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2015年7月3日，美国FDA批准Vertex制药公司ivacaftor+lumacaftor组成的固定剂量复方制剂（商品名Orkambi）用于治疗携带CFTR基因F508del纯合突变的12岁以上囊性纤维化（CF）患者，这是首个获准用于治疗该基因双拷贝突变（CF最常见类型）患者的药物。
Liver-related Adverse Reactions In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN elevations was similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including 2 reported as transaminase elevations and 1 as hepatic encephalopathy, compared to none in the placebo group. Of these three, one had elevated transaminases (>3 × ULN) associated with bilirubin elevation >2 × ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 × ULN. Among 6 patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of ORKAMBI [see Warnings and Precautions (5.1, 5.2)]. Respiratory Adverse Reactions In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%). The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pre-treatment FEV1. In patients treated with ORKAMBI, the majority of the events began during the first week of treatment [see Warnings and Precautions (5.3)]. Menstrual Abnormalities In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%) [see Warnings and Precautions (5.4) and Drug Interactions (7.11)]. 7 DRUG INTERACTIONS Potential for Other Drugs to Affect Lumacaftor/Ivacaftor 7.1 Inhibitors of CYP3A Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours (the approved dose of ivacaftor monotherapy). Therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking ORKAMBI. However, when initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce the ORKAMBI dose to 1 tablet daily (lumacaftor 200 mg/ivacaftor 125 mg total daily dose) for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose [see Dosage and Administration (2.3)]. Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole, and voriconazole telithromycin, clarithromycin. No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors. 7.2 Inducers of CYP3A Co-administration of lumacaftor/ivacaftor with rifampin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort, is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. No dose adjustment is recommended when used with moderate or weak CYP3A inducers. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs 7.3 CYP3A Substrates Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by approximately 80%. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease the therapeutic effect of the medicinal product. Co-administration of ORKAMBI is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)] such as: Benzodiazepines: midazolam, triazolam (consider an alternative to these benzodiazepines). Immunosuppressants: cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of ORKAMBI). 7.4 CYP2B6 and CYP2C Substrates In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates. 7.5 Digoxin and Other P-gp Substrates Based on in vitro results which showed P-gp inhibition and pregnane-X-receptor (PXR) activation, lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates. Monitor the serum concentration of digoxin and titrate the digoxin dose to obtain the desired clinical effect. 7.6 Anti-allergics and Systemic Corticosteroids ORKAMBI may decrease the exposure of montelukast, which may reduce its efficacy. No dose adjustment for montelukast is recommended. Employ appropriate clinical monitoring, as is reasonable, when co-administered with ORKAMBI. Concomitant use of ORKAMBI may reduce the exposure and effectiveness of prednisone and methylprednisolone. A higher dose of these systemic corticosteroids may be required to obtain the desired clinical effect. 7.7 Antibiotics Concomitant use of ORKAMBI may decrease the exposure of clarithromycin, erythromycin, and telithromycin, which may reduce the effectiveness of these antibiotics. Consider an alternative to these antibiotics, such as ciprofloxacin, azithromycin, and levofloxacin. 7.8 Antifungals Concomitant use of ORKAMBI may reduce the exposure and effectiveness of itraconazole, ketoconazole, posaconazole, and voriconazole. Concomitant use of ORKAMBI with these antifungals is not recommended. Monitor patients closely for breakthrough fungal infections if such drugs are necessary. Consider an alternative such as fluconazole. 7.9 Anti-inflammatories Concomitant use of ORKAMBI may reduce the exposure and effectiveness of ibuprofen. A higher dose of ibuprofen may be required to obtain the desired clinical effect. 7.10 Antidepressants Concomitant use of ORKAMBI may reduce the exposure and effectiveness of citalopram, escitalopram, and sertraline. A higher dose of these antidepressants may be required to obtain the desired clinical effect. 7.11 Hormonal Contraceptives ORKAMBI may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI. Concomitant use of ORKAMBI with hormonal contraceptives increased the menstrual abnormality events [see Adverse Reactions (6.1)]. Avoid concomitant use unless the benefit outweighs the risks. 7.12 Oral Hypoglycemics Concomitant use of ORKAMBI may reduce the exposure and effectiveness of repaglinide, and may alter the exposure of sulfonylurea. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for metformin. 7.13 Proton Pump Inhibitors, H2 Blockers, Antacids ORKAMBI may reduce the exposure and effectiveness of proton pump inhibitors such as omeprazole, esomeprazole, and lansoprazole, and may alter the exposure of ranitidine. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for calcium carbonate antacid. 7.14 Warfarin ORKAMBI may alter the exposure of warfarin. Monitor the international normalized ratio (INR) when warfarin co-administration with ORKAMBI is required. 