Date of approval.
Date of revision.
Cinacalcet Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Cinacalcet Hydrochloride Tablets
English name: Cinacalcet Hydrochloride Tablets
Hanyu Pinyin：Yansuan Xinakasai Pian
Ingredients
The main ingredient of this product is Cinacalcet Hydrochloride.
Chemical name: N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamine hydrochloride
Chemical structure formula.
Molecular formula: C22H22F3N-HCl
Molecular weight: 393.87
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is used for the treatment of secondary hyperparathyroidism in patients on maintenance dialysis for chronic kidney disease (CKD).
Specification
25mg (as C22H22F3N); 75mg (as C22H22F3N)
Dosage]
This product should be taken orally at an initial dose of 25mg once daily for adults. The medicine should be taken with meals, or immediately after meals. The medicine needs to be swallowed whole and is not recommended to be taken after cutting.
The dose may be gradually increased from 25mg to 75mg once daily based on adequate observation of the patient’s whole segment parathyroid hormone (iPTH) and serum calcium concentration and serum phosphorus concentration, and if hyperparathyroidism is still not corrected, the maximum daily dose of 100mg may be given. The incremental adjustment is 25mg each time, and the interval between incremental adjustment is not less than 3 weeks.
Adverse reactions
As reported in foreign literature.
The results of a clinical trial completed in Japan showed that 393 cases (68.6%) of adverse reactions (including abnormal clinical examination values) were found in 573 patients. Among them, the main adverse reactions were 124 cases (21.6%) of nausea and vomiting, 107 cases (18.7%) of gastric discomfort, 56 cases (9.8%) of loss of appetite, 34 cases (5.9%) of abdominal distension and other digestive symptoms, 84 cases (14.7%) of hypocalcemia (decreased serum calcium), and 33 cases (5.8%) of prolonged QT interval.
1. Serious adverse reactions
(1) Hypocalcemia (decreased serum calcium) (13.7%)
Because hypocalcemia can lead to clinical symptoms such as prolonged QT interval, paralysis, muscle spasm, depression, cardiac arrhythmia, decreased blood pressure, and seizures, serum calcium concentrations should be measured once a week during the initial phase of administration and dose adjustment, and at least once every 2 weeks during the maintenance period. If symptoms such as hypocalcemia occur, serum calcium concentrations should be measured immediately and calcium or vitamin D preparations should be administered as appropriate. The administered dose may be reduced or discontinued as appropriate (refer to “Precautions on Dosage”).
Prolonged QT interval (5.3%)
If prolonged QT interval occurs, serum calcium concentration should be measured and calcium and vitamin D preparations should be considered. And depending on the situation, the administered dose may be reduced or the product may be discontinued.
(3) Gastrointestinal bleeding and peptic ulcer (incidence unknown)
If symptoms such as gastrointestinal bleeding or peptic ulcers occur, discontinue the product immediately and take appropriate measures.
(4) Decreased level of consciousness (0.2%), transient loss of consciousness (0.2%)
If symptoms such as decreased level of consciousness or transient loss of consciousness occur, discontinue the product immediately and take appropriate measures.
(5) Sudden death (0.3%)
Sudden death of unknown cause has been reported in cases of administration of this product.
2. Other adverse reactions
Appropriate measures such as dose reduction or discontinuation should be taken when the following symptoms occur.
