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盐酸西那卡塞片|Sensipar (Cinacalcet Tablets)
【适应症】该药主要用于治疗肾病透析患者的继发性甲状旁腺机能亢进，或者甲状旁腺癌所致的高钙血症。
【药理及药代动力学】该药可与甲状旁腺中的钙敏感受体结合，减少甲状旁腺素的分泌，进而导致血清钙及磷酸钙产物水平的降低。通常而言，原发性甲状旁腺功能亢进患者会在服用该药第二剂后２小时内 观察到最初的治疗反应；在治疗开始后４～６周内观察到持续的治疗反应该药达峰时间为２～６小时。该药与高脂饮食同服时，可导致血药浓度和药时曲线下面积（ＡＵＣ）升高。该药蛋白结合率为９３％～９７％，分布容积达１０００升。细胞色素Ｐ４５０３Ａ４、２Ｄ６和１Ａ２均与该药代谢有关。代谢产物主要通过尿液（８０％）和粪便（１５％）排泄，消除半衰期为４０小时。
【注意事项】 该药可降低血清钙水平，因而可能引起低钙血症。患者应注意观察是否有感觉异常、肌痛、痉挛、手足抽搐和惊厥的发生。
【药物相互作用】该药是细胞色素Ｐ４５０２Ｄ６（ＣＹＰ２Ｄ６）同功酶的抑制剂，因此，当该药与同样通过ＣＹＰ２Ｄ６代谢，且治疗指数较小的药物（如氟卡胺、长春碱、硫利达嗪和大多数三环类抗抑郁药）合用时，后者可能需要调整给药剂量。开始应用或停用ＣＹＰ３Ａ４强抑制剂（如酮康唑、红霉素或伊曲康唑）时，均有可能导致同时应用的该药的血药浓度发生较大幅度改变，因而需相应调整该药剂量。
【不良反应】临床试验中该药最常见的不良事件为恶心和呕吐。其他发生率大于５％的不良事件还包括腹泻、肌痛、高血压、无力、食欲减退、非心脏性胸痛和通路感染（ａｃｃｅｓｓｉｎｆｅｃｔｉｏｎ）。此外，西那卡塞治疗组和安慰剂对照组的严重感染发生率基本相当。
【剂量及用药】该药为口服片剂，规格为３０ｍｇ／片。该药应整片吞服，初始剂量为３０ｍｇ／天，进食时服用。随后根据患者反应情况，每２～４周调整一次剂量（按６０ｍｇ／天、９０ｍｇ／天、１２０ｍｇ／天和１８０ｍｇ／天顺序依次递增），直至患者ＰＴＨ水平达到美国肾脏基金会临床指南推荐的标准（１５０～３００ｐｇ／ｍｌ）。该药可单独应用或与维生素Ｄ醇和磷酸盐结合剂合用。
【患者咨询】 服用该药期间，患者应避免怀孕或哺乳。许多药物可能与该药产生药物相互作用，因此服用该药时应尽量停用其他药物，包括非处方药和营养补充剂。提醒患者在出现下述不良反应时，应尽快与医师联系，并采取相应治疗措施。这些不良反应包括：腹部痉挛或疼痛；面部、口唇、舌头和手足出现烧灼感、麻痹、刺痛、瘙痒或麻刺感；背部或腿部出现痛性痉挛；抑郁；意识错乱；吞咽或呼吸困难；幻觉；易怒；面肌抽搐；肌痛或癫痫发作。
Sensipar® (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptortoactivation by extracellular calcium.
Its empirical formula is C22H22F3N HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base).
It has one chiral center having an R-absolute configuration.
The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.
Cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.
Sensipar® tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).
Cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3(trifluoromethylphenyl1aminopropanehydrochloride and has the following structural formula:
Inactive Ingredients: Sensipar® tablets are comprised of the active ingredient, and the following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate.
Tablets are coated with color (Opadry® II green) and clear film-coat (Opadry® clear), carnauba wax, and Opacode® black ink.
INDICATIONS Sensipar® is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis.
Sensipar® is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma.
DOSAGE AND ADMINISTRATIONSensipar® tablets should be taken whole and should not be divided. Sensipar® should be taken with food or shortly after a meal.
Dosge ageSecondary Hyperparathyroidism in Patients with Chronic Kidney Disease on DialysisThe recommended starting oral dose of Sensipar® is 30 mg once daily.
Serum calcium and serum phosphorus should be measured within 1 week and PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar®. Sensipar® should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 60, 90, 120, and 180 mg once daily to target iPTH consistent with the NKF-K/DOQI recommendation for CKD patients on dialysis of 150-300 pg/mL. PTH levels should be assessed no earlier than 12 hours after dosing with Sensipar®.
Sensipar® can be used alone or in combination with vitamin D sterols and/or phosphate binders.During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar® (see PRECAUTIONS).
Parathyroid CarcinomaThe recommended starting oral dose of Sensipar® is 30 mg twice daily.
The dosage of Sensipar® should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels.
