Calcemara^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmfirma Sotex, CJSC (Russia)

Manufactured By

Rapharma, JSC (Russia)

ATC Code

H05BX01 (Cinacalcet)

Active Substance

Cinacalcet (Rec.INN registered by WHO)

Dosage Forms

	Calcemara®	Film-coated tablets, 30 mg: 14, 20, or 28 pcs.
		Film-coated tablets, 60 mg: 14, 20, or 28 pcs.
		Film-coated tablets, 90 mg: 14, 20, or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light green to light green with a yellowish tint, oval, biconvex, with an engraving “C9CC” on one side, “30” on the other side; on cross-section, the core is white or almost white.

Excipients: pregelatinized starch, microcrystalline cellulose (MCC-102), crospovidone type A (Polyplasdone XL), crospovidone type B (Polyplasdone XL-10), povidone (K29/32), magnesium stearate, colloidal silicon dioxide.

Shell composition Opadry II 85F210088 green (polyvinyl alcohol, titanium dioxide (E171), macrogol 4000, talc, indigo carmine aluminum lake (E132), yellow iron oxide (E172)).

7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.

Film-coated tablets from light green to light green with a yellowish tint, oval, biconvex, with an engraving “C9CC” on one side, “60” on the other side; on cross-section, the core is white or almost white.

Excipients: pregelatinized starch, microcrystalline cellulose (MCC-102), crospovidone type A (Polyplasdone XL), crospovidone type B (Polyplasdone XL-10), povidone (K29/32), magnesium stearate, colloidal silicon dioxide.

Shell composition Opadry II 85F210088 green (polyvinyl alcohol, titanium dioxide (E171), macrogol 4000, talc, indigo carmine aluminum lake (E132), yellow iron oxide (E172)).

7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.

Film-coated tablets from light green to light green with a yellowish tint, oval, biconvex, with an engraving “C9CC” on one side, “90” on the other side; on cross-section, the core is white or almost white.

Excipients: pregelatinized starch, microcrystalline cellulose (MCC-102), crospovidone type A (Polyplasdone XL), crospovidone type B (Polyplasdone XL-10), povidone (K29/32), magnesium stearate, colloidal silicon dioxide.

Shell composition Opadry II 85F210088 green (polyvinyl alcohol, titanium dioxide (E171), macrogol 4000, talc, indigo carmine aluminum lake (E132), yellow iron oxide (E172)).

7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.

Clinical-Pharmacological Group

Antiparathyroid drug

Pharmacotherapeutic Group

Antiparathyroid agent

Pharmacological Action

Antiparathyroid agent. Calcium-sensing receptors located on the surface of the chief cells of the parathyroid glands are the main regulators of parathyroid hormone (PTH) secretion. Cinacalcet has a calcimimetic action, directly reducing PTH levels by increasing the sensitivity of this receptor to extracellular calcium. The reduction in PTH is accompanied by a decrease in serum calcium levels.

The reduction in PTH levels correlates with the concentration of cinacalcet. Soon after taking cinacalcet, PTH levels begin to decrease, with the maximum reduction occurring approximately 2-6 hours after a single dose, which corresponds to the C_max of cinacalcet. After this, the concentration of cinacalcet begins to decrease, and the PTH concentration increases over 12 hours after dose administration, and then PTH suppression remains at approximately the same level until the end of the 24-hour interval with a once-daily dosing regimen.

After reaching steady state, the serum calcium concentration remains constant throughout the interval between cinacalcet doses.

In patients with secondary hyperparathyroidism taking Cinacalcet, a significant decrease in intact PTH (iPTH), Ca × P (calcium-phosphorus product), and serum calcium and phosphorus levels was observed. The reduction in iPTH and Ca × P concentrations was maintained over 12 months of therapy. Cinacalcet reduced iPTH, Ca × P, calcium, and phosphorus levels regardless of baseline iPTH or Ca × P levels, dialysis regimen (peritoneal dialysis compared to hemodialysis), duration of dialysis, and whether vitamin D was used or not.

