Calcitriol for Hemochromatosis

INDICATIONS AND USAGE Predialysis Patients Calcitriol Oral Solution is indicated in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic renal failure (Ccr 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 Oral Solution is indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis. In these patients, Calcitriol Oral Solution 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. Hypoparathyroidism Patients Calcitriol Oral Solution is also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

DOSAGE AND ADMINISTRATION The optimal daily dose of Calcitriol Oral Solution must be carefully determined for each patient. Calcitriol Oral Solution can be administered as an oral solution (1 mcg/mL). Calcitriol Oral Solution therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium. The effectiveness of Calcitriol Oral Solution therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures. Because of improved calcium absorption from the gastrointestinal tract, some patients on Calcitriol Oral Solution may be maintained on a lower calcium intake. Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplementation at all. During the titration period of treatment with Calcitriol Oral Solution, serum calcium levels should be checked at least twice weekly. When the optimal dosage of Calcitriol Oral Solution has been determined, serum calcium levels should be checked every month (or as given below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet. Dialysis Patients The recommended initial dose of Calcitriol Oral Solution is 0.25 mcg/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 mcg/day at 4- to 8-week intervals. During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: GENERAL ). Phosphorus, magnesium, and alkaline phosphatase should be determined periodically. Patients with normal or only slightly reduced serum calcium levels may respond to Calcitriol Oral Solution doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day. Calcitriol Oral Solution may normalize plasma-ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyper-function, Calcitriol Oral Solution may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism. Hypoparathyroidism The recommended initial dosage of Calcitriol Oral Solution is 0.25 mcg/day given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals. During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, Calcitriol Oral Solution should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: GENERAL ). Careful consideration should also be given to lowering the dietary calcium intake. Serum calcium, phosphorus, and 24-hour urinary calcium should be determined periodically. Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily. Pediatric patients in the 1- to 5-year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily. The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations. Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of Calcitriol Oral Solution may be needed. Predialysis Patients The recommended initial dosage of Calcitriol Oral Solution is 0.25 mcg/day in adults and pediatric patients 3 years of age and older. This dosage may be increased if necessary to 0.5 mcg/day. For pediatric patients less than 3 years of age, the recommended initial dosage of Calcitriol Oral Solution is 10 to 15 ng/kg/day.

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 Oral Solution is the most potent metabolite of vitamin D available. The administration of Calcitriol Oral Solution 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 Oral Solution 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 nonaluminum phosphate-binding compound and a low-phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis. Magnesium-containing preparations (eg, antacids) and Calcitriol Oral Solution 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.

Drug Interactions Cholestyramine: Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol (see WARNINGS and PRECAUTIONS : General ). Phenytoin/Phenobarbital: The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of calcitriol, but may reduce endogenous plasma levels of 25(OH)D 3 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 coadministration 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 (see PRECAUTIONS : General ). 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 D 3 , pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcemia (see WARNINGS ). Calcium Supplements: Uncontrolled intake of additional calcium-containing preparations should be avoided (see PRECAUTIONS : General ). Magnesium: Magnesium-containing preparations (e.g., antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 3%) are hypercalcemia, hypercalciuria, and skin discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact: Galderma Laboratories, L.P. at 866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. VECTICAL Ointment was studied in two vehicle-controlled trials and one open label trial, resulting in 743 subjects exposed to VECTICAL Ointment. Table 1 describes adverse events in subjects treated with VECTICAL Ointment twice daily for 8 weeks. The population included subjects ages 13 to 87 years, males (284) and females (135), Caucasians (372) and non-Caucasians (47); with mild (105) to moderate (313) chronic plaque psoriasis. Four hundred and nineteen subjects were treated with VECTICAL Ointment twice daily for 8 weeks. The population included subjects ages 13 to 87, males (284) and females (135), Caucasians (372) and non-Caucasians (47); with mild (105) to moderate (313) chronic plaque psoriasis. Table 1. Selected Averse Events Occurring in at least 1% of Subjects in the Two Pooled Vehicle-Controlled Trials VECTICAL (n = 419) Vehicle Ointment (n = 420) Discomfort skin 3% 2% Pruritus 1% 1% Among subjects having laboratory monitoring, hypercalcemia was observed in 24% (18/74) of subjects exposed to active drug and in 16% (13/79) of subjects exposed to vehicle, the elevations were less than 10% above the upper limit of normal ) [see Warnings and Precautions ( 5.1 ) ]. The open label trial enrolled 324 subjects with psoriasis who were treated for up to 52 weeks and included 239 subjects exposed for 6 months and 116 subjects exposed for one year. Adverse events reported at a rate of greater than or equal to 3% of subjects treated with VECTICAL Ointment were lab test abnormality (8%), urine abnormality (4%), psoriasis (4%), hypercalciuria (3%), and discomfort of skin (3%). Kidney stones were reported in 3 subjects and confirmed in two. 6.2 Postmarketing Experience The following adverse reactions have been identified during world-wide post-approval use of VECTICAL Ointment: acute blistering dermatitis, erythema and skin burning sensation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.