Mimpara

Active material: Cinacalcet
When ATH: H05BX01
CCF: Antiparatireoidnыy preparation
ICD-10 codes (testimony): C75.0, E21
When CSF: 15.05.03
Manufacturer: AMGEN EUROPE B.V. (Netherlands)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated light green, Oval, with an inscription in black ink”AMGEN” on one side and “30” on the other side.

Excipients: pregelatinized corn starch, microcrystalline cellulose, povidone, krospovydon, colloidal silicon dioxide, magnesium stearate.

The composition of the shell: Opadry II green (lactose monohydrate, гипромеллоза 15cP, Titanium dioxide, triacetine, indigo alyuminievыy varnish, iron oxide yellow), Opadry clear (hypromellose 6cP, macrogol 400), carnauba wax; ink – opakod Black (shellac (20% esterified), iron oxide black).

14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (6) – packs cardboard.

Pills, Film-coated light green, Oval, with an inscription in black ink”AMGEN” on one side and “60” on the other side.

Excipients: pregelatinized corn starch, microcrystalline cellulose, povidone, krospovydon, colloidal silicon dioxide, magnesium stearate.

The composition of the shell: Opadry II green (lactose monohydrate, гипромеллоза 15cP, Titanium dioxide, triacetine, indigo alyuminievыy varnish, iron oxide yellow), Opadry clear (hypromellose 6cP, macrogol 400), carnauba wax; ink – opakod Black (shellac (20% esterified), iron oxide black).

14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (6) – packs cardboard.

Pills, Film-coated light green, Oval, with an inscription in black ink”AMGEN” on one side and “90” on the other side.

Excipients: pregelatinized corn starch, microcrystalline cellulose, povidone, krospovydon, colloidal silicon dioxide, magnesium stearate.

The composition of the shell: Opadry II green (lactose monohydrate, гипромеллоза 15cP, Titanium dioxide, triacetine, indigo alyuminievыy varnish, iron oxide yellow), Opadry clear (hypromellose 6cP, macrogol 400), carnauba wax; ink – opakod Black (shellac (20% esterified), iron oxide black).

14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (6) – packs cardboard.

* international non-proprietary name, recommended by the WHO – cinacalcet.

Pharmacological action

Antiparatireoidnoe means.

Kaltsiychuvstvitelnye receptors, located on the top surface of parathyroid cells, are key regulators of secretion of parathyroid hormone (PTG). Tsinakaltset has calcimimetic action, directly reduces the level of PTH, increasing the sensitivity of the receptor to extracellular calcium. Reduction of PTH associated with reduced calcium content in serum.

Reduction in PTH levels correlate with the concentration tsinakaltseta. Shortly after receiving tsinakaltseta PTH level begins to drop: wherein the maximum decrease occurs approximately 2-6 hr postdose, corresponding to C_max cinacalcet. Thereafter, the concentration starts to decrease tsinakaltseta, and the level increased during PTH 12 hr postdose, and then PTH suppression remains approximately at the same level until the end of the day interval when dosing regimen 1 time / day. PTH levels in Mimpara clinical trials of the drug were measured at the end of the dosing interval.

After reaching a stable phase in the serum calcium concentration remains at a constant level throughout the dosing interval of the drug.

Secondary hyperparathyroidism

Three clinical trials lasting 6 months (double-blind, placebo-controlled) conducted in patients diagnosed with end stage renal nedostatochnocti form with uncontrolled secondary hyperparathyroidism, dialysis (1136 patients).

The average initial indicators of concentration of intact parathyroid hormone (IPTG) in 3 clinical studies were 733 and 683 pg / ml (77.8 and 72.4 pmol / l) Group tsinakaltseta and placebo, respectively, 66% patients received vitamin D at baseline, and more 90% taking medications, svyazıvayuşçïe phosphate.

Patients, taking tsinakaltset, there was a significant reduction in iPTH, Ca x P (calcium-phosphorus product) serum, calcium and phosphorus content as compared with patients in the placebo group, who received standard therapy. Reduced levels of iPTH and Ca x P maintained throughout 12 months of therapy. Tsinakaltset decreased levels of iPTH, Ca x P, calcium and phosphorus levels regardless of the initial iPTH or Ca x P, dialysis regime (Peritoneal dialysis over hemodialysis), duration of dialysis, and the use of vitamin D.

