ORKAMBI

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Administer each dose with fat-containing food (e.g., eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products, such as whole milk, cheese, and yogurt).
-If a dose is missed within 6 hours of the time it is usually taken, the dose should be taken with fat-containing food as soon as possible. If more than 6 hours have passed since the dose is usually taken, skip that dose and resume with the usual dosing schedule.
-Oral granules: Mix the entire contents of each packet of oral granules with 5 mL of age-appropriate soft food (e.g., pureed fruits or vegetables, flavored yogurt or pudding, or applesauce) or liquid (e.g., water, milk, breast milk, infant formula, or juice); the mixture should be completely consumed. Food should be at room temperature or below. Each packet is for single use only. Once mixed, the product is stable for 1 hour and should be consumed during that time.

The overall safety profile of lumacaftor; ivacaftor is based on pooled data from two 24-week, double-blind, placebo-controlled, Phase 3 clinical trials, in which cystic fibrosis patients 12 years and older (n = 1,108) homozygous for the F508del mutation received at least 1 dose of study drug. Of these patients, 369 received lumacaftor; ivacaftor every 12 hours and 370 received placebo; 5% of patients treated with lumacaftor; ivacaftor and 2% of patients treated with placebo discontinued therapy due to adverse reactions. The safety profile of lumacaftor; ivacaftor in children 1 to 11 years is similar to that in older patients.

Rarely, serious adverse reactions related to elevated hepatic enzymes, sometimes associated with concomitant hyperbilirubinemia, have been reported in patients receiving lumacaftor; ivacaftor. In all patients, monitor AST, ALT, and bilirubin prior to initiating therapy, every 3 months during the first year of therapy, and annually thereafter. Consider more frequent monitoring in patients with a history of transaminase and/or bilirubin elevations. If elevations occur, monitor patients closely until abnormalities resolve. Discontinue lumacaftor; ivacaftor in patients with an ALT or AST more than 5 times the upper limit of normal (ULN) when not associated with elevated bilirubin. Interrupt therapy in patients with an ALT or AST more than 3 times ULN when associated with bilirubin elevations more than 2 times ULN. Upon resolution, carefully consider the benefits and risks before resuming therapy. During an open-label clinical trial in patients 1 to 2 years (n = 46), maximum transaminase (ALT or AST) concentrations more than 8 times ULN (2.2%), more than 5 times ULN (4.3%), and more than 3 times ULN (10.9%) were reported. No patients experienced an increase in total bilirubin concentrations more than 2 times ULN. One patient permanently discontinued treatment due to transaminase elevations. During an open-label clinical trial in patients 2 to 5 years (n = 60), maximum transaminase (ALT or AST) concentrations more than 8 times ULN (8.3%), more than 5 times ULN (11.7%), and more than 3 times ULN (15%) were reported. No patients experienced an increase in total bilirubin concentrations more than 2 times ULN. Three patients permanently discontinued treatment due to transaminase elevations. During an open-label clinical trial in patients 6 to 11 years (n = 58), maximum transaminase (ALT or AST) concentrations more than 8 times ULN (5%), more than 5 times ULN (9%), and more than 3 times ULN (19%) were reported. No patients experienced an increase in total bilirubin concentrations more than 2 times ULN. In all patients, except 1 who permanently discontinued treatment, lumacaftor; ivacaftor dosing was maintained or successfully resumed after interruption. During a placebo-controlled clinical trial in patients 6 to 11 years (total n = 204), maximum transaminase (ALT or AST) concentrations more than 8 times ULN (1%), more than 5 times ULN (5%), and more than 3 times ULN (13%) were reported. No patients experienced an increase in total bilirubin concentrations more than 2 times ULN. Two patients in the lumacaftor; ivacaftor and 2 patients in the placebo group discontinued treatment permanently due to transaminase elevation. During 2 clinical trials of patients 12 years and older (total n = 1,108), 2 actively treated patients reported transaminase elevations, 1 of which was more than 3 times ULN and associated with bilirubin elevation more than 2 times ULN; transaminases decreased to less than 3 times ULN after treatment interruption. Another patient receiving lumacaftor; ivacaftor developed hepatic encephalopathy. Among 6 patients with pre-existing cirrhosis and/or portal hypertension, 1 patient developed worsening liver function with AST, ALT, and bilirubin elevations and hepatic encephalopathy. The event occurred within 5 days of therapy initiation and resolved after drug discontinuation. Additionally, cases of liver function decompensation, including liver failure leading to death, have been reported during postmarketing surveillance in CF patients with pre-existing cirrhosis with portal hypertension receiving lumacaftor; ivacaftor therapy. Use lumacaftor; ivacaftor with caution in patients with hepatic disease; dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C).