7.15 Concomitant Drugs that do not Need Dose Adjustment No dosage adjustment of ORKAMBI or concomitant drug is recommended when ORKAMBI is given with the following: azithromycin, aztreonam, budesonide, ceftazidime, cetirizine, ciprofloxacin, colistimethate, colistin, dornase alfa, fluticasone, ipratropium, levofloxacin, pancreatin, pancrelipase, salbutamol, salmeterol, sulfamethoxazole and trimethoprim, tiotropium, and tobramycin. Based on the metabolism and route of elimination, ORKAMBI is not expected to impact the exposure of these drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects: Pregnancy Category B. There are no adequate and well-controlled trials of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women. Embryofetal development studies in rats and rabbits were conducted with the individual components of ORKAMBI, lumacaftor and ivacaftor. Because animal reproduction studies are not always predictive of human response, ORKAMBI should be used during pregnancy only if clearly needed. Lumacaftor Lumacaftor was not teratogenic in rats at approximately 8 times the maximum recommended human dose (MRHD) (on a lumacaftor AUC basis at a maternal oral dose of 2000 mg/kg/day). Lumacaftor was not teratogenic in rabbits at approximately 5 times the MRHD (on a lumacaftor AUC basis at a maternal oral dose of 200 mg/kg/day). Placental transfer of lumacaftor was observed in pregnant rats and rabbits. Ivacaftor Ivacaftor was not teratogenic in rats at approximately 15 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Ivacaftor was not teratogenic in rabbits at approximately 45 times the MRHD (on an ivacaftor AUC basis at a maternal oral dose of 100 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 8.3 Nursing Mothers Both lumacaftor and ivacaftor are excreted into the milk of lactating female rats. Excretion of lumacaftor or ivacaftor into human milk is probable. There are no human studies that have investigated the effects of lumacaftor and ivacaftor on breast-fed infants. Caution should be exercised when ORKAMBI is administered to a nursing woman. 8.4 Pediatric Use The safety and efficacy of ORKAMBI in patients with CF younger than age 12 years have not been established. 8.5 Geriatric Use CF is largely a disease of children and young adults. Clinical trials of ORKAMBI did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening (lumacaftor 600 mg/ivacaftor 375 mg total daily dose) is recommended for patients with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening (lumacaftor 400 mg/ivacaftor 250 mg total daily dose), or less, in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 8.7 Renal Impairment ORKAMBI has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using ORKAMBI in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease. 8.8 Patients with Severe Lung Dysfunction The Phase 3 trials included 29 patients receiving ORKAMBI with ppFEV1 <40 at baseline. The treatment effect in this subgroup was comparable to that observed in patients with ppFEV1 ≥40. 10 OVERDOSAGE There have been no reports of overdose with ORKAMBI. The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs). Adverse events reported at an increased incidence of ≥5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increased (18%), and generalized rash (10%). No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. 11 DESCRIPTION The active ingredients in ORKAMBI tablets are lumacaftor, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, and ivacaftor, a CFTR potentiator, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. The molecular formula for lumacaftor is C24H18F2N2O5 and for ivacaftor is C24H28N2O3. The molecular weights for lumacaftor and ivacaftor are 452.41 and 392.49, respectively. The structural formulas are:
lumacaftor Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL). Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL).
Absorption When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state. Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The median (range) tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state. Distribution Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Elimination The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF. Metabolism Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces. In vitro and in vivo data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation. Ivacaftor is extensively metabolized in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. Excretion Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). Specific Populations Age: Pediatric Population The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses: Pediatric patients 12 to less than 18 years of age Following oral administration of ORKAMBI tablets, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours, the mean lumacaftor (±SD) AUCss was 253 (68.6) µg/mL*h and is similar to the mean AUCss in adult patients administered ORKAMBI tablets, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours. The mean ivacaftor (±SD) AUCss was 3.84 (1.54) µg/mL*h and is similar to the mean AUCss in adult patients administered ORKAMBI tablets, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours [see Use in Specific Populations (8.4)]. Sex The pharmacokinetics of ORKAMBI was evaluated using a population PK analysis of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females. Renal Impairment Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment [see Use in Specific Populations (8.7)]. Hepatic Impairment Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC0-12h) and approximately 30% higher Cmax for both lumacaftor and ivacaftor compared with healthy subjects matched for demographics. Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.6)]. Drug Interaction Studies Drug interaction studies were performed with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)]. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction [see Drug Interactions (7.3)]. Based on in vitro results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates [see Drug Interactions (7.5)]. In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. In vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates [see Drug Interactions (7.4)]. Potential for Other Drugs to Affect Lumacaftor/Ivacaftor Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Drug Interactions (7)]. The effects of co-administered drugs on the exposure of lumacaftor and ivacaftor are shown in Table 3 [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Drug Interactions (7)]. Table 3: Impact of Other Drugs on Lumacaftor 200 mg q12h/Ivacaftor 250 mg q12h
