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.
Pharmacological properties
Calcium-sensing receptors located on the surface of the main cells of the parathyroid gland are the main regulators of the secretion of parathyroid hormone (PTH). Cinacalcet has a calcimimetic effect, directly reducing the concentration of PTH, increasing the sensitivity of this receptor to extracellular calcium. A decrease in PTH concentration is accompanied by a decrease in serum calcium. The decrease in PTH concentration correlates with the concentration of cinacalcet. Soon after cinacalcet administration, PTH concentrations begin to decrease; with the maximum decrease occurring approximately 2–6 hours after dosing, which corresponds to the maximum concentration of cinacalcet (Cmax). Thereafter, 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 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. After reaching a state of equilibrium, the concentration of calcium in the serum remains at a constant level throughout the entire interval between doses of the drug. 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, and 66% of patients were taking vitamin D before enrollment. , and >90% were taking phosphate binders. Patients taking cinacalcet had significant reductions in iPTH, serum calcium and phosphorus concentrations, and calcium-phosphorus product (Ca×P) 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, calcium and phosphorus, and Ca×P concentrations, regardless of initial iPTH or Ca×P concentrations, dialysis regimen (peritoneal dialysis versus hemodialysis), duration of dialysis, and whether or not vitamin D was used. Decreased PTH concentrations was associated with a nonsignificant decrease in the concentrations of markers of bone metabolism (specific bone alkaline phosphatase, N-telopeptides, bone turnover and bone fibrosis).
In a retrospective analysis of pooled data from 6- and 12-month clinical trials using the Kaplan-Meier method, bone fracture and parathyroidectomy rates 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 concentrations in a similar manner as in patients diagnosed with end-stage renal disease (ESRD) and secondary hyperparathyroidism. on dialysis. However, for patients with renal failure in the pre-dialysis stage, the effectiveness, safety, optimal dosage and target values of therapy have not been established. These studies showed that nondialysis patients with CKD receiving cinacalcet have a greater risk of developing hypocalcemia compared with dialysis patients with end-stage renal disease receiving cinacalcet, which may be due to lower initial calcium concentrations and/or residual calcium levels. kidney function. In the main study, 46 patients (29 patients diagnosed with parathyroid carcinoma, and 17 with primary HPT (in whom parathyroidectomy failed or was contraindicated) received cinacalcet for up to 3 years (mean 328 days for patients with parathyroid carcinoma and 347 days for patients with primary HPT).Cinacalcet was used in doses ranging from 30 mg 2 times a day to 90 mg 4 times a day. The main goal of therapy was to reduce the serum calcium concentration by ≥1 mg/dL (≥0.25 mmol/L In patients with parathyroid carcinoma, the mean calcium concentration decreased from 14.1 to 12.4 mg/dL (3.5–3.1 mmol/L), while in patients with primary HPT the serum calcium concentration decreased from 12.7 to 10.4 mg/dL (3.2 to 2.6 mmol/L) in 18 of 29 patients (62%) with parathyroid carcinoma and 15 of 17 patients (88%) with primary HPT a decrease in serum calcium concentration of ≥1 mg/dL (≥0.25 mmol/L) was achieved.
Pharmacokinetics
After oral administration of the drug Mimpara, the maximum concentration (Cmax) of cinacalcet in the blood plasma is achieved after approximately 2-6 hours. The absolute bioavailability of cinacalcet when taken on an empty stomach, established based on comparison of the results of various studies, was approximately 20-25%. Taking Mimpara with food increased the bioavailability of cinacalcet by approximately 50–80%.
