Regpara

Regpara

Manufacturer:

Kyowa Kirin

Distributor:

DCH Auriga - Healthcare
/
Four Star
Full Prescribing Info
Contents
Cinacalcet HCl.
Description
Each tablet also contains the following inactive ingredients: Pregelatinized starch, crystalline cellulose, povidone, crospovidone, light anhydrous silicic acid, talc, magnesium stearate, lactose hydrate, hypromellose, titanium oxide, triacetin, macrogol 400, yellow iron sesquioxide blue no. 2 aluminium lake.
Cinacalcet HCl is N-[(1R)-1-(naphthalen-1-yl) ethyl]-3-[3-(trifluoromethyl) phenyl] propan-1-amine monohydrochloride. Molecular formula: C22H22F3N·HCl. Molecular weight: 393.87.
Cinacalcet occurs as a white to slightly yellowish white, crystalline powder. It is freely soluble in N,N-dimethylformamide, methanol and ethanol (99.5), slightly soluble in water and practically insoluble or insoluble in hexane. Melting point is approximately 181°C.
Action
Pharmacology: Inhibition of Parathyroid Hormone (PTH) Secretion (In Vitro): Cinacalcet was shown to inhibit PTH secretion from the bovine parathyroid cells and human parathyroid cells dose-dependently.
Suppression of Proliferation of Parathyroid Cells: Following repeated-dose oral administration to partially nephrectomized rats, cinacalcet was shown to inhibit proliferation of parathyroid cells and thereby suppress progression of parathyroid hyperplasia.
Decrease in the Serum PTH and Calcium Levels: Following single-dose oral administration to normal rats and partially nephrectomized rats, cinacalcet was shown to decrease the serum PTH and calcium levels dose-dependently.
Suppression of Bone Disorder: In patients with secondary hyperthyroidism, bone disorder develops due to increased serum PTH. Following repeated-dose oral administration to partially nephrectomized rats, cinacalcet was shown to suppress symptoms associated with bone disorder due to increased serum PTH eg, marrow fibrosis, cortical osteoporosis and decreases in cortical done density and bone strength.
Mechanism of Action: Cinacalcet exerts its effects by acting on calcium receptors on the surface of parathyroid cells. Calcium receptors control synthesis of PTH and proliferation of parathyroid cells, as well as secretion of PTH. The drug decreases the serum PTH level by acting on calcium receptors and mainly suppressing PTH secretion. Furthermore, in repeated-dose administration, its effect of suppressing proliferation of parathyroid cells is also considered to contribute to a decrease in serum PTH level.
Pharmacokinetics: Plasma Concentration Profiles After Single Oral Administration: Single oral administration of cinacalcet at doses of 25, 50 and 100 mg during fasting condition to hemodialysis patients with secondary hyperparathyroidism (Japanese) was conducted to evaluate the pharmacokinetics of cinacalcet. The plasma concentration of cinacalcet increased dose dependently both on the non-dialysis day and dialysis day, and showed biphasic elimination. The pharmacokinetic parameters are summarized as follows and the influence of hemodialysis was not remarkable. See Figures 1 and 2, and Table 1.

