Rokaltrol

General characteristics. Structure:

Active agent: calcitriol of 0.25 mkg, 0.5 mkg

Fillers: butylated hydroxytoluene, butylated hydroxyanisole, the fractioned coconut oil.

Pharmacological properties:

Calcitriol - one of the most important active metabolites of vitamin D 3. Calcitriol promotes absorption of calcium in intestines and regulates a mineralization of bones. The pharmacological effect of a single dose of calcitriol lasts 3-5 days.
The key role of calcitriol in regulation of calcic exchange consisting in stimulation of activity of osteoblasts of a skeleton represents a reliable pharmacological basis for its therapeutic action at osteoporosis.
At persons with the expressed renal failure synthesis of endogenous calcitriol decreases or can even stop absolutely. Insufficiency of calcitriol plays the main role in emergence of a renal osteodystrophy.
At patients with a renal osteodystrophy Rokaltrol (synthetic calcitriol) normalizes reduced absorption of calcium in intestines, eliminates a hypocalcemia, the increased levels of an alkaline phosphatase and parathormone in serum. It reduces an ostealgia and muscles, and also eliminates the histologic changes happening at a fibrous osteit and other disturbances of a mineralization.
At patients with a postoperative and idiopathic hypoparathyrosis and a pseudohypoparathyroidism Rokaltrol reduces a hypocalcemia and its clinical manifestations.
At patients about vitamin - D-dependent rickets concentration of calcitriol in serum low or completely is absent. Considering insufficient endogenous synthesis of calcitriol in kidneys, Rokaltrol's reception can be considered at such patients as replacement therapy.
At patients about vitamin - D-resistant rickets and a hypophosphatemia with the low level of calcitriol in plasma treatment by Rokaltrol reduces canalicular removal of phosphates and in combination with administration of drugs of phosphorus normalizes development of bones.
Treatment by Rokaltrol helps also at other forms of rickets, for example, caused by neonatal hepatitis, an atresia of bilious ways, a cystinosis, and also alimentary insufficiency of calcium and vitamin D.

Pharmacokinetics. Absorption. Calcitriol is quickly soaked up in intestines. After single oral administration of 0.25-1.0 mkg of Rokaltrol the maximum concentration in serum is reached in 3-6 hours. At repeated reception equilibrium concentration are reached within 7 days and depend on dose size.

Distribution. After single oral administration of 0.5 mkg of Rokaltrol average value of concentration of calcitriol in serum rose from initial size 40.0 4.4 »¬ú/ml to 60.0 4.4 »¬ú/ml in 2 hours, and then fell to 53.0 6.9 in 4 hours, to 50.0 7.0 in 8 hours, to 44 4.6 in 12 hours and 41.5 5.1 »¬ú/ml in 24 hours.
In blood calcitriol and other metabolites of vitamin D contact specific plasma proteins.
It is possible to assume that exogenous calcitriol gets through a placental barrier and into breast milk.

Metabolism. Several metabolites of calcitriol were identified, each of which has various properties of vitamin D: 1α, 25-dihydroxy-24-oxocholecalciferol, 1,23,25-тригидрокси-24-оксохолекальциферол, 1α, 24R, 25-trigidroksikholekaltsiferol, 1,25R-дигидроксихолекальциферол-26,23S-лактон, 1α, 25S, 26-three-hydroxycholecalciferol, 1α, 25-dihydroxy-23-oxocholecalciferol, 1,25R,26-тригидрокси-23-оксохолекальциферол and 1-гидрокси-23-карбокси-24,25,26,27-тетранорхолекальциферол.

Removal. The calcitriol elimination half-life makes 9-10 hours of serum. However pharmacological action of a single dose of calcitriol lasts not less than 7 days. Calcitriol is removed with bile and is exposed to enterogepatichesky circulation. After intravenous administration of marked calcitriol to healthy volunteers within 24 hours about 27% of radioactivity are found to Calais and about 7% - in urine. After oral administration of 1 mkg of marked calcitriol by healthy volunteers about 10% of the general radioactivity are found in urine within 24 hours. For the 6th day after intravenous administration of marked calcitriol in urine 16%, and in Calais - 49% of total radioactivity are found.