Special PopulationsGeriatric patients: Age does not alter the pharmacokinetics of Sensipar®; no dosage adjustment is required for geriatric patients.
Patients with renal impairment: Renal impairment does not alter the pharmacokinetics of Sensipar®; no dosage adjustment is necessary for renal impairment.
Patients with hepatic impairment: Cinacalcet exposures, as assessed by AUC(0-inf), in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times higher, respectively, than in normals. In patients with moderate and severe hepatic impairment, PTH and serum calcium concentrations should be closely monitored throughout treatment with Sensipar® (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).
Drug InteractionsSensipar® is metabolized in part by the enzyme CYP3A4.
Co-administration of ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet exposure. Dose adjustment of Sensipar® may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole; see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).
HOW SUPPLIEDSensipar® 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with “AMGEN” on one side and “30”on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30)Sensipar® 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with “AMGEN” on one side and “60”on the
opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30)Sensipar® 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with “AMGEN” on one side and “90”on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30)StorageStore at 25°C (77°F); excursions permittedto 15-30°C (59-86°F). [See USP controlled room temperature].
Manufactured for: Amgen. Amgen Inc. One Amgen Center Drive, Thousand Oaks, CA 91320-1799.
FDA revision date: 12/19/2008SIDE EFFECTSSecondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysi9In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis received study drug (656 Sensipar®, 470
placebo) for up to 6 months. The most frequently reported adverse events (incidence of at least 5% in the Sensipar® group and greater than placebo) are provided in Table 2.
The most frequently reported events in the Sensipar® group were nausea, vomiting, and diarrhea.
Table 2. Adverse Event Incidence ( ≥ 5%) in Patients on Dialysis Event*:Placebo(n = 470)(%)Sensipar®(n = 656)(6Nausea1931Vomiting1527Diarrhea2021Myalgia1415Dizziness810Hypertension57Asthenia47Anorexia46Pain Chest, Non-Cardiac46
Access Infection45* Included are events that were reported at a greater incidence in the Sensipar ® group than in the placebo group.
The incidence of serious adverse events (29% vs. 31%) was similar in the Sensipar® and placebo groups, respectively.12-Month Experience with Sensipar®Two hundred and sixty-six patients from 2 phase 3 studies continued to receive Sensipar® or placebo treatment in a 6-month double-blind extension study (12-month total treatment duration).
The incidence and nature of adverse events in this study were similar in the two treatment groups, and comparable to those observed in the phase 3 studies.
Postmarketing Experience with Sensipar®Rash, hypersensitivity, diarrhea and myalgia have been identified as adverse reactions during post-approval use of Sensipar®.
Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Sensipar® -treated patients with impaired cardiac function in postmarketing safety surveillance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Parathyroid CarcinomaThe most frequent adverse events in this patient group were nausea and vomiting.
Laboratory valuesSerum calcium levels should be closely monitored in patients receiving Sensipar® (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
DRUG INTERACTIONS Drug Interactions and/or Drug/Laboratory Test InteractionsSee CLINICAL PHARMACOLOGY, Pharmacokinetics and DRUG INTERACTIONS.
Effect of Sensipar® on other drugs: Drugs metabolized by cytochrome P450 2D6 (CYP2D6): Sensipar® is a strong in vitro, as well as in vivo, inhibitor of CYP2D6.
Therefore, dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 (eg, metoprolol and carvedilol) and particularly those with a narrow therapeutic index (eg, flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required.
Desipramine: Concurrent administration of cinacalcet (90 mg) with desipramine (50 mg) increased the exposure of desipramine by 3.6 fold in CYP2D6 extensive metabolizers.
Amitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6 extensive metabolizers.
Midazolam: There were no significant differences in the pharmacokinetics of midazolam, a CYP3A4 and CYP3A5 substrate, in subjects receiving 90 mg cinacalcet once daily for 5 days and a single dose of 2 mg midazolam on day 5 as compared to those of subjects receiving 2 mg midazolam alone.
This suggests that cinacalcet would not affect the pharmacokinetics of drugs predominantly metabolized by CYP3A4 and CYP3A5.
Effect of other drugs on Sensipar® : Sensipar® is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4, CYP2D6, and CYP1A2.
Ketoconazole: Sensipar® is metabolized in part by CYP3A4.
Co-administration of ketoconazole, a strong inhibitor of CYP3A4, increased cinacalcet exposure following a single 90 mg dose of Sensipar® by 2.3 fold. Dose adjustment of Sensipar® may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g.,ketoconazole, erythromycin, itraconazole; see DOSAGE AND ADMINISTRATION).
WARNINGSSeizuresIn three clinical studies of CKD patients on dialysis, 5% of the patients in both the Sensipar® and placebo groups reported a history of seizure disorder at baseline. During the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656) of Sensipar® -treated patients and 0.4% (2/470) of placebo-treated patients.
Five of the nine Sensipar® -treated patients had a history of a seizure disorder and two were receiving anti-seizure medication at the time of their seizure. Both placebo-treated patients had a history of seizure disorder and were receiving anti-seizure medication at the time of their seizure. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar®, particularly in patients with a history of a seizure disorder (see PRECAUTIONS, Hypocalcemia).
