Rocaltrol, 0.25 mcg capsules 30 pcs

Rocaltrol – regulates calcium metabolism, stimulates osteogenesis, and normalizes calcium content in bone tissue.

Calcitriol is one of the most important active metabolites of vitamin D 3 . Calcitriol promotes the absorption of calcium in the intestine and regulates bone mineralization. The pharmacological effect of a single dose of calcitriol lasts 3-5 days.

The key role of calcitriol in regulation of calcium metabolism, consisting in stimulation of skeletal osteoblasts activity, is a reliable pharmacological basis for its therapeutic action in osteoporosis.

In individuals with severe renal insufficiency the synthesis of endogenous calcitriol is reduced or may even stop altogether. Calcitriol deficiency plays a major role in the occurrence of renal osteodystrophy.

In patients with renal osteodystrophy, Rocaltrol (synthetic calcitriol) normalizes reduced intestinal calcium absorption, eliminates hypocalcemia, elevated serum levels of alkaline phosphatase and parathormone. It reduces pain in bones and muscles, and eliminates the histological changes that occur in fibrous osteitis and other disorders of mineralization.

In patients with postoperative and idiopathic hypoparathyroidism and pseudohypoparathyroidism, Rocaltrol reduces hypocalcemia and its clinical manifestations.

In patients with vitamin-D-dependent rickets, the concentration of calcitriol in the serum is low or completely absent. Taking into account insufficient endogenous calcitriol synthesis in kidneys, taking Rocaltrol can be considered as replacement therapy in these patients.

In patients with vitamin-D-resistant rickets and hypophosphatemia with low plasma calcitriol levels, treatment with Rocaltrol reduces tubular excretion of phosphate and in combination with phosphorus medication normalizes bone development.
Treatment with Rocaltrol also helps with other forms of rickets, such as those caused by neonatal hepatitis, biliary atresia, cystinosis, and alimentary calcium and vitamin D deficiencies.

Pharmacokinetics

Intake
Calcitriol is rapidly absorbed in the intestine. After a single oral administration of 0.25-1.0 mcg of Rocaltrol, maximum serum concentrations are reached after 3-6 hours. With repeated administration, equilibrium concentrations are reached within 7 days and depend on the dose amount.

Distribution
After a single oral dose of 0.5 µg of Rocaltrol, the average serum calcitriol concentration rose from a baseline value of 40.0 4.4 pg/ml to 60.0 4.4 pg/ml after 2 hours and then dropped to 53.0 6.9 after 4 hours, to 50.0 7.0 after 8 hours, to 44 4.6 after 12 hours, and 41.5 5.1 pg/ml after 24 hours.
In the blood, calcitriol and other vitamin D metabolites bind to specific plasma proteins.
Exogenous calcitriol can be assumed to pass through the placental barrier and into breast milk.

Metabolism
Several calcitriol metabolites have been identified, each with different vitamin D properties: 1α,25-dihydroxy-24-oxocholecalciferol, 1α,23,25-trihydroxy-24-oxocholecalciferol, 1α,24R,25-trihydroxycholecalciferol, 1α,25R-dihydroxycholecalciferol-26,23S-lactone, 1α,25S,26-trihydroxy-cholecalciferol, 1α,25-dihydroxy-23-oxocholecalciferol, 1α,25R,26-trihydroxy-23-oxocholecalciferol and 1α-hydroxy-23-carboxy-24,25,26,27-tetranorocholecalciferol.

Elimation
The half-life of calcitriol from serum is 9-10 hours. However, the pharmacological action of a single dose of calcitriol lasts at least 7 days. Calcitriol is excreted with bile and undergoes enterohepatic circulation. After intravenous administration of labeled calcitriol healthy volunteers within 24 hours, about 27% of radioactivity is detected in the feces and about 7% – in the urine. After oral administration of 1 µg of labeled calcitriol to healthy volunteers, about 10% of total radioactivity is detectable in the urine within 24 hours. On day 6 after intravenous injection of labeled calcitriol, 16% of total radioactivity is detected in the urine and 49% of total radioactivity is detected in the feces.

Pharmacokinetics in special cases

In patients with nephrotic syndrome or in patients on hemodialysis, serum calcitriol levels are reduced and reaching maximum concentration is somewhat delayed.

Indications

Prevention of rickets,

• Confirmed postmenopausal osteoporosis;
• renal osteodystrophy in patients with chronic renal failure, especially those on hemodialysis;
• secondary hyperparathyroidism in patients with moderate to severe chronic renal failure (pre-dialysis);
• postoperative hypoparathyroidism;
• idiopathic hypoparathyroidism;
• pseudohypoparathyroidism;
• vitamin-D-dependent rickets;
• hypophosphatemic vitamin-D-resistant rickets (phosphate-diabetes).

