Cintrex
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CINTREX (CINTREX)
Composition:
Active substance: cinacalcet;
One film-coated tablet contains 30 mg of cinacalcet (as cinacalcet hydrochloride), or 60 mg of cinacalcet (as cinacalcet hydrochloride), or 90 mg of cinacalcet (as cinacalcet hydrochloride);
Excipients: microcrystalline cellulose, pregelatinized starch, crospovidone, magnesium stearate, talc;
Film coating of the tablet: Opadry® II Green 32K510043 (hypromellose, lactose monohydrate, titanium dioxide [E 171], triacetin, indigo carmine [E 132], iron oxide yellow [E 172]); Aquarius BP 19008 ICE (hypromellose, polyethylene glycol).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
30 mg: light green, oval, biconvex film-coated tablets with "H" on one side and "C6" on the other;
60 mg: light green, oval, biconvex film-coated tablets with "H" on one side and "C7" on the other;
90 mg: light green, oval, biconvex film-coated tablets with "H" on one side and "C8" on the other.
Pharmacotherapeutic group. Hormones for systemic use (excluding sex hormones and insulin). Medicinal products regulating calcium metabolism. Other anti-parathyroid agents. Cinacalcet.
ATC code H05B X01.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action
Calcium-sensing receptors located on the surface of chief cells of the parathyroid gland are the main regulators of parathyroid hormone (PTH) secretion. Cinacalcet exerts a calcimimetic effect by directly reducing PTH levels, increasing the sensitivity of the calcium-sensing receptor to extracellular calcium levels. Reduction in PTH levels is accompanied by a decrease in serum calcium concentration. The reduction in PTH levels correlates with cinacalcet concentration. After reaching steady state, serum calcium concentration remains at a constant level throughout the dosing interval.
Pharmacokinetics.
Absorption
Following oral administration, maximum plasma concentration (Cmax) of cinacalcet is reached approximately within 2–6 hours. Absolute bioavailability of cinacalcet when administered on an empty stomach, determined based on comparison of results from various studies, is approximately 20–25%. Administration of cinacalcet with food increases its bioavailability by approximately 50–80%. This increase in plasma cinacalcet concentration is observed independently of the fat content in food.
At doses exceeding 200 mg, absorption becomes saturated, likely due to low solubility.
Distribution
A high volume of distribution (approximately 1000 L) is observed, indicating extensive distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into erythrocytes.
Following absorption, the decline in cinacalcet concentration occurs in two phases; the initial half-life is approximately 6 hours, while the terminal half-life ranges from 30 to 40 hours. Steady-state levels of cinacalcet are achieved within 7 days with minimal accumulation. The pharmacokinetic properties of cinacalcet do not change over time.
Biotransformation
Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4 and CYP1A2 (the role of CYP1A2 has not been confirmed by clinical methods). The main circulating metabolites are inactive. According to in vitro data, cinacalcet is a potent inhibitor of CYP2D6; however, at concentrations achieved under clinical conditions, cinacalcet is not an inhibitor of other CYP enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, nor is it an inducer of CYP1A2, CYP2C19, and CYP3A4.
Elimination
After administration of a radiolabeled 75 mg dose to healthy volunteers, cinacalcet underwent rapid and extensive oxidative metabolism followed by conjugation. Elimination of radioactivity occurred primarily via renal excretion of metabolites. Approximately 80% of the administered dose was recovered in urine and 15% in feces.
Linearity/non-linearity
AUC (area under the curve) and Cmax (maximum concentration) of cinacalcet increase almost linearly over the dose range of 30 to 180 mg when administered once daily.
Pharmacokinetic/pharmacodynamic interactions
Shortly after cinacalcet administration, PTH levels begin to decrease and reach their lowest point approximately 2–6 hours later, corresponding to the time of Cmax attainment for cinacalcet. Thereafter, cinacalcet concentration begins to decline, while PTH levels increase over the 12 hours following dose administration; however, PTH suppression remains at approximately the same level until the end of the 24-hour dosing interval with once-daily dosing. PTH levels were measured at the end of the dosing interval in clinical trials of cinacalcet.
Elderly patients. No clinically significant differences in the pharmacokinetics of cinacalcet related to patient age have been observed.
