Vitanova®-D3 6L Injection

Cholecalciferol Injection IP

Each ml contains:

Cholecalciferol IP 6,00,000 IU (15mg)

Ethyl Oleate IP q.s.

Ampoule, 6,00,000 IU

For intramuscular use only.

4.1 Therapeutic Indication

Indicated for the treatment of Vitamin D3 deficiency

4.2 Posology and method of administration

Vitamin D3 injection is administered intramuscularly as a single dose of 6,00,000 IU once only or repeated after 6 months to 1 year, depending upon clinical response and requirements. The serum calcium levels should be checked every 3 - 6 months and the dose adapted according to the values.

4.3 Contraindications

• Hypersensitivity to the active substance(s) or to any of the excipients.
• Hypercalcaemia, evidence of vitamin D toxicity, hypervitaminosis D, decreased renal function, metastatic calcification.

4.4 Special warnings and precautions for use

• Adequate dietary calcium is necessary for clinical response to Cholecalciferol therapy.
• Caution should be used when the injectable forms are used in patients with vitamin D resistant rickets as the range between the toxic and therapeutic dosage is narrow.
• Vitamin D should be administered with caution to infants and patients who may have an increased sensitivity to its effects. Use with care in patients with renal impairment, renal calculi or heart disease or arteriosclerosis who might be at increased risk of organ damage if hypercalcaemia were to occur.
• Cholecalciferol is not recommended for use in hypoparathyroidism. In the event of hypoparathyroidism when Cholecalciferol is used, calcium, parathyroid hormone or dihydrotachysterol may be required.
• Dosage should be individualised. Frequent serum and urinary calcium, phosphate and urea nitrogen determinations should be carried out. Adequate fluid intake should be maintained.
• Should hyperglycaemia develop, Cholecalciferol should be discontinued immediately.
• Because of the effect on serum calcium, Cholecalciferol should only be administered to patients with renal stones when potential benefits outweigh possible hazards.
• Vitamin D3 supplementation may worsen hypercalcemia and/or hypercalciuria when administered to patients with diseases associated with unregulated overproduction of calcitriol (e.g., leukemia, 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, heart disease, sarcoidosis, pseudo hypoparathyroidism and who might be at increased risk of organ damage if hypercalcemia occurred.
• Plasma calcium and phosphate concentrations should be controlled during vitamin D3 therapy to reduce the risk of ectopic calcification.

4.5 Drugs interactions

• Rifampicin and isoniazid may reduce the effectiveness of vitamin D3.
• Corticosteroids may counteract the effect of vitamin D3. Cholecalciferol and
  • Magnesium-containing antacids: hypermagnesaemia may develop in patients on chronic renal dialysis.
  • Digitalis glycosides: hypercalcaemia in patients on digitalis may precipitate cardiac arrhythmias.
  • Verapamil: atrial fibrillation has recurred when supplemental calcium and Cholecalciferol have induced hypercalcaemia.
  • Anti-convulsants: Vitamin D requirements may be increased in patients taking anti-convulsants (e.g. carbamazepine, phenobarbital, phenytoin and primidone).
  • Thiazide diuretics: hypoparathyroid patients on Cholecalciferol may develop hypercalcaemia.

4.6 Use in special populations

• Pregnancy :- There are no or limited amount of data from the use of ergocalciferol in pregnant women. Cholecalciferol Injection should not be used in pregnancy unless the potential benefit outweighs the potential hazards to the foetus.
• Nursing Mothers :- Vitamin D3 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.
• Elderly: Requirements of vitamin D3 are increased in the elderly patients.
• Renal Insufficiency:- Patients with renal insufficiency will have decreased ability to form calcitriol metabolite, the effect on the calcium and phosphate balance should be supervised.

4.7 Effects on ability to drive and use machines

Cholecalciferol injection have no influence on the ability to drive and use machines. If patient feels drowsiness, affected patients should not drive or operate machinery.

4.8 Undesirable effects

Adverse events are generally associated with excessive intake of Cholecalciferol leading to the development of hypercalcaemia.

Signs and symptoms of vitamin D intoxication associated with hypercalcemia include muscle weakness, apathy, headache, anorexia, nausea, vomiting, bone pain, ectopic calcification, proteinuria, hypertension and cardiac arrhythmias. Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis, and rapid deterioration of renal function.

*In clinical studies on hypoparathyroidism and pseudohypopathyroidism, hypercalcaemia was noted on at least one occasion in about 1 in 3 patients and hypercalciuria in about 1 in 7. Elevated serum creatinine levels were observed in about 1 in 6 patients (approximately one half of whom had normal levels at baseline).

§ Possible early symptoms of hypercalcaemia

†Possible late symptoms of hypercalcaemia

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

Symptoms

Administration to patients in excess of their daily requirement can cause hypercalcaemia, hypercalciuria and hyperphosphataemia. Concomitant high intake of calcium and phosphate may lead to similar abnormalities.

Management

Treatment of chronic overdose with resulting hypercalcaemia consists of immediate withdrawal of the vitamin, a low calcium diet and generous fluid intake. Severe cases may require hydration with intravenous saline together with symptomatic and supportive treatment as indicated by the patient's clinical condition. Plasma calcium should 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.

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 (PTH) and hypophosphatemia. The known sites of action of calcitriol are intestine, bone, kidney and parathyroid gland. The principal action of calcitriol 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 PTH 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

After absorption, Vitamin D3 is rapidly distributed to the liver and lesser amount 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.

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

The mean urinary excretion of Vitamin D3 after 48 hours is 2.4% of the administered dose, and the mean fecal excretion after 48 hours is 4.9% of the administered dose as metabolites of the parent drug.

It was observed that, after intramuscular administration of 6,00,000 IU vitamin D3 in elderly patients, mean serum calcidiol concentration increases to 32.72±9.0 ng/ml at 6th week and up to 52.34±14.2 ng/ml at 12th week from baseline (11.76±7.6 ng/ml).

6.1 Animal Toxicology or Pharmacology

None stated.

Cholecalciferol is the naturally occurring form of vitamin D, also called vitamin D3. It is produced from 7-dehydrocholesterol, a sterol present in mammalian skin, after being exposed to ultraviolet radiation.

8.1 Incompatibilities

None stated.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

3 ampoules of 1 ml each

8.4 Storage and handing instructions

Store below 25°C. Protect from light. After opening the residual must be discarded. Caution: Do not use if solution is not clear or has suspended matter.

• Vitanova-D3 6L injection may interfere with cholesterol tests, hence please inform your physician and laboratory staff that you are taking Vitanova-D3 6L injection before undergoing blood tests.
• Clinical monitoring of serum electrolyte concentrations and cardiac function is recommended.