Cholecalciferol (Vitamin D3) Oral Solution 60000 IU

Each 5 ml syrup contains :

Cholecalciferol IP 60000 IU

In a flavoured base q.s.

Colour : Tartrazine

Appropriate overages of Vitamin added to compensate loss on storage.

Oral Solution, 60000 IU

4.1 Therapeutic indication

For the treatment of Vitamin D3 deficiency.

4.2 Posology and method of administration

Adults

Vitamin D3 60000 IU to be given once a week for a period of 8 weeks, followed by maintenance daily dose as directed by the Physician.

Pediatric use

As prescribed by the Physician only.

Hepatic insufficiency

The intestinal absorption of Cholecalciferol may be markedly impaired; conversion to Calcifediol may also be reduced significantly, with the requirement of high doses. Agents not requiring hepatic hydroxylation (e.g. Calcitriol, Alphacalcidol) are preferred.

Renal insufficiency

Although only small amounts of a Vitamin D dose are recovered in the urine, metabolic conversion to calcitriol is impaired and higher doses are generally required in most conditions. Agents not requiring hepatic hydroxylation (e.g. Calcitriol, Alphacalcidol) are preferred.

4.3 Contraindications

• Hypersensitivity to Cholecalciferol, Ergocalciferol or Vitamin D metabolites (e.g. Calcitriol, Calcifediol, Alfacalcidol, Calcipotriol).

• Hypercalcemia or hypercalciuria.

• Diseases and/or conditions, which lead to hypercalcaemia (e.g. nephrocalcinosis, myeloma, bone metastases, primar y hyperparathyroidism, sarcoidosis, prolonged immobilisation accompanied by hypercalcaemia).

• Nephrolithiasis

• Hypervitaminosis D

4.4 Special warnings and precautions for use

The product should be prescribed with caution to patients suffering from sarcoidosis due to risk of increased metabolism of Vitamin D into its active form. These patients should be monitored with regard to the calcium content in serum and urine. During long-term treatment, serum calcium levels should be followed and renal function should be monitored through measurements of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics and in patients with a high tendency to calculus formation.

In case of hypercalciuria or signs of impaired renal function the dose should be reduced or the treatment discontinued. The product 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. The content of Vitamin D should be considered when prescribing other medicinal products containing Vitamin D.

Additional doses of Vitamin D should be taken under close medical supervision. In such cases it is necessary to monitor serum calcium levels and urinary Calcium excretion frequently.

Caution is required in patients suffering from cardiac conditions like arteriosclerosis due to the possible exacerbation related to hypercalcaemia and in patients with hyperlipidemia due to possibility of LDL elevation.

The content of this product should be considered when prescribing other medicinal products containing Vitamin D and preparation containing calcium. Prescription of this product with other Vitamin D supplements should be done under close medical supervision. In such cases serum calcium levels should be monitored.

In patients with compromised Calcium metabolism serum concentrations of phosphate should be checked during the Vitamin D therapy to reduce the risk of ectopic calcification.

Medical supervision is recommended for use of this product in children.

4.5 Drugs interactions

Thiazide diuretics reduce the urinary excretion of Calcium. Due to the increased risk of hypercalcaemia, serum calcium should be regularly monitored during concomitant use of Thiazide diuretics.

Concomitant use of phenytoin or barbiturates may reduce the effect of Vitamin D since the metabolism increases. Concomitant use of Vitamin D with Vitamin D analogues, is not recommended due to the additive effect and increased toxic potential. Excessive dosing of Vitamin D can induce hypercalcaemia, which may increase the risk of digitalis toxicity and serious arrhythimias due to the additive inotropic effects. The electrocardiogram (ECG) and serum calcium levels of patients should be closely monitored. Glucocorticoid steroids may increase Vitamin D metabolism and elimination. Systemic corticosteroids reduce calcium absorption. Moreover, the effect of Vitamin D may be decreased. Simultaneous treatment with ion exchange resins such as Cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of Vitamin D. Therefore, a time interval as long as possible between the intakes is recommended. The absorption and therefore the efficacy of Ketoconazole will be decreased by the concomitant intake of this product. Concomitant treatment with rifampicin can decrease the effect of Vitamin D3 because of metabolic activation.

4.6 Use in special populations

Pregnancy

The product should be used during pregnancy only in case of a Vitamin D deficiency. It is not recommended during pregnancy in patients without a Vitamin D deficiency. Studies in animals have shown reproductive toxicity of high doses of Vitamin D. There are no indications that Vitamin D at therapeutic doses is teratogenic in humans. Overdose of Vitamin D has been associated with teratogenic effect in animals.

Lactation

Vitamin D can be used during breast feeding. Vitamin D3 passes into breast milk. This should be considered while giving additional Vitamin D to the child.

4.7 Effects on the ability to drive and use machines

There are no data on the effect of this product on driving capacity and use of machines. An effect is, however, unlikely.

4.8 Undesirable effects

High dose of cholecalciferol can cause weakness, fatigue, sleepiness, headache, loss of appetite, dry mouth, metallic taste, nausea and vomiting. Vitamin D toxicity, including nephrocalcinosis / renal failure, hypertension can occur with prolonged use of Cholecalciferol, relatively low doses can produce toxicity in hypersensitive infants and children.

Hypervitaminosis D is reversible upon discontinuation of treatment unless renal damage is severe. Metabolism and nutrition disorder like Hypercalcaemia and hypercalciuria is uncommon. Skin and subcutaneous disorders like pruritus, rash and urticaria are rarely observed.

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 : www.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

Treatment of hypercalcaemia

The treatment with Vitamin D must be discontinued. Treatment with Thiazide diuretics, Lithium, Vitamin A and Cardiac glycosides must also be discontinued.

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. In severe cases, ECG and CVP should be followed. In hypervitaminosis D cases of weakness, fatigue, muscle pain, polydipsia, polyuria, decreased appetite have been reported. Overdose can lead to hypervitaminosis and hypercalcemia.

Symptoms of hypercalcemia may include anorexia, thirst, nausea, vomiting, diarrhea, constipation, abdominal pain, muscle weakness, anorexia, nocturia, headache, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death.

Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification.

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 D3was 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

Non known animal toxicology data.

Cholecalciferol is the naturally occurring form of Vitamin D. It is produced from 7- dehydrocholesterol, a sterol present in mammalian skin, by ultraviolet irradiation.

Chemical name : (5Z,7E)-9, 10-Secocholesta-5,7, 10(19)-trien-3β-ol

Synonyms : Vitamin D3, Cholecalciferol

Chemical formula : C₂₇H₄₄O

Molecular weight : 384.6 g/mol

8.1 Incompatibilities

None stated.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 5 ml.

8.4 Storage and handling instructions

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

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. Instruct patients on the following points when administering the drug.

Inform the patient not to take Cholecalciferol if they have

• Allergic to Vitamin D or any of the other ingredients of this medicine.

• High levels of Vitamin D in your blood.

• Kidney stones or serious kidney problems.

• High levels of calcium in your blood and/or urine.

Remind patients to inform their healthcare provider immediately before taking Cholecalciferol if they have

• Problems with kidneys

• Sarcoidosis

• They are already taking other medicines or supplements containing Vitamin D.