During premarketing clinical trials, respiratory adverse reactions including productive cough (17.5% vs. 5.9%), nasal congestion (16.5% vs. 7.9%), dyspnea (13% vs. 8%), increased sputum (10.7% vs. 2%), abnormal respiration (9% vs. 6%), and chest discomfort were observed more commonly in patients initiated on lumacaftor; ivacaftor (22%) than those receiving placebo (14%). Most of these reactions began during the first week of treatment. Because the incidence of respiratory adverse reactions was more common in patients with a lower pre-treatment FEV1, patients with a ppFEV1 less than 40 (FEV1 less than 40% of predicted) should be monitored closely during therapy initiation. During a 24-week trial in patients 6 to 11 years old (n = 58), the incidence of respiratory symptom-related adverse reactions was 3% (2/58). During a 24-week trial in 46 patients 12 years and older with advanced lung disease (ppFEV1 less than 40; mean ppFEV1 29.1 at baseline), the incidence of respiratory symptom-related adverse reactions was 65%. During a 24-week trial in patients 6 through 11 years (mean ppFEV1 89.8 at baseline), the incidence of respiratory symptom-related adverse reactions was 11% in lumacaftor/ivacaftor patients and 9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post-dose spirometry assessments. The absolute change from pre-dose at 4 to 6 hours was -7.7 on Day 1 and -1.3 on Day 15 of therapy. The post-dose decline was resolved by Week 16. Other infectious/respiratory reactions reported during clinical trials include naso-pharyngitis (13% vs. 11%), upper respiratory tract infection (10% vs. 5%), rhinorrhea (6% vs. 4%), and influenza (5% vs. 2%). Pneumonia, hemoptysis, and cough occurred in 1% or less of actively treated patients, at a rate more frequent than those receiving placebo.

Gastrointestinal adverse reactions including nausea (13% vs. 8%), upper abdominal pain (12.6% vs. 6.9%), diarrhea (12% vs. 8%), and flatulence (7% vs. 3%) were more common in patients receiving lumacaftor; ivacaftor compared to those receiving placebo during premarketing clinical trials.

Increased blood creatinine phosphokinase (7% vs. 5%), headache (12.6% vs. 8.9%), fatigue (9% vs. 8%), and rash (unspecified) (7% vs. 2%) occurred more frequently in patients receiving lumacaftor; ivacaftor compared to those receiving placebo during premarketing clinical trials.

Cases of non-congenital lens opacities/cataracts have been reported in children and adolescents treated with ivacaftor monotherapy. Although other risk factors (e.g., corticosteroid use, radiation exposure) were present in some cases, a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ivacaftor treatment. Cataracts were also noted in juvenile rats receiving ivacaftor 10 mg/kg/day or more from postnatal day 7 to 35; this finding was not observed in older animals.

Overall, the incidence of abnormal menstrual reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregularity) was more common in female patients treated with lumacaftor; ivacaftor (10%) compared to those treated with placebo (2%) during clinical trials. Abnormalities occurred more frequently in patients who were using hormonal contraception (27%) compared to those not using hormonal contraception (3%).

Adverse reactions related to increases in blood pressure (e.g. hypertension, increased blood pressure) were reported in 1.1% (4/369) of patients receiving lumacaftor; ivacaftor and in no patients receiving placebo. The proportion of patients who experienced a systolic blood pressure value more than 140 mmHg or a diastolic blood pressure more than 90 mmHg on at least two occasions was 3.6% and 2.2%, respectively, in patients receiving lumacaftor; ivacaftor compared with 1.6% and 0.5%, respectively, in patients receiving placebo. Additionally, a maximum decrease in mean heart rate of up to 8 beats per minute (bpm) from baseline was observed with lumacaftor; ivacaftor treatment. Monitor blood pressure periodically in all patients being treated with lumacaftor; ivacaftor.

Hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, have been reported during postmarketing experience. Discontinue lumacaftor, ivacaftor and administer appropriate therapy if signs or symptoms of serious hypersensitivity reactions develop during treatment. Consider the benefits and risks when deciding whether to resume therapy.

If a patient's genotype is unknown, an FDA-cleared CF mutation test should be performed to detect the presence of the F508del mutation on both alleles of the CFTR gene. The safety and efficacy of lumacaftor; ivacaftor in CF patients with other types of mutations has not been established.

Use lumacaftor; ivacaftor with caution in patients with hepatic disease. Worsening of liver function, including hepatic encephalopathy, has been reported in some patients with advanced hepatic disease. In CF patients with pre-existing cirrhosis with portal hypertension, liver function decompensation, including liver failure leading to death, has been reported during lumacaftor; ivacaftor therapy. Use lumacaftor; ivacaftor in such patients only if the expected benefits outweigh the risks, and monitor patients closely. Dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C). Lumacaftor; ivacaftor has been associated with elevated liver transaminases and, in some cases, concomitant elevations in total serum bilirubin. Monitor AST, ALT, and bilirubin prior to initiating therapy, every 3 months during the first year of therapy, and annually thereafter. Consider more frequent monitoring in patients with a history of transaminase and/or bilirubin elevations. Patients who develop increased concentrations should be closely monitored until the abnormalities resolve. Temporarily discontinue lumacaftor; ivacaftor in patients with an ALT or AST more than 5 times the upper limit of normal when not associated with elevated bilirubin. Interrupt therapy in patients with an ALT or AST more than 3 times the upper limit of normal when associated with bilirubin elevations more than 2 times the upper limit of normal. Upon resolution, carefully consider the benefits and risks before resuming therapy.

Monitor patients with severe lung dysfunction closely during lumacaftor; ivacaftor initiation. Clinical experience in patients with ppFEV1 < 40 (FEV1 < 40% of predicted) is limited; however, patients with significant airway obstruction may be at increased risk for adverse respiratory events. During clinical trials, respiratory events (e.g., chest discomfort, dyspnea, abnormal respirations) were observed more commonly in patients initiated on lumacaftor; ivacaftor than those receiving placebo. In a phase 3 trial of 29 patients, patients with ppFEV1 < 40 experienced a similar treatment effect as those with ppFEV1 >= 40.

Use lumacaftor; ivacaftor with caution in patients with severe renal impairment (CrCl <= 30 mL/minute) or end stage renal disease. Lumacaftor; ivacaftor has not been studied in patients with any degree of renal impairment or renal disease.

Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor. Although other risk factors (e.g., corticosteroid use, radiation exposure) were present in some cases, a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended for children and adolescents initiating lumacaftor; ivacaftor treatment. Safety and efficacy have not been established in neonates, infants, or children younger than 1 year of age.

Lumacaftor; ivacaftor has not been studied in cystic fibrosis patients who have received an organ transplant. Use in transplanted patients is not recommended due to potential drug-drug interactions.

