Reduced Rate of Pulmonary Exacerbations Maintained up to 120 Weeks1,2

Number of pulmonary exacerbations through Week 24 was a secondary endpoint in Trials 1 and 2 and was not statistically significant in either trial.3

 

Annualized Pulmonary Exacerbation Rate1,2,a

Annual pulmonary exacerbation rate for trials 1 and 2Annual pulmonary exacerbation rate for extension study

Adapted from Konstan MW et al. Lancet Respir Med. 2017;5(2):107-118, with permission from Elsevier.

a The number of pulmonary exacerbations is expressed as a rate over 48 weeks. For Trials 1 and 2, this rate is based on 24 weeks of observation. For the Extension Study, this rate is based on the total number of weeks of ORKAMBI exposure.
b In the individual analyses of these trials, changes were not statistically significant with ORKAMBI vs placebo in Trials 1 or 2.2
c Results are based on a pooled analysis that was not prespecified and did not correct for multiple comparisons.
d Rate ratio for ORKAMBI vs placebo: 0.61, 95% CI (0.49, 0.76).
e Includes data from Trials 1 and 2.

TRIALS 1 AND 2 AND EXTENSION STUDY—POST HOC ANALYSIS

Reduced Rate of Hospitalizations Due to Pulmonary Exacerbations Maintained up to 120 Weeks1,2

 
The results for both pulmonary exacerbations requiring hospitalization and pulmonary exacerbations requiring IV antibiotic use included below are based on a post hoc analysis. These analyses did not ascertain whether findings were attributable to ORKAMBI.1,4

Annualized Rate of Pulmonary Exacerbations Requiring Hospitalization1,2,a

Annual pulmonary exacerbation rate for hospitalizations in trials 1 and 2Annual pulmonary exacerbation rate for hospitalizations in the extension study

Adapted from Konstan MW et al. Lancet Respir Med. 2017;5(2):107-118, with permission from Elsevier.

Reduced IV Antibiotic Use Due to Pulmonary Exacerbations Maintained up to 120 Weeks1,2,a

  • 56% reduction at Week 24 in the annualized rate of IV antibiotic use due to pulmonary exacerbations in Trials 1 and 22,b,e
    • The event rate per year was 0.25 (95% CI, 0.19 to 0.33) for ORKAMBI, and 0.58 (95% CI, 0.47 to 0.72) for placebo1
  • Reductions were maintained in the ORKAMBI-to-ORKAMBI group (120 weeks on therapy) and the placebo-to-ORKAMBI group (96 weeks on therapy)1,d
    • The event rate per year was 0.32 (95% CI, 0.26 to 0.38) for ORKAMBI-to-ORKAMBI, and 0.37 (95% CI, 0.29 to 0.49) for placebo-to-ORKAMBI
a The number of pulmonary exacerbations is expressed as a rate over 48 weeks. For Trials 1 and 2, this rate is based on 24 weeks of observation. For the Extension Study, this rate is based on the total number of weeks of ORKAMBI exposure.
b Results are based on a pooled analysis that was not prespecified and did not correct for multiple comparisons.
c Rate ratio for ORKAMBI vs placebo: 0.39, 95% CI (0.26, 0.56).5
d Includes data from Trials 1 and 2.
e Rate ratio for ORKAMBI vs placebo: 0.44, 95% CI (0.32, 0.59)6

TRIALS 1 AND 2–POST HOC ANALYSIS

Reduced Rate of Pulmonary Exacerbations Regardless of Changes in FEV17

The results are based on a post hoc analysis and therefore statistical significance cannot be determined. This analysis does not ascertain whether findings were attributable to ORKAMBI4,7

In patients with CF, pulmonary exacerbations are associated with FEV1 decline. Therefore, to minimize this potential bias, the earliest post-baseline FEV1 measure (at Day 15) was used to categorize lung function change in the ORKAMBI group.7
  • There were also fewer pulmonary exacerbations requiring hospitalization, regardless of changes in percent predicted FEV17

Pulmonary Exacerbation Event Rates and Rate Ratios at 24 Weeks by Absolute Change in FEV1 (From Baseline to Day 15): Post Hoc Pooled Analysis7

Annual pulmonary exacerbation rate ratiosAnnual rate ratios for pulmonary exacerbations requiring hospitalizations

The number of pulmonary exacerbations was reported through Week 24 and expressed as a rate over 48 weeks.7

a In patients with a decline or no change in ppFEV1, the rate ratio for ORKAMBI vs placebo was 0.7, 95% CI (0.6, 1.0) for PEs and 0.4, 95% CI (0.2, 0.7) for PEs requiring hospitalization.7
b In patients with an increase in ppFEV1, the rate ratio for ORKAMBI vs placebo was 0.5, 95% CI (0.54, 0.7) and 0.4, 95% CI (0.2, 0.6) for PEs requiring hospitalization.7

Trials 1 & 2 Study Design: Trials 1 and 2 were 24-week, Phase 3, randomized, double-blind, placebo-controlled trials of patients with CF who were homozygous for the F508del mutation and age 12 years and older. Patients received either ORKAMBI (lumacaftor 400 mg/ivacaftor 250 mg q12h) or placebo and continued to take their prescribed CF therapies.3

Extension Study Design: Patients who completed Trials 1 and 2 were eligible to enroll in a 96-week Extension Study. Of patients from Trials 1 and 2, 340 patients continued to receive ORKAMBI during the Extension Study and 176 rolled over from placebo to ORKAMBI.1

 
×
+

ORKAMBI® (lumacaftor/ivacaftor) INDICATIONS AND USAGE

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.


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.

IMPORTANT SAFETY INFORMATION

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF 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 dose should be reduced

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 greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN
  • Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

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. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

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

Drug Interactions

Substrates of CYP3A

  • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
  • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI

Strong CYP3A Inducers

  • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

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. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

Adverse Reactions

  • 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
  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile for patients age 6 through 11 years in an open-label Phase 3 trial (Trial 3; N=58) was similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information.

×
+

ORKAMBI® (lumacaftor/ivacaftor) INDICATIONS AND USAGE

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.


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.

IMPORTANT SAFETY INFORMATION

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF 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 dose should be reduced

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 greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN
  • Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

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. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

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

Drug Interactions

Substrates of CYP3A

  • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
  • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI

Strong CYP3A Inducers

  • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

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. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

Adverse Reactions

  • 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
  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile for patients age 6 through 11 years in an open-label Phase 3 trial (Trial 3; N=58) was similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information.