Renal impairment. The pharmacokinetic profile of cinacalcet in patients with mild, moderate, or severe renal impairment, as well as in patients undergoing hemodialysis or peritoneal dialysis, does not differ significantly from that in healthy volunteers.
Hepatic impairment. Mild hepatic impairment does not have a noticeable effect on the pharmacokinetics of cinacalcet. Compared to patients with normal liver function, mean AUC values were approximately 2-fold higher in patients with moderate hepatic impairment and approximately 4-fold higher in patients with severe hepatic impairment. The mean elimination half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. Hepatic impairment does not affect the extent of cinacalcet binding to plasma proteins. Since dose titration for each patient is based on efficacy and safety parameters, no additional dose adjustment is required for patients with hepatic impairment (see sections "Dosage and administration" and "Special precautions").
Gender. The clearance of cinacalcet may be lower in women than in men. As dosing is individualized, no additional dose adjustment based on patient gender is necessary.
Smoking. The clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of CYP1A2-mediated metabolism. If a patient stops or starts smoking, plasma levels of cinacalcet may change, and dose adjustment may be necessary.
Clinical Characteristics.
Indications.
For the treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on dialysis.
Cinacalcet may be administered as part of a combined therapy regimen including phosphate binders and/or vitamin D sterols (see section "Pharmacodynamics").
For the reduction of hypercalcemia in patients with:
- parathyroid carcinoma;
- primary HPT, when parathyroidectomy (according to established treatment guidelines) is indicated to lower serum calcium levels, but is not feasible or contraindicated due to the patient's condition.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
Hypocalcemia (see sections "Dosage and Administration" and "Special Warnings").
Interaction with other medicinal products and other forms of interaction.
Medicinal products that reduce serum calcium levels
Concomitant use of other medicinal products that lower serum calcium levels and cinacalcet may increase the risk of hypocalcemia (see section "Special Warnings"). Patients receiving cinacalcet should not be prescribed etelcalcetide (see section "Special Warnings").
Effect of other medicinal products on cinacalcet
Cinacalcet is metabolized by the enzyme CYP3A4. Concomitant administration of 200 mg ketoconazole twice daily, a strong CYP3A4 inhibitor, increased cinacalcet exposure by approximately 2-fold. Dose adjustment of cinacalcet may be necessary when a patient receiving cinacalcet starts or stops treatment with a strong inhibitor (e.g., ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (e.g., rifampicin) of this enzyme.
In vitro data indicate that cinacalcet is partially metabolized via CYP1A2. Smoking stimulates CYP1A2; plasma levels of cinacalcet observed in smokers were 36–38% higher than in non-smokers. The effect of CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) on plasma levels of cinacalcet has not been studied. Dose adjustment may be required if a patient starts or stops smoking or begins or discontinues concomitant therapy with a strong CYP1A2 inhibitor.
Calcium carbonate. Concomitant administration of calcium carbonate (single dose of 1500 mg) does not alter the pharmacokinetics of cinacalcet.
Sevelamer. Concomitant administration of sevelamer (2400 mg three times daily) does not affect the pharmacokinetics of cinacalcet.
Pantoprazole. Concomitant administration of pantoprazole (80 mg once daily) does not alter the pharmacokinetics of cinacalcet.
Effect of cinacalcet on other medicinal products
Medicinal products metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Cinacalcet is a strong inhibitor of CYP2D6. Therefore, dose adjustment may be necessary for concomitantly administered drugs that require individual dose titration and have a narrow therapeutic index, primarily metabolized by CYP2D6 (e.g., flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine) (see section "Special Warnings").
Desipramine. Concomitant administration of 90 mg cinacalcet once daily with 50 mg desipramine (a tricyclic antidepressant primarily metabolized by CYP2D6) significantly increased desipramine exposure by 3.6-fold (90% confidence interval (CI) 3.0) in CYP2D6 extensive metabolizers.
Dextromethorphan. During multiple dosing of cinacalcet 50 mg, the AUC of dextromethorphan (a substrate primarily metabolized by CYP2D6) administered at a dose of 30 mg increased 11-fold in CYP2D6 extensive metabolizers.
Warfarin. Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics of warfarin (as assessed by prothrombin time and coagulation factor VII levels).
The absence of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the lack of autoinduction in patients receiving multiple doses indicate that cinacalcet is not an inducer of CYP3A4, CYP1A2, or CYP2C9 in humans.