Reduced levels of PTH were associated with non-significant decrease in the levels of markers of bone metabolism (bone-specific alkaline phosphatase, N-телопептидов, bone turnover and bone marrow fibrosis). A retrospective analysis of the data pool, collected on the basis of 6 and 12-month clinical study using the Kaplan-Meier, parameters of bone fractures and parathyroidectomy were lower in the group tsinakaltseta compared with control group.

Preliminary studies in patients, chronic kidney disease (XBP) and secondary hyperparathyroidism, not on dialysis, indicates, tsinakaltset that reduced levels of PTH in the same way, both in patients diagnosed with end-stage renal failure (TSPN) and secondary hyperparathyroidism, dialysis.

However, for patients with renal nedostatochnoctyu in pre-dialysis stage efficacy have not been established, security, the optimal dosage and target therapy. These studies showed, In patients with CKD, not on dialysis and receiving tsinakaltset, there is a greater risk of hypocalcemia compared to patients, having end stage renal disease, tsinakaltset and receiving dialysis, which may be due to low starting levels of calcium and / or residual renal function.

Paraŝitovidnyh cancer glands

In the main study 29 patients: 21 patient diagnosed with cancer of the parathyroid glands, 8 - With uncontrolled primary hyperparathyroidism (after failure of a surgical operation or contraindications for surgery) tsinakaltset received over 2 years (the average duration of therapy was 188 days).

Tsinakaltset applied in doses of 30 mg 2 times / day to 90 mg 4 times / day every day. The primary objective was to reduce the level of serum calcium at ≥1 mg / dl (≥0.25 mmol / l). Patients with a diagnosis of carcinoma of the parathyroid glands average calcium levels declined from 14.5 mg / dl to 12.4 mg / dL (3.6 mmol / l – 3.1 mmol / l). In 15 from 21 patients with parathyroid carcinoma marked reduction of serum calcium at ≥1 mg / dl (≥ 0.25 mmol / l).

Pharmacokinetics

Absorption

After oral administration, C_max tsinakaltseta plasma levels achieved approximately 2-6 no. The absolute bioavailability in the fasting tsinakaltseta, established by comparing the results of different studies, It was approximately 20-25%. The drug Mimpara with food increases the bioavailability tsinakaltseta approximately 50-80%. Such an increase in concentration in blood plasma tsinakaltseta observed regardless of the content of fat in food.

Увеличение AUC и C_max tsinakaltseta occurs essentially linearly in a dosage range 30-180 mg 1 time / day. At doses above 200 mg observed absorption saturation, probably due to poor solubility. Pharmacokinetic parameters tsinakaltseta not change with time.

Distribution

C_ss tsinakaltseta achieved within 7 days with a minimum of cumulation. There big V_d about 1000 l, indicating a broad distribution. Tsinakaltset about 97% bound to plasma proteins and is distributed at the minimum level in erythrocytes.

Metabolism

Tsinakaltset metabolised mainly with the participation isozymes CYP3A4 and CYP1A2 (the role of CYP1A2 has not been confirmed by clinical methods). The main metabolites, detected in blood, inactive. According to studies in vitro, tsinakaltset is a potent inhibitor of CYP2D6. However, at concentrations, is achieved in the clinical setting, tsinakaltset does not inhibit the activity of other isoenzymes (in t. no. CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4) and not an inducer of CYP1A2, CYP2C19 и CYP3A4. After the introduction of healthy volunteers 75 mg labeled dose radioisotope method, tsinakaltset undergoes rapid and extensive oxidative metabolism, followed by conjugation.

Deduction

T_1/2 the initial phase is about 6 no, in the final phase – from 30 to 40 no.

The metabolites are mainly excreted by the kidneys: about 80% the dose found in the urine and 15% Calais.

Pharmacokinetics in special clinical situations

In the study of the pharmacokinetics tsinakaltseta elderly patients are not clinically significant differences, age-related.

Tsinakaltseta pharmacokinetic profile in patients with mild renal insufficiency, moderate and severe, and patients, on hemodialysis or peritoneal dialysis, comparable with parameters, observed in healthy volunteers.