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Plasma Concentration Profiles After Multiple Oral Administration: The plasma trough concentration profiles of cinacalcet after multiple oral administration to hemodialysis patients with secondary hyperparathyroidism (Japanese) were examined in a period of up to 53 weeks. No tendency of increasing or decreasing over time was observed in the trough concentration and the plasma concentration was confirmed to have reached a steady state following repeated-dose administration.
Food Effect: Single oral administration at a dose of 50 mg to healthy volunteers (Japanese) was conducted to evaluate the food-effect on the pharmacokinetics of cinacalcet. The pharmacokinetic parameters of non-fasting conditions were almost similar to those of fasting condition, suggesting that the effect of food on the pharmacokinetics of cinacalcet was small.
Protein Binding: In vitro protein-binding of cinacalcet (25-100 ng/mL) in human plasma was 96.33-97.67% in males and 94.33-97.67% in females, respectively, and no sex difference was observed. The protein binding of cinacalcet was also analyzed in special population clinical studies eg, hepatic and renal impairment population (non-Japanese). The protein binding was found to be similar among normal, hepatic impairment and renal impairment population, which was 94.9-97.1% for normal and hepatic impairment population, and 92.7-95.1% for normal and renal impairment population, respectively. Cinacalcet was considered to be bound to albumin and shown to have a high affinity to the site II.
Metabolism: Single oral administration of 14C-labelled cinacalcet at a dose of 75 mg to healthy volunteers (non-Japanese) was conducted to evaluate the metabolism of cinacalcet. Cinacalcet was extensively metabolized via N-dealkylation and oxidation of the naphthalene ring.
Excretion: The urinary excretion of unchanged drug after single oral administration to healthy volunteers (Japanese) was very low, and multiple administration of cinacalcet did not influence the excretion of unchanged drug. Following single-dose oral administration of 75 mg of 14C-labelled cinacalcet to healthy volunteers (non-Japanese), cinacalcet was confirmed to be excreted mainly in urine as metabolites.
Drug Interactions: The following clinical studies with healthy volunteers (non-Japanese) were conducted to confirm the drug-drug interactions of cinacalcet. The pharmacokinetics of cinacalcet is unaffected by the drugs that alter gastric pH (calcium carbonate). The pharmacokinetics of cinacalcet is also unaffected by the phosphate binder (sevelamer HCl). Cinacalcet has no effect on the pharmacokinetics of R and S-warfarin and pharmacodynamics of warfarin (ie, prothrombin time and the activity of clotting factor VII).
Clinical Studies: Placebo-Controlled Double-Blind Comparative Study (Hemodialysis): Cinacalcet or placebo was orally administered to 143 patients with secondary hyperthyroidism on hemodialysis (cinacalcet-treated group: 72, placebo-treated group: 71) for 14 weeks with an initial dose of 25 mg once daily, which was titrated up to 100 mg. As a result, the rate of patients in whom serum intact PTH concentrations reached the target level (≤250 pg/mL) was shown to be 51.4% in the cinacalcet-treated group, which was significantly higher than 2.8% in the placebo-treated group (X2=42.521, p<0.001).
Long-Term Administration Study (Hemodialysis): Cinacalcet was orally administered to 369 patients with secondary hyperthyroidism on hemodialysis for 1 year with an initial dose of 12.5* mg or 25 mg once daily, which was titrated up to 100 mg. As a result, its effect of decreasing the serum intact PTH concentration was maintained over a long period. When the administration was completed, the rate of patients in whom serum intact PTH concentrations reached the target level (≤250 pg/mL) was shown to be 48.2%.
*The initial dose for cinacalcet is 25 mg.
General Clinical Study (Peritoneal Dialysis): Cinacalcet was orally administered to 29 patients with secondary hyperthyroidism on peritoneal hemodialysis for 16 weeks with an initial dose of 25 mg once daily which was titrated up to 100 mg. Consequently, the rate of patients in whom serum intact PTH concentrations reached the target level (≤250 pg/mL) was shown to be 24.1% when the administration was completed. Thus, it was confirmed that cinacalcet had an effect of decreasing the serum intact PTH concentration in patients with secondary hyperthyroidism on peritoneal hemodialysis.
Indications/Uses
Secondary hyperparathyroidism in patients undergoing maintenance dialysis.
Dosage/Direction for Use
Adults: Starting Dose: 25 mg once daily to be orally administered. With careful management of the patient's serum PTH and calcium levels, the dose may then be adjusted within a range of 25-75 mg once daily. If no improvement is found in PTH, the dose may be increased up to 100 mg once daily. If dose increase is required, the dose should be increased by 25 mg at a time, at intervals of at least 3 weeks.
Regpara has an effect of decreasing calcium in blood. Therefore, it should be confirmed that the patient's serum calcium level is not low (≥9 mg/dL) prior to administration.
The serum calcium level should be determined once a week at the start of administration and during the dose adjustment period, and at least once every 2 weeks during the maintenance period. If serum calcium level decreases to ≤8.4 mg/dL, the following measures should be taken. (See Table 2.)

