英文药名:Kalydeco(ivacaftor filmcoated tablets) 中文药名:依伐卡托片 生产厂家:Vertex Pharmaceuticals Incorporated
Film-coated tablet (tablet)
Description of selected adverse reactions Rash During 48-week placebo-controlled clinical studies, the incidence of rash was 12.8% in Kalydeco-treated patients. Including data from all clinical trial and post-marketing data, most of these events were non-serious and most of these patients did not discontinue the treatment because of rash. Ear and labyrinth disorders During 48-week placebo-controlled clinical studies, the incidence of ear and labyrinth disorders was 9.2% in Kalydeco-treated patients. Most events were described as mild to moderate in severity, 1 event of ear pain was described as severe; none were serious; no patients discontinued treatment because of ear and labyrinth disorders. Nervous system disorders Headache During 48-week placebo-controlled clinical studies, the incidence of headache was 23.9% in Kalydeco-treated patients. Including data from all clinical trial and post-marketing data, most of these events were non-serious and most of these patients did not discontinue the treatment because of headache. Dizziness During 48-week placebo-controlled clinical studies, the incidence of dizziness was 9.2% in the Kalydeco-treated patients. Including data from all clinical trial and post-marketing data, most of these events were non-serious and most of these patients did not discontinue the treatment because of dizziness. Upper respiratory tract reactions During 48-week placebo-controlled clinical studies, the incidence of upper respiratory tract reactions (upper respiratory tract infection, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, and nasopharyngitis) was 63.3% in Kalydeco-treated patients. Most events were described as mild to moderate in severity, 1 event of upper respiratory tract infection and 1 event of nasal congestion were considered to be severe, none were serious, and no patients discontinued treatment because of upper respiratory tract reactions. Laboratory abnormalities Transaminase elevations During the placebo-controlled Phase 2b/3 clinical studies, up to 48 weeks, the incidence of maximum transaminase (ALT or AST) >8, >5 or >3 x ULN was 1.8%, 2.7% and 6.3% in Kalydeco-treated patients and 1.5%, 2.3% and 8.4% in placebo-treated patients, respectively. Three patients, 2 (1.5%) on placebo and 1 (0.5%) on Kalydeco permanently discontinued treatment for elevated transaminases, all >8x ULN. No Kalydeco-treated patients experienced a transaminase elevation >3x ULN associated with elevated total bilirubin >1.5x ULN. In Kalydeco-treated patients, most transaminase elevations up to 5x ULN resolved without treatment interruption. Kalydeco dosing was interrupted in most patients with transaminase elevations >5x ULN. In all instances where dosing was interrupted for elevated transaminases, Kalydeco dosing was able to be resumed (see section 4.4). Paediatric population Table 2 lists the adverse reactions by system organ class, preferred term, and frequency in Kalydeco–treated paediatric patients age 6 through to 17 in the two 48-week Phase 3 studies in patients with CF with a G551D mutation. The safety data is limited to 23 patients between 6 to 11 years of age, and 22 patients between 12 to 17 years of age. Adverse reactions are ranked under the MedDRA frequency classification: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and unknown (frequency cannot be estimated using the available data).