Hepatic impairment Mild has no significant effect on the pharmacokinetics tsinakaltseta. Compared with the group with normal liver function average AUC were approximately tsinakaltseta 2 times higher in the group with moderately impaired hepatic function, and about 4 times higher in severe hepatic insufficiency. Average T_1/2 tsinakaltseta in patients with moderate and severe hepatic impairment increases respectively 33% and 70%. Hepatic impairment does not affect the binding of proteins tsinakaltseta. Since the selection of doses for each patient is conducted based on the parameters of efficacy and safety, for patients with hepatic impairment is not required to conduct additional dose adjustment.

Tsinakaltseta clearance may be lower in women, than men. Since the selection of doses held individually, It is not required to conduct additional dose adjustment depending on the sex of the patient.

Tsinakaltseta pharmacokinetics has not been studied in patients under 18 years.

Tsinakaltseta clearance level is higher in smokers, than non-smokers. Apparently, This is due to induction of metabolism, CYP1A2-mediated. If a patient stops or starts smoking during therapy, tsinakaltseta level in plasma may change and dose adjustment is required.

Testimony

- secondary hyperparathyroidism in patients with end-stage renal disease, dialysis;

- hypercalcemia in patients with parathyroid carcinoma;

- as part of combination therapy with drugs, связывающими фосфаты и/или витамин D.

Dosage regimen

The drug is recommended to be taken orally with meals or soon after meals, tsinakaltseta since bioavailability is increased by taking the drug with food. Tablets should be taken as a whole.

Secondary hyperparathyroidism

Adults and elderly patients (> 65 years)

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

Dose adjustment should be carried out every 2-4 weeks to a maximum of 180 mg 1 time / day, whereby patients, located on the dialysis It reached the desired level in the range of PTG 150-300 pg / ml (15.9-31.8 mmol / l), defined by content iPTH. Determination of PTH levels should be carried out not earlier, than 12 h after dosing. In assessing the level of PTH must adhere to current guidelines.

Measurement of PTH levels should be carried out 1-4 weeks after initiation of therapy or correction dose. When you receive a maintenance dose of PTH level monitoring should be conducted about once a 1-3 of the month. To measure PTH levels can use the content of iPTH or biointaktnogo PTH (biPTG). Therapy with Mimpara does not alter the relationship between iPTH and biPTG.

During titration often necessary to monitor the level of calcium in blood serum, in t. no. through 1 week after initiation of therapy or correction dose. Upon reaching a maintenance dose level of serum calcium should be determined approximately 1 once a month. If calcium levels in the serum decreased below the normal range, you must take appropriate measures.

Concomitant therapy using drugs phosphate binders and / or vitamin D, You need to be adjusted as required.

Paraŝitovidnyh cancer glands

Adults and elderly patients (> 65 years)

The recommended starting dose of the drug is Mimpara 30 mg 2 times / day.

Dose adjustment should be carried out every 2-4 weeks following sequence changes dosage: 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 the concentration of calcium in blood serum to ULN or below this level. The maximum dose, is used in clinical trials, was 90 mg 4 times / day.

Determining the level of serum calcium should be carried out 1 week after initiation of therapy or correction dose. Upon reaching the maintenance dose of calcium levels in the blood serum is determined every 2-3 months. After adjusting doses up to the maximum dose of the drug should be periodic monitoring of serum calcium. If it is not possible to maintain a clinically significant reduction in serum calcium, should decide on the termination of therapy.

When treating patients hepatic insufficiency no need to change the starting dose. With care prescribe a drug patients with liver failure and secondary severe. It should be carefully monitored during treatment for dose titration and long-term therapy.

Side effect

Secondary hyperparathyroidism

The data were obtained during controlled clinical trials in 656 patients, taking the drug Mimpara, and 470 patients, placebo for up to 6 months. The most frequently observed nausea (31% in tsinakaltseta group; 19% placebo) and vomiting (27% in tsinakaltseta group; 15% placebo). Nausea and vomiting were mild to moderate severity and in most cases, were short-lived. Discontinuation of therapy as a result of adverse effects was caused by, mainly, toshnotoy (1% placebo; 5% in tsinakaltseta group) and vomiting (<1% placebo; 4% cinacalcet).

