of renal or hepatic functions due to other causes may alter drug metabolism; patients receiving concomitant long term therapy, especially the elderly, should be observed for potential side effects and their drug doses adjusted as needed, or the drug discontinued.

Gastrointestinal Effects

NSAIDs, including Etodolac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. Setolac®-P tablets should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. To minimize the potential risk for an adverse GI event in patients, the lowest effective dose should be used for the shortest possible duration. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Etodolac, due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Etodolac, should have their hemoglobin or haematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Patients receiving Setolac®-P tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematous (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Tablets should be discontinued at the first appearance of the skin rash, mucosal lesions, or any other sign of hypersensitivity

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Etodolac. Setolac®-P tablets should not be given to patients with the Aspirin triad.

Other Precautions

• S (+) Etodolac cannot be expected to substitute corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
• The pharmacological activity of Setolac®-P in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
• Setolac®-P tablets should be used with caution in patients with severe renal insufficiency (creatinine clearance 30 mL/min), Glucose-6-Phosphate Dehyrogenase (G6PD) deficiency, chronic alcoholism, excessive alcohol intake (3 or more alcoholic drinks every day), anorexia, bulimia or cachexia; chronic malnutrition (low reserves of hepatic glutathione), dehydration, and hypovolemia.

4.5 Drug interactions

ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

Aspirin: When Etodolac is administered with Aspirin, its protein binding is reduced, although the clearance of free Etodolac is not altered.

Busulfan: Busulfan is eliminated from the body via conjugation with Glutathione. Concomitant use with Paracetamol may result in reduced Busulfan clearance.

Other analgesics including cyclooxygenase-2 selective inhibitor: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4)

Anti-hypertensives: Reduced anti-hypertensive effect

Diuretics: Etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients with possible loss of blood pressure control. Caution should be paid to the concomitant intake of enzyme-inducing agents. Induction of metabolism of Paracetamol from enzyme inducers may result in an increased level of hepatotoxic metabolites. 

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: NSAIDs have produced an elevation of plasma Lithium levels and a reduction in renal Lithium clearance. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and Lithium are administered concurrently, subjects should be observed, carefully for signs of Lithium toxicity.

Cyclosporin, Digoxin, Methotrexate: Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of Cyclosporine, Digoxin, Methotrexate, and increased toxicity. Nephrotoxicity associated with Cyclosporine may also be enhanced. Concomitant diflunisal increases Paracetamol plasma concentrations and this may increase hepatotoxicity.

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4)

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4)

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is an evidence of an increased risk of haemarthroses and haemtoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Bilirubin tests can give a false positive result due to the presence of phenolic metabolites of Setolac®-P Tablets in the urine.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4)

Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Phenylbutazone: Phenylbutazone causes increase (by about 80%) in the free fraction of Etodolac though the clinical implication of the same is not known.

Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, the cholestyramine should not be taken within one hour if maximal analgesia is required.

Metoclopramide and Domperidone: The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

Warfarin: The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Chloramphenicol: Increased plasma concentration of chloramphenicol.

Phenytoin: Administered concomitantly may result in decreased Paracetamol effectiveness and an increased risk of hepatotoxicity.

Probenecid: Causes an almost 2-fold reduction in clearance of Paracetamol by inhibiting its conjugation with Glucuronic acid.

Salicylamide: May prolong the amount of time Paracetamol stays in the body.

4.6 Use in special populations

Fertility:

The use of Setolac®-P Tablets may impair female fertility and is not recommended in woman attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Setolac®-P Tablets should be considered.

Pregnancy:

In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. Drugs which inhibit prostaglandin biosynthesis may cause dystocia and delayed parturition as evidenced by studies in pregnant animals. Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system, some inhibitors of prostaglandin biosynthesis have been shown to interfere with the risk of closure of the ductus arteriosus, use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child.

From the 20th week of pregnancy onward, etodolac use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, etodolac should not be given unless clearly necessary. If etodolac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to etodolac for several days from gestational week 20 onward. Etodolac should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction (see above); the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, etodolac is contraindicated during the third trimester of pregnancy.

Lactation:

It is not known whether Setolac®-P is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from S (+) Etodolac, 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

Pediatric use:

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric use:

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose. Elderly patients may be more sensitive to the anti-prostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients. In particular, elderly or debilitated patients who receive NSAID therapy seem to have a lower tolerance for gastrointestinal ulceration or bleeding as compared to other individuals, and most spontaneous reports of fatal GI events are in this population. S (+) Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

4.7 Effects on ability to drive and use machines

Setolac®-P may cause dizziness. So, you should not drive or operate heavy machinery if you feel dizzy or not fully alert.

4.8 Undesirable effects

Most frequently reported adverse reactions (approx. 1 - 10%):

Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding / perforation, heartburn, nausea, GI ulcers (gastric / duodenal), vomiting.

Other events including: abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus.

