Mimpara. Instructions for use

Release form, composition and packaging

The tablets are light green, oval, film-coated, marked “AMG” on one side and “30”/”60”/”90” on the other.

One tablet contains:

active substance: cinacalcet* (in the form of hydrochloride) - 30 mg/60 mg/90 mg;

excipients: pregelatinized corn starch, microcrystalline cellulose, povidone, crospovidone, magnesium stearate, colloidal silicon dioxide, carnauba wax, opadry II green (lactose monohydrate, hypromellose 15cP, titanium dioxide, triacetin, indigo carmine aluminum varnish, yellow iron oxide), opadry transparent (hypromellose 6cP, macrogol 400).

14 pcs. - blisters (1) - cardboard packs. 14 pcs. - blisters (2) - cardboard packs. 14 pcs. - blisters (6) - cardboard packs.

* non-proprietary international name recommended by WHO - cinacalcet.

Compound

1 Mimpara tablet contains the active substance: cinacalcet hydrochloride 33.06 mg (in terms of cinacalcet - 30 mg).
Excipients: pregelatinized corn starch - 12.02 mg; MCC - 121.82 mg; povidone - 3.68 mg; crospovidone - 7.62 mg; magnesium stearate - 0.9 mg; colloidal silicon dioxide - 0.9 mg; carnauba wax - 0.018 mg; opadry II green (lactose monohydrate - 40%, hypromellose 15cP - 28%, titanium dioxide - 19.38%, triacetin - 8%, indigo carmine aluminum varnish - 2.78%, iron oxide yellow - 1.84%) - 7, 2 mg; opadry transparent (hypromellose 6cP - 90.9%, macrogol 400 - 9.1%) - 2.7 mg. 1 Mimpara tablet contains the active substance: cinacalcet hydrochloride 66.12 mg (in terms of cinacalcet - 60 mg). Excipients: pregelatinized corn starch - 24.04 mg; MCC - 243.64 mg; povidone - 7.36 mg; crospovidone - 15.24 mg; magnesium stearate - 1.8 mg; colloidal silicon dioxide - 1.8 mg; carnauba wax - 0.036 mg; opadry II green (lactose monohydrate - 40%, hypromellose 15cP - 28%, titanium dioxide - 19.38%, triacetin - 8%, indigo carmine aluminum varnish - 2.78%, iron oxide yellow - 1.84%) - 14, 4 mg; opadry transparent (hypromellose 6cP - 90.9%, macrogol 400 - 9.1%) - 5.4 mg. 1 Mimpara tablet contains the active substance: cinacalcet hydrochloride 99.18 mg (in terms of cinacalcet - 90 mg). Excipients: pregelatinized corn starch - 36.06 mg; MCC - 365.46 mg; povidone - 11.04 mg; crospovidone - 22.86 mg; magnesium stearate - 2.7 mg; colloidal silicon dioxide - 2.7 mg; carnauba wax - 0.054 mg; opadry II green (lactose monohydrate - 40%, hypromellose 15cP - 28%, titanium dioxide - 19.38%, triacetin - 8%, indigo carmine aluminum varnish - 2.78%, iron oxide yellow - 1.84%) - 21, 6 mg; opadry transparent (hypromellose 6cP - 90.9%, macrogol 400 - 9.1%) - 8.1 mg.

Indications

- secondary hyperparathyroidism in patients with end-stage renal failure on dialysis. Mimpara may also be prescribed as part of combination therapy including phosphate binders and/or vitamin D;

- hypercalcemia in patients (to reduce the severity) caused by the following diseases: parathyroid carcinoma and primary hyperparathyroidism, if, despite serum calcium concentrations, parathyroidectomy is clinically unacceptable or contraindicated.

Dosage

The drug is recommended to be taken orally during meals or shortly after meals, since the bioavailability of cinacalcet increases when taking the drug with food. The tablets should be taken whole, without chewing or splitting them.

Secondary hyperparathyroidism

The recommended starting dose of Mimpara is 30 mg 1 time / day.