Description: Lumacaftor; ivacaftor is an orally administered ion channel modulator approved for the treatment of cystic fibrosis (CF) in patients who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The F508del mutation is the most frequent genotype in patients with CF; approximately 45% of CF patients are homozygous for this allele. Ion channel modulators, such as ivacaftor; lumacaftor, aim to correct the underlying cellular defect (chloride ion transport) responsible for CF instead of the severity of symptoms. Although neither ivacaftor nor lumacaftor monotherapy have shown clinical benefit in patients homozygous for the F508del mutation, clinical trials have demonstrated that the combination corrector and potentiator treatment increases forced expiratory volume (FEV1), reduces pulmonary exacerbation rates, and decreases sweat chloride concentrations (a measure of CFTR function) in these patients when compared to placebo. During Phase 3 trials in patients 12 years and older (n = 1,108), mean improvement in FEV1 ranged from 2.6% to 4% in patients treated with lumacaftor; ivacaftor (p less than 0.001). Effects on pulmonary function were evident by 2 weeks and significant effects were maintained throughout the 24-week trial period. Pooled analysis showed the rate of pulmonary exacerbations was 30% to 39% lower in the active treatment group; events leading to hospitalization or the use of intravenous antibiotics were also lower in the treatment group. Changes in sweat chloride at 8 weeks were modest (-10.3 mmol/L for patients 12 years and older receiving lumacaftor 400 mg/ivacaftor 250 mg twice daily) but significant compared to the placebo group during Phase 2 trials. In patients 6 to 11 years (n = 58) receiving lumacaftor 200 mg/ivacaftor 250 mg twice daily, the reduction in sweat chloride at day 15 (-20.4 mmol/L) was sustained through week 24 (-24.8 mmol/L). The absolute change in sweat chloride from week 24 at week 26 after a 2-week washout period was 21.3 mmol/L. The efficacy of lumacaftor; ivacaftor in patients 6 to 11 years is extrapolated from efficacy in patients 12 years and older. Safety data were obtained from a 24-week Phase 3 clinical trial in patients 6 to 11 years (n = 58). In patients 2 to 5 years (n = 60) receiving either lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg twice daily, the reduction in sweat chloride at week 4 was sustained through week 24 (-31.7 mmol/L). The absolute change in sweat chloride from week 24 at week 26 after a 2-week washout period was 33 mmol/L. The safety profile in patients 2 to 5 years was similar to that in patients 6 years and older. The efficacy of lumacaftor; ivacaftor in patients 1 to 2 years is extrapolated from efficacy in patients 12 years and older. Safety data were obtained from a 24-week Phase 3 clinical trial in patients 1 to 2 years (n = 46). In patients 1 to 2 years (n = 46) receiving either lumacaftor 75 mg/ivacaftor 94 mg, lumacaftor 100 mg/ivacaftor 125 mg, or lumacaftor 150 mg/ivacaftor 188 mg twice daily, the reduction in sweat chloride at week 4 was sustained through week 24 (-29.1 mmol/L). The absolute change in sweat chloride from week 24 at week 26 after a 2-week washout period was 27.3 mmol/L. The safety profile in patients 1 to 2 years was similar to that in patients 2 years and older. Serious adverse reactions related to elevated liver transaminases have been reported in patients receiving lumacaftor; ivacaftor and, in pediatric patients, ivacaftor has been associated with the development of cataracts. Hence, liver function monitoring and eye exams are required at baseline and periodically throughout therapy. Lumacaftor; ivacaftor is FDA-approved in patients 1 year and older.

General dosing information:
-If a patient's genotype is unknown, an FDA-cleared CF mutation test should be performed to detect the presence of the F508del mutation on both alleles of the CFTR gene. The safety and efficacy of lumacaftor; ivacaftor in patients with other types of mutations in the CFTR gene has not been established.

For the treatment of cystic fibrosis in persons who are homozygous for the F508del mutation in the CFTR gene:
Oral dosage (tablets):
Children 6 to 11 years: 200 mg lumacaftor/250 mg ivacaftor PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 12 to 17 years: 400 mg lumacaftor/250 mg ivacaftor PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (granules):
Children 1 to 2 years weighing 7 to 8 kg: 75 mg lumacaftor/94 mg ivacaftor PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 1 to 5 years weighing 9 to 13 kg: 100 mg lumacaftor; 125 mg ivacaftor PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 1 to 5 years weighing 14 kg or more: 150 mg lumacaftor/188 mg ivacaftor PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 2 years weighing 7 to 8 kg: 2 oral granule packets/day PO (total daily dose: lumacaftor 150 mg/ivacaftor 188 mg).
1 to 5 years weighing 9 to 13 kg: 2 oral granule packets/day PO (total daily dose: lumacaftor 200 mg/ivacaftor 250 mg).
1 to 5 years weighing 14 kg or more: 2 oral granule packets/day PO (total daily dose: lumacaftor 300 mg/ivacaftor 376 mg).
6 to 11 years: 4 tablets/day PO (total daily dose: lumacaftor 400 mg/ivacaftor 500 mg).
12 years: 4 tablets/day PO (total daily dose: lumacaftor 800 mg/ivacaftor 500 mg).
-Adolescents
4 tablets/day PO (total daily dose: lumacaftor 800 mg/ivacaftor 500 mg).