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The serum calcium level should be determined before administration of Regpara so that the effect and safety of the drug may be properly evaluated. Furthermore, it is recommended that corrected serum calcium values should be used as a guide in patients with hypoalbuminemia (serum albumin <4 g/dL).
A corrected serum calcium value is to be calculated as follows:
Corrected serum calcium (mg/dL) = serum calcium (mg/dL) - serum albumin (g/dL) + 4
The serum PTH level should be periodically determined so that it may be maintained at the target level for management. It is recommended that the serum PTH level should be determined twice a month at the start of the administration and during the dose adjustment period (about 3 months after the start of administration), and at least once a month after the serum PTH level is confirmed to be almost stable. The serum PTH level should be determined before administration of Regpara so that the effect and safety of the drug may be properly evaluated.
Overdosage
Overdosage of Regpara is considered to cause hypocalcaemia. In the case of overdosage, the patient should be monitored for any signs or symptoms of hypocalcaemia. If hypocalcaemia occurs or may occur, drip infusion of calcium preparations should be taken into consideration. As Regpara is highly protein-bound, hemodialysis is not an effective treatment for overdosage.
Contraindications
Patients with history of hypersensitivity to any of the ingredients of Regpara.
Special Precautions
Regpara should be administered with care in the following patients:
Patients with hypocalcaemia: Hypocalcaemia may be aggravated.
Patients with seizure or a history of seizure: It has been reported in overseas studies that seizure occurred in patients with a history of seizure.
Patients with hepatic function disorder: The exposure amount will be increased since cinacalcet is metabolized in the liver.
During treatment with Regpara, sufficient caution should be exercised to avoid hypocalcaemia by periodical measurement of the serum calcium level. If hypocalcaemia occurs or may occur, it should be taken into account to use calcium or vitamin D preparations, as well as to reduce the dose of Regpara (see Dosage & Administration). If administration of calcium or vitamin D preparations is discontinued during treatment with Regpara, caution should be exercised for possible occurrence of hypocalcaemia. Symptoms likely to be associated with hypocalcaemia eg, prolonged QT interval, paresthesia, cramping, feeling unwell, arrhythmia, decreased blood pressure and seizure, etc have been reported in clinical studies on the drug.
At the start of administration and during the dose adjustment period, the patient's symptoms should be frequently monitored and caution should be exercised for possible occurrences of adverse reactions.
Others: In an overseas clinical study in which cinacalcet was used in patients with chronic renal failure accompanied by secondary hyperthyroidism who had not yet started dialysis, it has been reported that the blood calcium level tended to be lower than the lower limit of the normal range (8.4 mg/dL) compared to that in patients receiving dialysis. Use of Regpara in patients not yet on dialysis has not been approved.
It has been reported abroad that adynamic bone disease occurred due to an excessive decrease in PTH following administration of cinacalcet.
It has been reported abroad that hungry bone syndrome accompanied by hypocalcaemia and hypophosphatemia occurred due to a rapid decrease in PTH following administration of cinacalcet.
Use in pregnancy & lactation: It is recommended not to use Regpara in pregnant women or in women who may possibly be pregnant. The drug should be used in such patients only if the anticipated therapeutic benefits outweigh the potential risks associated with the treatment. The safety of Regpara during pregnancy has not been established. Hypocalcaemia, suppressed weight gain and decreased food consumption in mothers, as well as decreased weight in fetuses were observed in animal studies (using rats and rabbits). Furthermore, Regpara was reported to be transferred through the placenta in animal studies (using rats and rabbits).
Treatment with Regpara should be avoided in nursing mothers. When the use is necessary in such women, breastfeeding should be discontinued. In animal studies (using rats), Regpara was reported to be transferred into milk. Furthermore, suppressed weight gain was observed in newborns on breastfeeding.
