Active substance: Synthetic calcitriol (1,25-dihydroxycholecalciferol). Excipients: medium-chain triglycerides, gelatin, glycerol, sorbitol, mannitol, hydrolysed starch, titanium dioxide, yellow iron oxide, red iron oxide, antioxidants: E 320 (butylated hydroxyanisole); E 321 (butylated hydroxytoluene).
PROPERTIES AND EFFECTS
Mechanism of action: Calcitriol is the most active form of vitamin D3 in stimulating intestinal calcium transport. Calcitriol is one of the most important active metabolites of vitamin D3. This metabolite is normally formed in the kidney from its precursor, 25-hydroxycholecalciferol (25-HCC). Physiological daily production is normally 0.5–1.0 μg and is somewhat higher during periods of increased bone formation (e.g. growth, pregnancy). Calcitriol promotes intestinal calcium absorption and regulates bone mineralisation. The main function of calcitriol in the regulation of calcium homeostasis, which also includes stimulating effects on osteoblastic activity in the skeleton, provides a sound pharmacological basis for its therapeutic effects in postmenopausal osteoporosis. In patients with marked renal impairment, endogenous calcitriol synthesis is correspondingly reduced or even completely abolished. This deficiency plays a key role in the development of renal osteodystrophy. In patients with renal osteodystrophy, oral administration of Rocaltrol® normalises reduced intestinal calcium absorption, hypocalcemia, increased serum alkaline phosphatase and serum parathyroid hormone concentration. Rocaltrol® alleviates bone and muscle pain and corrects the histological alterations that occur in osteitis fibrosa and other mineralisation defects. In patients with postoperative hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism, hypocalcemia and its clinical manifestations are alleviated by Rocaltrol® therapy. In patients with vitamin D-dependent rickets, serum levels of calcitriol are low or absent. Since endogenous calcitriol production in the kidney is insufficient, treatment with Rocaltrol® is considered a replacement therapy. In patients with vitamin D-resistant rickets and hypophosphatemia with reduced plasma calcitriol levels, treatment with Rocaltrol® reduces tubular phosphate elimination and, in conjunction with concurrent phosphate treatment, normalises bone formation. Rocaltrol® therapy has also proved useful in patients with various other forms of rickets, e.g. in association with neonatal hepatitis, biliary atresia, cystinosis, and dietary calcium or vitamin D deficiency. Pharmacodynamics: The two known sites of action of calcitriol are intestine and bone. A calcitriol receptor-binding protein appears to exist in the mucosa of human intestine. Additional evidence suggests that calcitriol also acts on the kidney and parathyroid glands. In acutely uremic rats calcitriol has been shown to stimulate intestinal calcium absorption. The kidneys of uremic patients cannot adequately synthesise calcitriol, the active hormone formed from a vitamin D precursor. Resultant hypocalcemia and secondary hyperparathyroidism are the main causes of the metabolic bone disease of renal failure. However, other bone-toxic substances which accumulate in uremia (e.g. aluminium) may also contribute. The beneficial effect of Rocaltrol® in renal osteodystrophyappears to result from correction of hypocalcemia and secondary hyperparathyroidism. It is uncertain whether Rocaltrol® produces other independent beneficial effects.
Absorption: Peak plasma concentrations following a single oral dose of 0.25–1.0 μg Rocaltrol® were found within 2–6 hours. Distribution: During transport in the blood, calcitriol and other vitamin D metabolites are bound to specific plasma proteins. Metabolism: Calcitriol is hydroxylated and oxidised in the kidney and liver by a specific cytochrome P450 isoenzyme, CYP24A1. Various metabolites with different degrees of vitamin D activity have been identified.
Elimination: The serum elimination half-life of calcitriol ranges from 5 to 8 hours. The elimination and absorption kinetics of calcitriol remain linear in a very broad dose range up to a 165 μg single oral dose. The pharmacological effect of a single calcitriol dose lasts 4 days. Calcitriol is excreted in the bile and is subject to enterohepatic circulation. Pharmacokinetics in special patient groups: In patients with nephrotic syndrome or in those undergoing hemodialysis, serum levels of calcitriol were reduced and time to peak levels was prolonged.
Reproductive toxicity studies in rats indicated that oral doses up to 300 ng/kg/day (30 times the usual human dose) did not adversely affect reproduction. In rabbits, in addition to signs of embryotoxicity, fetal abnormalities (skeletal and visceral malformations) were observed in two litters at an oral maternally toxic dose of 300 ng/kg/day. Abnormalities were also noted in one litter at 80 ng/kg/day, but not at a dose of 20 ng/kg/day (twice the usual human dose). Although the observed changes were not statistically significant, involvement of calcitriol cannot be ruled out.
PHARMACEUTICAL FORM AND QUANTITY OF ACTIVE SUBSTANCE PER UNIT
Capsules 0.25 μg.
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.
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.
Rocaltrol® (or any drug of the same class) is contraindicated:
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.
INTERACTIONS: Patients should strictly follow the dietary instructions on supplemental calcium intake and avoid uncontrolled intake of additional calcium- containing medications. Concomitant use of a thiazide diuretic in patients with hypoparathyroidism increases the risk of hypercalcemia. Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias. Functional antagonism exists between vitamin D analogues and corticosteroids. Vitamin D analogues promote calcium absorption, corticosteroids inhibit it. Drugs that contain magnesium (e.g. antacids) must not be administered to chronic dialysis patients during treatment with calcitriol as they may cause hypermagnesemia. Since calcitriol also affects phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be determined on the basis of serum phosphate levels (normal range: 2–5 mg/100 ml or 0.6–1.6 mmol/l). Patients with vitamin D-resistant rickets (familial hypophosphatemic rickets) should continue their oral phosphate therapy. However, possible stimulation of intestinal phosphate absorption by calcitriol should be taken into account since this may modify supplemental phosphate requirements. Bile acid sequestrants such as colestyramine and sevelamer may reduce intestinal absorption of fat-soluble vitamins and thus impair intestinal calcitriol absorption.
Treatment of asymptomatic hypercalcemia: See Special dosage instructions. Since calcitriol is a vitamin D metabolite, overdose presents with the same features as vitamin D overdose. Intake of high doses of calcium and phosphate together with Rocaltrol® may give rise to similar symptoms. The serum calcium times phosphate (Ca × P) product should not be allowed to exceed 70 mg2/dl2. A high calcium level in the dialysate may contribute to hypercalcemia. Acute symptoms of vitamin D intoxication: Anorexia, headache, vomiting, constipation.
Chronic signs and symptoms: Dystrophy (weakness, weight loss), sensory disturbances, possibly fever with thirst, polyuria, dehydration, apathy, arrested growth and urinary tract infections.
Hypercalcemia occurs, with metastatic calcification of the renal cortex, myocardium, lungs and pancreas. The following measures should be considered in treatment of accidental overdosage: Immediate gastric lavage or induction of vomiting to prevent further absorption. Administration of liquid paraffin to promote fecal excretion. Repeated serum calcium determinations are indicated.
If elevated serum calcium levels persist, phosphates and corticosteroids may be administered and measures instituted to achieve adequate forced diuresis.
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.
Each box contains 3x10’s capsule in blister pack.
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.
Version : 04/CDS:04