Additional NSAID Adverse Experiences Reported Occasionally with Body as a whole: Allergic reaction, anaphylactic / anaphylactoid reactions (including shock), chills, fever, sepsis.

Digestive system: Anorexia, cholestatic hepatitis / jaundice, dry mouth, duodenitis, esophagitis, gastritis, gastric peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a)non-specific allergic reactions and anaphylaxis (b)respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c)assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:

Congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic). Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Hepatic: 

Abnormal liver function, hepatitis and jaundice Metabolic and nutritional:

Hyperglycemia in previously controlled diabetic patients.

Neurological and special senses: Visual disturbances, photophobia, blurred vision, optic neuritis, headaches, paraethesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematous, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness. Anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo.

Blood and lymphatic system:

Agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia and aplastic anaemia. There have been reports of blood dyscrasias including methaemoglobenaemia and agranulocytosis, but these were not necessarily causality related to paracetamol.

Respiratory system:

Asthma, dyspnea, pulmonary infiltration with eosinophilia.

Dermatological: 

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity. Angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash. Fixed drug eruption (FDE) is associated with Paracetamol use.

Urogenital system:

Dysuria, elevated BUN, oliguria / polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency, Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome.

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: http://www.zuventus.co.in/safety.aspx By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Etodolac

Symptoms include headache, nausea, vomiting, epigastric pain, gastro-intestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Management: Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of indigestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. The standard practices of gastric lavage, activated charcoal administration and general supportive therapy should be undertaken.

Paracetamol

Symptoms of paracetamol over dosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management: Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol however, the maximum protective effect is obtained up to 8 hours post ingestion. If required the patient should be given intravenous-N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit

5.1 Mechanism of Action

S (+) Etodolac is the pharmacologically active component of racemate Etodolac. The anti-inflammatory, analgesic, and antipyretic activities of S (+) Etodolac have been observed to be due to inhibition of cyclooxygenase-2 (COX-2) resulting in inhibition of prostaglandin synthesis.

The precise mechanism of the analgesic and antipyretic properties of Paracetamol has yet to be established. It acts both centrally as well as peripherally. Paracetamol is an antipyretic with good analgesic property.

5.2 Pharmacodynamic properties

Etodolac

Inhibition of prostaglandin synthesis and COX-2 selectivity: All non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the formation of prostaglandins. It is this action which is responsible both for their therapeutic effects and some of their side-effects. The inhibition of prostaglandin synthesis observed with etodolac differs from that of other NSAIDs. In an animal model at an established anti-inflammatory dose, cytoprotective PGE concentration in the gastric mucosa have been shown to be reduced to a lesser degree and for a shorter period than other NSAIDs. This finding is consistent with subsequent in-vitro studies which have found etodolac to be selective for induced cyclo-oxygenase 2 (COX-2, associated with inflammation) over COX-1 (cytoprotective).

Furthermore, studies in human cell models have confirmed that etodolac is selective for the inhibition of COX-2.

The clinical benefit of preferential COX-2 inhibition over COX-1 has yet to be proven.

Anti-inflammatory effects: Experiments have shown etodolac to have marked anti-inflammatory activity, being more potent than several clinically established NSAIDs.

Paracetamol

Analgesic – The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic – Paracetamol probably produces anti-pyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

5.3 Pharmacokinetic properties

S (+) Etodolac is well absorbed and does not undergo significant first-pass metabolism following oral administration. The extent of absorption of S (+) Etodolac is not affected after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration.

Paracetamol is well absorbed from the gastrointestinal tract in humans. The ingestion of food along with Paracetamol does not seem to affect its absorption.

6.1 Animal Toxicology or Pharmacology

Etodolac: Not Available

Paracetamol: 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. Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available

(S)-etodolac is the S-enantiomer of etodolac. It is a preferential inhibitor of cyclo-oxygenase 2 and a non-steroidal anti-inflammatory, whereas the enantiomer, (R)-etodolac, is inactive. The racemate is commonly used for the treatment of rheumatoid arthritis and osteoarthritis, and for the alleviation of postoperative pain. Chemical Name: 2-[(1S)-1,8-diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl]acetic acid Molecular Formula: C17H21NO3 Molecular Weight: 287.35 g/mol

Structure:

Paracetamol is a well-established analgesic.

Chemical Name: N-(4-hydroxyphenyl)acetamide

Molecular Formula: C₈H₉NO₂

Molecular Weight: 151.2 g/mol

Structure:

8.1 Incompatibilities

None

8.2 Shelf life

Refer on the pack.

8.3 Packaging Information

PVC-Alu blister strip of 10 tablets

8.4 Storage and handling instructions

Store below 30ºC. Protect from light and moisture. Keep out of reach of children. Tablet should be swallowed whole & not to be broken, chewed or crushed.

Any unused product or waste material should be disposed of in accordance with local requirements.