Dose titration should be carried out every 2-4 weeks to a maximum dose of 180 mg 1 time / day, at which in patients on dialysis the required PTH concentration is achieved in the range of 150-300 pg/ml (15.9-31.8 mmol/l), determined by iPTH content. Determination of PTH concentration should be carried out no earlier than 12 hours after taking the drug. When assessing PTH concentrations, it is necessary to adhere to current recommendations.

PTH concentrations should be measured 1 to 4 weeks after initiation of therapy or dose adjustment. When taking a maintenance dose, PTH concentrations should be monitored approximately every 1-3 months. To determine the concentration of PTH, the content of iPTH or biointact PTH (biPTH) can be used. Treatment with Mimpara does not change the relationship between iPTH and biPTH.

During dose titration, it is necessary to frequently monitor serum calcium concentrations, incl. 1 week after initiation of therapy or dose adjustment. Once the target PTH concentration is achieved and the maintenance dose is initiated, serum calcium concentrations should be assessed approximately once a month. If serum calcium concentrations fall below the normal range, appropriate measures should be taken, including adjustment of concomitant therapy.

Parathyroid carcinoma and primary hyperparathyroidism

The recommended starting dose of Mimpara is 30 mg 2 times a day.

Dose titration should be carried out every 2-4 weeks in the following sequence of dosage changes: 30 mg 2 times / day, 60 mg 2 times / day, 90 mg 2 times / day and 90 mg 3-4 times / day as needed to reduce concentrations serum calcium to or below ULN. The maximum dose used in clinical studies was 90 mg 4 times a day.

Determination of serum calcium concentration should be carried out 1 week after the start of therapy or dose adjustment. Once the target PTH concentration is achieved and the maintenance dose is switched to, serum calcium concentrations should be assessed every 2-3 months. After the titration period to the maximum dose has been completed, serum calcium concentrations should be periodically monitored. If a clinically significant decrease in serum calcium concentration is not achieved when taking a maintenance dose, the issue of discontinuing therapy with Mimpara should be considered.

When treating patients with liver failure, the initial dose does not need to be changed. Prescribe the drug with caution to patients with moderate to severe liver failure. Treatment should be monitored closely during dose titration and during long-term therapy.