Pharmacokinetics in special cases.
At patients with a nephrotic syndrome or at the patients who are on a hemodialysis, calcitriol levels in serum are reduced, and achievement of the maximum concentration is slowed a little down.

Indications to use:

The confirmed post-menopausal osteoporosis; a renal osteodystrophy at patients with a chronic renal failure, especially at being on a hemodialysis; a secondary hyperparathyreosis at patients with the moderated and expressed degree of a chronic renal failure (pre-dialysis); postoperative hypoparathyrosis; idiopathic hypoparathyrosis; pseudohypoparathyroidism; vitamin - D-dependent rickets; gipofosfatemichesky vitamin - D-resistant rickets (phosphate diabetes).

Route of administration and doses:

Standard mode of dosing
Inside. The initial daily dose makes 0.25 mkg. The optimum daily dose of Rokaltrol needs to be selected carefully for each patient depending on the content of calcium in serum. Treatment by Rokaltrol always needs to be begun with as it is possible a smaller dose and to raise it only at careful control of calcium level in serum.
Necessary condition for optimum efficiency of therapy by Rokaltrol is sufficient, but not excess intake of calcium with food from an initiation of treatment (for adults - about 800 mg a day). In certain cases calcium administration of drugs can be required by the patient. Thanks to improvement of absorption of calcium in digestive tract, some patients receiving Rokaltrol there can be sufficient also a lowered calcium consumption. Patients with a tendency to a hypercalcemia should appoint drugs only in small doses or in general to cancel them.
The general daily consumption of calcium (with food and if it takes place, with medicines) has to make, on average, about 800 mg and not exceed 1000 mg.
At a stage of stabilization of therapy by Rokaltrol concentration of calcium in serum should be defined at least two weekly. After selection of an optimum dose of Rokaltrol serumal levels of calcium need to be checked monthly (or according to recommendations about separate indications, see further). Blood for definition of calcium should be taken without use of a plait.
As soon as serum calcium level on 1 mg / 100 ml (250 µmol/l) exceeds norm (9-11 mg / 100 ml or 2250-2750 µmol/l) or creatinine of serum will exceed 120 µmol/l, Rokaltrol's reception should be stopped immediately before normalization of level of calcium in blood.
At a hypercalcemia levels of calcium and phosphates in serum need to be determined daily. After their normalization treatment by Rokaltrol can be continued, having reduced a former dose by 0:25 mkg. It is necessary to estimate daily consumption of calcium with food and, if necessary, to introduce amendments in a diet.

Dosing in special cases at adults
Post-menopausal osteoporosis: 0.25 mkg 2 times a day. Content of calcium and creatinine should be determined in 4 weeks, 3 and 6 months after an initiation of treatment, and then - each 6 months.
Renal osteodystrophy (patients on dialysis): an initial daily dose - 0.25 mkg. Patients with the normal or only slightly lowered level of serumal calcium have enough dose of 0.25 mkg every other day. If biochemical indicators and a clinical picture do not improve, the daily dose should be increased by 0:25 bucketed mkg in 2-4 weeks. During this period it is necessary to define serumal calcium at least two weekly. At most of patients the therapeutic effect occurs on a daily dose of 0.5-1.0 mkg.
Hypoparathyrosis and rickets: an initial dose - 0.25 mkg a day in the morning. If improvement of biochemical indicators and a clinical picture is not observed, the dose can be increased bucketed in 2-4 weeks. During this period it is necessary to define serumal calcium at least two weekly. At patients with a hypoparathyrosis absorption disturbances including calcium that can demand increase in a dose of Rokaltrol can sometimes be observed.
If Rokaltrol appoint to the pregnant woman with a hypoparathyrosis, then in the second half of pregnancy increase in a dose of drug, and after the delivery can be required and during a lactation - its reduction.

