Calcitriol
Nefkalci® (calcitriol) is considered to be the most potent metabolite of vitamin D in humans. Renal production of calcitriol is stimulated in response to PTH, low calcium and low phosphate. Calcitriol plays a role in plasma calcium regulation in concert with parathyroid hormone (PTH) by enhancing absorption of dietary calcium and phosphate from the gastrointestinal tract, promoting renal tubular reabsorption of calcium in the kidneys, and stimulating the release of calcium stores from the skeletal system. In addition to promoting fatty acid synthesis and inhibiting lipolysis,Nefkalci® (Calcitriol) has been demonstrated to increase energy efficiency by suppressing UCP2 expression, which is modulated by signaling pathways of classical nuclear receptors (nVDR), where calcitriol acts as a natural ligand. Nefkalci® (Calcitriol) effectively decreases PTH levels, decreases bone resorption, improves endosteal fibrosis and mineralization, and to some extent helps in the bone pains associated with renal osteodystrophy
Presentation
Blister pack of Nefkalci® in one strip 10 tablets and 10 strips in a box
Composition
Nefkalci® : Each Nefkalci® Tablet contains Calcitriol 0.25mcg Tablet
Mode Of Action :
Calcitriol acts on cells in the gastrointestinal tract to increase the production of calcium transport proteins, termed calbindin-D proteins, which results in increased uptake of calcium from the gut into the body.Calcitriol has a direct inhibiting effect on PTH synthesis. It inhibits parathyroid gland activity by decreasing parathyroid hormone synthesis and release.
Calcitriol increases blood calcium levels ([Ca2+]) by:
- Promoting absorption of dietary calcium from the gastrointestinal tract.
- Increasing renal tubular reabsorption of calcium, thus reducing the loss of calcium in the urine.
- Stimulating release of calcium from bone. For this it acts on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL (Receptor activator of nuclear factor kappa-Β ligand), which in turn activates osteoclasts.
Absorption
Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations (above basal values) were reached within 3 to 6 hours following oral administration of single doses of 0.25 to 1.0 mcg of Nefkalci®.
Distribution
Following single oral dose of 0.5 microgram, mean serum concentrations of Calcitriol rose from a baseline value of 40.0 + 4.4 (S.D.) pg/ml to 60.0 + 4.4 pg/ml at 2 hours and declined to 53.0 + 6.9 at 4 hours, 50 + 7.0 at 8 hours, 44 + 4.6 at 12 hours and 41.5 + 5.1 at 24 hours. Calcitriol and other Vitamin D metabolites are transported approximately 99.9% bound to specific plasma proteins in the blood.
Metabolism
In vivo and in vitro studies indicate the presence of two pathways of metabolism for calcitriol. The first pathway involves the 24-hydroxylase as the first step in catabolism of calcitriol. There is definite evidence of 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1α, 25R(OH)2-26, 23S-lactone D3. The lactone appears to be the major metabolite circulating in humans, with mean serum concentrations of 131 ± 17 pg/mL. In addition, several other metabolites of calcitriol have been identified: 1α, 25(OH)2-24-oxo-D3; 1α, 23,25(OH)3-24-oxo-D3; 1α, 24R,25(OH)3D3; 1α, 25S,26(OH)3D3; 1α, 25(OH)2-23-oxoD3; 1α, 25R,26(OH)3-23-oxo-D3; 1α, (OH)24,25,26,27-tetranor-COOH-D3.
Excretion
The elimination of half-life of Calcitriol from serum was found to range from 3 to 6 hours. However, the pharmacological effect of a single dose of Calcitriol lasts about three to five days. Enterohepatic recycling and biliary excretion occurs. Following intravenous administration of radiolabeled Calcitriol in normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine respectively within 24 hours. When a 1 microgram oral dose of radiolabeled Calcitriol was administered to normals, approximately 10% of the total radioactivity appeared in urine within 24 hours. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled Calcitriol averaged 16% in urine and 49% in feces. There is evidence that maternal Calcitriol may enter the fetal circulation.
Indications
- Renal osteodystrophy Hypophosphatemia
- Hypoparathyroidism Hypocalcemia
Contraindications
Hypercalcaemia or Vitamin D toxicity. Hypersensitivity to Calcitriol or drugs of the same class, or any of the excipients in Nefkalci®.
Precautions
Concomitant therapy with other Vitamin D compounds
Since Calcitriol is the most potent metabolite of Vitamin D available, other Vitamin D compounds should be withheld during treatment in order to avoid the development of hypervitaminosis D. If patients are ‘changed over’ from ergocalciferol to Calcitriol, it may take many months for blood levels of ergocalciferol to return to pre-treatment values. Overdosage of any form of Vitamin D is dangerous. Chronic hypocalcaemia can lead to generalised vascular calcification, nephrocalcinosis and other soft-tissue calcification.
