Rotocalcet - instructions for use, dose, side effects, contraindications

Active substanceTsinakaltsetTsinakaltset

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Rotocalcet®

pills inwards

Rowecq Limited United Kingdom

Dosage form: & nbspTfilm-covered abeys.

Composition:

Tablets 30 mg

One tablet contains:

Active substance:

Zincalcet hydrochloride - 33.06 mg (in terms of cinacalcet - 30,00 mg).

Excipients:

Cellulose microcrystalline - 123.54 mg, sodium carboxymethyl starch - 10.80 mg, hypromellose - 2.70 mg, calcium hydrophosphate anhydrous - 9.00 mg, magnesium stearate - 0.90 mg.

Composition of the film shell:

Opapray II green (85F21865) - 5.40 mg.

Composition of Otpadra II green (85F21865):

Polyvinyl alcohol is 2.1600 mg, titanium dioxide is 1.0935 mg, macrogol is 1.0908 mg, talc is 0.7992 mg, indigo carmine dye is 0.0950 mg, an iron oxide yellow color is 0.0902 mg, a colorant is a diamond blue - 0.0713 mg.

Tablets 60 mg

One tablet contains:

Active substance:

Zincalcet hydrochloride is 66.12 mg (in terms of cinacalcetol - 60.00 mg).

Excipients:

Cellulose microcrystalline -247.08 mg, carboxymethyl starch sodium - 21.60 mg, hypromellose - 5.40 mg, calcium hydrophosphate anhydrous - 18.00 mg, magnesium stearate - 1.80 mg.

Composition of the film shell:

Opapray II green (85F21865) - 10.80 mg.

Composition of Otpadra II green (85F21865):

Polyvinyl alcohol is 4.3200 mg, titanium dioxide is 2.1870 mg, macrogol is 2.1816 mg, talc is 1.5984 mg, indigo carmine dye 0.1901 mg, iron oxide yellow oxide is 0.1804 mg, a colorant is a brilliant blue - 0.1426 mg.

Tablets 90 mg

One tablet contains:

Active substance:

Zincalcet hydrochloride - 99.18 mg (in terms of cinacalcet - 90,00 mg).

Excipients:

Cellulose microcrystalline -370.62 mg, sodium carboxymethyl starch -32.40 mg, hypromellose-8.10 mg, calcium hydrophosphate anhydrous - 27.00 mg, magnesium stearate - 2.70 mg.

Composition of the film shell:

Opapray II green (85F21865) 16.20 mg.

Composition of Otpadra II green (85F21865):

Polyvinyl alcohol - 6,4800 mg, titanium dioxide - 3,2805 mg, macrogol - 3,2724 mg, talc - 2,3976 mg, indigo carmine dye - 0.2851 mg, iron oxide yellow dye - 0.2705 mg, colorant diamond blue - 0.2138 mg.

Description:

Tablets 30 mg

Oval, biconvex tablets, coated with a film shell of light green color, with engraving, stamping, "30" on one side and smooth on the other side.

Tablets 60 mg

Oval, biconvex tablets, covered with a film shell of light green color, with engraving, stamping, "60" on the one hand and smooth on the other side.

Tablets 90 mg

Oval, biconvex tablets, covered with a film shell of light green color, with engraving, stamping, "90" on one side and smooth on the other side.

Pharmacotherapeutic group:antiparrethoid agent

ATX: & nbsp

H.05.B.X.01 Tsinakaltset

Pharmacodynamics:

Calcium-sensitive receptors located on the surface of the main cells of the parathyroid glands are the main regulators of the secretion of parathyroid hormone (PTH). Tsienkalcet has a calcimimetic effect that directly reduces the concentration of PTH, increasing the sensitivity of this receptor to extracellular calcium. Reduction in the concentration of PTH is accompanied by a decrease in the serum calcium level.

Reduction in the concentration of PTH correlates with the concentration of zincalcet.

After reaching the equilibrium state, the concentration of calcium in the serum remains at a constant level during the entire interval between doses of the drug.

Secondary Hyperparathyroidism

Three clinical trials of 6 months (double-blind, placebo-controlled) included patients with end-stage renal failure (PDSS) on dialysis with an uncontrolled form of secondary hyperparathyroidism (1,136 patients).