The reduction in PTH levels was associated with a non-significant decrease in bone metabolism markers (specific bone alkaline phosphatase, N-telopeptides, bone turnover, and bone fibrosis).

In clinical studies in patients with parathyroid carcinoma and primary hyperparathyroidism, Cinacalcet in doses from 30 mg twice daily to 90 mg four times daily caused a reduction in serum calcium concentration by ≥1 mg/dL (≥ 0.25 mmol/L).

Pharmacokinetics

After oral administration, the C_max of cinacalcet in plasma is reached approximately 2-6 hours later. The absolute bioavailability when taken on an empty stomach, established based on comparisons of results from various studies, was approximately 20-25%.

Increase in AUC and C_max of cinacalcet occurs almost linearly in the dose range of 30-180 mg once daily. At doses above 200 mg, absorption saturation is observed, likely due to poor solubility. The pharmacokinetic parameters of cinacalcet do not change over time.

C_ss of cinacalcet is reached within 7 days with minimal accumulation. There is a large V_d of approximately 1000 L, indicating wide distribution. Plasma protein binding is about 97%, with minimal distribution in red blood cells.

Cinacalcet is metabolized primarily by the CYP3A4 and CYP1A2 isoenzymes (the role of CYP1A2 has not been confirmed by clinical methods). The main metabolites found in the blood are inactive. According to in vitro studies, Cinacalcet is a potent inhibitor of CYP2D6. However, at concentrations achieved under clinical conditions, Cinacalcet does not suppress the activity of other isoenzymes (including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4) and is also not an inducer of CYP1A2, CYP2C19, and CYP3A4. After administration of a 75 mg radioisotope-labeled dose to healthy volunteers, Cinacalcet underwent rapid and significant oxidative metabolism followed by conjugation.

The decrease in cinacalcet concentration occurs in 2 stages: the initial T_1/2 is approximately 6 hours, the terminal T_1/2 is 30-40 hours.

Metabolites are mainly excreted by the kidneys: approximately 80% of the dose was found in urine and 15% in feces.

Compared to the group with normal liver function, the mean AUC values of cinacalcet were approximately 2 times higher in the group with moderate liver impairment, and approximately 4 times higher in severe liver failure. The mean T_1/2 of cinacalcet in patients with moderate and severe liver failure increases by 33% and 70%, respectively.

Clearance of cinacalcet may be lower in women than in men.

Clearance of cinacalcet is higher in smokers than in non-smokers. This appears to be due to induction of CYP1A2-mediated metabolism. If a patient stops or starts smoking during therapy, the plasma concentration of cinacalcet may change and dose adjustment may be required.

Indications

Secondary hyperparathyroidism in patients with end-stage renal disease on dialysis; hypercalcemia in patients (for the purpose of reducing severity) caused by the following conditions: parathyroid carcinoma and primary hyperparathyroidism, if, despite serum calcium concentrations, parathyroidectomy is clinically unacceptable or contraindicated.

ICD codes

Dosage Regimen

Take orally once daily, with food or shortly after a meal.

Swallow tablets whole; do not split, crush, or chew.

Initiate treatment at a starting dose of 30 mg once daily.

Measure serum parathyroid hormone (PTH) and corrected serum calcium concentrations no earlier than 12 hours after the dose.

Titrate the dose no more frequently than every 2 to 4 weeks.

Increase the dose sequentially through 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg once daily.

For secondary hyperparathyroidism in dialysis patients, do not exceed a maximum dose of 180 mg daily.

For parathyroid carcinoma and primary hyperparathyroidism, titrate up to a maximum dose of 360 mg daily, administered as 90 mg four times daily.

Monitor serum calcium levels frequently during therapy initiation and dose titration.

If hypocalcemia develops, initiate appropriate treatment with calcium supplements, vitamin D sterols, and/or adjust dialysate calcium.

For persistent hypocalcemia, reduce the dose or discontinue therapy based on clinical severity.

Adjust the dose or discontinue treatment if PTH levels are suppressed below the target range.

Evaluate patients with moderate to severe hepatic impairment for signs of toxicity; dose adjustment may be necessary.