pharmachologic effect

Antiparathyroid drug. Calcium-sensing receptors located on the surface of the main cells of the parathyroid glands are the main regulators of the secretion of parathyroid hormone (PTH). Cinacalcet has a calcium-mimetic effect that directly reduces PTH levels, increasing the sensitivity of this receptor to extracellular calcium. A decrease in PTH is accompanied by a decrease in serum calcium. The decrease in PTH levels correlates with the concentration of cinacalcet. Soon after taking cinacalcet, PTH levels begin to decrease: the maximum decrease occurs approximately 2-6 hours after dosing, which corresponds to the Cmax of cinacalcet. After this, the concentration of cinacalcet begins to decrease, and the concentration of PTH increases within 12 hours after dosing, and then PTH suppression remains at approximately the same level until the end of the daily interval with a dosing regimen of 1 time per day. PTH concentrations in clinical studies of Mimpara were measured at the end of the dosing interval. After reaching a stable phase, the serum calcium concentration remains at a constant level throughout the entire interval between doses of the drug. Secondary hyperparathyroidism Three 6-month clinical studies (double-blind, placebo-controlled) included end-stage renal disease patients on dialysis with uncontrolled secondary hyperparathyroidism (1136 patients). The mean initial intact parathyroid hormone (iPTH) concentrations in the three clinical trials were 733 and 683 pg/mL (77.8 and 72.4 pmol/L) in the cinacalcet and placebo groups, respectively, 66% of patients were taking vitamin D before enrollment, and more than 90 % took phosphate binders. Patients taking cinacalcet had significant reductions in iPTH, Ca x P (calcium-phosphorus product), serum calcium and phosphorus compared with patients in the placebo group who received standard therapy. The decrease in iPTH and Ca × P concentrations was maintained throughout 12 months of therapy. Cinacalcet reduced iPTH, Ca×P, calcium, and phosphorus levels independently of initial iPTH or Ca×P levels, dialysis regimen (peritoneal dialysis versus hemodialysis), duration of dialysis, and whether or not vitamin D was used. Reductions in PTH levels were associated with an insignificant decrease in the levels of markers of bone metabolism (specific bone alkaline phosphatase, N-telopeptides, bone turnover and bone fibrosis). In a retrospective analysis of a pool of data collected from 6- and 12-month clinical trials using the Kaplan-Meier method, rates of bone fractures and parathyroidectomies were lower in the cinacalcet group compared with the control group. Preliminary studies in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism not on dialysis indicate that cinacalcet reduced PTH levels in a similar manner as in patients diagnosed with end-stage renal disease (ESRD) and secondary hyperparathyroidism on on dialysis. However, for patients with renal failure in the predialysis stage, the effectiveness, safety, optimal dosage and goals of therapy have not been established. These studies showed that CKD patients not on dialysis receiving cinacalcet have a greater risk of developing hypocalcemia compared with patients with end-stage renal disease on dialysis and receiving cinacalcet, and this may be due to lower initial concentrations. calcium and/or residual renal function. Parathyroid carcinoma and primary hyperparathyroidism In the main study, 46 patients (29 patients diagnosed with parathyroid carcinoma, and 17 with primary hyperparathyroidism in whom parathyroidectomy was unsuccessful or contraindicated) received cinacalcet for up to 3 years (mean 328 days for patients with parathyroid carcinoma and 347 days for patients with primary hyperparathyroidism). Cinacalcet was used in doses from 30 mg 2 times/day to 90 mg 4 times/day. The primary goal of therapy was to reduce serum calcium concentrations by ≥1 mg/dL (≥0.25 mmol/L). In patients with parathyroid carcinoma, the mean serum calcium concentration decreased from 14.1 mg/dL to 12.4 mg/dL (3.5-3.1 mmol/L), while in patients with primary hyperparathyroidism, the serum calcium concentration decreased from 12.7 mg/dL to 10.4 mg/dl (3.2-2.6 mmol/l). Eighteen of 29 patients (62%) with parathyroid carcinoma and 15 of 17 patients (88%) with primary hyperparathyroidism achieved a decrease in serum calcium concentration of ≥1 mg/dL (≥ 0.25 mmol/L).

Overdose

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

An overdose of Mimpara can lead to hypocalcemia. In case of overdose, patients should monitor calcium concentrations for timely detection of hypocalcemia. Symptomatic and supportive therapy should be provided. Since the degree of binding of cinacalcet to proteins is high, cinacalcet is not excreted during hemodialysis, i.e. hemodialysis in case of overdose is not effective.

Pregnancy

There are no clinical data on the use of cinacalcet during pregnancy. As preclinical studies on rabbits have shown, cinacalcet penetrates the placental barrier. In animal experiments, no direct negative effects on the course of pregnancy, childbirth or postnatal development were revealed. Neither embryotoxic nor teratogenic effects were also detected during experiments on pregnant female rats and rabbits, with the exception of a decrease in the body weight of fetuses in rats when toxic doses were used in pregnant females. During pregnancy, Mimpara should only be used if the potential benefit justifies the potential risk to the fetus. To date, the possibility of excretion of cinacalcet into breast milk has not been studied. Cinacalcet is excreted into the breast milk of lactating rats, with a high ratio of concentrations in milk to plasma concentrations. After a careful assessment of the risk/benefit ratio, a decision should be made to stop breastfeeding or taking Mimpara.

Drug interactions

Effect of other drugs on cinacalcet

Cinacalcet is partially metabolized by the CYP3A4 isoenzyme. Co-administration of ketoconazole (a strong CYP3A4 inhibitor) at a dose of 200 mg 2 times a day resulted in an approximately 2-fold increase in cinacalcet concentrations. If concomitant use of strong inhibitors (for example, ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducers of CYP3A4 (for example, rifampicin) is necessary, a dose adjustment of Mimpara may be required.