The mean initial concentrations of intact parathyroid hormone (IPTG) in the three clinical trials were 733 and 683 pg / ml(77.8 and 72.4 pmol / L) in the zincalcet and placebo groups, respectively, 66% of the patients took a vitamin D before enrollment, and more than 90% of patients took phosphate binding drugs.

In patients taking zincalcet, there was a significant reduction in the concentration of ipPH, calcium and phosphorus in the serum, calcium phosphorus product (Ca x P) compared to patients in the placebo group who received standard therapy. Reduction in the concentration of IPPG and Ca x P was maintained for 12 months of therapy. Cinacalcete reduced the concentrations of IPPH, calcium and phosphorus and Ca x P irrespective of the initial concentrations of IPP or Ca x P, the dialysis regime (peritoneal dialysis or hemodialysis), the duration of dialysis, and whether or not the vitamin was applied D.

Reduction of PTH concentration was associated with an insignificant decrease in the concentration of bone metabolism markers (specific bone alkaline phosphatase, N- telopeptides, bone tissue and bone fibrosis). In a retrospective analysis of the pool of data collected from 6 and 12-month clinical studies using the Kaplan-Meier method, bone fracture and parathyroidectomy rates were lower in the zincalcetone group compared to the control group.

Preliminary studies in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism not on dialysis indicate that cinnacalcet reduced PTH concentrations in a similar manner as in patients with PDSS and secondary hyperparathyroidism who are on dialysis. However, for patients with renal insufficiency in the pre-dialysis stage, efficacy, safety, optimal doses and target values of therapy were not established. These studies have shown that in patients with CKD not on dialysis and receiving zincalcete, there is a greater risk of developing hypocalcemia compared to patients with dialysis-mediated TSHD receiving zincalcete, which may be due to a lower initial concentration of calcium and / or residual kidney function.

Primary hyperparathyroidism and parathyroid carcinoma

227 patients with primary HPT or parathyroid carcinoma participated in a clinical study for use of cinacalcet. In patients with parathyroid carcinoma and primary hyperparathyroidism, the mean calcium concentration decreased from 14.1 mg / dL to 12.4 mg / dl (from 3.5 mmol / L to 3.1 mmol / L) and from 12.7 mg / dL to 10.4 mg / dL (from 3.2 mmol / L to 2.6 mmol / L), respectively.In patients with primary GPT, including patients with recurrent primary GPT after parathyroidectomy, zincalcetet normalized serum calcium concentration in approximately 80% of patients and maintained this value for 4.5 years. A significant number of patients with primary GPT receiving zincalcetet and meeting the criteria for parathyroidectomy based on the total serum calcium concentration> 11.3 mg / dL (2.82 mmol / L) and <12.5 mg / dL (3, 12 mmol / L), but not parathyroidectomy, the total serum calcium concentration was <10.3 mg / dL (2.57 mmol / L) and the total serum calcium concentration was reduced by> 1 mg / dL (0.25 mmol / L) compared with patients taking placebo (75.8% compared with 0%, p <0.001 and 84.8% compared with 5.9%, p <0.001, respectively nano).

Pharmacokinetics:

Suction

After oral administration, the maximum concentration (C_mOh) of zincalcet in the blood plasma is reached after about 2-6 hours. Absolute bioavailability of zincalcet at fasting, established on the basis of comparing the results of various studies, is approximately 20-25%.When taking zincalcetas together with food, its bioavailability increases by approximately 50-80%. Such an increase in the concentration of zincalcet in the blood plasma is observed regardless of the fat content in the food. At doses in excess of 200 mg absorption saturation is observed, probably due to poor solubility.

Distribution

There is a high volume of distribution (approximately 1000 liters), which indicates a large distribution. Cinacalcet approximately 97% bound to plasma proteins and is distributed in a minimum amount of the erythrocytes. After absorption reduction cinacalcet concentrations occur in 2 stages with an initial half-life of about 6 hours and final half-life of 30 hours to 40 hours. An equilibrium state cinacalcet concentration is achieved within 7 days with minimal cumulation. The pharmacokinetic parameters of the cynocaletus do not change with time.

Metabolism

Cinacalcet is metabolized by microsomal enzymes of the liver, mainly CYP3A4 and CYP1A2 (role CYP1A2 has not been confirmed by clinical methods). The main circulating metabolites are inactive. According to research data in vitro, Cinacalcet is a potent inhibitor CYP2D6, however, at concentrations attained in clinical settings, zincalcetet does not inhibit the activity of other enzymes CYP. in t.ch. CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4, and is also not an inductor CYP1A2, CYP2C19 and CYP3A4.