• Take it with food to avoid getting an upset stomach.
• The drug should be taken precisely as it has been prescribed. Meant for oral consumption, Setolac®-P Tablet should be taken whole. Do not chew or crush it as it may reduce its effect on the body.
• It is best that you do not stop the medication mid-course as the pain may reoccur. Complete the entire treatment course for the best results.
• Avoid consuming alcohol when taking Setola®-P Tablet as it may cause excessive drowsiness and increase the risk of liver damage.
• Do not take it with any other medicine containing acetaminophen (drugs for pain / fever or cough-and-cold) without asking your doctor first.

Chlorpheniramine Maleate & Dextromethorphan Hydrobromide syrup

Each 5 ml Contains:

Dextromethorphan Hydrobromide IP 10 mg

Chlorpheniramine maleate IP 2 mg

Excipients q. s.

Colour: Sunset Yellow FCF

In a mentholated flavoured syrup base

Syrup

100 ml bottle

4.1 Therapeutic Indication

For the temporary relief of cough due to throat irritation, sneezing & running nose.

4.2 Posology and method of administration

2 to 5 years of age: 2.5 ml (1/2 teaspoonful) 3 to 4 times a day.

6 to 12 years of age: 5 ml (1 teaspoonful) 3 to 4 times a day.

Adult (> 12 years of age): 10 ml (2 teaspoonful) 3 to 4 times a day.

4.3 Contraindications

• Hypersensitivity to Chlorpheniramine, Dextromethorphan or to any component of the formulation.
• Receiving monoamine oxidase inhibitors [MAOIs] (drugs for depression, psychiatric or emotional conditions, or Parkinson's disease) with or within 2 weeks.
• Patients with risk of developing respiratory failure
• Acute Asthma
• Patient with liver disease
• Persistent or chronic productive cough

4.4 Special warnings and precautions for use

Chlorpheniramine maleate

This medicine should be given with caution to patients with epilepsy, severe cardiovascular disorders, liver disorders, renal impairment, glaucoma, urinary retention, prostatic enlargement, pyloroduodenal obstruction, asthma, bronchitis, bronchiectasis, thyrotoxicosis and severe hypertension.

Special care should be taken when using chlorpheniramine maleate in children and the elderly as they are more likely to experience the neurological anticholinergic effects and paradoxical excitation (e.g. Increased energy, restlessness, nervousness). Avoid use in elderly patients with confusion.

The anticholinergic properties of chlorphenamine may cause drowsiness, dizziness, blurred vision and psychomotor impairment in some patients which may seriously affect ability to drive and use machinery. The effects of alcohol may be increased and therefore concurrent use should be avoided.

Should not be used with other antihistamine containing products, including antihistamine containing cough and cold medicines.

Concurrent use with drugs which cause sedation such as anxiolytics and hypnotics may cause an increase in sedative effects, therefore medical advice should be sought before taking chlorphenamine concurrently with these medicines.

Dextromethorphan Hydrobromide

Dextromethorphan should not be given to patients at risk of developing respiratory failure. Caution is needed in patients with a history of asthma and it should not be given during an acute attack. Care is also advisable in patients with bronchitis, emphysema, or in other conditions where chronic or persistent cough occurs.

4.5 Drugs interactions

Chlorpheniramine maleate

This medicine may enhance the sedative effects of alcohol, hypnotics, anxiolytics, sedatives, opioid analgesics and neuroleptics.

The anti-muscarinic effects of chlorpheniramine are enhanced by other anti-muscarinic drugs and both anti-muscarinic and sedative effects are enhanced by monoamine oxidase inhibitors and tricyclic antidepressants.

Metabolism of phenytoin may be inhibited by chlorpheniramine with the possible development of phenytoin toxicity.

Dextromethorphan Hydrobromide

Monoamine Oxidase Inhibitors (MAOIs): Dextromethorphan should not be used concurrently in patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs as there is a risk of serotonin syndrome (pyrexia, hallucinations, gross excitation or coma, hypertension, arrhythmias).

CYP2D6 inhibitors: Dextromethorphan is metabolized by CYP2D6 and has an extensive first-pass metabolism. Concomitant use of potent CYP2D6 enzyme inhibitors can increase the dextromethorphan concentrations in the body to levels multi-fold higher than normal. This increases the patient's risk for toxic effects of dextromethorphan (agitation, confusion, tremor, insomnia, diarrhoea and respiratory depression) and development of serotonin syndrome. Potent CYP2D6 enzyme inhibitors include SSRIs such as fluoxetine and paroxetine, quinidine and terbinafine. In concomitant use with quinidine, plasma concentrations of dextromethorphan have increased up to 20-fold, which has increased the CNS adverse effects of the agent. Amiodarone, flecainide and propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine and thioridazine also have similar effects on the metabolism of dextromethorphan. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, the patient should be monitored and the dextromethorphan dose may need to be reduced.