Midazolam. Concomitant administration of cinacalcet (90 mg) and oral midazolam (2 mg), a substrate of CYP3A4 and CYP3A5, did not alter the pharmacokinetics of midazolam. These data suggest that cinacalcet does not affect the pharmacokinetics of drugs metabolized by CYP3A4 and CYP3A5, including certain immunosuppressants such as cyclosporine and tacrolimus.
Special precautions for use.
Serum calcium levels
There have been reports of life-threatening events and fatal cases in adults and children receiving cinacalcet therapy. Potential manifestations of hypocalcemia include paresthesia, muscle pain, spasms, tetany, and seizures. Decreased serum calcium levels may also lead to QT interval prolongation, which could potentially cause ventricular arrhythmia in the setting of hypocalcemia. Cases of QT interval prolongation and ventricular arrhythmia have been reported in patients receiving cinacalcet therapy (see section "Adverse reactions"). The drug should be used with caution in patients with other risk factors for QT interval prolongation, such as patients with congenital long QT syndrome or patients receiving medicinal products known to induce QT interval prolongation.
Since cinacalcet reduces serum calcium levels, patients should be closely monitored for the development of hypocalcemia (see section "Dosage and administration"). Serum calcium levels should be measured within 1 week after initiation or dose adjustment of cinacalcet.
Cinacalcet therapy should not be initiated in patients with serum calcium levels (corrected for albumin) below the lower limit of the normal range.
In approximately 30% of patients with chronic kidney disease (CKD) on dialysis receiving cinacalcet, serum calcium concentrations less than 7.5 mg/dL (1.9 mmol/L) were observed at least once.
CKD patients not on dialysis
Cinacalcet is not indicated for use in CKD patients not on dialysis. Studies have shown that CKD patients not on dialysis have an increased risk of developing hypocalcemia (serum calcium < 8.4 mg/dL [2.1 mmol/L]) when treated with cinacalcet compared to dialysis-dependent CKD patients receiving cinacalcet. This may be related to low baseline calcium levels and/or residual kidney function.
Seizures
There have been reports of seizures in patients receiving cinacalcet (see section "Adverse reactions"). The seizure threshold is lowered with significant reductions in serum calcium concentration. Therefore, careful monitoring of serum calcium levels is required in patients receiving cinacalcet, particularly in those with a history of seizures.
Arterial hypotension and/or worsening of heart failure
There have been reports of arterial hypotension and/or worsening of heart failure in patients with cardiac disease. A causal relationship between cinacalcet use and these adverse events cannot be entirely excluded, as they may be related to decreased serum calcium levels (see section "Adverse reactions").
Concomitant use with other medicinal products
Cinacalcet should be used with caution in patients receiving other medicinal products that lower serum calcium levels. Careful monitoring of serum calcium levels is required.
Patients taking cinacalcet should not be prescribed etelcalcetide. Concomitant use may lead to severe hypocalcemia.
General warnings
Chronic suppression of PTH concentration to levels 1.5 times below the upper limit of the normal range for intact PTH (iPTH) may lead to adynamic bone disease. If PTH levels fall below the recommended range in patients receiving cinacalcet, the dose of the drug and/or vitamin D should be reduced or therapy discontinued.
Testosterone levels
Testosterone levels are generally lower than normal in patients with end-stage chronic kidney disease. Data from a clinical study in adult patients with ESRD on dialysis showed that free testosterone concentrations decreased by an average of 31.3% in patients receiving cinacalcet and by 16.3% in the placebo group after 6 months of treatment. The open-label extension phase of this study did not show further decline in free and total testosterone concentrations over a 3-year treatment period with cinacalcet. The clinical significance of this reduction in serum testosterone levels is unknown.
Hepatic impairment
Due to the potential 2- to 4-fold increase in plasma cinacalcet levels in patients with moderate and severe hepatic impairment (Child-Pugh classification), cinacalcet should be used with caution in these patients, and their clinical status should be closely monitored (see sections "Dosage and administration" and "Pharmacokinetics").
Lactose
This medicinal product is contraindicated in patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Pregnancy
There are no clinical data on the use of cinacalcet in pregnant women. Animal studies do not indicate direct harmful effects on pregnancy, delivery, or postnatal development. Embryonal/fetal toxicity was not observed in pregnant animals, except for reduced fetal body weight at doses associated with maternal toxicity.
