Tsinakaltset-Edvansd (Tablets) Instructions for Use

Marketing Authorization Holder

Advanced Pharma, LLC (Russia)

ATC Code

H05BX01 (Cinacalcet)

Active Substance

Cinacalcet (Rec.INN registered by WHO)

Dosage Forms

	Cinacalcet-Advanced	Film-coated tablets 30 mg: 10, 20, 30 or 60 pcs.
		Film-coated tablets 60 mg: 10, 20, 30 or 60 pcs.
		Film-coated tablets 90 mg: 10, 20, 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light green to green, round, biconvex; on the cross-section the core is from almost white to white.

Excipients: microcrystalline cellulose, sodium starch glycolate, hypromellose, anhydrous calcium hydrogen phosphate, magnesium stearate.

Shell composition Wincoat WT-1447 blue shell (hypromellose, polyethylene glycol 3350, titanium dioxide, talc, brilliant blue aluminum lake), quinoline yellow dye.

10 pcs. – blister (1, 2, 3 or 6) – cardboard packs.
10, 20, 30 or 60 pcs. – jar (1) – cardboard packs.

Film-coated tablets from light green to green, round, biconvex; on the cross-section the core is from almost white to white.

Excipients: microcrystalline cellulose, sodium starch glycolate, hypromellose, anhydrous calcium hydrogen phosphate, magnesium stearate.

Shell composition Wincoat WT-1447 blue shell (hypromellose, polyethylene glycol 3350, titanium dioxide, talc, brilliant blue aluminum lake), quinoline yellow dye.

10 pcs. – blister (1, 2, 3 or 6) – cardboard packs.
10, 20, 30 or 60 pcs. – jar (1) – cardboard packs.

Film-coated tablets from light green to green, round, biconvex; on the cross-section the core is from almost white to white.

Excipients: microcrystalline cellulose, sodium starch glycolate, hypromellose, anhydrous calcium hydrogen phosphate, magnesium stearate.

Shell composition Wincoat WT-1447 blue shell (hypromellose, polyethylene glycol 3350, titanium dioxide, talc, brilliant blue aluminum lake), quinoline yellow dye.

10 pcs. – blister (1, 2, 3 or 6) – cardboard packs.
10, 20, 30 or 60 pcs. – jar (1) – 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 effect, directly reducing PTH levels by increasing the sensitivity of this receptor to extracellular calcium. The decrease 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, the PTH level begins to decrease: the maximum reduction occurs 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 concentration of PTH increases within 12 hours after taking the dose, 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) levels, 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 at 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 in approximately 2-6 hours. The absolute bioavailability when taken on an empty stomach, established based on the comparison of results from various studies, was approximately 20-25%.

The 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, probably 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 radiolabeled dose to healthy volunteers, Cinacalcet underwent rapid and extensive 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 hepatic impairment, and approximately 4 times higher in severe hepatic failure. The mean T_1/2 of cinacalcet in patients with moderate and severe hepatic impairment increases by 33% and 70%, respectively.

The clearance of cinacalcet may be lower in women than in men.

The 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 a 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 diseases: parathyroid carcinoma and primary hyperparathyroidism, if, despite serum calcium concentrations, parathyroidectomy is clinically unacceptable or contraindicated.

ICD codes

Dosage Regimen

Take orally with food or shortly after a meal. Swallow tablets whole; do not split, crush, or chew.

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

For secondary hyperparathyroidism in dialysis patients, titrate the dose no more frequently than every 2 to 4 weeks. Sequential dose adjustments should be to 60 mg, 90 mg, 120 mg, and 180 mg once daily, based on tolerability and therapeutic response.

For parathyroid carcinoma and primary hyperparathyroidism, titrate the dose every 2 to 4 weeks. Sequential dose adjustments should be to 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily.

Monitor serum parathyroid hormone (PTH) and calcium concentrations closely during dose titration and after reaching the maintenance dose. Measure PTH levels 12 to 24 hours after the most recent dose.

For dialysis patients, the target intact PTH (iPTH) concentration is typically 150 to 300 pg/mL. For primary hyperparathyroidism and parathyroid carcinoma, the target is a reduction in serum calcium.

If serum calcium falls below the normal range, initiate appropriate management with calcium supplements, calcium-containing phosphate binders, and/or vitamin D sterols. For persistent or symptomatic hypocalcemia, reduce the dose or discontinue therapy.

The maximum daily dose is 180 mg for secondary hyperparathyroidism and 360 mg for parathyroid carcinoma and primary hyperparathyroidism.

In patients with moderate to severe hepatic impairment, initiate therapy at the lowest available dose and titrate cautiously. Monitor plasma drug concentrations if possible.

Adjust the dose if a patient starts or stops smoking, or begins or ends concomitant therapy with a potent CYP3A4 inhibitor or inducer.

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: isolated idiosyncratic cases of decreased blood pressure and/or worsening of heart failure were recorded in patients with heart failure.

Other often – asthenia, hypocalcemia.

Contraindications

Children and adolescents under 18 years of age; hypersensitivity to cinacalcet.

Use in Pregnancy and Lactation

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

The possibility of excretion of cinacalcet into 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 decrease in fetal body weight in rats when using doses that caused toxicity in pregnant females. Cinacalcet is excreted in breast milk in 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, seizures, 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 (according to the 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 the iPTH assay 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. Concomitant 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 concomitant 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 with the drug the patient starts/stops smoking or starts/stops concomitant 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 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.