Patients with Hepatic Impairment Dosing
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): For patients 1 to 5 years, reduce the dosage to 1 packet of oral granules in the morning and 1 packet of oral granules every other day in the evening. For patients 6 years and older, reduce the dosage to 2 tablets in the morning and 1 tablet in the evening.
Severe impairment (Child-Pugh Class C): For patients 1 to 5 years, reduce the dosage to 1 packet of oral granules once daily in the morning or less frequently. For patients 6 years and older, reduce the dosage to 1 tablet every 12 hours or less frequently. Use with caution; this drug has not been studied in patients with severe hepatic impairment.

Patients with Renal Impairment Dosing
CrCl more than 30 mL/minute: No dosage adjustment necessary.
CrCl 30 mL/minute or less: Use with caution; specific guidelines for dosage adjustments are not available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Lumacaftor; ivacaftor is a modulator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel present at the surface of epithelial cells in multiple organs. Patients with cystic fibrosis (CF) have a mutation in the CFTR gene that encodes the protein. In patients with the F508del mutation, CFTR protein misfolding causes a defect in cellular processing and trafficking that targets the protein for degradation, resulting in a lower quantity of CFTR at the cell surface. The small amount of F508del-CFTR that does reach the cell surface is less stable and has low channel-open probability compared to the wild-type CFTR protein. Lumacaftor improves the conformational stability of F508del-CFTR, which results in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that increases chloride transport by potentiating the channel-opening probability of the CFTR protein. In vitro studies have demonstrated that both lumacaftor and ivacaftor increase chloride ion transport by increasing the quantity, stability, and function of F508del-CFTR at the cell surface.

Pharmacokinetics: Lumacaftor; ivacaftor is administered orally. Lumacaftor and ivacaftor are both approximately 99% protein bound, with lumacaftor binding primarily to albumin and ivacaftor binding primarily to albumin and alpha1-acid glycoprotein. The mean apparent Vd of lumacaftor is 86 +/- 67 L at steady state in patients with cystic fibrosis. Lumacaftor is primarily metabolized via oxidation and glucuronidation; however, metabolism is not extensive. The majority of the drug (51%) is excreted in the feces unchanged. Ivacaftor is extensively metabolized, primarily by CYP3A, to the major metabolites M1 (pharmacologically active; one-sixth the potency of parent drug) and M6 (pharmacologically inactive). Ivacaftor is primarily eliminated in the feces (88%). Minimal amounts of lumacaftor and ivacaftor are eliminated in the urine. Typical apparent clearance of lumacaftor is estimated to be 2.38 L/hour for patients with cystic fibrosis (CF); half-life is approximately 26 hours (CF patients). When given in combination with lumacaftor, the typical apparent clearance of ivacaftor is estimated to be 25.1 L/hour (CF patients); half-life is approximately 9 hours (healthy patients).

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2C19, CYP2C9, CYP2C8, CYP2B6, and P-gp
Ivacaftor is a sensitive substrate of CYP3A. Lumacaftor is a strong inducer of CYP3A. When given in combination, lumacaftor decreases ivacaftor exposure by approximately 80%; therefore, the ivacaftor dose contained in the combination product is higher than the dose when ivacaftor is given as monotherapy (500 mg/day vs. 300 mg/day for adolescents). Ivacaftor exposure is further decreased when given together with other CYP3A inducers and increased when given with concomitant CYP3A inhibitors. As monotherapy, ivacaftor is a weak inhibitor of CYP3A; however, the net effect of lumacaftor; ivacaftor therapy is strong CYP3A induction. This induction may result in decreased systemic exposure and decreased therapeutic effect of other drugs that are metabolized by CYP3A. Coadministration with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates and/or drugs transported by P-glycoprotein (P-gp) may alter the exposure of these substrates. In vitro studies suggest lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed. Ivacaftor has been shown to inhibit CYP2C9 in vitro. In addition, lumacaftor has the potential to both inhibit and induce P-gp, while ivacaftor is a weak P-gp inhibitor.