Dosing at patients of senile age
It is not required to patients of senile age of dose adjustment. It is necessary to adhere to the general recommendations about control of the level of calcium and creatinine in serum.

Dosing at babies and children of younger age
As well as at adults, the optimum daily dose for children has to be defined on the basis of the level of serumal calcium. Within the first two years of life it is recommended to appoint a daily dose from 0.01 to 0.1 mg/kg of body weight.

Intermittent (pulse-) therapy
Intermittent (pulse, discontinuous) therapy (Rokaltrol's reception 2-3 times a week) is effective even at patients, refractory to continuous therapy.

Features of use:

There is close connection between treatment by calcitriol and emergence of a hypercalcemia. The hypercalcemia can develop at increase in intake of calcium in an organism at change of food (for example, the increased consumption of dairy products) or uncontrolled administration of drugs of calcium. Patients and members of their families should be informed on obligation of strict observance of the ordered diet; they should be trained also to distinguish hypercalcemia symptoms.
Patients are exposed to especially big risk of development of a hypercalcemia, it is long being on a bed rest, for example, undergone an operation.
Calcitriol increases the content of inorganic phosphates in serum. This effect, being desirable at patients with a hypophosphatemia, demands care in relation to patients with a renal failure because of danger of ectopic calcification. In such cases it is necessary to support the content of phosphates in plasma at the normal level (2-5 mg / 100 by ml, or 0.65-1.62 mmol/l) by oral administration of the drugs connecting phosphates and a low-phosphatic diet.
Patients about vitamin - the D-resistant rickets (a family hypophosphatemia) receiving Rokaltrol need to continue oral administration of phosphates. It is necessary to remember, however, stimulation of intestinal absorption of phosphates under the influence of Rokaltrol as this effect can change the need for additional purpose of phosphates. It is regularly necessary to determine the content of calcium, phosphorus, magnesium and an alkaline phosphatase in serum, and also calcium and phosphates in daily urine. During the stabilizing (initial) phase of treatment by Rokaltrol it is necessary to control the content of calcium in blood serum at least two weekly.
As calcitriol - the most effective metabolite of vitamin D from all existing, during treatment by Rokaltrol it is not necessary to appoint other drugs of vitamin D in order to avoid development of a hypervitaminosis of D.
If the patient is transferred from ergocalciferol (D2 vitamin) on calcitriol, normalization of content of ergocalciferol in blood can take several months (see. "Overdose").
The patients with normal function of kidneys accepting Rokaltrol need to avoid dehydration, monitoring sufficient intake of liquid.
It is necessary to observe extra care at purpose of drug to children up to 18 years.

Pregnancy and lactation
At peroral purpose of sublethal doses of vitamin D to pregnant doe-rabbits at fruits the nadklapanny aortal stenosis developed. There are no data on teratogenecity of vitamin D, even its very high doses, for the person. It is necessary to appoint Rokaltrol to pregnant women only if the expected advantage of treatment surpasses possible risk for a fruit.
Apparently, exogenous calcitriol gets into breast milk. Taking into account possible hypercalcemias at mother and side reactions at babies, the women accepting Rokaltrol can continue feeding by a breast only on condition of monitoring of concentration of calcium in serum at mother and the child.

Influence on ability to driving of transport and work with cars and mechanisms
Taking into account the known profile of a pharmacodynamics and the described side effects it is considered that drug does not influence or will hardly affect similar types of activity.