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No specific antidote is available for overdose with Kalydeco. Treatment of overdose consists of general supportive measures including monitoring of vital signs, liver function tests and observation of the clinical status of the patient. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other respiratory system products ATC code: R07AX02 Mechanism of action Ivacaftor is a selective potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating to enhance chloride transport. However, the exact mechanism leading ivacaftor to prolong the gating activity of some mutant CFTR forms has not been completely elucidated. Pharmacodynamic effects In clinical trials (Studies 1 and 2) in patients with the G551D mutation in one allele of the CFTR gene, ivacaftor led to rapid (15 days), substantial [the mean change in sweat chloride from baseline through week 24 was -48 mmol/L (95% CI -51, -45) and -54 mmol/L (95% CI -62, -47) respectively], and sustained (through 48 weeks) reduction in sweat chloride concentration. Clinical efficacy and safety The efficacy of Kalydeco has been evaluated in two Phase 3 randomised, double-blinded, placebo-controlled, multi-centre studies of clinically stable patients with CF who had the G551D mutation in the CFTR gene on at least 1 allele and had FEV1 ≥40% predicted. Patients in both studies were randomised 1:1 to receive either 150 mg of Kalydeco or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted. Study 1 evaluated 161 patients who were 12 years of age or older; 122 (75.8%) of patients had the F508del mutation in the second allele. At the start of the study, patients in the placebo group used some medicinal products at a higher frequency than the ivacaftor group. These medications included dornase alfa (73.1% versus 65.1%), salbutamol (53.8% versus 42.2%), tobramycin (44.9% versus 33.7%), and salmeterol/fluticasone (41.0% versus 27.7%). At baseline, mean predicted FEV1 was 63.6% (range: 31.6% to 98.2%), and mean age was 26 years (range: 12 to 53 years). Study 2 evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) body weight was 30.9 (8.63) kg; 42 (80.8%) of patients had the F508del mutation in the second allele. At baseline, mean predicted FEV1 was 84.2% (range: 44.0% to 133.8%), and mean age was 9 years (range: 6 to 12 years); 8 (30.8%) of patients in the placebo group and 4 (15.4%) of patients in the ivacaftor group had an FEV1 less than 70% predicted at baseline. The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment. The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (8.6; 12.6) in study 1 and 12.5 percentage points (6.6; 18.3) in study 2. The treatment difference between ivacaftor and placebo for the mean relative change (95% CI) in percent predicted FEV1 from baseline through Week 24 was 17.1% (13.9, 20.2) in study 1 and 15.8% (8.4, 23.2) in study 2. The mean change from baseline through Week 24 in FEV1 (L) was 0.37 L in the ivacaftor group and 0.01 L in the placebo group in study 1 and 0.30 L in the ivacaftor group and 0.07 L in the placebo group in study 2. In both studies, improvements in FEV1 were rapid in onset (Day 15) and durable through 48 weeks. The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through Week 24 in patients 12 to 17 years of age in study 1 was 11.9 percentage points (5.9; 17.9). The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through Week 24 in patients with baseline predicted FEV1 greater than 90% in study 2 was 6.9 percentage points (-3.8; 17.6). The results on clinically relevant secondary endpoints are shown in Table 3.
Study 3: study in patients with CF with the F508del mutation in the CFTR gene Study 3 (Part A) was a 16-week, 4:1 randomised, double-blind, placebo-controlled, parallel-group Phase 2 study of ivacaftor (150 mg every 12 hours) in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted. The mean absolute change from baseline through Week 16 in percent predicted FEV1 (primary efficacy endpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 1.7 percentage points (95% CI: -0.6, 4.1); this difference was not statistically significant (P = 0.15). Study 4: open-label extension study Study 4 is an ongoing, open-label extension study to evaluate the efficacy and safety of long-term treatment of orally administered ivacaftor (150 mg every 12 hours) in patients continuing from studies 1 and 2. The percent predicted FEV1 range at the beginning of study 4 was 29.1% to 126.7%. The use of inhaled hypertonic saline was permitted. A pre-specified interim analysis was performed after all patients from study 1 received 48 weeks and all patients from study 2 received 24 weeks of treatment with ivacaftor in study 4. In patients treated with placebo in study 1, 48-week treatment with ivacaftor in study 4 (63 patients) resulted in an improvement in the mean absolute change in percent predicted FEV1 through Week 48 of 9.4 percentage points, similar to that observed in patients treated with ivacaftor in the placebo-controlled study 1. In patients treated with ivacaftor in study 1, 48-week treatment with ivacaftor in study 4 (73 