CNS depressants: Dextromethorphan might exhibit additive CNS depressant effects when co-administered with alcohol, antihistamines, psychotropics, and other CNS depressant drugs.

4.6 Use in special populations

Pregnant Women

There are no adequate and well-controlled studies of this combination in pregnant women. There are no adequate controlled studies of chlorpheniramine in pregnant women and therefore should not be used during pregnancy. There are no adequate and well-controlled studies of Dextromethorphan in pregnant women. Dextromethorphan should not be used during pregnancy or lactation unless the potential benefit of treatment to the mother outweighs the possible risk to the developing foetus or nursing infant.

Caution is advised when Soventus®-DX Syrup is used during pregnancy.

Lactating Women

Chlorpheniramine may be secreted in breast milk. Hence, it is not recommended in nursing mothers because of the risk of adverse effects, such as unusual excitement or irritability in infants. Chlorpheniramine may also inhibit lactation. It is not known whether dextromethorphan or its metabolites are excreted in breast milk. 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.

Paediatric Patients

Safety and efficacy of this formulation in neonates and children below 2 years of age has not been established. Thus, Soventus®-DX Syrup is not recommended for use in paediatric patients below 2 years of age.

Geriatric Patients

The elderly patients taking Chlorpheniramine are more likely to experience neurological anticholinergic effects. Elderly patients with normal renal and hepatic function may be given the same dose as recommended for adults. Elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment Patients

Caution should be exercised while using Soventus®-DX syrup in patients with significant renal dysfunction. Dose should be reduced or the dosing interval must be extended in patients with severe renal impairment.

Hepatic Impairment Patients

In hepatic impairment, Soventus®-DX syrup should be used with caution.

4.7 Effects on ability to drive and use machines

Soventus®-DX Syrup may cause side effects which could affect your ability to drive. Chlorpheniramine may cause blurred vision, dizziness, drowsiness and interfere with human performance and therefore may seriously influence the ability to drive and operate machinery. Dextromethorphan can impair cognitive function and can affect a patient's ability to drive safely.

4.8 Undesirable Effects

Chlorpheniramine maleate

Adverse reactions identified during post-marketing use with chlorphenamine are listed below. As these reactions are reported voluntarily from a population of uncertain size, the frequency of some reactions is unknown but likely to be rare or very rare:

Children and the elderly are more susceptible to neurological anticholinergic effects and paradoxical excitation (e.g. increased energy, restlessness, nervousness)

Dextromethorphan Hydrobromide

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence cannot be estimated, frequency category is listed as 'Not known’.

frequency category is listed as 'Not known’.

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 : http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

The estimated lethal dose of chlorphenamine is 25 to 50mg/kg body weight. Symptoms and signs include sedation, paradoxical excitation of the CNS, toxic psychosis, convulsions, apnoea, anticholinergic effects, dystonic reactions and cardiovascular collapse including arrhythmias. Symptomatic and supportive measures should be provided with special attention to cardiac, respiratory, renal and hepatic functions and fluid and electrolyte balance. If overdosage is by the oral route, treatment with activated charcoal should be considered provided there are no contraindications for use and the overdose has been taken recently (treatment is most effective if given within an hour of ingestion.) Treat hypotension and arrhythmias vigorously. CNS convulsions may be treated with i.v. diazepam. Haemoperfusion may be used in severe cases.

Dextromethorphan is thought to be of low toxicity, but the effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms of overdose may include mydriasis, nausea and vomiting, CNS depression, excitation, lethargy, nystagmus, psychomotor hyperactivity, serotonin syndrome, somnolence (drowsiness), dizziness, dysarthria (slurred speech), mental confusion, psychotic disorder (psychosis), and respiratory depression. Treatment should be symptomatic and supportive. Gastric lavage may be of use. Naloxone has Patients should be kept under observation and symptomatic and supportive treatment is advised. been used successfully to reverse central or peripheral opioid effects of dextromethorphan in children (0.01mg/kg body weight).

5.1 Mechanism of Action

Chlorpheniramine maleate

Chlorpheniramine is a first-generation alkylamine antihistamine. It is a less sedating H1 blocker with autonomic effects (anti-cholinergic action), used in the prevention of the symptoms of allergic conditions such as rhinitis.

Dextromethorphan Hydrobromide

Dextromethorphan (D-3-methoxy-N-methylmorphinan) is the D-isomer of the codeine analog methorphan. It is an antitussive drug and one of the active ingredients used to prevent coughs.

5.2 Pharmacodynamic properties

Chlorpheniramine maleate

Chlorphenamine is a potent antihistamine (H1-antagonist). Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity. Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes and have been shown to prevent the migration of inflammatory mediators. The actions of chlorphenamine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis.

Dextromethorphan Hydrobromide

Dextromethorphan is the dextrorotatory isomer of 3-methoxy-N-methyl-morphinan. It is a synthetic morphine derivative that, in contrast to its levo-rotatory isomer, has no significant analgesic, respiratory depressant or physical dependency properties at recommended doses.