Excretion

After administration of healthy volunteers with a radiolabeled radioacetopic method of zincalcet in a dose of 75 mg, he undergoes rapid and significant oxidative metabolism followed by conjugation. Excretion of radioactivity occurs mainly as a result of excretion of metabolites by the kidneys - approximately 80% of the administered dose is excreted by the kidneys and 15% by the intestine.

Linearity

The increase in the area under the concentration-time curve (AUC) and C_mOh zincalceti occurs almost linearly in the dose range from 30 mg to 180 mg 1 time per day.

Pharmacokinetic / pharmacodynamic interactions

Soon after taking the zincalcet, the concentration of PTH begins to decrease; with the maximum decrease occurring approximately 2 to 6 hours after administration, which corresponds to C_mOh zincalcet. After this, the concentration of the cinacalcin begins to decrease, and the concentration of PTH increases within 12 hours after the administration of the drug; then the suppression of PTH remains approximately the samelevel to the end of the daily interval with the dosing regimen 1 time per day. The concentration of PTH in clinical studies of the zincalcet was measured at the end of the dosing interval.

Elderly: In the pharmacokinetics of cinacalcet, there were no clinically significant differences associated with the age of the patients.

Renal insufficiency: the pharmacokinetic profile of the cynocalcium with mild, moderate and severe renal failure, and in hemodialysis or peritoneal dialysis, comparable to the pharmacokinetic profile of the zincalcetus in healthy volunteers.

Liver failure: mild liver failure does not have a significant effect on the pharmacokinetics of the zincalcet. Compared with the group with normal liver function, the mean AUC of the cynocalet was approximately 2 times higher in the group with a disturbed liver function of moderate severity, and approximately 4 times higher with severe hepatic insufficiency. The average half-life of the cinacalcet in patients with moderate and severe hepatic insufficiency is prolonged by 33 and 70%, respectively.Hepatic insufficiency does not affect the degree of binding of the zincalcet with proteins. Since the selection of doses is based on efficacy and safety parameters, patients with hepatic insufficiency do not need to undergo additional dose adjustment (see the sections "Dosing and Administration", "Special instructions").

Floor: in women, the zinkalcet's clearance may be lower than that of men. Since the selection of doses is carried out individually, no additional dose adjustment is required, depending on the patient's sex.

Children: the pharmacokinetics of cinacalts was studied in 12 children (6-17 years) with CKD on dialysis, after a single oral intake of 15 mg. The mean values of AUC and C_mOh(23.5 (range 7.22 to 77.2) ng h / ml and 7.26 (range 1.80 to 17.4) ng / ml, respectively) were within approximately 30% of the mean AUC values and FROM_mOh, observed in one study in healthy adults after a single oral dose at a dose of 30 mg (33.6 (range from 4.75 to 66.9) ng hour / mL and 5.42 (range 1.41 to 12.7 ) ng / ml, respectively). Due to limited data in children, a potentially more pronounced exposure to a certain dose of zincalcet in young children, with a lower body weight,compared with older children, who have a large body weight. The pharmacokinetics of repeated doses in children have not been studied.

Smoking: the clearance of the zincalcet is higher in smokers than in non-smokers. Apparently, this is due to the induction of metabolism, which takes place with the participation of CYP1A2.

If the patient stops or starts smoking during therapy, the concentration of zincalcet in the plasma may change and dose adjustment may be required. Preclinical safety studies

During the preclinical studies, neither genotoxic nor carcinogenic potential of the zincalcet was detected. The safe range, according to toxicology studies, is narrow enough, because in studies on animals, the dose-limiting factor was hypocalcemia. The development of cataracts and clouding of the lens were observed during toxicological and carcinogenic studies on rodents with multiple doses. However, such phenomena were not observed in studies on dogs or monkeys, or in clinical studies, where monitoring was conducted with respect to the formation of cataracts.It is known that cataracts in rodents can occur as a consequence of hypocalcemia.