A similar increase in plasma concentrations of cinacalcet was observed regardless of dietary fat content. The decrease in cinacalcet concentration occurs in two stages; The initial half-life is approximately 6 hours, the final half-life is 30 to 40 hours. Steady-state is achieved within 7 days with minimal accumulation. The increase in the area under the concentration-time curve (AUC) and Cmax of cinacalcet occurs almost linearly in the dosage range of 30–180 mg once daily. At dosages above 200 mg, saturation of absorption occurs, probably due to poor solubility. The pharmacokinetic parameters of cinacalcet do not change over time. There is a high volume of distribution (approximately 1000 L), indicating widespread distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributed at a minimal level in erythrocytes. Cinacalcet is metabolized by liver microsomal enzymes, predominantly CYP3A4 and CYP1A2 (the role of CYP1A2 has not been confirmed clinically). The main circulating metabolites are inactive. According to in vitro studies, cinacalcet is a potent inhibitor of CYP2D6, however, at concentrations achieved in clinical conditions, cinacalcet does not inhibit the activity of other CYP enzymes, incl. CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4, and is also not an inducer of CYP1A2, CYP2C19 and CYP3A4. Following administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet underwent rapid and significant oxidative metabolism followed by conjugation. Excretion of radioactivity occurred mainly as a result of excretion of metabolites through the kidneys. Approximately 80% of the administered dose was found in urine and 15% in feces. Elderly: There were no clinically significant differences in the pharmacokinetics of cinacalcet associated with the age of patients. Renal failure: The pharmacokinetic profile of cinacalcet in mild, moderate and severe renal failure, and in hemodialysis or peritoneal dialysis, is comparable to the pharmacokinetic profile of the drug in healthy volunteers. Hepatic impairment: 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 2 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 and severe degrees of liver failure is prolonged 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. Gender: 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 was studied in 12 children (6–17 years) with CKD on dialysis following 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 approximately 30% of the mean AUC and Cmax values observed in one study in healthy adults 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 cannot be ruled out in younger, lighter children compared to older, heavier children. 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 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.
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.
MIMPARA
special instructions
Seizures
In clinical studies, seizures occurred in 1.4% of patients treated with Mimpara and in 0.7% of patients treated with placebo. Although the reasons for the reported differences in seizure occurrence are unclear, the seizure threshold is lowered when serum calcium concentrations are significantly reduced.
Hypotension and/or worsening heart failure
In patients with heart failure taking cinacalcet during post-marketing surveillance, isolated idiosyncratic cases of hypotension and/or worsening of heart failure have been reported, 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 receiving cinacalcet and 12% of patients receiving placebo, and heart failure in 2% of patients receiving cinacalcet or placebo.
Serum calcium
Therapy with Mimpara should not be administered when serum calcium concentrations (corrected for albumin) are below the minimum limit of the normal range.
Life-threatening events and deaths associated with hypocalcemia have been reported in patients treated with Mimpara, including children. Manifestations of hypocalcemia may include paresthesia, myalgias, spasms, tetany, and convulsions. A decrease in serum calcium may also prolong the QT interval and, as a result, lead to the development of ventricular arrhythmias. In patients taking cinacalcet, cases of prolongation of the QT interval and the development of ventricular arrhythmias due to hypocalcemia have been reported (see section "Side effects"). Caution should be exercised when treating patients with other risk factors for QT prolongation, such as patients diagnosed with congenital long QT syndrome or patients taking medications known to prolong the QT interval.
Since cinacalcet reduces the concentration of calcium in the blood serum, careful monitoring is necessary for the development of hypocalcemia (see section "Dosage and Administration"). Serum calcium should be determined within 1 week after initiation of therapy or dose adjustment of Mimpara. After establishing a maintenance dose, serum calcium should be determined approximately once a month. If serum calcium decreases below 8.4 mg/dL (2.1 mmol/L), but not below 7.5 mg/dL (1.875 mmol/L), or if symptoms of hypocalcemia develop, a drug may be prescribed to increase serum calcium concentrations. calcium-containing phosphate binders, vitamin D, and/or adjust dialysate calcium concentration. If hypocalcemia cannot be eliminated in this way, it is necessary to reduce the dose or discontinue taking Mimpara. If serum calcium levels fall below 7.5 mg/dL (1.875 mmol/L) or symptoms of hypocalcemia persist and vitamin D dosage cannot be increased, Mimpara therapy should be withheld until serum calcium levels reach 8.0 mg. /dl (2.0 mmol/l) and/or symptoms of hypocalcemia will not resolve. Therapy should be restarted using the next lowest dose of Mimpara.