Side effects:

As Rokaltrol has activity of vitamin D, its side effects are similar to those which arise at vitamin D overdose, i.e. to a syndrome of a hypercalcemia or intoxication calcium (depending on weight and duration of a hypercalcemia). Acute symptoms can include anorexia, a headache, vomiting, gastralgias, intestinal colic, increase in activity of "hepatic" transaminases and locks. Because of the short biological period of semi-life of calcitriol calcium level in serum is normalized in several days after Rokaltrol's cancellation, that is much quicker, than at treatment by D3 vitamin drugs.
At long reception there can be dystrophy, disorders of sensitivity, fever, thirst, a polyuria and dehydration, apathy, a growth inhibition and infections of urinary tract.
Frequency of each of the side reactions described at a clinical use of Rokaltrol according to all indications in 15 years is very low (including a hypercalcemia) and does not exceed 0.001%.
At a simultaneous hypercalcemia and a hyperphosphatemia there can be calcification of soft tissues which is found radiological.
At patients with normal function of kidneys the chronic hypercalcemia can lead to increase in creatinine of serum.
At sensitive persons hypersensitivity reactions (an itch, rash, urticaria, and very seldom erythematic damages of skin) can develop.

Interaction with other medicines:

As calcitriol - one of the most important active metabolites of D3 vitamin, in order to avoid possible additive effects and a hypercalcemia for the period of treatment by Rokaltrol it is necessary to stop reception of medicinal doses of vitamin D and its derivatives.
Patients need to observe strictly the dietary recommendations which are especially concerning calcium consumption and also to avoid not controlled additional administration of drugs, calciferous.
Simultaneous treatment by thiazide diuretics increases risk of a hypercalcemia. The patient receiving foxglove drugs, it is necessary to select a dose of calcitriol very carefully as the hypercalcemia at them can provoke arrhythmias.
There is a functional antagonism between vitamin D analogs which strengthen calcium absorption, and corticosteroids which suppress it.
The drugs containing magnesium (for example, antacids), can cause a gipermagniyemiya and therefore should not be appointed the patient on a chronic hemodialysis, during treatment by Rokaltrol.
As Rokaltrol influences transport of phosphates in intestines, kidneys and bones, the dose of the drugs connecting phosphates has to be corrected depending on the level of phosphates in serum (normal - 2-5 mg / 100 by ml, or 0.65-1.62 mmol/l).
Use of such inductors of enzymes as Phenytoinum or phenobarbital, can strengthen metabolism and by that to reduce concentration of calcitriol in serum therefore at simultaneous use of these drugs higher doses of calcitriol can be required.
Holestiramin can reduce intestinal absorption of fat-soluble vitamins and, including, calcitriol.

Contraindications:

All diseases which are followed by a hypercalcemia; hypersensitivity to drug (or to medicines of the same class) or to its fillers.
With care - atherosclerosis, a pulmonary tuberculosis, heart failure, a phosphatic nephrolithiasis, a sarcoidosis and other granulomatoses, advanced age (can promote development of atherosclerosis). Lactation period.

Overdose:

Treatment of an asymptomatic hypercalcemia see in the section "Route of administration".
As Rokaltrol is derivative vitamin D, the same symptoms of overdose are characteristic of it. Reception of high doses of calcium and phosphates along with Rokaltrol can cause similar symptoms. Development of a hypercalcemia can be promoted by the high content of calcium in dialyzate.
Symptoms of acute poisoning with vitamin D: anorexia, headache, vomiting, locks.
Symptoms of chronic poisoning: dystrophy (weakness, loss of weight), disorders of sensitivity, is possible fever with thirst, a polyuria, dehydration, apathy, a growth inhibition and infections of uric ways. Effects of a hypercalcemia are focal calcification of a bast layer of kidneys, a myocardium, lungs and a pancreas.
Treatment of accidental overdose: an immediate gastric lavage or giving vomitive for the prevention of further absorption. With a stake as laxative apply a liquid paraffin to removal of drug. It is recommended to determine repeatedly calcium level in serum. If the increased level of serumal calcium remains, it is possible to appoint phosphates and corticosteroids, and also to take measures for providing a sufficient diuresis.

Storage conditions:

List B.
Bottles
To store at a temperature up to 30 °C in the place protected from light.
Blisters
To store at a temperature up to 25 °C in the place protected from light.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 0:25 mkg and on 0.5 mkg in bottles and blisters on 30 and 100 pieces.