Use in children: The safety of Regpara in low birth weight infants, newborns, sucklings, infants and children has not been established (no clinical experience).
Use in the elderly: Caution should be exercised when Regpara is administered to patients ≥65 years, because they have been reported to show higher incidences of adverse reactions (prolonged QT intervals in particular) than those younger than 65 years. If any adverse reactions are observed, appropriate measures eg, reducing the dose should be taken.
Use In Pregnancy & Lactation
It is recommended not to use Regpara in pregnant women or in women who may possibly be pregnant. The drug should be used in such patients only if the anticipated therapeutic benefits outweigh the potential risks associated with the treatment. The safety of Regpara during pregnancy has not been established. Hypocalcaemia, suppressed weight gain and decreased food consumption in mothers, as well as decreased weight in fetuses were observed in animal studies (using rats and rabbits). Furthermore, Regpara was reported to be transferred through the placenta in animal studies (using rats and rabbits).
Treatment with Regpara should be avoided in nursing mothers. When the use is necessary in such women, breastfeeding should be discontinued. In animal studies (using rats), Regpara was reported to be transferred into milk. Furthermore, suppressed weight gain was observed in newborns on breastfeeding.
Adverse Reactions
Adverse reactions (including laboratory abnormalities) were observed in 393 (68.6%) of 573 patients evaluated for safety at the time of approval.
The major adverse reactions included digestive symptoms eg, nausea/vomiting (124 events, 21.6%), gastric discomfort (107 events, 18.7%), anorexia (56 events, 9.8%) and abdominal distention (34 events, 5.9%), as well as hypocalcaemia/decreased serum calcium (84 events, 14.7%) and prolonged QT interval (33 events, 5.8%).
Clinically Significant Adverse Reactions: Hypocalcaemia/Decreased Serum Calcium (14.7%): Symptoms considered attributable to hypocalcaemia (prolonged QT interval, paresthesia, cramping, feeling unwell, arrhythmia, decreased blood pressure, seizure, etc) may occur. Therefore the serum calcium level should be determined once a week at the start of administration and during the dose adjustment period, and once every 2 weeks during the maintenance period. If any abnormalities are observed, the serum calcium level should be confirmed and administration of calcium or vitamin D preparations taken into consideration. Moreover, it should also be considered to reduce the dose of Regpara or discontinue the treatment as needed (see Dosage & Administration).
Prolonged QT Intervals (5.8%): The QT interval may be prolonged. If any abnormalities are observed, the serum calcium level should be confirmed and administration of calcium or vitamin D preparations taken into consideration. Moreover, it should also be considered to reduce the dose of Regpara or discontinue the treatment as needed.
Decreased Level of Consciousness (0.2%), Temporary Loss of Consciousness (incidence unknown): Decreased level of consciousness, temporary loss of consciousness, etc may occur. If any abnormalities are observed, appropriate measures including discontinuation of the treatment should be taken.
Sudden Death (0.3%): Unexplained sudden death has been reported in patients treated with Regpara.
Others: If any of the following symptoms are observed, appropriate measures eg, dosage reduction or discontinuation should be taken. See Table 3.

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Drug Interactions
Regpara should be administered with care when co-administered with the following drugs: See Table 4.

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Caution For Usage
In case of press-through package (PTP), the patient should be instructed to remove the drug from the package prior to use. It has been reported that if a PTP sheet is mistakenly swallowed, the sharp corners of the sheet may puncture the esophageal mucosa and thereby cause perforation, leading to serious complications eg, mediastinitis.
ATC Classification
H05BX01 - cinacalcet ; Belongs to the class of other anti-parathyroid agents. Used in the management of calcium homeostasis.
Presentation/Packing
Film-coated tab 25 mg (light-green to light yellowish green) x 100's.
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