In vitro experimental studies have shown that cinacalcet is partially metabolized with the participation of the CYP1A2 isoenzyme. Smoking stimulates CYP1A2 activity. The clearance of cinacalcet is 36-38% higher in smokers than in non-smokers. The effect of CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) on plasma concentrations of cinacalcet has not been studied. Dose adjustment may be required if, during drug therapy, the patient starts/stops smoking or starts/stops concomitant use of strong CYP1A2 inhibitors.

The pharmacokinetics of cinacalcet did not change when used simultaneously with calcium carbonate (single dose 1500 mg), sevelamer (2400 mg 3 times/day), pantoprazole (80 mg 1 time/day).

Effect of cinacalcet on other drugs

Cinacalcet is a potent inhibitor of CYP2D6. The combined use of cinacalcet and drugs with a narrow therapeutic index and/or variable pharmacokinetics that are metabolized by the CYP2D6 isoenzyme (for example, flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine) may require dose adjustment of these drugs.

When co-administering cinacalcet at a dose of 90 mg 1 time / day with desipramine (a tricyclic antidepressant metabolized by CYP2D6) at a dose of 50 mg, the exposure level of desipramine increases by 3.6 times (90% CI3.0, 4.4) in patients with active metabolism of CYP2D6.

Repeated oral administration of cinacalcet did not affect the pharmacokinetics or pharmacodynamics of warfarin (prothrombin time and factor VII were measured).

The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the lack of enzyme autoinduction in patients after repeated dosing indicates that cinacalcet is not an inducer of CYP3A4, CYP1A2 or CYP2C9 in humans.

Concomitant use of cinacalcet 90 mg and oral midazolam 2 mg, a CYP3A4 and CYP3A5 substrate, does not affect the pharmacokinetics of midazolam. These data indicate that cinacalcet does not affect the pharmacokinetics of drugs metabolized by CYP3A4 and CYP3A5, such as some immunosuppressants, including cyclosporine and tacrolimus.

Side effects

Secondary hyperparathyroidism

special instructions

In three studies of patients with CKD on dialysis, 5% of patients in each Mimpara or placebo group had a history of seizures at the start of therapy. In these studies, seizures occurred in 1.4% of patients receiving Mimpara and 0.4% of patients receiving placebo. Although the reasons for the reported differences in seizures are unclear, the seizure threshold is lowered when serum calcium levels are significantly reduced.

In patients with heart failure taking cinacalcet, isolated cases of idiosyncratic arterial hypotension and/or worsening of heart failure have been reported during post-marketing studies, in which a causal relationship with cinacalcet cannot be completely excluded and may be due to a decrease in serum calcium concentrations. . Clinical trial data showed that hypotension occurred in 7% of patients treated with cinacalcet and in 12% of patients treated with placebo, and heart failure occurred in 2% of patients treated with cinacalcet or placebo.

Therapy with Mimpara should not be administered when serum calcium concentrations (corrected for albumin) are below the minimum limit of the normal range. Since cinacalcet reduces serum calcium concentrations, patients should be closely monitored for the development of hypocalcemia. In patients diagnosed with CKD on dialysis, when taking Mimpara, serum calcium concentrations in 4% of cases were below 7.5 mg/dL (1.875 mmol/L). In case of hypocalcemia, calcium-containing phosphate binders, vitamin D, and/or correction of calcium concentration in the solution during dialysis can be used to increase serum calcium levels. If hypocalcemia persists, reduce the dose or discontinue Mimpara. Potential signs of the development of hypocalcemia may include paresthesia, myalgia, convulsions, and tetany.

Cinacalcet is not indicated in patients diagnosed with CKD who are not on dialysis due to an increased risk of hypocalcemia (serum calcium concentration <8.4 mg/dL or <2.1 mmol/L) compared with patients on dialysis, which may be due to more low initial calcium levels and/or the presence of residual renal function.

When PTH concentrations are chronically suppressed below approximately 1.5% of ULN by iPTH assay, adynamic bone disease may develop. If PTH concentrations fall below the recommended range, reduce the dose of Mimpara and/or vitamin D or discontinue therapy.