Hypercalcaemia
A strong relationship exists between Calcitriol therapy and the development of hypocalcaemia. In some trials in uremic osteodystrophy, up to 40% of patients receiving Calcitriol treatment became hypercalcaemic. Sudden increases in calcium consumption due to dietary change (e.g., dairy products) or injudicious calcium supplements may precipitate hypocalcaemia. Patients and relatives should receive instruction in dietary management, be informed about the symptoms of hypocalcaemia and be warned of the consequences of not adhering to dietary recommendations. Although an adequate dietary intake of calcium is important in patients with postmenopausal osteoporosis, Calcitriol does increase calcium absorption in these patients and calcium supplements may lead to hypocalcaemia and are not recommended unless the dietary intake is clearly inadequate. In patients with normal renal function, chronic hypocalcaemia may be associated with an increase in serum creatinine.
Serum Phosphate Levels
Calcitriol raises serum inorganic phosphate levels. While this is a desirable effect in patients with hypophosphataemic states, caution must be taken in patients with renal failure.
Hypophosphataemic Rickets
Patients with hypophosphataemic rickets (familial hypophosphataemia) should pursue their oral phosphate therapy. However, the possible stimulation of intestinal phosphate absorption may modify the requirement for phosphate supplements. During the stabilisation phase of treatment with Calcitriol, serum calcium levels should be checked at least twice weekly.
Ectopic Calcification
Calcitriol may increase plasma phosphate levels. While this effect is desirable in hypophosphataemic osteomalacia, it may cause ectopic calcification, especially in patients with renal failure. Plasma phosphate levels should be kept normal in such patients by the oral administration of phosphate binding agents. Patients with normal renal function who are taking Calcitriol should avoid dehydration. Adequate fluid intake should be maintained.
Immobilisation
Patients immobilised after surgical procedures are more at risk of developing hypocalcaemia, and therefore more frequent monitoring is recommended.
Use in patients with impaired renal function
Special care should be taken when administering Calcitriol to patients with renal dysfunction. More frequent monitoring in these patients is appropriate.
Use in Children
Paediatric patients on long-term treatment with Calcitriol are at risk of development of nephrocalcinosis. The younger the age at the commencement of therapy and the higher the dose of Calcitriol is needed, the greater is the risk. The drug should be used only if the benefits clearly outweigh the risks.
Use in the Elderly
It is advised that in elderly patients suffering from ischemic heart disease, serum calcium levels should be carefully monitored. If hypocalcaemia is observed, Calcitriol therapy should be suspended immediately. It should also be remembered that geriatric patients receive many other drugs and that their compliance may not be ideal.
Carcinogenicity/Mutagenicity
Long term animal studies have not been conducted to evaluate the carcinogenic potential of Calcitriol. Calcitriol is not mutagenic in vitro in the Ames test. No significant effects of Calcitriol on fertility and/or general reproductive performances were observed in a study in rats at oral doses of up to 0.3 mcg/kg (approximately 3 times the maximum recommended dose based on body surface area).
Use in Pregnancy
There are no adequate and well-controlled studies in pregnant women. Calcitriol has been found to be teratogenic in rabbits when given at doses of 0.08 and 0.3 mcg/kg (approximately 1 and 5 times the maximum recommended dose based on mg/m2). All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared to controls. Teratogenicity studies in rats up to 0.3 mcg/kg (approximately twice the maximum recommended dose based on mg/m2) showed no evidence of teratogenic potential. Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Lactation
It should be assumed that exogenous Calcitriol passes into the breast milk. In view of the possible adverse effects on the infant, mothers should not breastfeed while taking Calcitriol.
Drug Interactions
Cholestyramine: Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol. Phenytoin/Phenobarbital: The co-administration of phenytoin or phenobarbital will not affect plasma concentrations of calcitriol, but may reduce endogenous plasma levels of 25(OH)D3 by accelerating metabolism. Since blood level of calcitriol will be reduced, higher doses of calcitriol may be necessary if these drugs are administered simultaneously. Thiazides: Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine. Some reports have shown that the concomitant administration of thiazides with calcitriol causes hypercalcemia. Therefore, precaution should be taken when co-administration is necessary. Digitalis: Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias. Ketoconazole: Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in serum endogenous calcitriol concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men. However, in vivo drug interaction studies of ketoconazole with calcitriol have not been investigated. Corticosteroids: A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption. Phosphate-Binding Agents: Since calcitriol also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration. Vitamin D: Since calcitriol is the most potent active metabolite of vitamin D3, pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcemia.