Dextromethorphan is a non-opioid antitussive drug. It exerts its antitussive activity by acting on the cough centre in the medulla oblongata, raising the threshold for the cough reflex. The onset of antitussive effects are realised within 15 to 30 minutes of oral administration, lasting for approximately 3 to 6 hours.

The major metabolite of dextromethorphan, dextrorphan, binds with high affinity to σ-receptors to produce its antitussive activity without exhibiting the classic opiate effects that occur from binding into μ- and δ-receptors. Dextrorphan also exhibits binding activity at serotonergic receptors and was shown to enhance serotonin activity by inhibiting the reuptake of serotonin. In larger than therapeutic doses, dextrorphan is also an antagonist of N-methyl-D-aspartate (NMDA) receptors.

5.3 Pharmacokinetic properties

Chlorpheniramine maleate

Chlorpheniramine maleate is almost completely absorbed after administration by mouth, peak plasma concentrations occurring at about 2.5 to 6 hours. The drug is widely distributed including passage into the CNS, with a volume of distribution of between 1 and 10L/KG. About 70% of chlorpheniramine in the circulation is protein-bound. Chlorpheniramine undergoes some first pass metabolism and enterohepatic recycling. Chlorpheniramine is extensively metabolised, principally to inactive desmethylated metabolites which are excreted primarily in the urine, together with about 35% unchanged drug. Only trace amounts are excreted in the faeces. The mean elimination half-life has been reported to be about 30 hours, with mean values ranging from 2 to 43 hours.

Dextromethorphan Hydrobromide

Absorption: Dextromethorphan is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations reached in approximately 2 to 2.5 hours. The low plasma levels of dextromethorphan suggest low oral bioavailability secondary to extensive first-pass (pre-systemic metabolism) in the liver. The maximum clinical effects occur 5 to 6 hours after ingestion of dextromethorphan.

Distribution: Dextromethorphan is widely distributed in the human body. Dextromethorphan and its active metabolite, dextrorphan, are actively taken up and concentrated in brain tissue. It is not known if dextromethorphan or dextrorphan are excreted in breast milk or cross the placenta.

Metabolism: Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver after oral administration. Genetically controlled O-demethylation (CYD2D6) is the main determinant of dextromethorphan pharmacokinetics in human volunteers. It appears that there are distinct phenotypes for this oxidation process resulting in highly variable pharmacokinetics between subjects. Unmetabolised dextromethorphan, together with the three demethylated morphinan metabolites dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3- hydroxymorphinan and 3-methoxymorphinan have been identified as conjugated products in the urine. Dextrorphan, which also has antitussive action, is the main metabolite. In some individuals metabolism proceeds more slowly and unchanged dextromethorphan predominates in the blood and urine.

Excretion: Dextromethorphan is primarily excreted via the kidney as unchanged parent drug and its active metabolite, dextrorphan. Dextrorphan and 3-hydroxy-morphinan are further metabolised by glucuronidation and are eliminated via the kidneys. The elimination half-life of the parent compound is between 1.4 to 3.9 hours; dextrorphan is between 3.4 to 5.6 hours. The half-life of dextromethorphan in poor metabolisers is extremely prolonged, in the range of 45 hours.

6.1 Animal Toxicology or Pharmacology

Chlorpheniramine maleate

The antihistaminic potency of chlorpheniramine is confined mainly to its (+)-isomer. The racemate is similarly or slightly more toxic because of the contribution of (-)-isomer. The toxicity may therefore be non-specific, perhaps attributable to local anaesthetic action and the toxic effects (excitation/sedation, coma, convulsions and death) resemble those of other classic H1antihistamines. Toxic doses may cause hypotension attributable to myocardial depression, an effect which is clearer with the (-)-isomer. The experimental data on the carcinogenicity and mutagenicity of chlorpheniramine indicate lack of these adverse effects, but the racemate and the (+)-isomer have shown some embryotoxicity in fertility tests. Effective antihistaminic concentrations of chlorpheniramine in vitro are about 1-10µg/L and oral doses of 0.2-1 mg/kg antagonise histamine-induced bronchospasm in guinea pigs.

Dextromethorphan Hydrobromide

General toxicology: Acute oral toxicity studies conducted with Dextromethorphan report the following LD50 values (mg/kg): mouse, 210 and rat, 116. Acute subcutaneous toxicity with Dextromethorphan reports the LD50 value (mg/kg): mouse, 112. Acute intravenous toxicity with Dextromethorphan reports the LD50 value (mg/kg): rat, 16.3.

Repeat dose toxicity studies conducted in rats for 13-week duration at doses up to 100 mg/kg and 27 weeks at 10 mg/kg, and of 14 weeks in dogs by oral gavage at doses up to 4 mg/kg on five days per week. The only effect recorded was of reduced body weight gain in the rat 13-week study at the highest dose.

