Limitations of Use

The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

2.1 Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older

The recommended dosage of ORKAMBI in adults and pediatric patients aged one year and older is based on patient's age and weight as described in Table 1.

2.2 Dosage Adjustment for Patients with Hepatic Impairment

For dosage adjustment for patients with hepatic impairment, refer to Table 2.

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 or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Patient Counseling Information (17)].

2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors

No dosage adjustment is necessary when CYP3A inhibitors are initiated in patients already taking ORKAMBI. However, when initiating ORKAMBI in patients currently taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment based on age as follows [see Dosage and Administration (2.1) and Drug Interactions (7.1)]:

• 1 through 5 years of age: 1 packet of granules every other day
• 6 years of age and older: 1 tablet daily

Following this one-week period, resume the recommended daily dosage.

If ORKAMBI is interrupted for more than one-week and then re-initiated while taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment re-initiation based on age as follows:

• 1 through 5 years of age: 1 packet of granules every other day
• 6 years of age and older: 1 tablet daily

Following this one-week period, resume the recommended daily dosage.

5.1 Use in Patients with Advanced Liver Disease

Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dosage should be reduced [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

5.2 Liver-related Events

Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin.

It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve.

Dosing should be interrupted in patients with ALT or AST >5 × upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 × ULN when associated with bilirubin elevations >2 × ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing [see Adverse Reactions (6.1)].

5.3 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI.

5.4 Respiratory Events

Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy [see Adverse Reactions (6.1)].

5.5 Effect on Blood Pressure

Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI [see Adverse Reactions (6.1)].

5.6 Drug Interactions

5.7 Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded [see Use in Specific Populations (8.4)]. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ORKAMBI treatment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The overall safety profile of ORKAMBI is based on the pooled data from 1108 patients with CF aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in two double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2).

In addition, the following clinical trials have been conducted:

• A 24-week, open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation.
• A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation.
• A 24-week, open-label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV1 <40).
• A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation.
• A 24-week, open-label trial (Trial 7) in 46 patients aged 1 through 2 years homozygous for the F508del-CFTR mutation.

Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 patients received placebo.

The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with ORKAMBI and 2% for patients who received placebo.

Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients.

Table 3 shows adverse reactions occurring in ≥5% of patients with CF aged 12 years and older treated with ORKAMBI who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials.

The safety profile from two pediatric trials in CF patients aged 6 through 11 years who are homozygous for the F508del-CFTR mutation, a 24-week, open-label, multicenter safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled, clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo), was similar to that observed in Trials 1 and 2. Adverse reactions that are not listed in Table 3, and that occurred in ≥5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥3% higher than placebo included: productive cough (17.5% vs 5.9%), nasal congestion (16.5% vs 7.9%), headache (12.6% vs 8.9%), abdominal pain upper (12.6% vs 6.9%), and sputum increased (10.7% vs 2.0%).

In a 24-week, open-label, multicenter, study in 60 patients aged 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation (Trial 6) the safety profile was similar to that observed in studies in patients aged 6 years and older [see Clinical Pharmacology (12.2)].

In a 24-week, open-label, multicenter, study in 46 patients aged 1 through 2 years with CF who were homozygous for the F508del-CFTR mutation (Trial 7) the safety profile was similar to that observed in studies in patients aged 2 years and older [see Clinical Pharmacology (12.2)].

Additional information on selected adverse reactions from trials is detailed below:

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ORKAMBI. 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.

Hepatobiliary: liver function decompensation including liver failure leading to death in patients with pre-existing cirrhosis with portal hypertension [see Warnings and Precautions (5.1)].

Immune system disorders: anaphylaxis, angioedema

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 dosage 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 dosage as recommended 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 dosage 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 (Hypericum perforatum), is not recommended [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

No dosage 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 which are substrates of CYP3A, thereby decreasing 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 (5.6) 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 dosage 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 dosage adjustment may be required to obtain the desired clinical effect. No dosage 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 Dosage 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, trimethoprim, tiotropium, and tobramycin. Based on the metabolism and route of elimination, ORKAMBI is not expected to impact the exposure of these drugs.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 [see Warnings and Precautions (5.6) and Drug Interactions (7.11)].

8.4 Pediatric Use

The safety and effectiveness of ORKAMBI in pediatric patients aged one year and older have been established. Use of ORKAMBI in these age groups is supported by evidence from adequate and well-controlled studies of ORKAMBI in patients aged 12 years and older [see Clinical Studies (14) and Adverse Reactions (6.1)] with additional data as follows:

• Extrapolation of efficacy in patients aged 12 years and older homozygous for the F508del mutation in the CFTR gene to pediatric patients aged 1 through 11 years with support from population pharmacokinetic analyses showing similar drug exposure levels in patients aged 12 years and older and in patients aged 1 through 11 years [see Clinical Pharmacology (12.3)].
• Safety data were obtained from a 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years, mean age 9 years (Trial 3) and a 24-week, placebo-controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4). Trial 3 evaluated subjects with a screening ppFEV1 ≥40 [mean ppFEV1 91.4 at baseline (range: 55 to 122.7)]. Trial 4 evaluated subjects with a screening ppFEV1 ≥70 [mean ppFEV1 89.8 at baseline (range: 48.6 to 119.6)]. The safety profile of ORKAMBI in pediatric patients 6 through 11 years of age was similar to that in patients aged 12 years and older [see Adverse Reactions (6.1)]. In Trial 3, spirometry (ppFEV1) was assessed as a planned safety endpoint. The within-group LS mean absolute change from baseline in ppFEV1 at Week 24 was 2.5 percentage points. At the Week 26 safety follow-up visit (following a planned discontinuation) ppFEV1 was also assessed. The within-group LS mean absolute change in ppFEV1 from Week 24 at Week 26 was -3.2 percentage points.
• Additional safety data were obtained from Trial 6, a 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years at screening (mean age at baseline 3.7 years). The safety profile in Trial 6 was similar to that in patients aged 6 years and older [see Adverse Reactions (6.1)].
• Additional safety data were obtained from Trial 7, a 24-week, open-label, clinical trial in 46 patients aged 1 to 2 years at screening (mean age at baseline 18.1 months). The safety profile in Trial 7 was similar to that in patients aged 2 years and older [see Adverse Reactions (6.1)].
• Safety was evaluated in a 96-week open-label clinical trial (Trial 8) in 52 patients (39 rolled over from Trial 7 and 13 ORKAMBI naïve) aged 1 to 2 years. Adverse reactions from trial 8 were generally similar to those reported in Trial 7.

The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established.

Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded [see Warnings and Precautions (5.7)].

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 dosage 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 is recommended for patients aged 6 years and older with moderate hepatic impairment (Child-Pugh Class B). A dose reduction to 1 packet of oral granules in the morning daily and 1 packet of oral granules in the evening every other day is recommended for patients aged 1 to 5 years old 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 or less frequently, or 1 packet of oral granules once daily or less frequently 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 dosage 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 ≤30 mL/min) or end-stage renal disease.

8.8 Patients with Severe Lung Dysfunction

The Phase 3 trials (Trials 1 and 2 [see Clinical Studies (14)]) 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.

8.9 Patients After Organ Transplantation

ORKAMBI has not been studied in patients with CF who have undergone organ transplantation. Use in transplanted patients is not recommended due to potential drug-drug interactions [see Drug Interactions (7.3)].

12.1 Mechanism of Action

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein.

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor.

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.

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) aged 18 years 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 (see 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 1 and Trial 2.
LS = Least Squares; q12h = every 12 hours

Key secondary efficacy variables included relative change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24; absolute change from baseline in BMI at Week 24; absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain score at Week 24, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing; proportion of patients achieving ≥5% relative change from baseline in ppFEV1 using the average of Week 16 and Week 24; and number of pulmonary exacerbations through Week 24. For the purposes of these trials, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.

Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

Advanced Liver Disease

Inform patients that worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease occurred in some patients treated with ORKAMBI. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI [see Warnings and Precautions (5.1)].

Abnormalities in Liver Function and Testing

Inform patients that abnormalities in liver function have occurred in patients treated with ORKAMBI. Blood tests to measure transaminases (ALT and AST) and bilirubin will be performed prior to initiating ORKAMBI, every 3 months during the first year of therapy, and annually thereafter. Advise patients to contact their healthcare provider if they develop symptoms consistent with hepatotoxicity [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions including angioedema and anaphylaxis are possible with use of ORKAMBI. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of ORKAMBI immediately and contact their physician or go to the emergency department if these symptoms occur.

Respiratory Events

Inform patients that chest discomfort, dyspnea, and respiration abnormal were more common during initiation of ORKAMBI therapy, especially in patients with advanced lung disease and to contact their healthcare provider if they develop any of these symptoms [see Warnings and Precautions (5.4)].

Effect on Blood Pressure

Inform patients that increased blood pressure has been observed in some patients treated with ORKAMBI and that periodic monitoring of their blood pressure during treatment is recommended and to contact their healthcare provider if they develop elevated blood pressure or notice elevations in pre-existing high blood pressure [see Warnings and Precautions (5.5)].

Drug Interactions with CYP3A Inhibitors and Inducers

• Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products during the first week after treatment initiation with ORKAMBI [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)].
• Instruct post-menarchal patients including females of reproductive potential on alternative methods of birth control because hormonal contraceptives should not be relied upon as an effective method of contraception. ORKAMBI may decrease the effectiveness of hormonal contraceptives and there is an increased incidence of menstruation-related adverse reactions when co-administered with ORKAMBI [see Warnings and Precautions (5.6), Adverse Reactions (6.1), and Drug Interactions (7.11)].

Cataracts

Inform patients that abnormalities of the eye lens (cataract) have been noted in some children and adolescents receiving ORKAMBI. Advise pediatric patients and their caregivers that they will receive ophthalmological examinations before initiating and during ORKAMBI treatment. Advise pediatric patients and/or their caregivers to contact their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)].

Administration

Inform patients that ORKAMBI should be taken with fat-containing food. A typical CF diet will satisfy this requirement. Examples of fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

Inform patients and caregivers that ORKAMBI oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice.

Inform patients that if a dose is missed and they remember the missed dose within 6 hours, the patients should take the dose with fat-containing food. If more than 6 hours elapsed after the usual dosing time, the patients should skip that dose and resume the normal schedule for the following dose. Patients should be informed not to take a double dose to make up for the forgotten dose [see Dosage and Administration (2.1)].