Re-evaluate the cinacalcet dose if a patient starts or stops smoking, or begins or ends therapy with a potent CYP3A4 inhibitor.

Adverse Reactions

From the digestive system very often – nausea, vomiting; often – anorexia; sometimes – dyspepsia, diarrhea.

From the nervous system: often – dizziness, paresthesia; sometimes – seizures.

From the musculoskeletal system: often – myalgia.

From the endocrine system often – decreased testosterone levels.

Dermatological reactions: often – rash.

Allergic reactions sometimes – hypersensitivity reactions.

From the cardiovascular system: in patients with heart failure, isolated idiosyncratic cases of decreased blood pressure and/or worsening of heart failure have been reported.

Other often – asthenia, hypocalcemia.

Contraindications

Childhood and adolescence under 18 years; hypersensitivity to cinacalcet.

Use in Pregnancy and Lactation

There are no clinical data on the use of cinacalcet during pregnancy. Use during pregnancy is only possible if the expected benefit to the mother outweighs the potential risk to the fetus.

The possibility of cinacalcet excretion in human breast milk has not been studied to date. If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be considered.

In experimental studies during preclinical studies of cinacalcet in rabbits, it was shown that Cinacalcet crosses the placental barrier. No direct negative impact on the course of pregnancy, childbirth, or postnatal development was identified. No embryotoxic or teratogenic effects were identified in experiments on pregnant rats and rabbits, except for a reduction in fetal body weight in rats when using doses that caused toxicity in pregnant females. Cinacalcet is excreted in the breast milk of lactating rats, with a high milk/plasma concentration ratio noted.

Special Precautions

Cinacalcet should not be used when the serum calcium concentration (adjusted for albumin) is below the lower limit of the normal range. Since Cinacalcet lowers serum calcium concentration, careful monitoring of patients for the development of hypocalcemia is necessary.

In case of hypocalcemia, to increase serum calcium levels, calcium-containing phosphate binders, vitamin D, and/or adjustment of the calcium concentration in the dialysis solution can be used. In case of persistent hypocalcemia, the dose of cinacalcet should be reduced or its use discontinued. Potential signs of developing hypocalcemia may include paresthesia, myalgia, cramps, tetany.

Cinacalcet is not indicated for patients with chronic kidney disease not on dialysis, due to an increased risk of developing hypocalcemia (serum calcium concentration <8.4 mg/dL or <2.1 mmol/L) compared to patients on dialysis, which may be due to lower baseline calcium levels and/or the presence of residual renal function.

Cinacalcet should be used with caution and under careful monitoring of liver function in patients with moderate and severe hepatic impairment (Child-Pugh scale), because in such cases, the plasma concentration of cinacalcet may be 2-4 times higher.

Chronic suppression of PTH concentration below a concentration of approximately 1.5% of the upper limit of normal according to iPTH assay results may lead to the development of adynamic bone disease. If the PTH concentration falls below the recommended range, the dose of cinacalcet and/or vitamin D should be reduced, or therapy should be discontinued.

Effect on ability to drive vehicles and operate machinery

Some adverse reactions of cinacalcet may affect the ability to drive vehicles or operate machinery.

Drug Interactions

Cinacalcet is partially metabolized by the CYP3A4 isoenzyme. Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) at a dose of 200 mg twice daily led to an approximately 2-fold increase in the plasma concentration of cinacalcet. If concurrent use of potent inhibitors (e.g., ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducers of CYP3A4 (e.g., rifampicin) is necessary, dose adjustment of cinacalcet may be required.

In vitro experimental studies have shown that Cinacalcet is partially metabolized by 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 the plasma concentration of cinacalcet has not been studied. Dose adjustment may be required if during therapy the patient starts/stops smoking or starts/stops concurrent use of potent CYP1A2 inhibitors.

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

Concomitant administration of cinacalcet at a dose of 90 mg once daily with desipramine (a tricyclic antidepressant metabolized by CYP2D6) at a dose of 50 mg increased the exposure level of desipramine by 3.6 times in patients with active CYP2D6 metabolism.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.