INDICATIONS AND POTENTIAL USES Postmenopausal osteoporosis. Renal osteodystrophy in patients with chronic renal failure, particularly those undergoing hemodialysis. Postoperative hypoparathyroidism. Idiopathic hypoparathyroidism. Pseudohypoparathyroidism. Vitamin D-dependent rickets. Vitamin D-resistant rickets with hypophosphatemia.

Vitamins and Minerals

DOSAGE AND ADMINISTRATION Standard dosage: The optimal daily dose of Rocaltrol® must be carefully determined for each patient on the basis of the serum calcium level. Rocaltrol® therapy should always be started at the recommended dose and increased only with careful monitoring of serum calcium. Once the optimal dosage of Rocaltrol® has been determined, serum calcium levels should be checked monthly (or as stated below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet. As soon as serum calcium rises to 1 mg/100 ml (0.25 mmol/l) above normal levels (9–11 mg/100 ml or 2.25–2.75 mmol/l) or serum creatinine rises to >120 μmol/l, treatment with Rocaltrol® should be stopped immediately until normocalcemia is achieved. Serum calcium and phosphate levels must be determined daily as long as hypercalcemia persists. When normal levels have been restored, treatment with Rocaltrol® can be continued at a daily dose 0.25 μg lower than that previously used. The prerequisite for optimal efficacy of Rocaltrol® is adequate but not excessive calcium intake at the start of treatment. Calcium supplements may be required, which should be used in accordance with the current scientific recommendations. Because of improved calcium absorption from the gastrointestinal tract, it may be possible to reduce calcium intake in some patients taking Rocaltrol®. Patients with a tendency to hypercalcemia may require only low calcium doses or no supplementation at all. Special dosage instructions: Postmenopausal osteoporosis: The recommended dose is 0.25 μg twice daily; the capsules should be swallowed whole.Serum calcium and creatinine levels must be determined after 4 weeks, 3 and 6 months, and then every 6 months. Renal osteodystrophy (dialysis patients): The initial daily dose is 0.25 μg. In normocalcemic or only mildly hypocalcemic patients, alternate-day dosing with 0.25 μg is sufficient. If a satisfactory response in clinical and biochemical parameters is not observed within two to four weeks, the dose may be increased by 0.25 μg/day at two- to four-week intervals. During this period, serum calcium should be determined at least twice weekly. Most patients respond to a dose of 0.5–1.0 μg daily. Dose modifications may be required during concomitant use of barbiturates or anticonvulsants. An oral Rocaltrol® pulse therapy with an initial dosage of 0.1 μg/kg/week – split into two or three equal doses given at night – was also found to be effective even in patients refractory to continuous therapy. A total cumulative dose of 12 μg per week should not be exceeded. Hypoparathyroidism and rickets:The recommended initial dose of Rocaltrol® is 0.25 μg daily, given in the morning. If a satisfactory response is not observed in biochemical and clinical disease parameters, the dose may be increased at two- to four-week intervals. During this period, serum calcium levels should be determined at least twice weekly. Malabsorption is occasionally noted in patients with hypoparathyroidism; higher doses of Rocaltrol® may be needed in such cases. If the physician decides to prescribe Rocaltrol® to a pregnant woman with hypoparathyroidism, a higher dose may be required during the further course of pregnancy, which must be reduced again postpartum or during lactation. Elderly patients: No specific dosage modifications are required in elderly patients. The general recommendations for monitoring serum calcium and creatinine should be followed. Infants and young children: The safety and efficacy of calcitriol capsules have not been studied sufficiently in children to permit a dose recommendation.

CONTRAINDICATIONS Rocaltrol® (or any drug of the same class) is contraindicated: in all diseases associated with hypercalcemia, in patients with hypersensitivity to the active substance or any of the constituent excipients if there is evidence of vitamin D related adverse effects.