patients) resulted in a mean absolute change in percent predicted FEV1 from the baseline value in study 1 to Week 96 of 9.5 percentage points, similar to that observed at Week 48 (9.4 percentage points) in study 1. In patients treated with placebo in study 2, 24-week treatment with ivacaftor in study 4 (22 patients) resulted in an improvement in the mean absolute change in percent predicted FEV1 through Week 24 of 8.1 percentage points, similar to that observed in patients treated with ivacaftor in the placebo-controlled study 2. In patients treated with ivacaftor in study 2, 24-week treatment with ivacaftor in study 4 (26 patients) resulted in a mean absolute change in percent predicted FEV1 from the baseline value in study 2 to Week 72 of 10.1 percentage points, similar to that observed at Week 48 (10.2 percentage points) in study 2. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Kalydeco in one or more subsets of the paediatric population in cystic fibrosis. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties The pharmacokinetics of ivacaftor are similar between healthy adult volunteers and patients with CF. After oral administration of a single 150 mg dose to healthy volunteers in a fed state, the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 12 hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9. Absorption Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. The exposure of ivacaftor increased approximately 2- to 4-fold when given with food containing fat. Therefore, ivacaftor should be administered with fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state. Distribution Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. The apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (±SD) apparent volume of distribution was 353 (122) L. Biotransformation Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. Elimination Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The mean (±SD) of CL/F for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects at steady state. Dose/time proportionality The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 25 mg to 250 mg. Pharmacokinetic/pharmacodynamic relationships Based on pooled data from Phase 2a and Phase 3 studies in patients with a G551D mutation, population PK/PD analysis showed a relationship between FEV1 and ivacaftor exposure in an Emax model with an EC50 of 45 ng/mL and a corresponding EC90 of 405 ng/mL. Therefore, median Cmin at EC90 was chosen as the target PK parameter for efficacy. Hepatic impairment Following a single dose of 150 mg of ivacaftor, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean (±SD) of 735 (331) ng/mL), but an approximately two-fold increase in ivacaftor AUC0-∞ (mean (±SD) of 16800 (6140) ng*hr/mL) compared with healthy subjects matched for demographics. Simulations for predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 150 mg q12h to 150 mg once daily, subjects with moderate hepatic impairment would have comparable steady-state Cmin values as those obtained with a dose of 150 mg q12h in subjects with CF. Therefore, a reduced dose of 150 mg once daily is recommended in patients with moderate hepatic impairment. The impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C, score 10 to 15), but exposure is expected to be higher than in patients with moderate hepatic impairment. The use of Kalydeco in patients with severe hepatic impairment is therefore not recommended unless the benefits outweigh the risks. In such case, the starting dose should be 150 mg every other day. Dosing intervals should be modified according to clinical response and tolerability (see sections 4.2 and 4.4). Renal impairment Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment. In a human pharmacokinetic study, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). There was negligible urinary excretion of ivacaftor as unchanged parent (less than 0.01% following a single oral dose of 500 mg). Therefore, no dose adjustments are recommended for mild and moderate renal impairment. However, caution is recommended when administering ivacaftor to patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end stage renal disease (see sections 4.2 and 4.4). Paediatric population Based on population PK analysis, the absorption in children (2.99 h for zero-order absorption and 0.546 h-1 for absorption rate constant, ka) is not different from adults. However, the predicted total body clearance was lower in children (e.g., 10 L/h for a 20 kg male) than in adults (e.g., 18.9 L/h for a 70 kg male), which resulted in a higher AUC by exposure determination from observed data in children than in adults. Based on exposure determinations from observed data in Phase 2 and 3 studies, the 150 mg q12h dose regimen resulted in median and mean (SD) ivacaftor Cmin of 752 and 1180 (854) ng/mL for 6-11 year old subjects, 492 and 556 (356) ng/mL for 12-17 year old subjects and 690 and 774 (468) ng/mL for the adult subjects. The corresponding AUC median and mean values were 16560 and 18200 (6547) ng/mL.h for children 6 to 11 years old, 8122 and 8536 (3064) ng/mL.h for adolescents 12 to 17 years old, and 8770 and 9508 (3763) ng/mL.h for adults. Elderly population Clinical studies of ivacaftor did not include patients age 65 years and older. Thus, the efficacy and safety of ivacaftor in elderly patients have not been established. Gender The effect of gender on ivacaftor pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of ivacaftor. No dose adjustments are necessary based on gender. 