Adverse Reactions, hypothetically associated with the use tsinakaltseta, considering the prevalence of side effects in the treatment group compared with the placebo group, observed during the double-blind clinical trials, given below in accordance with the following criteria: Often (>1/10); often (>1/100, <1/10); sometimes (>1/1000, <1/100); rarely (>1/10 000, <1/1000); rarely (<1/10 000).

From the digestive system: Often – nausea, vomiting, anorexia; sometimes – dyspepsia, diarrhea.

From the central and peripheral nervous system: often – dizziness, paresthesia; sometimes – convulsions.

On the part of the musculoskeletal system: often – myalgia.

On the part of the endocrine system: often – a decrease in testosterone levels.

Dermatological reactions: often – rash.

Allergic reactions: sometimes – hypersensitivity reactions.

Other: often – asthenia, hypocalcemia.

Paraŝitovidnyh cancer glands

The safety profile of Mimpara in this patient population is generally consistent with the picture, observed in patients with chronic kidney disease. The most common side effects were nausea and vomiting.

Post-marketing surveillance

In patients with heart failure and receiving tsinakaltset, during post-marketing studies, recorded isolated cases of idiosyncrasy, at which the observed hypotension and / or worsening heart failure.

Contraindications

- Childhood and adolescence up 18 years;

- Hypersensitivity to the drug.

Pregnancy and lactation

Clinical data on the use in pregnancy tsinakaltseta. Use of the drug during pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus.

So far, not been studied the possibility of allocating tsinakaltseta with breast milk in humans.

If necessary, use during lactation should decide the issue of termination of breastfeeding.

IN experimental studies at the preclinical study in rabbits shows preparation, tsinakaltset that crosses the placental barrier. The animals showed no direct negative impact on the course of pregnancy, childbirth or postnatal development. It was also not revealed any embryotoxic, no teratogenic effects in experiments on pregnant female rats and rabbits, except for reducing body weight in rat embryos at doses, Caller toxicity in the pregnant females.

Tsinakaltset excreted in breast milk in lactating rats, It is noted at the highest concentration ratio in milk / plasma.

Cautions

In the course of 3 studies in patients with CKD, dialysis, It revealed: in 5% patients in each group, receiving placebo or drug Mimpara, at the start of therapy was documented information about the attacks of convulsions. In carrying out these studies, seizures were observed in 1.4% patients, receiving Mimpara, and 0.4% patients in the placebo group. Although the reasons for the reported difference in convulsions unclear, threshold for the onset of seizures is reduced while substantially reducing the level of calcium in blood serum.

In patients with heart failure, taking tsinakaltset, during post-marketing studies recorded isolated cases of idiosyncrasy, hypotension and / or worsening heart failure, which can not be completely ruled out a causal link with tsinakaltsetom, but may be due to a decrease in the level of calcium in the blood serum. Data from clinical studies showed, hypotension that occurs in 7% patients, taking tsinakaltset, and 12% patients, placebo, as well as heart failure in 2% patients, tsinakaltset treated or placebo.

Therapy with Mimpara should not be performed in patients with calcium levels in the blood serum (adjusted for albumin) below the minimum limit of the normal range. Since tsinakaltset lowers the level of calcium in the blood serum, necessary to carry out careful monitoring of patients with regard to the development of hypocalcemia. In patients diagnosed with CKD, dialysis, while taking the drug Mimpara in serum calcium levels 4% cases was lower 7.5 mg / dL (1.875 mmol / l).

In the case of hypocalcemia, to increase the level of calcium in the blood serum, You can use the calcium-containing phosphate binders, vitamin D and / or carry out the correction of calcium concentration in the dialysis solution. When persistent hypocalcemia should reduce the dose or stop taking Mimpara. Potential symptoms of hypocalcemia may be paresthesia, mialgii, convulsions, tetany and konvulysii.

Tsinakaltset not indicated for patients diagnosed with CKD, not on dialysis, in connection with an increase in the risk of developing hypocalcemia (serum calcium levels <8.4 mg / dL or <2.1 mmol / l) compared to patients, on dialysis, that may be due to low starting levels of calcium and / or presence of residual renal function.

In chronic suppressing PTH concentration below, approximately 1.5% from the upper limit of normal on the results of the analysis of iPTH, may develop adynamic bone disease. If PTH levels decrease below the recommended range, Patients on background therapy with Mimpara should reduce the dose of the drug and / or vitamin D or terminate therapy.