* Incidence unknown
Incidence of adverse reactions (%) 5% or more 1-5% 1% or less or incidence unknown Digestive system nausea and vomiting (25.1%), stomach upset (17.1%), loss of appetite, abdominal distension epigastric pain, abdominal pain, abdominal discomfort, diarrhea, constipation, gastric ulcer, gastritis and duodenitis, reflux esophagitis, dyspepsia, abnormal gastrointestinal function gastric ulcer, stomatitis, gastroenteritis, stool occult blood, hemorrhoids, epigastric discomfort, hiatal hernia circulatory system elevated blood pressure, arrhythmia decreased blood pressure, myocardial infarction, myocardial ischemia, ventricular prophase contraction, supraventricular prophase contraction, atrial fibrillation, palpitations, tachycardia, worsening heart failure* mental and nervous paralysis, dizziness, headache, hallucinations, insomnia sensory abnormalities*, cerebrovascular accident* musculoskeletal muscle spasm, extremity pain arthralgia, muscle pain, stiffness, non-dynamic bone disease* Metabolism Elevated serum phosphocreatine kinase isoenzyme (CK (CPK)), elevated serum lactate dehydrogenase (LDH), elevated blood glucose, hyperlipidemia, dehydration, elevated total cholesterol Sensory organs Taste abnormalities Liver Elevated alkaline phosphatase (ALP) Liver function abnormalities (elevated glutathione aminotransferase AST (GOT), elevated glutathione aminotransferase ALT (GPT), elevated bilirubin Elevated*, elevated serum γ-glutamyl transpeptidase (γ-GTP)*) Eyes Conjunctival hemorrhage, dry eyes Skin Itchy rash, hair loss, subcutaneous bleeding Endocrine Goiter Blood Anemia Thrombocytopenia Other Lethargy, puffiness Depressed mood, fatigue, chest discomfort, thirst, weight loss, fistula occlusion, chest pain, fever, erectile dysfunction [Contraindication
It is contraindicated for those who are hypersensitive to this product and its components.
Precautions
1. Use with caution in the following patients.
(1) Patients with hypocalcemia (may lead to worsening of hypocalcemia).
(2) Patients at risk of seizures or with a prior history of seizures (cases of seizures have been reported in foreign clinical trials in patients with a prior history of epilepsy)
(3) Patients with abnormal liver function (the product is metabolized by the liver, so drug exposure is increased in patients with abnormal liver function)
(4) Patients with gastrointestinal bleeding or a prior history of peptic ulcers (potential for worsening of symptoms or recurrence)
2. Important Precautions
(1) Serum calcium values should be measured regularly during treatment with this product and close attention should be paid to avoid hypocalcemia. If hypocalcemia occurs or is likely to occur, consider reducing the dose of this product along with the use of calcium or vitamin D preparations as appropriate. If the use of calcium or vitamin D is discontinued during the course of this product, the occurrence of hypocalcemia should be noted. As symptoms that may be associated with hypocalcemia, prolonged QT interval, paresthesia, muscle cramps, poor mood, cardiac arrhythmia, decreased blood pressure and seizures have been reported in clinical trials of this product.
(2) Patients’ symptoms should be closely observed during the initial stage of administration and dose adjustment, and attention should be paid to the occurrence of adverse reactions, etc.
3. Precautions on dosage
(1) This product has the effect of lowering blood calcium concentration, so it should be started only after it is determined that the patient does not have a decrease in serum calcium (usually above 9.0 mg/dL).
(2) The serum calcium concentration should be measured at least once a week during the initial phase of administration and dose adjustment, and at least once every 2 weeks during the maintenance phase. If the serum calcium concentration is below 8.4 mg/dL, the following measures should be taken.
Serum calcium value measures this product dosing adjustment method treatment measures check increment or re-administration between 8.4mg/dL ~7.5mg/dL in principle no increment (may be reduced as appropriate) consider the use of calcium preparations or vitamin D preparations. Serum calcium should be measured at least once a week, and it is recommended to perform electrocardiography. For incremental doses, make sure that serum calcium recovers above 8.4 mg/dL before incremental doses are allowed. For immediate discontinuation of dosing below 7.5 mg/dL, make sure that serum calcium is restored above 8.4 mg/dL and start dosing from the pre-discontinuation dose or lower. To properly determine the effectiveness and safety of this product, it is recommended that serum calcium be checked prior to administration.
When hypoalbuminemia (serum albumin value below 4.0g/dL) is present, calibrated serum calcium is recommended as an indicator for observation.
Calculation of corrected calcium concentration.
Corrected calcium concentration (mg/dL) = serum calcium (mg/dL) – serum albumin (g/dL) + 4.0
(3) In order to maintain iPTH at the regulatory target value, iPTH levels need to be measured periodically. The iPTH concentration should be measured once every two weeks during the initial phase of administration and during the dose adjustment phase (target is approximately 3 months after the start of administration), and once a month after the iPTH level has basically stabilized. In order to properly determine the effectiveness and safety of this product, it is recommended that iPTH be measured prior to administration.