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Active ingredient

Calcitriol

Composition

Active ingredient:

Calcitriol0.25 mcg;

Associates:

butylhydroxyanisole;

butylhydroxytoluene;

medium-chain triglycerides;

Capsule shell:

gelatin; 85% glycerol (glycerin); Carion 83 (contains – 2-4% mannitol, 27-35% sorbitol, 61-71% hydrolyzed hydrogenated starch); titanium dioxide (E171); iron oxide red dye (E172); iron oxide yellow dye (E172)

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How to take, the dosage

Standard dosing regimen

Intravenously. The initial daily dose is 0.25 mcg. The optimal daily dose of Rocaltrol should be carefully selected for each patient depending on the serum calcium content. The treatment with Rocaltrol should always be started with the lowest possible dose and increased only with careful monitoring of serum calcium levels.

A prerequisite for optimal effectiveness of Rocaltrol therapy is sufficient, but not excessive intake of calcium with food from the beginning of treatment (for adults – about 800 mg per day). In some cases the patient may need to take calcium medication. Due to improved absorption of calcium in the gastrointestinal tract, a reduced calcium intake may be sufficient in some patients receiving Rocaltrol. Patients with a tendency to hypercalcemia should be prescribed only low doses or should be discontinued altogether.

The total daily calcium intake (with food and, if applicable, with medications) should average about 800 mg and not exceed 1000 mg.

During the stabilization phase of Rocaltrol therapy, serum calcium concentrations should be determined at least twice weekly. Once the optimal dose of Rocaltrol has been selected, serum calcium levels should be checked monthly (or as recommended for individual indications, see below). Blood should be drawn for calcium determination without the use of a tourniquet.
Once serum calcium levels are 1 mg/100 ml (250 μmol/L) higher than normal (9-11 mg/100 ml or 2250-2750 μmol/L) or serum creatinine exceeds 120 μmol/L, RocalTrol should be stopped immediately until blood calcium levels normalize.

In hypercalcemia, serum calcium and phosphate levels should be determined daily. After their normalization the treatment with Rocaltrol can be continued reducing the previous dose by 0.25 mcg. Daily dietary calcium intake should be assessed, and adjustments should be made if necessary.

Dosing in special cases in adults

Postmenopausal osteoporosis: 0.25 mcg 2 times daily. Calcium and creatinine content should be determined after 4 weeks, 3 and 6 months after the beginning of treatment and then every 6 months.

Renal osteodystrophy (patients on dialysis): initial daily dose is 0.25 mcg. In patients with normal or only slightly decreased level of serum calcium the dose of 0.25 mcg every other day is enough. If biochemical parameters and clinical picture do not improve, the daily dose should be increased by 0.25 mcg at intervals of 2-4 weeks. Serum calcium should be determined at least twice a week during this period. In most patients the therapeutic effect comes on a daily dose of 0.5-1.0 mcg.

Hypoparathyroidism and rickets: the initial dose is 0.25 mcg daily in the morning. If there is no improvement of biochemical parameters and clinical picture the dose can be increased with 2-4 weeks intervals. During this period serum calcium should be determined at least twice a week. Patients with hypoparathyroidism may sometimes have disorders of absorption, including calcium, which may require increasing the dose of Rocaltrol.

If Rocaltrol is prescribed to a pregnant woman with hypoparathyroidism, the dose of the drug may need to be increased in the second half of pregnancy and decreased after delivery and during lactation.

Dosing in patients of advanced age

Patients of advanced age do not need dose adjustment. General recommendations for monitoring serum calcium and creatinine levels should be followed.

Dosing in infants and young children

As in adults, the optimal daily dose for children should be determined based on serum calcium levels. For the first two years of life, a daily dose of 0.01 to 0.1 mg/kg body weight is recommended.

Intermittent (pulse) therapy
Intermittent (pulse, intermittent) therapy (taking Rocaltrol 2-3 times per week) is effective even in patients refractory to continuous therapy.

Interaction

Since calcitriol is one of the most important active metabolites of vitamin D3, in order to avoid possible additive effects and hypercalcemia during the treatment with Rocaltrol, the administration of medicinal doses of vitamin D and its derivatives should be stopped.
Patients should strictly follow dietary recommendations, especially regarding calcium intake, and avoid uncontrolled additional intake of drugs containing calcium.

Concomitant treatment with thiazide diuretics increases the risk of hypercalcemia. The dose of calcitriol should be chosen very carefully in patients receiving preparations of digitalis, because hypercalcemia in them may provoke arrhythmias.
There is functional antagonism between vitamin D analogues, which increase calcium absorption, and corticosteroids, which inhibit it.

Drugs containing magnesium (e.g., antacids) can cause hypermagnesemia and therefore should not be administered to patients on chronic hemodialysis while treated with Rocaltrol.

Because Rocaltrol affects phosphate transport in the intestine, kidneys and bones, the dose of phosphate-binding drugs should be adjusted depending on serum phosphate levels (normal is 2-5 mg/100 ml, or 0.65-1.62 mmol/L).

The use of enzyme inducers such as phenytoin or phenobarbital may increase metabolism and thereby decrease the concentration of calcitriol in the serum, so higher doses of calcitriol may be required when these drugs are used simultaneously.

Cholestyramine may decrease intestinal absorption of fat-soluble vitamins and, among others, calcitriol.