Among patients with CKD on dialysis treated with Mimpara, 29% of patients in the 6-month registration studies and 21% and 33% of patients (in the first 6 months and overall, respectively) in the EVOLVE clinical trial had at least once the serum calcium concentration was less than 7.5 mg/dL (1.875 mmol/L).
Cinacalcet is not indicated for patients diagnosed with CKD who are not on dialysis. Preliminary studies have shown that patients diagnosed with CKD who are not on dialysis have an increased risk of developing hypocalcemia (serum calcium <8.4 mg/dL [2.1 mmol/L]) compared with patients on dialysis, which may be due to a lower initial calcium concentration and/or the presence of residual renal function.
Are common
When PTH concentrations are chronically suppressed below approximately 1.5 times the upper limit of normal as determined by iPTH assay, adynamic bone disease may develop. If PTH concentrations fall below the recommended range, reduce the dose of Mimpar and/or vitamin D or discontinue therapy.
Neoplasm
In the EVOLVE study, which included 3883 dialysis patients, neoplasm incidence rates were 2.9 and 2.5 patients per 100 patient-years in the Mimpara and placebo groups, respectively. A cause-and-effect relationship with the use of Mimpara has not been established.
Testosterone concentration
Testosterone concentrations are often below normal in patients with end-stage renal disease. Data from a clinical trial involving patients with ESRD 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 the decrease in serum testosterone concentrations has not been established.
Liver failure
The drug should be prescribed with caution to patients with moderate to severe hepatic impairment (according to the Child-Pugh classification), since plasma concentrations of cinacalcet may be 2-4 times higher; careful monitoring is required during treatment (see sections “Method of administration and dose", "Pharmacokinetic properties").
Fertility
There are no clinical data demonstrating the effects of cinacalcet on fertility. Animal experiments have shown no effects on fertility.
Lactose
Mimpara contains lactose as an excipient (each 30 mg tablet contains 2.74 mg lactose, each 60 mg tablet contains 5.47 mg lactose, each 90 mg tablet contains 8.21 mg lactose). Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucogalactose malabsorption should not take the drug.
Side effects
Secondary hyperparathyroidism
From the digestive system: nausea, vomiting, anorexia, dyspepsia, diarrhea.
From the central nervous system and peripheral nervous system: dizziness, paresthesia, convulsions.
From the musculoskeletal system: myalgia.
From the endocrine system: decreased testosterone levels.
Dermatological reactions: rash.
Allergic reactions: hypersensitivity reactions, angioedema, urticaria.
Other: asthenia, hypocalcemia.
Parathyroid carcinoma and primary hyperparathyroidism
The safety profile of Mimpara in this group of patients is generally consistent with that observed in patients with chronic kidney disease. The most common side effects were nausea and vomiting.
In patients with heart failure and taking cinacalcet, isolated idiosyncratic cases of decreased blood pressure and/or worsening of heart failure have been reported;
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
Convulsions
In clinical studies, seizures were reported in 1.4% of patients treated with Mimpara and in 0.7% of patients treated with placebo. Although the reasons for the reported differences in seizure occurrence are unclear, the seizure threshold is lowered when serum calcium concentrations are significantly reduced.
Hypotension and/or worsening heart failure
In patients with heart failure taking cinacalcet during post-marketing surveillance, isolated idiosyncratic cases of hypotension and/or worsening of heart failure have been reported, 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 receiving cinacalcet and 12% of patients receiving placebo, and heart failure in 2% of patients receiving cinacalcet or placebo.
Serum calcium
Therapy with Mimpara should not be administered when serum calcium concentrations (corrected for albumin) are below the minimum limit of the normal range.