4. Other Precautions
(1) It has been reported in foreign literature that in foreign clinical trials, patients with chronic renal insufficiency with secondary hyperparathyroidism prior to dialysis induction were more likely to develop hypocalcemia after the use of this product compared to patients on dialysis
(serum calcium concentration below 8.4 mg/dL), and the indication for its use prior to dialysis induction is not approved.
(2) There are reports in the foreign literature of non-dynamic bone disease due to an excessive decrease in iPTH as a result of administration of this product in foreign countries.
(3) It has been reported in foreign literature that starvation bone syndrome with hypocalcemia and hypophosphatemia has occurred due to a dramatic decrease in iPTH after administration.
Pregnant women and nursing mothers
1. This product is not recommended for use in pregnant women or women who may become pregnant, but should only be administered if the therapeutic benefit is judged to be greater than the risk. Hypocalcemia, inhibition of body weight gain and decreased food intake, and fetal weight loss have been observed in maternal animals in animal studies (rats and rabbits), and the drug has been reported to pass through the placenta in animal studies (rats and rabbits)]. Pregnancy grade C.
2. Avoid the use of this product in lactating women and discontinue breast-feeding if use is unavoidable [drug has been reported to be secreted into breast milk in animal studies (rats) and inhibition of weight gain in lactating neonates has been observed].
Pediatric Dosage]
The safety of the drug in low birth weight infants, neonates, infants and children has not been established (no experience with its use).
Geriatric use]
Since the incidence of adverse reactions (especially prolonged QT interval) is higher in patients over 65 years of age than in patients under 65 years of age, the dose should be reduced or discontinued promptly when adverse reactions are detected.
Drug Interactions
1. Precautions for combined drug use
Drug name clinical symptoms, measures and methods mechanism/risk factors azole antifungal drugs
Itraconazole, etc.
Macrolide antibiotics
Erythromycin
Clarithromycin, etc.
Amiodarone hydrochloride
Grapefruit juice may lead to increased blood levels and enhanced action of this product. When this product is combined with ketoconazole, the AUC of the drug increases nearly twofold. The metabolism of this drug is mainly related to CYP3A4, so when it is combined with CYP3A4 inhibitors, the metabolism of this drug may be inhibited, which may lead to an increase in blood concentration. Tricyclic antidepressants
Amitriptyline hydrochloride
Promethazine hydrochloride, etc.
Butyrylbenzene-type antipsychotics
Haloperidol, etc.
flecainide hydrochloride
The blood concentration of these drugs may be elevated with perphenazine sulfate. When this product is combined with dextromethorphan hydrobromide, the AUC of dextromethorphan increases nearly 11-fold. Due to the inhibitory effect of this product on CYP2D6, the metabolism of the drugs listed on the left (all metabolized by the CYP2D6 pathway) is hindered, resulting in an increase in their blood concentrations. Calcitonin
Bisphosphonate bone resorption inhibitors
Pamidronate disodium
Alendronate sodium hydrate
Incadronate disodium hydrate, etc.
Adrenocorticosteroids
Cortisone
Prednisolone
Dexamethasone, etc. Serum calcium values may decrease and the effect of this product in lowering blood calcium concentration may be enhanced. Digitalis toxins
Diazepam, etc. may affect the blood concentration of this product due to the high plasma protein binding rate (refer to [Pharmacokinetics]) 2. Drug Interactions
The results of foreign studies in healthy adults show that drugs affecting gastric pH (e.g. calcium carbonate) have no effect on the pharmacokinetics of this product. The results of clinical studies on phosphorus adsorbent (sevelamer hydrochloride) have shown that sevelamer hydrochloride has no effect on the pharmacokinetics of this product. In addition, overseas studies on the pharmacokinetics and pharmacodynamics of warfarin in healthy adults showed no effect on the pharmacokinetics and pharmacodynamics (prothrombin time and coagulation factor VII activity) of R- and S-warfarin.