Special Instructions

There is a strong association between calcitriol treatment and the occurrence of hypercalcemia. Hypercalcemia can occur when calcium intake is increased by dietary changes (e.g., increased consumption of dairy products) or by uncontrolled intake of calcium medications. Patients and their families should be informed about the necessity of strict adherence to the prescribed diet; they should also be trained to recognize the symptoms of hypercalcemia.

Patients who have been on bed rest for long periods of time, such as those who have had surgery, are at particularly high risk of developing hypercalcemia.

Calcitriol increases inorganic phosphate in the serum. This effect, while desirable in patients with hypophosphatemia, requires caution in patients with renal insufficiency because of the danger of ectopic calcification. In such cases, plasma phosphate levels should be maintained at normal levels (2-5 mg/100 ml, or 0.65-1.62 mmol/L) by oral administration of phosphate-binding agents and a low-phosphate diet.

Patients with vitamin-D-resistant rickets (familial hypophosphatemia) receiving Rocaltrol should continue oral phosphate administration. However, be aware of the stimulation of intestinal phosphate absorption by Rocaltrol, as this effect may alter the need for additional phosphate administration. Calcium, phosphorus, magnesium, and alkaline phosphatase in serum and calcium and phosphate in daily urine should be determined regularly. During stabilizing (initial) phase of Rocaltrol treatment serum calcium content should be monitored at least twice a week.
Since calcitriol is the most effective vitamin D metabolite of all existing, no other vitamin D preparations should be prescribed during treatment with Rocaltrol to avoid development of hypervitaminosis D.

If a patient is switched from ergocalciferol (vitamin D2) to calcitriol, normalization of ergocalciferol in the blood may take several months (see “Overdose”).

Patients with normal renal function taking Rocaltrol should avoid dehydration by making sure they get enough fluids.

Particular caution should be exercised when prescribing the drug in children under 18 years of age.

Contraindications

All diseases accompanied by hypercalcemia; hypersensitivity to the drug (or to drugs of the same class) or its excipients.

With caution: atherosclerosis, pulmonary tuberculosis, heart failure, phosphate nephrolithiasis, sarcoidosis and other granulomatosis, advanced age (may contribute to atherosclerosis). Lactation period.

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Side effects

Because Rocaltrol® has vitamin D activity, its side effects are similar to those of vitamin D overdose, i.e., hypercalcemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcemia). Acute symptoms may include anorexia, headache, vomiting, gastralgia or abdominal pain, and constipation. Because of the short biological half-life of calcitriol, serum calcium levels normalize a few days after withdrawal of Rocaltrol®, which is much faster than with treatment with vitamin D3 drugs.

Long-term use may result in dystrophy, sensory disorders, fever, thirst, polyuria, dehydration, apathy, growth retardation and urinary tract infections.

The incidence of each of the adverse reactions described in the clinical use of Rocaltrol® for all indications over 15 years is very low (including hypercalcemia) and does not exceed 0.001%.

With simultaneous hypercalcemia and hyperphosphatemia >6 mg/100 ml or >1.9 mmol/L, soft tissue calcification may occur and is detectable radiologically.

In patients with normal renal function, chronic hypercalcemia may result in increased serum creatinine.
Sensitive individuals may develop hypersensitivity reactions (itching, rash, urticaria and very rarely erythematous skin lesions).

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Overdose

Treatment of asymptomatic hypercalcemia (see section “Dosage and administration”).

Because Rocaltrol® is a vitamin D derivative, it is characterized by the same symptoms of overdose. Taking high doses of calcium and phosphate at the same time as Rockaltrol® may cause similar symptoms. The product of calcium and phosphorus concentration in serum (CaP) should not exceed 70 mg2 /dl2. The development of hypercalcemia may be promoted by high levels of calcium in the dialysate.

Symptoms of acute vitamin D poisoning: anorexia, headache, vomiting, constipation.

The symptoms of chronic poisoning: dystrophy (weakness, weight loss), sensory disorders, possible fever with thirst, polyuria, dehydration, apathy, growth retardation and urinary tract infections. Consequences of hypercalcemia are focal calcification of the cortical layer of the kidneys, myocardium, lungs and pancreas.

The treatment of accidental overdose: immediate gastric lavage or administration of drugs causing vomiting to prevent further absorption. Vaseline oil is used as a laxative for excretion of the drug in the feces. It is recommended that serum calcium levels be determined repeatedly. If elevated serum calcium levels persist, phosphates and corticosteroids may be prescribed, and measures may be taken to ensure adequate diuresis.

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Pregnancy use

Orally administered sublethal doses of vitamin D to pregnant rabbits resulted in fetuses developing supraclavicular aortic stenosis. There is no evidence of teratogenicity of vitamin D, even at very high doses, in humans.

The administration of Rocaltrol to pregnant women should be made only for absolute indications, if the expected effect on the mother exceeds the possible risk to the fetus.

It appears that exogenous calcitriol penetrates into breast milk. Because of possible hypercalcemia in mother and adverse reactions in breastfed children, it is not recommended to take the drug during breastfeeding.

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