Testosterone concentrations are often below normal in patients with end-stage renal disease. Data from a clinical trial in patients with end-stage renal disease on dialysis showed that free testosterone concentrations decreased by an average of 31.3% in patients taking Mimpara and by 16.3% in patients in the placebo group after 6 months. therapy. The open-label extension phase of this study showed no further reduction in free and total testosterone concentrations in patients over the 3-year treatment period with Mimpara. The clinical significance of decreased serum testosterone levels has not been established.

Since plasma levels of cinacalcet may be 2-4 times higher in patients with moderate to severe hepatic impairment (Child-Pugh score), such patients should take Mimpara with caution and closely monitor liver function during treatment.

Mimpara contains lactose as an excipient (each 30 mg tablet contains 2.74 mg of lactose, each 60 mg tablet contains 5.47 mg of lactose, each 90 mg tablet contains 8.21 mg of lactose). Patients with rare hereditary galactose intolerance, lapp lactase deficiency or glucose/galactose malabsorption should not take the drug.

Impact on the ability to drive vehicles and operate machinery

Studies have not been conducted to study the effect of the drug on the ability to drive a car or operate complex machinery. However, some adverse reactions may affect the ability to drive a car or operate complex machinery.

Results of preclinical safety studies

Preclinical studies have not revealed any genotoxic or carcinogenic potential of cinacalcet. The safe range according to toxicological studies is quite narrow, since hypocalcemia was the dose-limiting factor in animal experiments. Cataract development and lens opacification have been observed in repeated-dose toxicology and carcinogenicity studies in rodents. However, such phenomena have not been observed in experiments on dogs or monkeys or in clinical studies where cataract formation was monitored. It is known that cataracts can occur in rodents as a consequence of hypocalcemia.

For impaired renal function

Cinacalcet is not indicated for patients diagnosed with CKD who are not on dialysis.

For liver dysfunction

Since plasma levels of cinacalcet may be 2-4 times higher in patients with moderate to severe hepatic impairment (Child-Pugh classification), such patients should take Mimpara with caution and be closely monitored during treatment.

Mimpara

Suction

After oral administration of the drug Mimpara, the maximum concentration of cinacalcet in the blood plasma is achieved after approximately 2-6 hours. The absolute bioavailability of cinacalcet when taken on an empty stomach, based on a comparison of the results of various studies, was approximately 20-250/0. When taking Mimpara with food, the bioavailability of cinacalcet increases by approximately 50-8094. Similar increases in plasma cinacalcet concentrations were observed regardless of dietary fat content.

At dosages above 200 mg, saturation of absorption occurs, probably due to poor solubility.

Distribution

There is a high volume of distribution (approximately 1000 liters), indicating widespread tissue distribution. Cinacalcet is approximately 97% bound to plasma proteins and is distributed in minimal quantities in erythrocytes.

Once absorbed, the decrease in cinacalcet concentration occurs in two stages, with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. The equilibrium state of cinacalcet concentration is achieved within 7 days with minimal accumulation. The pharmacokinetic parameters of cinacalcet do not change over time.

Metabolism

Cinakacet is metabolized by a group of enzymes, mainly CYP3A4 and CYPlA2 (the role of CYPIA2 has not been confirmed by clinical methods). The main circulating metabolites are inactive.

in vitro studies

, cinacalcet is a potent inhibitor of CYP2G)6; however, at concentrations achieved in clinical settings, cinacalcet does not suppress the activity of other CYP enzymes, including CYPIA2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, and is also not an inducer of CYPIA2, CYP2C19, and СYРЗА4.

Removal

Following administration of a radiolabeled dose of 75 mg to healthy volunteers, cinacalcet underwent rapid and significant oxidative metabolism followed by conjugation. Elimination of radioactivity occurred mainly through excretion of metabolites by the kidneys. Approximately 80% of the administered dose was found in urine and 15% in feces.

Linearity/nonlinearity

The increase in the area under the concentration-time curve (AUC) and Cmax of cinacalcet occurs almost linearly in the dosing range of 30-180 mg once daily.