Overdose]
Overdose of this product may cause hypocalcemia. Signs and symptoms of hypocalcemia should be observed when overdose is suspected or definite, and intravenous calcium supplementation should be considered when hypocalcemia occurs or is likely to occur. Because of the high protein binding rate of this product, hemodialysis cannot be an effective treatment for drug overdose.
Pharmacology and Toxicology
Pharmacological effects
Cinacalcet hydrochloride acts on the calcium receptors present on the surface of parathyroid cells, thereby inhibiting the secretion of parathyroid hormone (PTH) and reducing the serum PTH concentration.
Toxicological studies
Repeated administration toxicity
Repeated administration toxicity tests in animals have shown a decrease in plasma calcium ion (Ca2+) concentrations associated with the pharmacological effects of cenacaser hydrochloride.
Ca2+) concentrations were reduced.
In the 26-week repeated administration test in rats, histological examination of the 5 mg/kg group showed mucosal hyperplasia of the cecum, with no toxic reactions at doses <5 mg/kg.
In a 4-week repeated dosing trial in dogs: cenacaser hydrochloride was administered at doses of 5, 50 and 100 mg/kg. vomiting, increased urine output and changes in urinary electrolyte concentrations were seen in the middle and high dose groups; reduced spontaneous movements, tremor and decreased red blood cell count were seen in the high dose group. The dose of no toxic reaction in this test was 5mg/kg.
Repeated toxicity test in monkeys: 13-week test: inhibition of weight gain due to reduced food intake, vomiting and loose or watery stools were seen in the cenacaser hydrochloride 50 and 100 mg/kg groups; prolongation of QT and QTc intervals, changes in hematological values (decrease in Hb and Ht values, prolongation of PT and APTT) and changes in blood biochemical values (increase in AST, ALT and TG) were seen in the above 100 mg/kg dose group. In the 52-week trial, inhibition of weight gain due to decreased food intake, vomiting and loose or watery stools were seen in the 50 and 100 mg/kg groups; decreased erythrocytes and increased ALT, AST and TG were seen in the 50 mg/kg group. Testosterone concentrations decreased in all male animals in the cenacaser hydrochloride administration group, but no pathological changes in the testes and paragenital organs associated with the decrease in testosterone concentrations were seen. The non-toxic response dose for this test was 5 mg/kg.
Genotoxicity
The results of Ames test, mammalian cell mutation test and chromosomal aberration test and mouse micronucleus test were all negative for cenacaser hydrochloride.
Reproductive toxicity
No significant effects on fertility and early embryonic development were observed in maternal rats. Reduced body weight gain was seen in rats (above 15 mg/kg) and rabbits (above 12 mg/kg) and rhodopsin was seen above 25 mg/kg in pregnant maternal animals given orally with cinacalcet hydrochloride. In rabbits, decreased feces, respiratory distress, rales and death were seen at 200 mg/kg. In the rat and rabbit embryo-fetus developmental toxicity test, reduced fetal body weight was observed in the group above 25 mg/kg, and no teratogenicity was observed. reduced body weight gain was observed in the rat offspring (F1) during lactation in the group above 15 mg/kg. No effect was seen on maternal animals and F2 generation.
Cinacalcet hydrochloride can be transferred from the mother to the fetus.
Carcinogenicity
A 104-week carcinogenicity test in mice and rats was performed and no carcinogenicity was observed. A reduced incidence of parathyroid follicular cell (C-cell) adenomas was seen in rats and was more pronounced in males. Mineral deposition was seen in testicular vessels and renal tubules in mice, and in heart, kidney, lung, sciatic nerve, epididymis and testicular vessels and spinal cord spinal cells, and gastric muscle layer in rats.
Pharmacokinetics]
According to foreign literature, it is reported that.
1. Blood concentration at single oral dosing
In hemodialysis patients (Japanese dialysis patients) given 25, 50 and 100 mg of this product orally in a single dose on an empty stomach, plasma concentrations of cilnacaser increased with increasing dose on non-dialysis days and on dialysis days, with a biphasic elimination. The pharmacokinetic parameters are shown in the table below and were not affected by dialysis.