Hypotension and/or Worsening Heart FailureIn postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar® could not be completely excluded and which may be mediated by reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% of Sensipar® -treated patients and 12% of placebo-treated patients, heart failure occurred in 2% of both Sensipar® - and placebo-treated patients.
PRECAUTIONSGeneralHypocalcemiaSensipar® lowers serum calcium, and therefore patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, cramping, tetany, and convulsions.
Sensipar® treatment should not be initiated if serum calcium is less than the lower limit of the normal range (8.4 mg/dL).
Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar®. Once the maintenance dose has been established, serum calcium should be measured approximately monthly (see DOSAGE AND ADMINISTRATION).
If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar® until serum calcium levels reach 8.0 mg/dL, and/or symptoms of hypocalcemia have resolved.
Treatment should be re-initiated using the next lowest dose of Sensipar® (see DOSAGE AND ADMINISTRATION).
In the 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar® compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.
Sensipar® is not indicated for CKD patients not on dialysis. In CKD patients with secondary HPT not on dialysis, the long-term safety and efficacy of Sensipar® have not been established. Clinical studies indicate that Sensipar® -treated CKD patients not on dialysis have an increased risk for hypocalcemia compared to Sensipar® -treated CKD patients on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 subjects (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg at the completion of the study, 80% of Sensipar® -treated patients experienced at least one serum calcium value < 8.4 mg/dL compared to 5% of patients receiving placebo.
Adynamic Bone DiseaseAdynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with Sensipar® for one year.
Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar®.
Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In the three 6-month, phase 3 studies conducted in CKD patients on dialysis, 11% of patients treated with Sensipar® had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below the NKF-K/DOQI recommended target range (150-300
pg/mL) 1 in patients treated with Sensipar®, the dose of Sensipar® and/or vitamin D sterols should be reduced or therapy discontinued.
Hepatic InsufficiencyCinacalcet exposure as assessed by AUC(0-inf) in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times higher, respectively, than that in normals. Patients with moderate and severe hepatic impairment should be monitored throughout treatment with Sensipar® (see CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Laboratory TestsPatients with CKD on Dialysis with Secondary HyperparathyroidismSerum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar®. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH every 1 to 3 months (see DOSAGE AND ADMINISTRATION). All iPTH measurements during the Sensipar® trials were obtained using the Nichols IRMA.
In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled trial in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following six months of treatment with Sensipar®. Levels of total testosterone decreased by a median of 15.8% in the Sensipar® -treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar® -treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.
Patients with Parathyroid CarcinomaSerum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar®. Once maintenance dose levels have been established, serum calcium should be measured every 2 months (see DOSAGE AND ADMINISTRATION).
Carcinogenesis, Mutagenesis, and Impairment of FertilityCarcinogenicityStandard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given dietary doses of 15, 50, 125 mg/kg/day in males and 30, 70, 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, 35 mg/kg/day in males and 5, 20, 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.
MutagenicityCinacalcet was not genotoxic in the Ames bacterial mutagenicity assay or in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation or in the in vivo mouse micronucleus assay.
Impairment of FertilityFemale rats were given oral gavage doses of 5, 25, 75 mg/kg/day beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks post-mating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.
Pregnancy Category CIn pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day during gestation no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).
In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day during gestation no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons).
Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day.
In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day during gestation through lactation no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day (exposures 2-3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain. Sensipar® has been shown to cross the placental barrier in rabbits.
There are no adequate and well-controlled studies in pregnant women.
Sensipar® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactating WomenStudies in rats have shown that Sensipar® is excreted in the milk with a high milk-toplasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats and because many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in infants from Sensipar®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.
Pediatric UseThe safety and efficacy of Sensipar® in pediatric patients have not been established.
Geriatric UseOf the 1136 patients enrolled in the Sensipar® phase 3 clinical program, 26% were 65 years old, and 9% were 75 years old. No differences in the safety and efficacy of Sensipar® were observed in patients greater or less than 65 years of age (see DOSAGE AND ADMINISTRATION, Geriatric Patients).
REFERENCES
1. National Kidney Foundation: K/DOQI clinical practice guidelines: bone metabolism and disease in chronic kidney disease. American Journal of Kidney Disease 4 2:S1-S201, 2003OVERDOSEDoses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar® may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels (see PRECAUTIONS).
Since Sensipar® is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar®.
CONTRAINDICATIONSSensipar® is contraindicated in patients with hypersensitivity to any component(s) of this product.
原产地英文商品名:
SENSIPAR 60mg/tablet 30tablets/bottle
原产地英文药品名:
cinacalcet HCI
中文参考商品译名:
SENSIPAR 60毫克/片 30片/瓶
中文参考药品译名:
盐酸西那卡塞
生产厂家中文参考译名:
安进公司
生产厂家英文名:
AMGEN
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