Adverse Effects
Since Calcitriol exerts Vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive Vitamin D intake. Hypercalcaemia related to mechanism of action is the most important side effect and is manageable by dose modification. Hypercalcaemia has been demonstrated not to be an issue for Calcitriol in the treatment of postmenopausal osteoporosis at the recommended dosage of 0.25 microgram twice daily. Acute hypocalcaemia may give rise to cardiac arrhythmia and/or arrest. Signs and symptoms of Vitamin D intoxication associated with hypocalcaemia include – Acute: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, abdominal pain, muscle pain, bone pain and metallic taste. Chronic: Dystrophy, sensory disturbances, fever with thirst, polyuria, polydypsia/thirst, dehydration, apathy, arrested growth, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolaemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, urinary tract infections and, rarely, overt psychosis. Prolonged chronic hypocalcaemia or concurrent hypocalcaemia and hyperphosphataemia of > 1.9 mmol/L can result in metastatic calcification of soft tissues; this can be seen radiographically. In patients with normal renal function, chronic hypocalcaemia may be associated with an increase in serum creatinine.
The following adverse reactions have been reported in clinical trials involving Calcitriol therapy:
• Serious or life threatening reactions:Severe dehydration
• More common reactions:
Metabolic: Hypercalcaemia
Central Nervous System: Drowsiness, weakness
Gastrointestinal: Nausea
• Less common reactions:
Dermatological: Pruritus (associated with hypocalcaemia)
Gastrointestinal tract: Diarrhoea, constipation
Genitourinary: Impairment of renal functions
Musculoskeletal: Metastatic or ectopic calcification
• Hypersensitivity reactions: Pruritus, rash, urticaria or very rarely severe erythematous skin disorders may occur in susceptible individuals.
Dosage and Administration
The optimal daily dose of Nefkalci® must be carefully determined for each patient and indication.
Dosage optimisation should be accompanied by regular monitoring of serum calcium concentration. If hypocalcaemia occurs, the drug should be immediately discontinued until normocalcaemia ensues.
Adults
Established Osteoporosis:
The recommended dose of Nefkalci® is 0.25 microgram twice daily. If a satisfactory response is not obtained with this dose, it may be increased, with regular serum calcium monitoring to a maximum of 0.5 microgram twice daily. This increased dose should rarely be necessary.
Corticosteroid-Induced Osteoporosis:
The recommended dose of Nefkalci® is 0.25 microgram twice daily for steroid doses equivalent to < 10 mg/day of oral prednisone increasing to 0.75 microgram/day for steroid doses > 10 mg/day oral prednisone. Dietary calcium intake should not exceed 1000 mg/day.
Uremic Osteodystrophy:
The recommended initial dose of Nefkalci® is 0.25 microgram/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 microgram/day at intervals of two to four weeks. Patients with normal or only slightly reduced serum calcium levels may respond to Nefkalci® doses of 0.25 microgram every other day. Most patients undergoing haemodialysis respond to doses between 0.5 and 1 microgram daily.
Hypoparathyroidism and Rickets:
The recommended initial dose of
Nefkalci® is 0.25 microgram/day when given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease are not observed, the dose may be increased at intervals of two to four weeks. Malabsorption is occasionally noted in patients with hypoparathyroidism and therefore larger doses of Nefkalci® may be needed.
Paediatric
The doses are similar to those used in adults with greater variability between subjects. Patients in one to five years age group with hypoparathyroidism have usually been given Nefkalci® 0.25 to 0.75 microgram daily.
Geriatric
No dosage adjustment is necessary in elderly patients.
Overdosage
Since Calcitriol is a derivative of Vitamin D, the symptoms of overdose are the same as for an overdose of Vitamin D. Administration of Nefkalci® to patients in excess of their daily requirements can cause hypocalcaemia, hypercalciuria and hyperphosphataemia. High intake of calcium and phosphate concomitant with Nefkalci® may lead to similar symptoms. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2. In patients with uremic osteodystrophy, high levels of calcium in the dialysate may contribute to the development of hypocalcaemia. Acute symptoms of Vitamin D intoxication include anorexia, headache, vomiting and constipation. Chronic symptoms include dystrophy (weakness, loss of weight), sensory disturbances, possibly fever with thirst, polyuria, dehydration, apathy, arrested growth and urinary tract infections. Hypercalcaemia ensues with metastatic calcification of the renal cortex, myocardium, lungs and pancreas.
Storage
Store in a cool, dry place. Protect from light and moisture.
Disclaimer:
This information is for registered medical practitioner only. Anyone other than medical practitioner should consult medical practitioner before using this product.