Miraprimed (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Tyumen, LLC (Russia)

ATC Code

H05BX01 (Cinacalcet)

Active Substance

Cinacalcet (Rec.INN registered by WHO)

Dosage Forms

	Miraprimed	Film-coated tablets, 30 mg: 10, 14, 28, 30, 60, or 84 pcs.
		Film-coated tablets, 60 mg: 10, 14, 28, 30, 60, or 84 pcs.
		Film-coated tablets, 90 mg: 10, 14, 28, 30, 60, or 84 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: hypromellose E6 – 9 mg, anhydrous calcium hydrogen phosphate – 149 mg, sodium carboxymethyl starch – 12 mg, copovidone – 22 mg, silicified microcrystalline cellulose – 100 mg, sodium stearyl fumarate – 6.94 mg.
The mass of the tablet core is 332 mg.

Film coating composition polyvinyl alcohol – 2.4 mg, macrogol 4000 – 1.2 mg, talc – 1.32 mg, titanium dioxide – 1.08 mg.
The mass of the film coating is 6 mg.
The mass of the film-coated tablet is 338 mg.

10 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
14 pcs. – contour cell blisters (1) – cardboard packs.
14 pcs. – contour cell blisters (2) – cardboard packs.
14 pcs. – contour cell blisters (6) – cardboard packs.
14 pcs. – polyethylene jars (1) – cardboard packs.
28 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
60 pcs. – polyethylene jars (1) – cardboard packs.
84 pcs. – polyethylene jars (1) – cardboard packs.

Film-coated tablets from light yellow to yellow, oval, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: hypromellose E6 – 18 mg, anhydrous calcium hydrogen phosphate – 298 mg, sodium carboxymethyl starch – 24 mg, copovidone – 44 mg, silicified microcrystalline cellulose – 200 mg, sodium stearyl fumarate – 13.88 mg
The mass of the tablet core is 664 mg.

Film coating composition polyvinyl alcohol – 4.8 mg, macrogol 4000 – 2.4 mg, talc – 2.64 mg, titanium dioxide – 2.08 mg, iron oxide yellow dye – 0.08 mg.
The mass of the film coating is 12 mg.
The mass of the film-coated tablet is 676 mg.

10 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
14 pcs. – contour cell blisters (1) – cardboard packs.
14 pcs. – contour cell blisters (2) – cardboard packs.
14 pcs. – contour cell blisters (6) – cardboard packs.
14 pcs. – polyethylene jars (1) – cardboard packs.
28 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
60 pcs. – polyethylene jars (1) – cardboard packs.
84 pcs. – polyethylene jars (1) – cardboard packs.

Film-coated tablets white or almost white, oval, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: hypromellose E6 – 27 mg, anhydrous calcium hydrogen phosphate – 447 mg, sodium carboxymethyl starch – 36 mg, copovidone – 66 mg, silicified microcrystalline cellulose – 300 mg, sodium stearyl fumarate – 20.82 mg.
The mass of the tablet core is 996 mg.

Film coating composition polyvinyl alcohol – 7.2 mg, macrogol 4000 – 3.6 mg, talc – 3.96 mg, titanium dioxide – 3.24 mg.
The mass of the film coating is 18 mg.
The mass of the film-coated tablet is 1014 mg.

10 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
14 pcs. – contour cell blisters (1) – cardboard packs.
14 pcs. – contour cell blisters (2) – cardboard packs.
14 pcs. – contour cell blisters (6) – cardboard packs.
14 pcs. – polyethylene jars (1) – cardboard packs.
28 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
60 pcs. – polyethylene jars (1) – cardboard packs.
84 pcs. – polyethylene jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antiparathyroid drug

Pharmacotherapeutic Group

Drugs regulating calcium metabolism; antiparathyroid drugs, other antiparathyroid drugs

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 the level of PTH 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 level correlates with the concentration of cinacalcet. Soon after taking cinacalcet, the PTH level begins 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 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 the level of intact PTH (iPTH), Ca × P (calcium-phosphorus product), and serum calcium and phosphorus content was observed. The reduction in iPTH and Ca × P concentrations was maintained over 12 months of therapy. Cinacalcet reduced levels of iPTH, Ca × P, calcium, and phosphorus 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 markers of bone metabolism (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 blood plasma is reached in approximately 2-6 hours. The absolute bioavailability on an empty stomach, established based on the comparison of results from various studies, was approximately 20-25%.

An increase in the 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 achieved 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 extensive oxidative metabolism followed by conjugation.

The decrease in cinacalcet concentration occurs in 2 phases: 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 the urine and 15% in the 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 hepatic insufficiency. The mean T_1/2 of cinacalcet in patients with moderate and severe hepatic insufficiency 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 is apparently 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 once daily 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.

Measure serum calcium and iPTH levels within one week after initiation or any dose adjustment.

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

Increase dosage sequentially through available strengths: 30 mg, 60 mg, then 90 mg.

For secondary hyperparathyroidism, the target dose range is 30 mg to 180 mg daily.

For parathyroid carcinoma and primary hyperparathyroidism, the maximum daily dose is 360 mg.

Divide total daily doses above 180 mg into two administered doses.

If serum calcium falls below the normal range but remains ≥ 7.5 mg/dL, manage with calcium supplements, vitamin D sterols, and/or dialysate calcium adjustment.

If serum calcium falls below 7.5 mg/dL or symptoms of hypocalcemia occur, immediately withhold cinacalcet administration.

Resume therapy at the next lower dose after serum calcium normalizes.

For patients with moderate to severe hepatic impairment, initiate at the lowest starting dose of 30 mg and monitor closely.

Monitor iPTH levels every 1 to 3 months during maintenance therapy.

Avoid adynamic bone disease by adjusting or discontinuing therapy if iPTH falls below 100 pg/mL.

Adverse Reactions

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

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

From the musculoskeletal system: common – myalgia.

From the endocrine system common – decreased testosterone level.

Dermatological reactions: common – 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 were recorded.

Other common – 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 decided.

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 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 the serum calcium level, calcium-containing phosphate-binding drugs, 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.

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

With chronic suppression of PTH concentration below a concentration of approximately 1.5% of the upper limit of normal according to the iPTH assay, adynamic bone disease may develop. 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 the ability to drive vehicles and mechanisms

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 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 30°C (86°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.