Cinacalcet may be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Breastfeeding
It is unknown whether cinacalcet passes into human breast milk. Cinacalcet is excreted into the milk of rats, with a high milk-to-plasma concentration ratio. After careful assessment of benefit/risks, a decision should be made either to discontinue breastfeeding or to discontinue cinacalcet therapy.
Fertility
There are no clinical data on the effect of cinacalcet on fertility. No effects on fertility were observed in animal studies.
Ability to affect reaction speed when driving or operating machinery
Cinacalcet may have a significant influence on the ability to drive vehicles or operate machinery, as dizziness and seizures have been reported in patients receiving this medicinal product (see section "Adverse reactions").
Dosage and Administration
Secondary Hyperparathyroidism
Adults, including elderly patients (> 65 years of age)
The recommended initial dose of the medicinal product for adults is 30 mg once daily. Dose titration of cinacalcet should be performed every 2–4 weeks up to the maximum dose of 180 mg once daily, to achieve the target parathyroid hormone (PTH) concentration of 150–300 pg/mL (15.9–31.8 pmol/L) in hemodialysis patients. The target PTH concentration should be determined by measuring intact PTH (intact PTH assay). PTH concentration should be measured no sooner than 12 hours after cinacalcet administration. For assessment of PTH concentration, reference should be made to current treatment guidelines.
PTH concentration should be measured 1–4 weeks after initiation of therapy or after dose adjustment of cinacalcet. During maintenance therapy, PTH concentration should be monitored every 1–3 months. For monitoring PTH concentration, either intact PTH (iPTH) or bio-intact PTH (bio-PTH) may be used. Treatment with cinacalcet does not alter the ratio between iPTH and bio-PTH.
Dose adjustment based on serum calcium levels
Serum calcium levels (corrected) should be measured and monitored and must be at or above the lower limit of the normal range prior to the first dose of cinacalcet (see section "Special Warnings and Precautions for Use"). The normal reference range for calcium may vary depending on the assay method used by your laboratory.
During dose titration, serum calcium levels should be monitored more frequently and no later than 1 week after initiation of treatment or dose adjustment of cinacalcet. After the maintenance dose has been established, serum calcium levels should be measured approximately monthly. If corrected serum calcium levels fall below 8.4 mg/dL (2.1 mmol/L) and/or symptoms of hypocalcemia occur, the following measures are recommended:
| Serum calcium level or clinical symptoms of hypocalcemia |
Recommendations |
| < 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL (1.9 mmol/L) or presence of clinical symptoms of hypocalcemia |
Calcium-based phosphate binders, vitamin D sterols, and/or adjustment of calcium concentration in dialysis fluid may be used to increase serum calcium levels according to clinical assessment. |
| < 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL (1.9 mmol/L) or persistent symptoms of hypocalcemia despite attempts to increase serum calcium levels |
Reduce dose or discontinue cinacalcet. |
| ≤ 7.5 mg/dL (1.9 mmol/L) or persistent symptoms of hypocalcemia and inability to increase vitamin D levels |
Discontinue cinacalcet until serum calcium level reaches at least 8.0 mg/dL (2.0 mmol/L) and/or hypocalcemia symptoms resolve. |
Transition from etelcalcetide to cinacalcet
The implications of switching from etelcalcetide to cinacalcet and the corresponding drug washout period in patients have not been studied. For patients who have discontinued etelcalcetide, cinacalcet should not be initiated earlier than after completion of three consecutive hemodialysis sessions. During this period, serum calcium levels should be monitored. Before initiating cinacalcet therapy, it is essential to ensure that serum calcium levels are within the normal range (see sections “Special precautions” and “Adverse reactions”).
Parathyroid carcinoma and primary hyperparathyroidism
Adults, including elderly patients (>65 years of age)
The recommended initial dose of cinacalcet for adults is 30 mg twice daily.
The cinacalcet dose should be titrated every 2–4 weeks in the following dose escalation sequence: 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and up to 90 mg three or four times daily, as needed, to reduce serum calcium concentration to the upper limit of normal or below. The maximum dose used in clinical trials was 90 mg four times daily.
Serum calcium levels should be measured within 1 week after initiation of therapy or after any dose adjustment of cinacalcet. After reaching the maintenance dose, serum calcium should be monitored every 2–3 months. Following completion of dose titration to the maximum dose, serum calcium levels should be monitored periodically; if a clinically meaningful reduction in serum calcium is not achieved, discontinuation of cinacalcet therapy should be considered (see section “Pharmacodynamics”).
