Pharmacodynamics

Calcitriol is the most important active metabolite of Vitamin D3. It is normally formed in the kidney from its precursor 25-hydroxycholecalciferol (25-HCC). Physiological daily production is normally 0.5 – 1.0µg and is somewhat higher during periods of increased bone synthesis (e.g. growth or pregnancy). The natural supply of Vitamin D in humans depends mainly on exposure to ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to Vitamin D3 (cholecalciferol). Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active as a regulator of calcium and phosphorus metabolism at target tissues. The initial transformation of Vitamin D3 is catalysed by a Vitamin D3-25-hydroxylase enzyme (25-OHase) present in the liver and the product of this reaction is 25-hydroxyvitamin D3 [25-(OH) D3]. Hydroxylation of 25-(OH) D3 occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D3-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)2 D3 (Calcitriol), the active form of Vitamin D3.

Calcitriol binds to an intracellular receptor, a member of the steroid receptor superfamily. The calcitriolreceptor complex interacts with specific DNA sequences that regulate transcription and protein synthesis in a variety of cells including osteoblasts, mucosal cells of the intestine, renal tubular cells and parathyroid cells. The changes in protein synthesis induced in these cells by Calcitriol are responsible for its profound physiological effects. A Vitamin D-resistant state exists in uremic patients because of the failure of the kidney to convert precursors to the active compound. The uremic state may also inhibit the binding of the Calcitriol receptor to its specific DNA responsive elements. The key role of Calcitriol in the regulation of bone and calcium homeostasis, which includes stimulating effects on osteoblastic activity in the skeleton, provides a sound pharmacological basis for its therapeutic effects in osteoporosis. Treatment of established osteoporosis with Calcitriol is associated with an increase in bone density and a reduction in new vertebral fractures. Established osteoporosis is defined as the finding of: bone mineral density measurements of 2 or more standard deviations below the gender specific peak bone mass; or the presence or history of osteoporotic fracture. Calcitriol also reduces bone loss associated with corticosteroid therapy.

In patients with marked renal impairment, synthesis of endogenous Calcitriol is correspondingly limited or may even cease altogether. This deficiency plays a key role in the development of renal osteodystrophy. In patients with renal osteodystrophy, administration of Calcitriol normalises reduced intestinal absorption of calcium, hypocalcaemia, increased serum alkaline phosphatase and serum parathyroid hormone concentration.

In patients with hypophosphataemic rickets and hypophosphataemia, treatment with Calcitriol reduces tubular elimination of phosphates and, in conjunction with concurrent phosphate treatment, corrects some skeletal abnormalities.

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 microgram of Neo D.

Distribution

Following a 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

Several metabolites of Calcitriol, each exerting different Vitamin D activities, have been identified: 1a,25-dihydroxy-24-oxo-cholecalciferol, 1a,23,25-trihydroxy-24-oxo-cholecalciferol, 1a,24R,25 trihydroxycholecalciferol, 1a,25R-dihydroxycholecalciferol-26,23S-lactone, 1a,25S,26-trihydroxycholecalciferol, 1a25-dihydroxy-23-oxo-cholecalciferol, 1a25R,26-trihydroxy-23-oxocholecalciferol and 1a-hydroxy-23-carboxy-24,25,26,27-tetranorcholecalciferol. 1a, 25Rdihydroxycholecalciferol- 26,23S-lactone is the major metabolite in humans.

Excretion

The elimination 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 occur. Following intravenous administration of radiolabelled Calcitriol in normal subjects, approximately 27% and 7% of the radioactivity appeared in the faeces and urine respectively, within 24 hours. When a 1 microgram oral dose of radiolabelled 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 radiolabelled Calcitriol averaged 16% in urine and 49% in faeces. There is evidence that maternal Calcitriol may enter the fetal circulation.

Indications

Calcitriol is indicated for the treatment of established osteoporosis diagnosed by objective measuring techniques, such as densitometry, or by radiographic evidence of a traumatic fracture. Calcitriol is also indicated for the prevention of corticosteroid-induced osteoporosis in patients commencing oral steroid therapy in a dose and regimen expected to result in a significant bone loss. Calcitriol is indicated in the treatment of hypocalcaemia in patients with uremic osteodystrophy, hypoparathyroidism and in hypophosphataemic rickets.

Contraindications

Hypercalcaemia or Vitamin D toxicity. Hypersensitivity to Calcitriol or drugs of the same class, or any of the excipients in NEO D.

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, 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 needed, the greater 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 micrograms/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 micrograms/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 micrograms/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 breast-feed while taking Calcitriol.

Interactions With Other Medicines

Since Calcitriol is one of the most important active metabolites of Vitamin D3, pharmacological doses of Vitamin D and its derivatives should be withheld during treatment with Calcitriol to avoid possible additive effects and hypocalcaemia. In patients being treated for osteoporosis, calcium-containing preparations should be avoided unless required for specific dietary purposes.

Cholestyramine has been reported to reduce intestinal absorption of fat soluble vitamins; as such, it may impair intestinal absorption of Calcitriol. A relationship of functional antagonism exists between Vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit it. Magnesium containing antacids and Calcitriol should not be used concomitantly, because such use may lead to the development of hypermagnesaemia. Calcitriol should be given cautiously to patients on digitalis because hypocalcaemia in such patients may precipitate cardiac arrhythmias. The concomitant use of thiazide diuretics may precipitate hypocalcaemia. 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 concentration (normal value: 0.6-1.6 mmol/L). Administration of enzyme inducers such as phenytoin or phenobarbital may lead to increased metabolism and hence reduced serum concentrations of Calcitriol. Therefore, higher doses of Calcitriol may be necessary if these drugs are administered simultaneously.

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:
  Central Nervous System:Drowsiness, weakness.
  Gastrointestinal: Nausea.
• Less common reactions:
  Dermatological:Pruritus (associated with hypocalcaemia).
  Gastrointestinal tract: Diarrhoea, constipation.
  Genitourinary: Impairment of renal function.
  Musculoskeletal: Metastatic or ectopic calcification.
• Hypersensitivity reactions, such as pruritus, rash, urticaria or very rarely severe erythematous skin disorders may occur in susceptible individuals.

The optimal daily dose of Neo D 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 Neo D 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 Neo D 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 Neo D 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 NEO D 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 Neo D is 0.25 microgram/day 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, therefore larger doses of Neo D may be needed.

The doses are similar to those used in adults with greater variability between subjects. Patients in the one to five year age group with hypoparathyroidism have usually been given Neo D 0.25 to 0.75 microgram daily.

No dosage adjustment is necessary in elderly patients.

Since Calcitriol is a derivative of Vitamin D, the symptoms of overdose are the same as for an overdose of Vitamin D. Administration of Neo D to patients in excess of their daily requirements can cause hypocalcaemia, hypercalciuria and hyperphosphataemia. High intake of calcium and phosphate concomitant with Neo D 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.

Store in a cool, dry place. Protect from light and moisture.

NEO D is available as soft gelatin capsules containing 0.25 micrograms of Calcitriol, supplied in blister strips of 10 capsules and 10 such strips in a box.