-Route-Specific Pharmacokinetics
Oral Route
During clinical trials, the median Tmax of both lumacaftor and ivacaftor was approximately 4 hours (lumacaftor range: 2 to 9 hours; ivacaftor range: 2 to 6 hours) in the fed state. At steady state, the peak plasma concentrations of lumacaftor and ivacaftor were 25 (+/- 8) mcg/mL and 0.602 (+/- 0.3) mcg/mL, respectively, in CF patients receiving a dose of 2 tablets (lumacaftor 400 mg/ivacaftor 250 mg) every 12 hours. Exposure (AUC) was 198 (+/- 65) mcg x hour/mL for lumacaftor and 3.66 (+/- 2.25) mcg x hour/mL for ivacaftor. With repeated dosing, drug exposure increased proportionally to the dose at a range of 200 mg every 24 hours to 400 mg every 12 hours for lumacaftor and 150 mg every 12 hours to 250 mg every 12 hours for ivacaftor. In healthy patients, steady-state plasma concentrations of lumacaftor and ivacaftor were reached approximately 7 days after twice-daily treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. It is important to remember that ivacaftor exposure is lower at steady state compared to day 1 of therapy because of lumacaftor's induction of CYP3A. Administration of lumacaftor; ivacaftor with fat-containing foods increased lumacaftor exposure 2-fold and ivacaftor exposure 3-fold compared to fasting state; hence, administration with fat-containing foods is recommended.


-Special Populations
Pediatrics
Pediatric patients 1 to 2 years

Based on population pharmacokinetic analysis, the exposure of lumacaftor; ivacaftor in pediatric patients 1 to 2 years is comparable to patients 12 years and older. In pediatric patients receiving lumacaftor 75 mg/ivacaftor 94 mg every 12 hours, the mean AUC was 234 mcg x hour/mL for lumacaftor and 7.98 mcg x hour/mL for ivacaftor. In pediatric patients receiving lumacaftor 100 mg/ivacaftor 125 mg every 12 hours, the mean AUC was 191 (+/- 40.6) mcg x hour/mL for lumacaftor and 5.35 (+/- 1.61) mcg x hour/mL for ivacaftor. In pediatric patients receiving lumacaftor 150 mg/ivacaftor 188 mg every 12 hours, the mean AUC was 116 mcg x hour/mL for lumacaftor and 5.82 mcg x hour/mL for ivacaftor.

Pediatric patients 2 to 5 years
Based on population pharmacokinetic analysis, the exposure of lumacaftor; ivacaftor in pediatric patients 2 to 5 years is comparable to patients 12 years and older. In pediatric patients receiving lumacaftor 100 mg/ivacaftor 125 mg every 12 hours, the mean AUC was 180 (+/- 45.5) mcg x hour/mL for lumacaftor and 5.92 (+/- 4.61) mcg x hour/mL for ivacaftor. In pediatric patients receiving lumacaftor 150 mg/ivacaftor 188 mg every 12 hours, the mean AUC was 217 (+/- 48.6) mcg x hour/mL for lumacaftor and 5.9 (+/- 1.93) mcg x hour/mL for ivacaftor.

Pediatric patients 6 to 11 years
Based on population pharmacokinetic analysis, the exposure of lumacaftor; ivacaftor in pediatric patients 6 to 11 years is comparable to patients 12 years and older. In pediatric patients receiving lumacaftor 200 mg/ivacaftor 250 mg every 12 hours, the mean AUC was 203 (+/- 57.4) mcg x hour/mL for lumacaftor and 5.26 (+/- 3.08) mcg x hour/mL for ivacaftor.

Pediatric patients 12 to 17 years
Based on population pharmacokinetic analysis, the exposure of lumacaftor; ivacaftor is similar in pediatric patients 12 years and older and adults. In pediatric patients receiving lumacaftor 400 mg/ivacaftor 250 mg every 12 hours, the mean AUC was 241 (+/- 61.4) mcg x hour/mL for lumacaftor and 3.9 (+/- 1.56) mcg x hour/mL for ivacaftor.

Hepatic Impairment
Compared to those of healthy subjects, the AUC and Cmax of both lumacaftor and ivacaftor were approximately 50% and 30% higher, respectively, in patients with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) after repeated dosing for 10 days. Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe (Child-Pugh Class C, score 10 to 15) impairment receiving lumacaftor; ivacaftor.