Kokotsina

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KOKOTSINA (KOKOTSINA)

Composition:

Active substance: cinacalcet hydrochloride;

One film-coated tablet contains 33.06 mg or 66.12 mg or 99.18 mg of cinacalcet hydrochloride, equivalent to 30 mg or 60 mg or 90 mg of cinacalcet;

Excipients: microcrystalline cellulose, pregelatinized starch, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Film coating: hydroxypropylmethyl 6 cps/hypromellose, titanium dioxide (E 171), hydroxypropylmethylcellulose 3 cps/hypromellose, lactose monohydrate, triacetin/glycerin triacetate, yellow iron oxide (E 172), FD&C Blue 2/indigo carmine aluminum lake (12–14% dye) (E 132), HPMC/hypromellose, macrogol/PEG.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg: light green, oval, film-coated tablets, marked "30" on one side;

60 mg: light green, oval, film-coated tablets, marked "60" on one side;

90 mg: light green, oval, film-coated tablets, marked "90" on one side.

Pharmacotherapeutic group. Hormonal preparations for systemic use (excluding sex hormones and insulin). Medicinal products regulating calcium metabolism. Other anti-parathyroid agents. Cinacalcet. ATC code H05BX01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Calcium-sensing receptors located on the surface of the chief cells of the parathyroid gland are the main regulators of parathyroid hormone (PTH) secretion. Cinacalcet exerts a calcimimetic effect, directly reducing PTH levels by 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 a 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 administered under fasting conditions, determined based on comparison of results from different 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 the meal.

During administration of 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, and 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.

Metabolism.

Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4 and CYP1A2 (the role of CYP1A2 has not been confirmed clinically). 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 through renal excretion of metabolites. Approximately 80% of the administered dose was recovered in urine and 15% in feces. Linearity/non-linearity.

The increase in the area under the pharmacokinetic concentration–time curve (AUC) and Cmax is nearly linear over the dose range of 30 mg to 180 mg administered once daily.

Pharmacokinetic/pharmacodynamic relationship.

Shortly after administration of cinacalcet, PTH levels begin to decrease and reach the lowest point approximately 2–6 hours later, corresponding to the time of Cmax of cinacalcet. Thereafter, cinacalcet concentration begins to decline, and PTH levels increase over the 12 hours following dose administration; however, PTH suppression remains approximately at 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 during clinical trials with 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. In patients with mild hepatic impairment, no notable effect on the pharmacokinetics of cinacalcet has been observed. 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. Gender. Clearance of cinacalcet may be lower in women than in men. However, since dose titration is individualized, no additional dose adjustment based on patient gender is necessary. A population pharmacokinetic analysis was conducted to assess the impact of demographic characteristics. This analysis did not show a significant effect of age, gender, race, body surface area, or body weight on the pharmacokinetics of cinacalcet.

Smoking. Clearance of cinacalcet is higher in smokers compared to non-smokers, likely due to CYP1A2-mediated metabolism induction. If a patient stops or starts smoking, plasma levels of cinacalcet may change, and dose adjustment may be required.

Clinical characteristics.

Indications.

Secondary hyperparathyroidism.

Adults.

Treatment of secondary hyperparathyroidism (sHPT) in adult patients with end-stage renal disease (ESRD) on maintenance hemodialysis. The medicinal product can be administered as part of a combination therapy including phosphate binders and/or vitamin D (see section Pharmacological properties). Parathyroid carcinoma and primary hyperparathyroidism in adults.

Reduction of hypercalcemia in adult patients with:

• parathyroid carcinoma;
• primary hyperparathyroidism, when parathyroidectomy is indicated (according to established treatment guidelines) to reduce serum calcium levels, but surgery is not feasible or contraindicated.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Hypocalcemia (see sections "Special precautions for use" and "Method of administration and dosage").

Interaction with other medicinal products and other forms of interaction.

Medicinal products known to reduce serum calcium levels.

Concomitant use of medicinal products that reduce serum calcium levels with cinacalcet may increase the risk of hypocalcemia. Etelcalcetide should not be prescribed to patients receiving cinacalcet.

Effect of other medicinal products on cinacalcet.

Cinacalcet is metabolized by the CYP3A4 enzyme. Concomitant administration of 200 mg ketoconazole, a strong CYP3A4 inhibitor, resulted in approximately a 2-fold increase in cinacalcet levels. 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 show 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 when a patient starts or stops smoking or when concomitant therapy with a strong CYP1A2 inhibitor is initiated or discontinued.

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 cytochrome P450 2D6 (CYP2D6). Cinacalcet is a strong inhibitor of CYP2D6; therefore, dose adjustment may be necessary for concomitant medicinal products with a narrow therapeutic index that are primarily metabolized by CYP2D6 (e.g., flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine).