* ↑ = increase, ↓ = decrease, ↔ = no change. † The net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ORKAMBI; however, studies are available for individual components, lumacaftor and ivacaftor, as described below. Lumacaftor A 26-week study was conducted in transgenic Tg.rasH2 mice to assess carcinogenic potential of lumacaftor. No evidence of tumorigenicity was observed in Tg.rasH2 mice at lumacaftor oral doses up to 1500 and 2000 mg/kg/day in female and male mice, respectively. Lumacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats at an oral dose of 1000 mg/kg/day (approximately 3 and 8 times, respectively, the MRHD on a lumacaftor AUC basis). Ivacaftor Two-year studies were conducted in mice and rats to assess carcinogenic potential of ivacaftor. No evidence of tumorigenicity was observed in mice and rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 3 and 10 times the MRHD based on summed AUCs of ivacaftor and its metabolites). Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Ivacaftor impaired fertility and reproductive performance indices in male and female rats at an oral dose of 200 mg/kg/day (approximately 15 times the MRHD based on summed AUCs of ivacaftor and its metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations, and viable embryos in rats at 200 mg/kg/day (approximately 15 times the MRHD based on summed AUCs of ivacaftor and its metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity. No effects on male or female fertility and reproductive performance indices were observed at an oral dose of ≤100 mg/kg/day (approximately 8 times the MRHD based on summed AUCs of ivacaftor and its metabolites). 13.2 Animal Toxicology and/or Pharmacology Cataracts were seen in juvenile rats dosed with ivacaftor from postnatal day 7-35 at oral dose levels of 10 mg/kg/day and higher (approximately 0.3 times the MRHD for the ivacaftor component of ORKAMBI based on summed AUCs of ivacaftor and metabolites). This finding has not been observed in older animals. 14 CLINICAL STUDIES Dose Ranging Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, multiple-cohort trial which included 97 Caucasian patients with CF (homozygous for the F508del mutation) 18 years of age and older with a screening ppFEV1 ≥40. In the trial, 76 patients (homozygous for the F508del mutation) were randomized to receive lumacaftor alone at once-daily doses of 200 mg, 400 mg, or 600 mg or 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h and 27 patients (homozygous or heterozygous for the F508del mutation) received placebo. During the initial 28-day lumacaftor monotherapy period, treatment with lumacaftor demonstrated a dose-dependent decrease in ppFEV1 compared to placebo. Changes from Day 1 at Day 28 in ppFEV1 compared to placebo were 0.24, -1.4, -2.7, and -4.6 for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in ppFEV1 compared to placebo were 3.8, 2.7, 5.6, and 4.2, respectively. Sweat chloride was also assessed in this trial. Following the initial 28 days of lumacaftor monotherapy, the changes from Day 1 at Day 28 in sweat chloride compared to placebo were -4.9, -8.3, -6.1, and -8.2 mmol/L for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in sweat chloride compared to placebo were -5.0, -9.8, -9.5, and -11 mmol/L, respectively. These data supported the evaluation of lumacaftor 400 mg/ivacaftor 250 mg q12h (ORKAMBI) and lumacaftor 600 mg once daily/ivacaftor 250 mg q12h in the confirmatory trials. Confirmatory The efficacy of ORKAMBI in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received ORKAMBI twice daily. Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with ppFEV1 at screening between 40-90 [mean ppFEV1 60.7 at baseline (range: 31.1 to 94.0)]. Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV1 at screening between 40-90 [mean ppFEV1 60.5 at baseline (range: 31.3 to 99.8)]. Patients with a history of colonization with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had 3 or more abnormal liver function tests (ALT, AST, AP, GGT ≥3 × the ULN or total bilirubin ≥2 × the ULN) were excluded. Patients in both trials were randomized 1:1:1 to receive either ORKAMBI (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; or lumacaftor 600 mg once daily/ivacaftor 250 mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with ORKAMBI resulted in a statistically significant improvement in ppFEV1. The treatment difference between ORKAMBI and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 (P<0.0001). These changes persisted throughout the 24-week treatment period (Figure 1). Improvements in ppFEV1 were observed regardless of age, disease severity, sex, and geographic region. Figure 1. Absolute Change From Baseline at Each Visit in Percent Predicted FEV1 in Trial
LS = least squares; q12h = every 12 hours
Assessed as the average of the treatment effects at Week 16 and Week 24. ‡ Indicates statistical significance confirmed in the hierarchical testing procedure. Other efficacy measures considered not statistically significant. 16 HOW SUPPLIED/STORAGE AND HANDLING ORKAMBI (lumacaftor 200 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, printed with "2V125" in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-809-01 Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