Life-threatening events and deaths associated with hypocalcemia have been reported in patients treated with Mimpara, including children. Manifestations of hypocalcemia may include paresthesia, myalgias, spasms, tetany, and convulsions. A decrease in serum calcium may also prolong the QT interval and, as a result, lead to the development of ventricular arrhythmias. In patients taking cinacalcet, cases of prolongation of the QT interval and the development of ventricular arrhythmias due to hypocalcemia have been reported (see section "Side effects"). Caution should be exercised when treating patients with other risk factors for QT prolongation, such as patients diagnosed with congenital long QT syndrome or patients taking medications known to prolong the QT interval.
Since cinacalcet reduces serum calcium concentrations, careful monitoring is necessary for the development of hypocalcemia (see section "Dosage and Administration"). Serum calcium should be determined within 1 week after initiation of therapy or dose adjustment of Mimpara. After establishing a maintenance dose, serum calcium should be determined approximately once a month. If serum calcium decreases below 8.4 mg/dL (2.1 mmol/L), but not below 7.5 mg/dL (1.875 mmol/L), or if symptoms of hypocalcemia develop, a drug may be prescribed to increase serum calcium concentrations. calcium-containing phosphate binders, vitamin D, and/or adjust dialysate calcium concentration. If hypocalcemia cannot be eliminated in this way, it is necessary to reduce the dose or discontinue taking Mimpara. If serum calcium levels fall below 7.5 mg/dL (1.875 mmol/L) or symptoms of hypocalcemia persist and vitamin D dosage cannot be increased, Mimpara therapy should be withheld until serum calcium levels reach 8.0 mg. /dl (2.0 mmol/l) and/or symptoms of hypocalcemia will not resolve. Therapy should be restarted using the next lowest dose of Mimpara.
Among patients with CKD on dialysis treated with Mimpara, 29% of patients in the 6-month registration studies and 21% and 33% of patients (in the first 6 months and overall, respectively) in the EVOLVE clinical trial had at least once the serum calcium concentration was less than 7.5 mg/dL (1.875 mmol/L).
Cinacalcet is not indicated for patients diagnosed with CKD who are not on dialysis. Preliminary studies have shown that patients diagnosed with CKD who are not on dialysis have an increased risk of developing hypocalcemia (serum calcium <8.4 mg/dL [2.1 mmol/L]) compared with patients on dialysis, which may be due to a lower initial calcium concentration and/or the presence of residual renal function.
Are common
When PTH concentrations are chronically suppressed below approximately 1.5 times the upper limit of normal as determined by iPTH assay, adynamic bone disease may develop. If PTH concentrations fall below the recommended range, reduce the dose of Mimpar and/or vitamin D or discontinue therapy.
Neoplasm
In the EVOLVE study, which included 3883 dialysis patients, neoplasm incidence rates were 2.9 and 2.5 patients per 100 patient-years in the Mimpara and placebo groups, respectively. A cause-and-effect relationship with the use of Mimpara has not been established.
Testosterone concentration
Testosterone concentrations are often below normal in patients with end-stage renal disease. Data from a clinical trial involving patients with ESRD 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 the decrease in serum testosterone concentrations has not been established.
Liver failure
The drug should be prescribed with caution to patients with moderate to severe hepatic impairment (Child-Pugh classification), since plasma concentrations of cinacalcet may be 2-4 times higher, careful monitoring is required during treatment (see sections “Method of administration and dose", "Pharmacokinetic properties").
Fertility
There are no clinical data demonstrating the effects of cinacalcet on fertility. Animal experiments have shown no effects on fertility.
Lactose
Mimpara contains lactose as an excipient (each 30 mg tablet contains 2.74 mg lactose, each 60 mg tablet contains 5.47 mg lactose, each 90 mg tablet contains 8.21 mg lactose). Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucogalactose malabsorption should not take the drug.