Changes in plasma cilnacaser concentrations over time during a single oral administration
Observed time after administration (hours)
Observation time after administration (hours)
Pharmacokinetic parameters of cenacaser hydrochloride when given as a single dose to hemodialysis patients
Administration (mg) Pharmacokinetic parameters Non-dialysis day Dialysis day25Cmax(ng/mL)5.16±2.349.92±6.64tmax(hr)5.6±1.14.8±1.4AUC(ng-hr/mL)57.6±25.185.4±26.0t1/2(hr)28.45±14.2432.94± 14.5250Cmax(ng/mL)17.89±10.0020.71±13.71tmax(hr)6.0±1.14.6±1.6AUC(ng-hr/mL)207.1±91.8218.6±99.6t1/2(hr)38.58±20.1933.96±10.23100 Cmax(ng/mL)26.92±15.8036.70±26.09tmax(hr)4.8±1.84.4±1.8AUC(ng-hr/mL)383.3±126.5408.4±125.8t1/2(hr)38.47±8.6240.12±7.50Cmax, tmax n=8 , other n=7 Mean±standard deviation
2. Blood concentration at multiple oral dosing
The changes in plasma cenacaser valley concentrations during multiple dosing were studied in hemodialysis patients (Japanese dialysis patients), which had a maximum follow-up period of 53 weeks. No fluctuations in plasma cenacaser trough concentration values were found in patients after multiple dosing, confirming that plasma cenacaser concentrations reached a steady state after multiple dosing.
3. Effect of diet
The effect of diet on the pharmacokinetics of this product was studied in healthy adults (Japanese) given a single oral dose of 50 mg of this product. Since the pharmacokinetic parameters presented essentially the same values during fasting and postprandial administration, the effect of diet on the pharmacokinetics of the drug was considered to be minimal.
4. Plasma protein binding rate
Data from in vitro drug trials in healthy adults (Japanese) showed that the plasma protein binding rate of cenacaser (25-100 ng/mL) was high, ranging from 96.67% to 97.67% in men and 94.33% to 97.67% in women, with no difference between men and women. In addition, after a single oral administration of cenacaser hydrochloride, the drug plasma protein binding rates ranged from 94.7% to 97.1% in patients with normal liver function and patients with abnormal liver function (non-Japanese), and from 92.7% to 95.1% in patients with normal renal function and patients with abnormal renal function (non-Japanese), with essentially the same values. This indicates that cenacaser binds mainly to albumin and has high binding to site II, the binding site on albumin.
5. Metabolism
A single oral dose of 75 mg of the14 C-labeled drug was administered to healthy adults (non-Japanese), and observations showed that cenacaser was rapidly metabolized by N-dealkylation or oxidation of the naphthalene ring.
6. Excretion
Pharmacokinetic studies in healthy adults (Japanese) showed that the excretion of the prototype drug in the urine was very low and multiple dosing had no effect on the rate of excretion of the drug from the urine. A single oral dose of 75 mg of 14C-labeled drug in healthy adults (non-Japanese) showed that the product was excreted in urine mainly as metabolites.
Storage】
Keep airtight, not more than 25℃.
Package】
Aluminum-plastic blister package, 1×7 tablets/plate/box, 1×10 tablets/plate/box, 1×12 tablets/plate/box, 1×24 tablets/plate/box.
Expiration date】 24 months
【Execution standard
Approval number】
[Drug Marketing License Holder
Holder’s name: Renhe Yikang Group Co.
Address of the holder: 2/F, Hongchang Science and Technology Park, No. 238 Changjiang Avenue, Shijiazhuang High-tech Zone
Postal Code: 050000
Telephone number: 0311-86990977
Fax number: 0311-67690512
Manufacturer
Company Name: Hebei Renhe Yikang Pharmaceutical Co.
Production Address: Qingliangdian Town, Wuyi County, Hengshui City
Postal Code: 053400
Telephone number: 0311-86964685
Fax number: 0311-86964820