UNDESIRABLE EFFECTS The adverse effects listed below reflect the experience acquired in clinical studies of Rocaltrol® and postmarketing experience. The most commonly reported adverse reaction was hypercalcemia. The adverse effects are presented by system organ class and frequency categories, defined as follows: very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Immune system disorders: Frequency unknown: hypersensitivity, urticaria. Metabolism and nutrition disorders: Very common: hypercalcemia ,Uncommon: decreased appetite Frequency unknown: polydipsia, dehydration Psychiatric disorders: Frequency unknown: apathy. Nervous system disorders: Common: headache. Frequency unknown: muscle weakness, sensory disturbance Gastrointestinal disorders: Common: abdominal pain, nausea Uncommon: vomiting. Frequency unknown: constipation, Skin and subcutaneous tissue disorders: Common: rash. Frequency unknown: erythema, pruritus. Musculoskeletal, connective tissue and bone disorders: Frequency unknown: growth retardation Renal and urinary disorders: Common: urinary tract infection Frequency unknown: polyuria General disorders and administration site conditions Frequency unknown: calcinosis, pyrexia, thirst Investigations Uncommon: blood creatinine increased. Frequency unknown: weight decreased Since calcitriol possesses vitamin D activity, it may lead to “side effects” consistent with vitamin D overdosage, namely hypercalcemia syndrome or calcium intoxication, depending on the duration and severity of hypercalcemia (see Dosage and administration and Warnings and precautions). Acute symptoms are decreased appetite, headache, nausea, vomiting, abdominal pain, constipation and apathy. Coexistence of hypercalcemia with hyperphosphatemia (>6 mg/100 ml, or >1.9 mmol/l) may lead to radiographically visible calcinosis. Pharmacokinetic studies indicate that because of the short biological half-life of calcitriol, hypercalcemia is normalised within a few days of treatment withdrawal or dose reduction, i.e. much more rapidly than during treatment with vitamin D3 preparations. Possible signs and symptoms of chronic hypercalcemia: muscle weakness, weight decreased, sensory disturbances, fever, thirst, polyuria, polydipsia, dehydration, apathy, growth retardation, urinary tract infections and, very rarely as complications of hypercalcemia, ectopic calcification and pancreatitis. Hypersensitivity reactions (including rash, erythema, pruritus,urticaria and, very rarely, severe erythematous skin changes) may occur in susceptible individuals. EFFECTS ON ABILITY TO DRIVE AND USE MACHINES On the basis of the pharmacodynamic profile, this product is presumed to be safe or unlikely to adversely affect such activities.

PREGNANCY AND LACTATION Pregnancy: Animal studies have shown fetotoxicity (see Preclinical data). However, there is no evidence to suggest that vitamin D is teratogenic in humans even at very high doses. Rocaltrol® should be used during pregnancy only if clearly necessary. Lactation: Exogenous calcitriol may pass into breast milk. In view of the potential for hypercalcemia in the mother and for adverse reactions to Rocaltrol® in nursing infants, mothers may breastfeed while taking Rocaltrol® only if the serum calcium levels of the mother and infant are monitored.

WARNINGS AND PRECAUTIONS There is a close correlation between treatment with calcitriol and the development of hypercalcemia. In studies in uremic osteodystrophy, hypercalcemia occurred in up to 40% of patients treated with calcitriol. An abrupt increase in calcium intake as a result of dietary changes (e.g. increased consumption of dairy products) or uncontrolled intake of calcium preparations may trigger hypercalcemia. Patients and their families should be explicitly instructed to strictly follow their dietary instructions and be informed about the signs and symptoms of possible hypercalcemia. As soon as serum calcium rises to 1 mg/100 ml (250 μmol/l) above normal levels (9–11 mg/100 ml or 2250–2750 μmol/l) or serum creatinine rises to >120 μmol/l, treatment with Rocaltrol® should be stopped immediately until normocalcemia is restored (see Dosage and administration). Immobilised patients, e.g. those who have undergone surgery, are particularly exposed to the risk of hypercalcemia. In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine. Caution is indicated in patients with a history of kidney stones or coronary heart disease. Calcitriol increases serum inorganic phosphate levels. While this is desirable in patients with hypophosphatemia, caution is required in patients with renal failure in view of the danger of ectopic calcification. In such cases plasma phosphate should be maintained at the normal level (2–5 mg/100 ml or 0.65–1.62 mmol/l) by oral administration of phosphate binders such as aluminium hydroxide or aluminium carbonate and a low-phosphate diet. The serum calcium times phosphate (Ca × P) product should not be allowed to exceed 70 mg2/dl2. Patients with vitamin D-resistant (familial hypophosphatemic) rickets who are being treated with Rocaltrol® must continue their oral phosphate therapy. However, it must be borne in mind that possible stimulation of intestinal phosphate absorption may reduce exogenous phosphate requirements. Required regular laboratory investigations include serum determinations of calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphate. During the equilibration phase of treatment with Rocaltrol®, serum calcium levels should be checked at least twice weekly (see Dosage and administration). Since calcitriol is the most effective available vitamin D metabolite, no other vitamin D preparations should be prescribed during treatment with Rocaltrol® to avoid the development of hypervitaminosis D. When switching treatment from ergocalciferol (vitamin D2) to calcitriol, it may take several months for ergocalciferol blood levels to return to baseline values (see Overdosage). Patients with normal renal function who are taking Rocaltrol® should avoid dehydration. Care should be taken to ensure adequate fluid intake.

ADDITIONAL INFORMATION Stability: This medicinal product must not be used after the expiry date (EXP) shown on the pack. Special precautions for storage: Do not store above 25 °C. Store in the original pack to protect the contents from light and moisture.