Pharmacokinetic/pharmacodynamic interactions

Soon after administration of cinacalcet, PTH levels begin to decrease; the maximum decrease occurs approximately 2-6 hours after administration, which corresponds to the maximum concentration of cinacalcet (Cmax). Thereafter, cinacalcet concentrations begin to decline and PTH levels rise for 12 hours after dosing, and PTH suppression then remains at approximately the same level for the remainder of the 24-hour interval with a once-daily dosing regimen. PTH concentrations in clinical studies of Mimpara were measured at the end of the dosing interval.

Elderly

There were no clinically significant differences associated with the age of patients in the pharmacokinetics of cinacalcet.

Kidney failure

The pharmacokinetic profile of cinacalcet in patients with mild, moderate and severe renal impairment and patients on hemodialysis or peritoneal dialysis is comparable to the pharmacokinetic profile of healthy volunteers.

Liver failure

Mild hepatic impairment does not have a significant effect on the pharmacokinetics of cinacalcet. Compared with the group with normal liver function, the mean AUC of cinacalcet was approximately two times higher in the group with moderate hepatic impairment, and approximately 4 times higher in the group with severe hepatic impairment. The average half-life of cinacalcet in patients with moderate to severe hepatic impairment increases by 33% and 70%, respectively. Liver failure does not affect the degree of protein binding of cinacalcet. Since dose selection is based on efficacy and safety parameters, no additional dose adjustment is required for patients with liver failure (see sections “Dosage and Administration” and “Special Instructions”).

Floor

The clearance of cinacalcet may be lower in women than in men. Since the selection of doses is carried out individually, there is no need to make additional dose adjustments depending on the gender of the patient.

Children

The pharmacokinetics of cinacalcet were studied in 12 children (6–17 years old) with CKD on dialysis after a single oral dose of 15 mg. The mean AUC and Cmax values (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 and Cmax values observed in one study in healthy adult volunteers following a single 30 mg oral dose (33.6 (range, 4.75 to 66.9) ng*h/mL and 5.42 (range, 1.41 to 12.7) ng/ml, respectively). Due to limited data in children, a potentially greater exposure to a given dose of cinacalcet in younger, lighter children than in older, heavier children cannot be ruled out.

The pharmacokinetics of repeated doses in children have not been studied.

Smoking

The clearance of cinacalcet is higher in smokers than in non-smokers. Apparently, this is due to the induction of metabolism involving CYP1A2. If the patient stops or starts smoking during therapy, the plasma concentration of cinacalcet may change and a dose adjustment may be required.

Preclinical safety studies

Cinacalcet had no teratogenic effect in rabbits when used at doses corresponding to 0.4% (based on AUC values) of the maximum dose of the drug when used in humans for secondary HPT (180 mg/day). The drug did not exhibit teratogenic activity in rats at doses exceeding 4.4 times (based on AUC values) the maximum dose of the drug when used in humans for secondary HPT.

The drug did not affect fertility in males or females when exposed to doses up to 4 times the human dose of 180 mg/day (safe range values for a patient population treated at the maximum clinical dose of 360 mg/day would be approximately half of the above values ).

In pregnant rats, a slight decrease in body weight and food intake was recorded when using the drug at the maximum dose. A decrease in fetal body weight was also observed when the drug was used in females at doses that caused severe hypocalcemia. Cinacalcet was shown to cross the placental barrier in rabbits.

Neither genotoxic nor carcinogenic potential of cinacalcet has been identified. According to toxicological studies, the safe range is quite narrow, since hypocalcemia was the dose-limiting factor in animal experiments. Cataract development and lens opacification have been observed in repeated-dose toxicology and carcinogenicity studies in rodents. However, such phenomena have not been observed in experiments on dogs or monkeys or in clinical studies where cataract formation was monitored. It is known that cataracts can occur in rodents as a consequence of hypocalcemia.

In in
vitro
, the IC50 values for the serotonin transporter and KATP channels were 7 and 12 times higher, respectively, compared with the EC50 value for the calcium-sensing receptor under the same experimental conditions. The clinical significance of this phenomenon is unknown, but the potential for cinacalcet to act on these additional targets cannot be completely excluded.