Use in Specific Populations

Pregnancy1

  • There are limited and incomplete human data from clinical trials and postmarketing reports on use of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk

Lactation1

  • There is no information regarding the presence of lumacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORKAMBI and any potential adverse effects on the breastfed child from ORKAMBI or from the underlying maternal condition

Females and males of reproductive potential1

  • 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

Pediatric use1

  • The safety and efficacy of ORKAMBI in patients younger than age 6 years 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
 

Geriatric use1

  • 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

Hepatic impairment1

  • No dose adjustment is necessary for patients with mild hepatic impairment. A dose reduction is recommended for patients with moderate hepatic impairment. Studies have not been conducted in patients with severe hepatic impairment, but exposure is expected to be higher than in patients with moderate hepatic impairment. A dose reduction is recommended for patients with severe hepatic impairment. Use with caution in patients with severe hepatic impairment after weighing the risks and benefits of treatment. See dose chart below for recommended dose adjustments
Recommended Dose Adjustments for Patients With Hepatic Impairment1,2
Degree of Hepatic Impairment Child-Pugh Class (score) ORKAMBI Dose Adjustment
Mild A
(score 5 to 6)
None
Moderate B
(score 7 to 9)
Reduce to 2 tablets in the morning and 1 tablet in the evening
Severe C
(score 10 to 15)
Use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening, or less, after weighing the risks and benefits of treatment

Renal impairment1

  • 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 ≤30 mL/min) or end-stage renal disease
Degree of Renal Impairment ORKAMBI
Mild to Moderate No dosage adjustment
Severe (creatinine clearance ≤30 mL/min) Caution is recommended
End-Stage Renal Disease Caution is recommended

Patients with severe lung dysfunction1

  • The Phase 3 trials (Trials 1 and 2) included 29 patients receiving ORKAMBI with percent predicted FEV1 <40 at baseline. The treatment effect in this subgroup was comparable to that observed in patients with percent predicted FEV1 ≥40. 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 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Patients after organ transplantation1

  • 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
 
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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.