Testosterone levels are often below the normal range in patients with TSPN. Data from clinical trials involving patients with TSPN, dialysis, shown, that the level of free testosterone decreased, average, on 31.3% patients, taking Mimpara, and 16.3% patients in the placebo group through 6 months after initiation of therapy. Clinically significant reduction of serum testosterone levels is not installed.

Since patients with hepatic insufficiency, moderate and severe (classification Child-Pugh), tsinakaltseta level in the blood plasma can be 2-4 times higher, such patients should take the drug with caution Mimpara and careful monitoring of liver function during treatment.

Simultaneous application Mimpara with potent inhibitors or inducers of CYP3A4 and / or CYP1A2 may require correction of the dose.

Smokers tsinakaltseta plasma concentration may be lower as a result of metabolic induction, passing involving CYP1A2 isozyme. You may need a dose adjustment, if a patient starts or stops smoking during therapy tsinakaltsetom.

Effects on ability to drive vehicles and management mechanisms

Studies on the effect of the drug on the ability to drive a car, and management mechanisms have not been conducted.

The results of experimental studies

During the pre-clinical studies did not reveal any genotoxic, Our kantserogennogo potential cinacalcet. safe range, According to toxicological studies, It is sufficiently narrow, since in experiments on animals dose-limiting factor was hypocalcemia. Cataract and cataract were observed during the toxicological and carcinogenicity studies in rodents with repeated dosing. However, such phenomena were not observed in the experiments in dogs or monkeys or in clinical trials, where monitoring was conducted against cataract formation. Known, rodents that cataracts can occur as a result of hypocalcemia.

Overdose

Symptoms: hypocalcemia (possible paresthesia, mialgii, convulsions, tetany and konvulysii).

Treatment: should be symptomatic and supportive therapy, monitor symptoms of hypocalcemia. Since the degree of binding proteins with high tsinakaltseta, hemodialysis is not an effective therapeutic method of overdose.

Drug Interactions

The effect of other drugs on tsinakaltset

Tsinakaltset partially metabolized isoenzyme CYP3A4. Simultaneous treatment with ketoconazole (a potent inhibitor of CYP3A4) dose 200 mg 2 times / day led to an increase in the concentration of about tsinakaltseta 2 times. It may be necessary to adjust the dose, if the patient during therapy starts or stops taking a potent inhibitor (ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducers of enzyme activity (rifampicin).

In experimental studies in vitro shows, that tsinakaltset partially metabolized by the CYP1A2 isoenzyme. Smoking stimulates the activity of CYP1A2. Clearance on tsinakaltseta 36-38% higher in smokers, than non-smokers. Effect of CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) tsinakaltseta concentration has not been studied in plasma. You may need a dose adjustment, if during therapy with the patient starts / stops smoking or starts / stops the simultaneous reception of potent inhibitors of CYP1A2.

Pharmacokinetics tsinakaltseta not changed while the use of calcium carbonate (single dose of 1500 mg), sevelamer (2400 mg 3 times / day), pantoprazolom (80 mg 1 time / day).

Effect tsinakaltseta other drugs

Tsinakaltset is a potent inhibitor of CYP2D6. If drugs, метаболизирующиеся CYP2D6, They have a narrow therapeutic index and require individual selection of doses (flekainid, propafenone, metoprolol, desipramine, nortryptylyn, clomipramine), It may require adjustment of dose, while taking a drug Mimpara.

At the same time taking a dose tsinakaltseta 90 mg 1 time / day with desipramine (tricyclic antidepressant, метаболизирующийся CYP2D6) dose 50 mg increases the level of exposure to desipramine 3.6 times (90% CI3.0, 4.4) patients with active CYP2D6 metabolism.

Multiple oral tsinakaltseta did not affect the pharmacokinetics or pharmacodynamics of warfarin (measured by prothrombin time and factor VII).

No effect on the pharmacokinetics of R tsinakaltseta- and S-warfarin and absence autoinduction enzymes in patients following multiple dose indicates, that tsinakaltset not an inducer of CYP3A4, CYP1A2 или CYP2C9 у человека.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 4 year.