INDICATIONS AND USAGE Predialysis Patients Calcitriol is indicated in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic renal failure (C cr 15 to 55 mL/min) not yet on dialysis.

In children, the creatinine clearance value must be corrected for a surface area of 1.73 square meters.

A serum iPTH level of ≥ 100 pg/mL is strongly suggestive of secondary hyperparathyroidism.

Dialysis Patients Calcitriol is indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis.

In these patients, calcitriol administration enhances calcium absorption, reduces serum alkaline phosphatase levels, and may reduce elevated parathyroid hormone levels and the histological manifestations of osteitis fibrosa cystica and defective mineralization.

Hypoparathydroidism Patients Calcitriol is also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

WARNINGS Overdosage of any form of vitamin D is dangerous (see OVERDOSAGE ).

Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention.

Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg 2 /dL 2 .

Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Calcitriol is the most potent metabolite of vitamin D available.

The administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia.

Therefore, pharmacologic doses of vitamin D and its derivatives should be withheld during calcitriol treatment to avoid possible additive effects and hypercalcemia.

If treatment is switched from ergocalciferol (vitamin D 2 ) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see OVERDOSAGE ).

Calcitriol increases inorganic phosphate levels in serum.

While this is desirable in patients with hypophosphatemia, caution is called for in patients with renal failure because of the danger of ectopic calcification.

A non-aluminum phosphate-binding compound and a low-phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis.

Magnesium-containing preparations (e.g., antacids) and calcitriol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

Studies in dogs and rats given calcitriol for up to 26 weeks have shown that small increases of calcitriol above endogenous levels can lead to abnormalities of calcium metabolism with the potential for calcification of many tissues in the body.

ADVERSE REACTIONS Since calcitriol is believed to be the active hormone which exerts vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive vitamin D intake, i.e., hypercalcemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcemia) (see WARNINGS ).

Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalization of elevated serum calcium within a few days of treatment withdrawal, i.e., much faster than in treatment with vitamin D 3 preparations.

The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include: Early: weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, and anorexia, abdominal pain or stomach ache.

Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT (AST) and SGPT (ALT), ectopic calcification, nephrocalcinosis, hypertension, cardiac arrhythmias, dystrophy, sensory disturbances, dehydration, apathy, arrested growth, urinary tract infections, and, rarely, overt psychosis.

In clinical studies on hypoparathyroidism and pseudohypoparathyroidism, hypercalcemia was noted on at least one occasion in about 1 in 3 patients and hypercalciuria in about 1 in 7 patients.

Elevated serum creatinine levels were observed in about 1 in 6 patients (approximately one half of whom had normal levels at baseline).

In concurrent hypercalcemia and hyperphosphatemia, soft-tissue calcification may occur; this can be seen radiographically (see WARNINGS ).

In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine (see PRECAUTIONS , General ).

Hypersensitivity reactions (pruritus, rash, urticaria, and very rarely severe erythematous skin disorders) may occur in susceptible individuals.

One case of erythema multiforme and one case of allergic reaction (swelling of lips and hives all over the body) were confirmed by rechallenge.

To report SUSPECTED ADVERSE REACTIONS, contact TEVA Pharmaceuticals USA, Inc.

at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.