Indications:

- Secondary hyperparathyroidism in patients with PDSD on dialysis. Rotocalcet® can also be administered as part of a combination therapy, including phosphate binding and / or vitamin binding drugs D;

- hypercalcemia in patients (with the purpose of reducing the severity), caused by the following diseases:

carcinoma of the parathyroid glands;
primary hyperparathyroidism, if, despite the concentration of calcium in the serum, parathyroidectomy is clinically unacceptable or contraindicated.

Contraindications:

- Hypersensitivity to the active ingredient or any other components of the drug;

- Children under 18 years of age (effectiveness and safety not studied);

- the period of breastfeeding.

Carefully:

Pregnancy, hepatic insufficiency of moderate and severe severity, the presence of risk factors for lengthening the interval QT.

Pregnancy and lactation:

Pregnancy

Clinical data on the use of zincalcite during pregnancy are absent. As preclinical studies on rabbits have shown, zincalcetet penetrates the placental barrier.In animal experiments, there was no direct adverse effect on pregnancy, childbirth or postnatal development. There was also no embryotoxic or teratogenic effect in studies on pregnant female rats and rabbits, except for a decrease in embryo body weight in rats when toxic doses were administered to pregnant females. In pregnancy, the drug Rotocalcet® should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Until now, the possibility of penetration of the zincalcite into breast milk has not been studied. Zincalcetet penetrates into the breast milk of lactating rats, with a high concentration of concentration in milk and a concentration in the blood plasma. After a thorough assessment of the risk / benefit ratio, a decision should be made to stop breastfeeding or taking Rotocalcet®.

Dosing and Administration:

Inside, during a meal or shortly after a meal, as the studies have shown that the bioavailability of the zincalcet is increased when the drug is taken with food (see section "Pharmacokinetics").Tablets should be taken whole, not chewing and not dividing them.

Secondary Hyperparathyroidism

Adults and the elderly (> 65 years): the recommended initial dose of the drug Rotocalcet in adults is 30 mg 1 time per day. Titration of the dose of the drug Rotocalcet should be carried out every 2-4 weeks to a maximum dose of 180 mg (1 time per day), in which patients in dialysis achieve a target concentration of PTH in the range of 150-300 pg / ml (15.9-31.8 pmol / l), determined by the concentration of IPPH. The determination of the concentration of PTH should be carried out no earlier than 12 hours after the administration of the drug Rotocalcet®. When assessing the concentration of PTH should adhere to the current recommendations.

Determination of the concentration of PTH should be carried out 1-4 weeks after the start of therapy or correction of the dose of Rotocalcet®. When taking a maintenance dose, monitoring of PTH concentration should be performed approximately 1 time in 1-3 months. To determine the concentration of PTH, the content of ipTG or bio-active PTH (biPTG) can be used; therapy with the drug Rotocalcet® does not change the relationship between ipTG and biPTG.

During the titration of the dose, it is often necessary to monitor the concentration of calcium in the serum, incl. 1 week after the start of therapy or correction of the dose of Rotocalcet.When the target concentration of PTH is reached and the transition to the maintenance dose, the concentration of calcium in the blood serum should be estimated approximately 1 time per month. If the concentration of calcium in the blood serum drops below the normal range, appropriate measures should be taken, including correction of concomitant therapy (see section "Special instructions").

Parathyroid carcinoma and primary hyperparathyroidism

Adults and the elderly (> 65 years): the recommended initial dose of the drug Rotocalcet® in adults is 30 mg, the frequency of administration is 2 times a day. Titration of the dose of Rotoccalet should be performed in increments of 2-4 week as follows, increasing the dose of the drug: 30 mg 2 times a day; 60 mg 2 times a day; 90 mg 2 times a day and 90 mg 3 or 4 times a day as needed to reduce the serum calcium concentration to the upper limit of the normal range or lower. The maximum dose used in clinical trials was 90 mg with a multiplicity of 4 times per day. The concentration of calcium in the blood serum should be determined 1 week after the start of therapy or the dose adjustment step of Rotocalcet®.

When the target concentration of PTH is reached and the transition to a maintenance dose, the serum calcium concentration should be evaluated every 2-3 months. At the end of the titration period to the maximum dose, periodic monitoring of serum calcium concentration should be performed.

If a clinically significant decrease in serum calcium concentration is not achieved on a maintenance dose, the question of stopping therapy with Rotocalcet® should be resolved (see the section "Pharmacodynamics").