Children
Cinacalcet is not indicated for use in children and adolescents due to lack of data on safety and efficacy (see section “Special precautions”).
Hepatic impairment
No initial dose adjustment is required. Cinacalcet should be used with caution in patients with moderate to severe hepatic impairment. Close monitoring of these patients is necessary during dose titration and long-term treatment (see sections “Special precautions” and “Pharmacodynamics”).
Method of administration
For oral use. Tablets should be taken with food or immediately after a meal, as studies have shown that the bioavailability of cinacalcet is increased when administered with food (see section “Pharmacodynamics”). Tablets should be swallowed whole and must not be crushed or divided.
Children.
The medicinal product is not indicated for use in children. Safety and efficacy in this patient population have not been established.
Overdose.
Titrated doses up to 300 mg once daily have been safely administered to dialysis patients.
Overdose of cinacalcet may lead to hypocalcemia. In case of overdose, patients should be evaluated for symptoms of hypocalcemia, and treatment should be symptomatic and supportive. Since cinacalcet is highly protein-bound, hemodialysis is not an effective method for managing overdose.
Adverse Reactions
Secondary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism
Based on available results from placebo-controlled studies involving patients receiving cinacalcet, the most commonly reported adverse reactions were nausea and vomiting, which were mostly mild to moderate in severity and transient in nature. Nausea and vomiting were generally mild to moderate in intensity and reversible in the majority of patients. Discontinuation of therapy due to adverse reactions was primarily attributed to nausea and vomiting.
Adverse reactions considered to be possibly related to the use of cinacalcet, observed in placebo-controlled and uncontrolled studies, are listed below according to frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
| MedDRA System Organ Classes |
Frequency |
Adverse Reaction |
| Immune system disorders |
Common* |
Hypersensitivity reactions |
| Metabolism and nutrition disorders |
Common |
Anorexia Decreased appetite |
| Nervous system disorders |
Common |
Seizures** Dizziness Paraesthesia Headache |
| Cardiac disorders |
Frequency unknown* |
Worsening of heart failure** QT interval prolongation and ventricular arrhythmia associated with hypocalcemia** |
| Common |
Hypotension |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Upper respiratory tract infections Dyspnoea Cough |
| Gastrointestinal disorders |
Very common |
Nausea Vomiting |
| Common |
Dyspepsia Diarrhoea Abdominal pain Upper abdominal pain Constipation |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash |
| Musculoskeletal and connective tissue disorders |
Common |
Myalgia Muscle spasms Back pain |
| General disorders and administration site conditions |
Common |
Asthenia |
| Investigations |
Common |
Hypocalcemia** Hyperkalaemia Decreased testosterone levels** |
⃰ ⃰ See section "Special precautions".
*See section "Description of selected adverse reactions".
Description of selected adverse reactions
Hypersensitivity reactions
Hypersensitivity reactions, including angioedema and urticaria, have been reported during the post-marketing period of cinacalcet use. The frequency of individual adverse reactions, including angioedema and urticaria, cannot be estimated from the available data.
Hypotension and/or worsening of heart failure
There have been reports of individual cases of hypotension and/or worsening of heart failure in patients with cardiac dysfunction receiving cinacalcet during the post-marketing surveillance period; based on the available data, the frequency of such cases cannot be determined.
QT interval prolongation and ventricular arrhythmia associated with hypocalcemia
QT interval prolongation and ventricular arrhythmia associated with hypocalcemia have been observed during the post-marketing use of cinacalcet. The frequency of these reactions cannot be estimated from the available data (see section "Special precautions").
Paediatric population
Cinacalcet is not intended for use in children. Data on the safety and efficacy of cinacalcet in paediatric patients are lacking. A fatal case was reported in a child with severe hypocalcemia (see section "Special precautions").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy through the Automated Information System of Pharmacovigilance at the following link: https://aisf.dec.gov.ua/.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 ºC.
Keep out of reach and sight of children.
Packaging.
14 tablets in a blister, 2 blisters in a cardboard box; 30 tablets in a container, 1 container in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Hetero Labs Limited.
Manufacturer's address and location of operations.
Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India /
Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.