5.3 Preclinical safety data Effects on non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Ivacaftor produced concentration-dependent inhibitory effect on hERG (human ether-a-go-go related gene) tail currents, with an IC15 of 5.5 µM, which is comparable to the Cmax (5.0 µM) for ivacaftor at the therapeutic dosage. However, no ivacaftor-induced QT prolongation was observed in a dog telemetry study at single doses of up to 60 mg/kg, or in ECG measurements from repeat-dose studies of up to 1 year duration at the 60 mg/kg/day dose level in dogs (Cmax after 365 days = 36.2 to 47.6 μM). Ivacaftor produced a dose-related, but transient increase in the blood pressure parameters in dogs at single oral doses of up to 60 mg/kg. Ivacaftor did not cause reproductive system toxicity in male and female rats at 200 and 100 mg/kg/day, respectively. In females, dosages above this were associated with reduction in overall fertility index, number of pregnancies, number of corpora lutea and implantation sites, as well as changes in the oestrous cycle. In males, slight decreases of the seminal vesicle weights were observed. Ivacaftor was not teratogenic when orally dosed to pregnant rats and rabbits during the organogenesis stage of foetal development at doses approximately 6 and 12 times the exposure in humans at the therapeutic dose, respectively. At maternally toxic doses in rats, ivacaftor produced reductions in foetal body weight, an increase in the incidence of cervical ribs, hypoplastic ribs, wavy ribs and sternal irregularities, including fusions. The significance of these findings for humans is unknown. Ivacaftor did not cause developmental defects in the offspring of pregnant rats dosed orally from pregnancy through parturition and weaning at 100 mg/kg/day. Dosages above this produced 92% and 98% reduction of survival and lactation indices, respectively, as well as reductions in pup body weights. Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 with dose levels of 10 mg/kg/day and higher (0.12 times the maximum recommended human dose based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in foetuses derived from rat dams treated on gestation day 7 to 17, in rat pups exposed to a certain extent through milk ingestion up to postnatal day 20, in 7-week-old rats, or in 4- to 5-month-old dogs. The potential relevance of these findings in humans is unknown. Two-year studies in mice and rats to assess carcinogenic potential of ivacaftor demonstrated that ivacaftor was not carcinogenic in either species. Plasma exposures to ivacaftor in mice at the non-carcinogenic dosage (200 mg/kg/day, the highest dosage tested) were approximately 4- to 7-fold higher than the plasma levels measured in humans following ivacaftor therapy. Plasma exposures to ivacaftor in rats at the non-carcinogenic dosage (50 mg/kg/day, the highest dosage tested) were approximately 17- to 31-fold higher than the plasma levels measured in humans following ivacaftor therapy. Ivacaftor was negative for genotoxicity in a standard battery of in vitro and in vivo tests. 6.Pharmaceutical particulars 6.1 List of excipients Tablet core Cellulose, microcrystalline Lactose monohydrate Hypromellose acetate succinate Croscarmellose sodium Sodium laurilsulfate Colloidal silicon dioxide Magnesium stearate Tablet film coat Polyvinyl alcohol Titanium dioxide (E171) Macrogol Talc Indigo carmine aluminum lake (E132) Carnauba wax Printing ink Shellac Iron oxide black (E172) Propylene glycol Ammonium hydroxide 6.2 Incompatibilities Not applicable. 6.3 Shelf life 30 months 6.4 Special precautions for storage Store below 30°C. 6.5 Nature and contents of container Kalydeco tablets are packaged in a thermoform (polychlorotrifluoroethylene (PCTFE)/foil) blister or a high-density polyethylene (HDPE) bottle with a polypropylene, foil-lined induction seal closure and molecular sieve dessicant. The following pack sizes are available: − Blister pack containing 56 film-coated tablets − Bottle containing 56 film-coated tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements 7. Marketing authorisation holder Vertex Pharmaceuticals (U.K.) Limited Cardinal Point Park Road Rickmansworth Herts WD3 1RE United Kingdom Tel: +44 (0) 1923 437672 Fax: +44 (0)1923 432870 8. Marketing authorisation number(s) EU/1/12/782/001-002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 23 July 2012 10. Date of revision of the text April 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 欧盟批准Vertex囊性纤维化药物Kalydeco用于8种非G551D门控突变 |
依伐卡托片|Kalydeco(ivacaftor filmcoated tablets)简介:
英文药名:Kalydeco(ivacaftor tablets)
中文药名:依伐卡托片
生产厂家:Vertex Pharmaceuticals Incorporated药品介绍7月27日,欧盟委员会已批准Kalydeco(通用名:ivacaftor)用于6岁及以上年龄 ... 责任编辑:admin |
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