Liver failure

Patients with hepatic insufficiency do not need correction of the initial dose. The drug Rotocalcet should be administered with caution to patients with hepatic insufficiency of moderate to severe severity. Careful clinical observation of the patient during the dose selection period (titration) and continuation of therapy is necessary (see sections "Special instructions" and "Pharmacokinetics").

Side effects:

Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism

According to the available data, nausea and vomiting were the most common adverse reactions in patients receiving zincalcetet in placebo-controlled studies and non-comparative studies.In most patients, nausea and vomiting were mild or moderate and of a transient nature. The reasons for the abolition of therapy due to adverse reactions were mainly nausea and vomiting.

The following are undesirable reactions that, based on the results of the causal analysis, have been judged on the basis of conclusive evidence, at least as related to the therapy with zincalcetate in placebo-controlled and non-comparative clinical trials, using the following frequency gradient: very often (≥1 / 10); often (≥1 / 100 - <1/10); infrequently (≥1 / 1000 - <1/100); rarely (≥1 / 10000 - <1/1000); very rarely (<1/10000); frequency is unknown.

Immune system disorders:

often * - hypersensitivity reactions.

Disorders from the metabolism and nutrition:

often anorexia, decreased appetite.

Disturbances from the nervous system:

often - convulsions **, dizziness, paresthesia, headache.

Heart Disease:

frequency unknown: worsening of the course of heart failure **, lengthening interval QT and ventricular arrhythmias as a consequence of hypocalcemia **.

Vascular disorders:

often: hypotension.

Disturbances from the respiratory system, chest and mediastinal organs:

often: infection of the upper respiratory tract, shortness of breath, cough.

Disorders from the gastrointestinal tract:

very often - nausea, vomiting; often - dyspepsia, diarrhea, abdominal pain, epigastric pain, constipation.

Disturbances from the skin and subcutaneous tissues:

often - a rash.

Disturbances from musculoskeletal and connective tissue:

often - myalgia, muscle spasm, back pain.

General disorders and disorders at the site of administration:

often: asthenia.

Laboratory and instrumental data:

often - hypocalcemia **, hypokalemia, decreased testosterone concentration **.

* - see section "Special instructions".

** - see subsection "Description of individual adverse reactions".

Description of individual adverse reactions

Hypersensitivity reactions

With the use of zincalcet in routine practice, hypersensitivity reactions, including angioedema and urticaria, were identified. The frequency of development of individual reactions, including angioedema and hives, can not be estimated on the basis of available data.

Arterial hypotension and / or worsening of heart failure

In patients with heart failure who took zincalcet in post-marketing safety observations, individual idiosyncratic cases of arterial hypotension and / or worsening of the course of heart failure were recorded; the frequency of development of these cases can not be estimated on the basis of available data.

Interval lengthening QT and ventricular arrhythmias as a consequence of hypocalcemia

When using zincalcet in routine practice, cases of lengthening of the interval QT and ventricular arrhythmias caused by hypocalcemia, but the rate of development of these disorders can not be estimated on the basis of available data (see section "Special instructions").

Children

Zincalcet is contraindicated in children. The effectiveness and safety of zincalcetes in children have not been studied. In a clinical study, a case of death in a patient with severe hypocalcemia was documented in children (see section "Special instructions").

Overdose:

Doses titrated up to 300 mg (1 time per day) are safe for patients on dialysis.

Symptoms: an overdose of the drug Rotocalcet® can lead to hypocalcemia. In case of an overdose, patients should monitor the concentration of calcium for the timely detection of hypocalcaemia.

Treatment: should be symptomatic and supportive therapy. Since the degree of binding of the zincalcete to the plasma proteins is high, the cinacalcet is not excreted in hemodialysis, i.e. Hemodialysis in an overdose is ineffective.

Interaction:

The effect of the combined use of other drugs on the pharmacokinetics of zincalcus

Tsienkalcet is partially metabolized by isoenzyme CYP3A4. Simultaneous administration of ketoconazole at a dose of 200 mg 2 times a day (a potent inhibitor CYP3A4) led to an increase in the concentration of the zincalcet by approximately 2-fold. If it is necessary to simultaneously take powerful inhibitors (eg, ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducers (eg rifampicin) CYP3A4, it may be necessary to adjust the dose of zincalcite (see section "Special instructions").