Genetic Toxicology: Dextromethorphan hydrobromide was negative in the bacterial reverse mutation assay (Ames test). Dextromethorphan 39 mg/kg is reported to be negative in in-vivo mouse micronucleus test and comet assay. Dextromethorphan was reported to be negative in in vitro chromosome aberration assay tested up to 200 μg/ml.

Carcinogenicity: There are no known reports of animal carcinogenicity studies for Dextromethorphan. The overall weight of evidence for Dextromethorphan and its structural analogues, support the conclusion that this class of phenanthrene-based chemicals, and Dextromethorphan, in particular, are not genotoxic in vitro or in vivo

Teratogenicity: There was no association between dextromethorphan and malformations.

Fertility: Mating, gestation, fertility, littering and lactation were studied in rats at doses up to 50 mg/kg and no adverse effects were found.

Each 5 ml of Soventus®-DX syrup contains 10 mg of Dextromethorphan hydrobromide and 2 mg of chlorpheniramine maleate for oral administration.

Chlorpheniramine maleate

Chlorphenamine is a potent antihistamine (H1-antagonist). Antihistamines diminish or abolish the actions of histamine in the body by competative reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity. Molecular Weight: 390.9 g/mol Molecular Formula: C₁₆H₁₉ClN₂.C₄H₄O₄ Chemical Name: (Z)-but-2-enedioic acid;3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine

Dextromethorphan Hydrobromide

Dextromethorphan is the dextrorotatory isomer of 3-methoxy-N-methyl-morphinan. It is a synthetic morphine derivative. Dextromethorphan is a non-opioid antitussive drug. It exerts its antitussive activity by acting on the cough centre in the medulla oblongata, raising the threshold for the cough reflex.

Molecular Weight: 352.3 g/mol

Molecular Formula: C₁₈H₂₆BrNO

Chemical Name:

(1S,9S,10S)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene;hydrobromide

8.1 Incompatibilities

Not applicable

8.2 Shelf life

Refer on Pack

8.3 Packaging information

100 ml bottle

8.4 Storage and handling information

Store in a cool & dark place. Keep out of reach of children

• Take exactly as directed by your doctor or on the label. Do not increase the dosage or take for longer than is recommended. Use a proper measuring cup or spoon to measure the dosage.
• If you are drowsy after taking Soventus®-DX Syrup, you should not drive or operate any machinery.
• Inform your doctor if you have a history of stomach ulcers or asthma.
• Inform your doctor if you are taking any other medications, e.g., anti-depressants.
• Consult your doctor if you do not see any improvement and have a cough for > 7 days.
• Avoid consuming alcohol while taking Soventus DX Syrup as it can cause excessive drowsiness.

Cholecalciferol Granules

Each sachet of 1gm contains:

Cholecalciferol IP 60000 IU.

Excipients q.s.

Granules, 60000 IU per sachet

4.1 Therapeutic indication

For the treatment of Vitamin-D3 deficiency.

4.2 Posology and method of administration

1/4 to 1 sachet with milk or as directed by the physician

4.3 Contraindications

• Hypersensitivity to vitamin D or any of the excipients in the product
• Hypervitaminosis D
• Nephrolithiasis
• Diseases or conditions resulting in hypercalcaemia and/or hypercalciuria
• Severe renal impairment

4.4 Special warnings and precautions for use

• Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D3 supplementation and measurement of 25-hydroxyvitamin D should be considered.
• Vitamin D3 supplementation may worsen hypercalcemia and/or hypercalciuria when administered to patients with diseases associated with unregulated overproduction of 1,25 dihydroxyvitamin D (e.g., leukaemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.
• It should be used with caution in patients with renal impairment or calculi, or heart disease, who might be at increased risk of organ damage if hypercalcaemia occurred.
• Plasma phosphate concentrations should be controlled during vitamin D3 therapy to reduce the risk of ectopic calcification.
• It is advised that patients receiving pharmacological doses of vitamin D3 should have their plasma-calcium concentration monitored at regular intervals, especially initially or if symptoms suggest toxicity.

4.5 Drugs interactions

• Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D3.
• Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.
• There is an increased risk of hypercalcaemia if vitamin D3 is given with thiazide diuretics, calcium, or phosphate. Plasma-calcium concentrations should be monitored in such situations.
• Some antiepileptics may increase vitamin D3 requirements (e.g. carbamazepine, phenobarbital, phenytoin, and primidone).
• Rifampicin and isoniazid may reduce the effectiveness of vitamin D3.
• Corticosteroids may counteract the effect of vitamin D3.

4.6 Use in special populations

Pregnancy

No data are available for cholecalciferol (vitamin D3). There are no studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

Cholecalciferol and some of its active metabolites pass into breast milk. Infants should be closely monitored for hypercalcemia or clinical manifestations of vitamin D toxicity if the mother is taking pharmacological doses of vitamin D3.