Desipramine. Concomitant administration of 90 mg cinacalcet once daily with 50 mg desipramine (a tricyclic antidepressant primarily metabolized by CYP2D6) significantly increased the exposure to desipramine by 3.6-fold (90% confidence interval (CI) 3.0) in CYP2D6 extensive metabolizers.

Dextromethorphan. Multiple doses of 50 mg cinacalcet increased the AUC of dextromethorphan (mainly metabolized by CYP2D6) by 11-fold.

Warfarin. Multiple oral doses of cinacalcet did not affect the pharmacokinetics and pharmacodynamics of warfarin (as assessed by prothrombin time and factor VII clotting activity).

The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of autoinduction in patients after multiple dosing 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.

Cinacalcet should not be initiated in patients with serum calcium levels (corrected for albumin) below the lower limit of the normal range.

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 result in ventricular arrhythmia due to hypocalcemia. Cases of QT interval prolongation and ventricular arrhythmias have been reported in patients treated with cinacalcet (see section "Adverse reactions"). The drug should be used with caution in patients with other risk factors for QT prolongation, such as patients with known congenital long QT syndrome or patients receiving medicinal products known to cause QT prolongation. Since cinacalcet lowers 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. After the maintenance dose has been established, serum calcium levels should be measured approximately once a month.

Approximately 30% of dialysis patients with chronic kidney disease (CKD) treated with cinacalcet had at least one serum calcium concentration below 7.5 mg/dL (1.9 mmol/L).

Cinacalcet is not indicated for use in CKD patients not on dialysis. Studies have shown that non-dialysis CKD patients treated with cinacalcet have an increased risk of developing hypocalcemia (serum calcium < 8.4 mg/dL [2.1 mmol/L]) compared to dialysis CKD patients treated with cinacalcet. This may be related to low baseline calcium levels and/or residual kidney function.

Seizures.

During clinical trials, seizures were reported in 1.4% of patients treated with cinacalcet and in 0.7% of patients in the placebo group. Although the reasons for the reported differences in seizure frequency are unclear, the seizure threshold is lowered with significant reductions in serum calcium concentration.

Arterial hypotension and/or worsening heart failure.

During post-marketing safety surveillance of cinacalcet, isolated cases of arterial hypotension and/or worsening heart failure were reported in patients with cardiac disease. A causal relationship between cinacalcet use and these adverse events, possibly related to reduced serum calcium levels, cannot be entirely ruled out. According to clinical trial data, arterial hypotension occurred in 7% of patients receiving cinacalcet and in 12% of patients receiving placebo, while heart failure occurred in 2% of patients receiving either cinacalcet or placebo.

General.

Chronic suppression of PTH concentration to levels 1.5 times below the upper normal limit for PTH may lead to adynamic bone disease. If PTH levels fall below the recommended range in patients treated with cinacalcet, the dose of the drug and/or vitamin D should be reduced or therapy discontinued.

Concomitant use with other medicinal products.

Cinacalcet should be used with caution in patients receiving any other medicinal products known to reduce serum calcium levels. Serum calcium levels should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Patients receiving cinacalcet should not be prescribed etelcalcetide. Concomitant use may lead to severe hypocalcemia.

Testosterone levels.

Testosterone levels are commonly below normal in patients with end-stage renal disease. Data from a clinical trial involving dialysis patients with ESRD showed that free testosterone concentration decreased by an average of 31.3% in patients treated with cinacalcet and by 16.3% in the placebo group after 6 months of therapy. 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 these reductions 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 condition should be closely monitored (see sections "Pharmacokinetics" and "Dosage and administration").

Important information about excipients.

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

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, parturition, or postnatal development. No embryotoxic/fetotoxic effects were observed in studies on pregnant animals, except for reduced fetal body weight at doses associated with maternal toxicity. Therefore, cinacalcet should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

It is unknown whether cinacalcet passes into human breast milk. Cinacalcet is excreted into the milk of lactating rats, with a high milk-to-plasma concentration ratio. After careful assessment of the benefit-risk ratio, a decision should be made whether to discontinue breastfeeding or 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.

The medicinal product may substantially affect the ability to drive or operate machinery, as dizziness and seizures have been reported in patients taking cinacalcet (see section "Special precautions for use").

Method of administration and dosage.

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, achieving the target parathyroid hormone (PTH) concentration of 150–300 pg/mL (15.9–31.8 pmol/L) in hemodialysis patients, as measured by intact PTH assay (PTH test). PTH concentration should be determined 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 determined 1–4 weeks after initiation of therapy or after dose adjustment of cinacalcet. For monitoring PTH concentration, measurement of iPTH or bio-intact PTH (bPTH) is recommended every 1–3 months during medical check-ups. Treatment with cinacalcet does not alter the ratio between iPTH and bPTH.

Dosage adjustment depending on serum calcium levels.

Serum calcium should be measured and controlled prior to the first dose of cinacalcet and should be at the lower limit of the normal range or above (see section "Special precautions"). The normal calcium range may vary depending on the methods used in the respective 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 should be measured approximately monthly.