The data obtained during the experiments in vitro indicate that the cinacalcet is partially metabolized by the enzyme CYP1A2.Smoking stimulates activity CYP1A2. It was noted that the clearance of zincalcetes in smokers is 36-38% higher than that of non-smokers. Effect of inhibitors CYP1A2 (fluvoxamine, ciprofloxacin) on plasma concentrations of zincalcete has not been studied. Dose adjustment may be required if, during therapy with cinacalcet, the patient begins or stops smoking, or begins or stops simultaneous administration of potent inhibitors CYP1A2.

Calcium carbonate: simultaneous application of calcium carbonate (a single dose of 1500 mg) did not alter the pharmacokinetics of the zincalcet.

Sevelamer: simultaneous application sevelamera (2400 mg 3 times a day) had no effect on the pharmacokinetics of the zincalcet.

Pantoprazole: simultaneous application of pantoprazole (80 mg 1 time per day) did not change the pharmacokinetics of the zincalcet.

Effect of zincalcet on the pharmacokinetics of other drugs

Medicines metabolized by isoenzyme CYP2D6: Cinacalcet is a potent inhibitor CYP2D6. Combined use of zincalcet and preparations with narrow therapeutic range and / or variable pharmacokinetics metabolized by isoenzyme CYP2D6 (eg, flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine) may require adequate dose adjustment for these drugs (see section "Specific guidance").

Desipramine: simultaneous reception of a cinacalcetine in a dose of 90 mg 1 time per day with desipramine at a dose of 50 mg, mainly metabolized CYP2D6, significantly increased the level of exposure to desipramine (3.6 times) (90% confidence interval 3.0, 4.4) in patients with active metabolism CYP2D6.

Warfarin: repeated oral administration of zincalcetine did not affect the pharmacokinetics or pharmacodynamics of warfarin (prothrombin time and factor VII activity were measured).

The absence of the effect of zincalcite on the pharmacokinetics R- and S-warfarin and the absence of autoinduced enzymes in patients after repeated administration of the drug indicates that the cinacalcet is not an inducer CYP3A4, CYP1A2 or CYP2C9 in humans.

Midazolam: simultaneous application of zincalcet (90 mg) and oral administration of midazolam (2 mg), substrate CYP3A4 and CYP3A5, does not affect the pharmacokinetics of midazolam. These data indicate that cinnacalcet does not affect the pharmacokinetics of a class of drugs metabolized by isoenzymes CYP3A4 and CYP3A5, such as some immunosuppressants, including ciclosporin and tacrolimus.

Incompatibility

Not applicable.

Special instructions:

Convulsions

In clinical studies, seizures were noted in 1.4% of patients receiving zincalcet and in 0.7% of patients in the placebo group. Although the causes of reported differences in the occurrence of seizures are unclear, the convulsive threshold decreases with a significant decrease in the serum calcium concentration.

Arterial hypotension and / or worsening of heart failure

In patients with heart failure who take zincalcetet during post-marketing observations, individual idiosyncratic cases of arterial hypotension and / or worsening of the course of heart failure were recorded in which the causal relationship with zincalcetate can not be completely excluded and may be due to a decrease in serum calcium concentration. Clinical studies have shown that 7% of patients who received cinnacalcet received an arterial hypotension, and 12% of patients who received placebo, and heart failure - in 2% of patients who received zincalcet or placebo.

Concentration of calcium in serum

Therapy with the drug Rotocalcet® should not be performed at a serum calcium concentration (adjusted for albumin) below the minimum limit of the normal range.

In patients taking zincalceti, including children, life-threatening events and deaths associated with hypocalcemia were documented. Manifestations of hypocalcemia may include paresthesia, myalgia, muscle spasms, tetany and convulsions. Reducing the concentration of calcium in the serum can also lengthen the interval QT and, as a result, lead to the development of ventricular arrhythmias. In patients taking zincalcet, cases of lengthening of the interval QT and the development of ventricular arrhythmias due to hypocalcemia (see section "Side effect"). Care should be taken when treating patients with other risk factors for lengthening the interval QT, for example, in patients with a diagnosed congenital syndrome of an elongated interval QT or in patients taking medications that are reportedly lengthening the interval QT.