Infants

Vitamin D3 should be used with caution in infants, who may have increased sensitivity to its effects.

4.7 Effects on ability to drive and use machines

It is not expected that Vitanova sachet would affect your ability to drive or to operate machinery.

4.8 Undesirable effects

Major & minor side effects for Vitanova D3 Sachet

• Increased blood calcium levels
• Increased calcium levels in urine
• Constipation
• Skin rash, hives, or itching
• Chest pain
• Shortness of breath

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: http://www.zuventus.co.in/safety.aspx
• By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is limited information regarding doses of cholecalciferol associated with acute toxicity, although intermittent (yearly or twice yearly) single doses of ergocalciferol (vitamin D2) as high as 600,000 IU have been given without reports of toxicity. Signs and symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness, and lethargy. Serum and urine calcium levels should be monitored in patients with suspected vitamin D toxicity.

Treatment

Standard therapy includes restriction of dietary calcium, hydration, and systemic glucocorticoids in patients with severe hypercalcemia. Dialysis to remove vitamin D would not be beneficial.

5.1 Mechanism of Action

The mechanism of action of 1,25(OH)2D(calcitriol) is mediated by the interaction of calcitriol with the vitamin D receptor (VDR). Calcitriol binds to cytosolic VDRs within target cells, and the receptor-hormone complex translocates to the nucleus and interacts with DNA to modify gene transcription. The VDR belongs to the steroid and thyroid hormone receptor supergene family. Calcitriol also exerts nongenomic effects that may require the presence of a functional VDR.

5.2 Pharmacodynamic properties

Vitamin D3 is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilizing hormone 1, 25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.

Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.

5.3 Pharmacokinetic properties

Absorption

Vitamin D substances are well absorbed from the gastrointestinal tract. The presence of bile is essential for adequate intestinal absorption; absorption may be decreased in patients with decreased fat absorption.

Distribution

Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.

Metabolism

Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.

Excretion

When radioactive vitamin D3 was intravenously administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4% of the administered dose, and the mean fecal excretion of radioactivity after 48 hours was 4.9% of the administered dose. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of vitamin D3 in the serum following an oral dose is approximately 14 hours.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Vitanova D3 contains cholecalciferol (Vitamin D3). Vitamin D3 is essential for the proper growth and development of the body. It is synthesized within the body after exposure to sunlight and is essential for many important functions of the human body. Vitamin D3 in Vitanova D3 also increases the Calcium absorption from the intestines.

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

4 sachets of 1 gram each

8.4 Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 25°C. Keep out of reach of children.

• Take exactly as directed by your doctor or on the label. Do not increase the dosage or take for longer than is recommended.
• Vitanova-D3 Sachets 1 gm may interfere with cholesterol tests, hence please inform your physician and laboratory staff that you are taking Vitanova-D3 Sachets 1 gm before undergoing blood tests.
• Clinical monitoring of serum electrolyte concentrations and cardiac function is recommended.

Cholecalciferol (Vitamin-D3) Capsules

Each soft gelatin capsules contains:

Cholecalciferol (Vitamin D3) IP 1500 mcg

equivalent to 60,000 IU

Excipients q.s.

Appropriate overages of vitamin added to compensate the loss on storage.

Soft Gelatin Capsules

60,000 IU

4.1 Therapeutic indication

For the treatment of vitamin D3 deficiency

4.2 Posology and method of administration

Adults and adolescent: One Vitanova-D3 SG Capsules (60,000 IU) to be given once a week for a period of 8 weeks, followed by one Vitanova-D3 SG Capsules (60,000 IU) once a month or daily maintenance dose as directed by the physician.

Certain populations are at high risk of vitamin D deficiency, and may require higher doses and monitoring of serum 25(OH)D:

• Institutionalised or hospitalised individuals
• Dark skinned individuals
• Individuals with limited effective sun exposure due to protective clothing or consistent use of sun screens
• Obese individuals
• Patients being evaluated for osteoporosis
• Use of certain concomitant medications (e.g., anticonvulsant medications, glucocorticoids)
• Patients with malabsorption, including inflammatory bowel disease and coeliac disease
• Those recently treated for vitamin D deficiency, and requiring maintenance therapy.

Infants and young children (0-12 years)

Vitanova-D3 SG Capsules should not be given to children under 12 years due to the risk of choking.

Method of administration

This medicine is taken orally.

The Vitanova-D3 SG capsule should be swallowed whole with water, preferably with the main meal of the day.