If serum calcium levels fall below 8.4 mg/dL (2.1 mmol/L) and/or symptoms of hypocalcemia occur, the following measures are recommended.

Table 1

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 dialysate 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 levels reach 8.0 mg/dL (2.0 mmol/L) and/or hypocalcemia symptoms resolve. Therapy should be resumed at the next lower dose of cinacalcet.

Transition from etelcalcetide to cinacalcet.

Transition from etelcalcetide to cinacalcet and the corresponding washout period has not been studied in patients. Patients who have discontinued etelcalcetide treatment should not initiate cinacalcet until after completion of at least three subsequent hemodialysis sessions, after which serum calcium levels should be measured. Before starting cinacalcet, it is necessary 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 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 initiating therapy or adjusting the cinacalcet dose. After reaching the maintenance dose, serum calcium should be monitored every 2–3 months. Following completion of the titration period 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 intended for use in children and adolescents due to lack of safety and efficacy data (see section "Special precautions"). Hepatic impairment.

No adjustment of the initial dose is required. Cinacalcet should be used with caution in patients with moderate and severe hepatic impairment. Such patients should be closely monitored during dose titration and long-term treatment (see sections "Pharmacodynamics" and "Special precautions").

Method of administration.

For oral use. Cinacalcet 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, without crushing or chewing.

Children.

The medicinal product is not indicated for use in children. Safety and efficacy for the treatment of parathyroid carcinoma and primary hyperparathyroidism in this patient population have not been established. No data are available.

Overdose.

Adult patients on dialysis have received doses titrated up to 300 mg once daily without adverse outcomes. One case was reported in a pediatric patient who received an administered daily dose of 3.9 mg/kg during dialysis in a clinical trial, resulting in mild abdominal pain, nausea, and vomiting. Symptoms. Overdose of cinacalcet may lead to hypocalcemia.

Treatment. In case of overdose, patients should be evaluated for symptoms of hypocalcemia, and treatment should be symptomatic and supportive. Because cinacalcet is highly protein-bound, hemodialysis is not an effective method for treating overdose.

Adverse Reactions

Summary of safety profile.

Secondary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism.

Based on available data from patients who received cinacalcet in placebo-controlled and uncontrolled studies, the most commonly reported adverse reactions were nausea and vomiting. In most patients, nausea and vomiting were of mild to moderate severity and transient. Discontinuation of therapy due to adverse reactions was primarily attributed to nausea and vomiting.

Tabulated list of adverse reactions.

Adverse reactions that are at least possibly related to cinacalcet treatment in placebo-controlled and uncontrolled studies, based on an assessment of causal relationship, are listed below by 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); frequency not known (cannot be estimated from available data).

Table 2

Frequency of adverse reactions based on controlled clinical studies and post-marketing experience.

MedDRA System Organ Class	Frequency of occurrence	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 due to hypocalcemia**, hypotension
Respiratory system disorders	common	upper respiratory tract infections, dyspnea, cough, dyspnoea
Gastrointestinal disorders	very common	nausea, vomiting
	common	dyspepsia, diarrhea, 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**, hyperkalemia, decreased testosterone levels**

** See section "Special precautions for use".

* See section "Description of selected adverse reactions".

Description of selected adverse reactions.

Hypersensitivity reactions.

Hypersensitivity reactions, including angioedema and urticaria, have been reported during post-marketing use of cinacalcet. The frequency of individual adverse reactions, including angioedema and urticaria, cannot be estimated from the available data.

Arterial hypotension and/or worsening of heart failure.

There have been reports of idiosyncratic cases of arterial hypotension and/or exacerbation of heart failure in patients with cardiac dysfunction during post-marketing safety surveillance of cinacalcet; the frequency cannot be estimated from the available data.

QT interval prolongation and ventricular arrhythmia due to hypocalcemia.

Prolongation of the QT interval and secondary ventricular arrhythmia due to hypocalcemia have been identified during post-marketing use of cinacalcet; the frequency cannot be estimated from the available data (see section "Special precautions for use").

Paediatric patients.

The safety of cinacalcet for the treatment of secondary hyperparathyroidism in paediatric patients with ESRD on dialysis was evaluated in two randomised controlled trials and one uncontrolled trial. Among all paediatric patients who received cinacalcet in clinical trials, at least one adverse reaction in the form of hypocalcemia occurred in 19 patients. A fatal outcome was reported in a patient with severe hypocalcemia. Cinacalcet should be used in children only when the expected benefit outweighs the potential risk.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging.

14 film-coated tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

DEVA Holding A.Ş.

Manufacturer's address and site of activity.

Karaagac Mahallesi, Ataturk Caddesi No 32, Cerkezkoy Organize Sanayi Bolgesi, Kapaklı, Tekirdag, 59510, Turkey