Since cinacalcete lowers the concentration of calcium in the blood serum, careful monitoring of the development of hypocalcemia (see section "Method of administration and dose") is necessary. The serum calcium concentration should be determined within 1 week after starting therapy or correcting the dose of Rotocalcet®. After establishing a maintenance dose, the concentration of calcium in the serum should be determined approximately 1 time per month. With a decrease in serum calcium concentration below 8.4 mg / dL (2.1 mmol / L), but not below 7.5 mg / dL (1.875 mmol / L), or with the development of symptoms of hypocalcaemia to increase serum calcium concentration blood can be prescribed calcium-containing phosphate-binding drugs, vitamin D and / or correct the calcium concentration in the dialysate. If hypocalcemia is not eliminated in this way, it is necessary to reduce the dose or to cancel the use of the drug Rotocalcet®. With a decrease in serum calcium concentration below 7.5 mg / dL (1.875 mmol / L) or with symptoms of hypocalcemia and with the impossibility of increasing the dose of vitamin D Rotocalcet® should be suspended until the serum calcium concentration reaches 8 mg / dl (2 mmol / L) and / or the symptoms of hypocalcemia are not resolved.Therapy should be resumed using the drug Rotocalcet® at the lowest dose. In 29% of patients with CKD who were on dialysis and taking zincalceti in the registration clinical studies for 6 months, and in 21% and 33% of patients with CKD who were on dialysis and who took zincalcet in a clinical trial EVOLVE for the first 6 months and as a whole, respectively, at least once the serum calcium concentration was below 7.5 mg / dl (1.875 mmol / L).

Cinacalcet is not indicated in patients with a diagnosis of CKD not on dialysis. Preliminary studies have shown that in patients diagnosed with CKD not on dialysis, the risk of developing giocalcemia (serum calcium concentration <8.4 mg / dL [2.1 mmol / L]) is increased compared to patients on dialysis, which may be is due to a lower initial concentration of calcium and / or the presence of residual renal function.

General Precautions

With chronic suppression of PTH concentration below the concentration of approximately 1.5 from the upper limit of the norm, as a result of the analysis of IPPH, adynamic bone disease may develop.If the PTH concentration falls below the recommended range, the dose of Rotocalcet® and / or vitamin D, or discontinue therapy.

Neoplasms

In a clinical study EVOLVE with the participation of 3,883 dialysis patients, the incidence of neoplasm development was recorded in 2.9 and 2.5 patients per 100 patient-years in the cynocalcet and placebo groups, respectively. A causal relationship with the use of zincalcites has not been established.

Concentration of testosterone

The concentration of testosterone is often below the norm in patients with TSRP. Data from a clinical trial involving patients with PDPD on dialysis showed that the concentration of free testosterone decreased on average by 31.3% in patients taking zincalcet and 16.3% in patients in the placebo group at 6 months after initiation of therapy . The open extended phase of this study did not show a further decrease in the concentration of free and total testosterone in patients over a 3-year period of treatment with cynocalcet.

The clinical significance of a decrease in testosterone concentration in serum is not established.

Liver failure

The drug should be administered with caution to patients with moderate to severe hepatic impairment (Child-Pugh classification). Since the concentration of zincalcet in the blood plasma can be 2-4 times higher, careful monitoring is necessary during treatment (see sections "Dosing and Administration", "Pharmacokinetics").

Fertility

Clinical evidence of the effect of zincalcete on fertility is lacking. Studies in animals have not revealed the influence of zincalcete on fertility.

Effect on the ability to drive transp. cf. and fur:

Studies to study the effect of the drug on the ability to drive vehicles or work with complex mechanisms have not been carried out. However, some undesirable reactions may affect the ability to drive vehicles and mechanisms (see the "Side effect" section).

Form release / dosage:

Film-coated tablets, 30 mg, 60 mg, 90 mg.

Packaging:

For 10 or 14 tablets in a blister of PVC / Al.

PAbout 1, 2 or 6 blisters together with the instruction for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003662

Date of registration:06.06.2016

Expiration Date:06.06.2021

The owner of the registration certificate:Rowecq LimitedRowecq Limited United Kingdom

Manufacturer: & nbsp

ROSLEKS PHARM, LLC Russia

VIVIMED LABS, Ltd. India

Representation: & nbspROUTEC LIMITEDROUTEC LIMITEDUnited Kingdom

Information update date: & nbsp23.07.2016

Illustrated instructions

Instructions

Rotocalcet® (Rotpcalcet®)