4.3 Contraindications

• Hypersensitivity to vitamin D or any of the excipients in the product
• Hypervitaminosis D
• Nephrolithiasis
• Diseases or conditions resulting in hypercalcaemia and/or hypercalciuria
• Severe renal impairment

4.4 Special warnings and precautions for use

• Vitamin D should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of Cholecalciferol is not metabolised normally and other forms of vitamin D should be used.
• Caution is required in patients receiving treatment for cardiovascular disease.
• Vitanova-D3 should be prescribed with caution to patients suffering from sarcoidosis because of the risk of increased metabolism of vitamin D to its active form. These patients should be monitored with regard to the calcium content in serum and urine.
• Allowances should be made for vitamin D supplements from other sources.
• The need for additional calcium supplementation should be considered for individual patients. Calcium supplements should be given under close medical supervision.
• Medical supervision is required whilst on treatment to prevent hypercalcaemia.

4.5 Drugs interactions

• Concomitant treatment with phenytoin or barbiturates can decrease the effect of vitamin D because of metabolic activation. Concomitant use of glucocorticoids can decrease the effect of vitamin D.
• The effects of digitalis and other cardiac glycosides may be accentuated with the oral administration of calcium combined with Vitamin D. Strict medical supervision is needed and, if necessary monitoring of ECG and calcium.
• Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.
• The cytotoxic agent actinomycin and imidazole antifungal agents interfere with vitamin D activity by inhibiting the conversion of 25-hydroxyvitamin D to 1,25- dihydroxyvitamin D by the kidney enzyme, 25-hydroxyvitamin D-1-hydroxylase.

4.6 Use in special populations

Pregnancy

No data are available for cholecalciferol (vitamin D3). There are no studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

Cholecalciferol and some of its active metabolites pass into breast milk. Infants should be closely monitored for hypercalcemia or clinical manifestations of vitamin D toxicity if the mother is taking pharmacological doses of vitamin D3.

Infants

Vitamin D3 should be used with caution in infants, who may have increased sensitivity to its effects.

4.7 Effects on ability to drive and use machines

Vitanova D3 has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: uncommon (>1/1,000, <1/100) or rare (>1/10,000, <1/1,000).

Metabolism and nutrition disorders

Uncommon: Hypercalcaemia and hypercalciuria. Skin and subcutaneous disorders

Rare: Pruritus, rash and urticaria.

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.

4.8 Overdose

The most serious consequence of acute or chronic overdose is hypercalcaemia due to vitamin D toxicity. Symptoms may include nausea, vomiting, polyuria, anorexia, weakness, apathy, thirst and constipation. Chronic overdoses can lead to vascular and organ calcification as a result of hypercalcaemia.

Treatment should consist of stopping all intake of vitamin D and rehydration. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids should be considered. Serum electrolytes, renal function and diuresis must be monitored.

5.1 Mechanism of Action

In its biologically active form vitamin D3 stimulates intestinal calcium absorption, incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of calcium and phosphate by promoting tubular resorption. The production of parathyroid hormone (PTH) in the parathyroids is inhibited directly by the biologically active form of vitamin D3. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active vitamin D3.

5.2 Pharmacodynamic properties

Vitamin D3 is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilizing hormone 1, 25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.

Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.

5.3 Pharmacokinetic properties

The pharmacokinetics of vitamin D is well known. Vitamin D is well absorbed from the gastro-intestinal tract in the presence of bile. It is hydroxylated in the liver to form 25-hydroxyCholecalciferol and then undergoes further hydroxylation in the kidney to form the active metabolite 1, 25 dihydroxy Cholecalciferol (calcitriol). The metabolites circulate in the blood bound to a specific α - globin, Vitamin D and its metabolites are excreted mainly in the bile and faeces.

6.1 Animal Toxicology or Pharmacology

Vitamin D is well known and is a widely used material and has been used in clinical practice for many years. As such toxicity is only likely to occur in chronic overdosage where hypercalcaemia could result.

Cholecalciferol has been shown to be teratogenic in high doses in animals (4-15 times the human dose). Offspring from pregnant rabbits treated with high doses of vitamin D had lesions anatomically similar to those of supravalvular aortic stenosis and offspring not showing such changes show vasculotoxicity similar to that of adults following acute vitamin D toxicity.

Vitanova D3 contains cholecalciferol (Vitamin D3). Vitamin D3 is essential for the proper growth and development of the body. It is synthesized within the body after exposure to sunlight and is essential for many important functions of the human body. Vitamin D3 in Vitanova D3 also increases the Calcium absorption from the intestines.

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

10 Blister strips of 4 capsules each

8.4 Storage and handing instructions

Store at a temperature not exceeding 30°C. Protect from direct sunlight.

Keep out of reach of children

Capsule should be swallowed whole & not to be opened, chewed or crushed

• Take exactly as directed by your doctor or on the label.
• Do not increase the dosage or take for longer than is recommended.
• Vitanova-D3 Capsules may interfere with cholesterol tests, hence please inform your physician and laboratory staff that you are taking Vitanova-D3 Capsules before undergoing blood tests.
• Clinical monitoring of serum electrolyte concentrations and cardiac function is recommended.