For patients age 2 years and older who are homozygous for the F508del mutation¹
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Indications and Usage
ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who are homozygous for the F508del mutation in the 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. 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 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. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 (ppFEV1) <40). Clinical experience in patients with 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 in patients age 6 through 11 years from an open-label Phase 3 trial (Trial 3; N=58) and a placebo-controlled Phase 3 trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased. The safety profile in patients age 2 through 5 years from an open-label Phase 3 trial (Trial 6; N=60) was similar to that in patients aged 6 years and older
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References:
References: 1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Milla CE, Ratjen F, Marigowda G, et al. On behalf of the VX13-809-011 Part B Investigator Group. Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00008(2); 2017. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01794; 2017. 5. Chilvers M, Owen CA, Marigowda G, et al. Safety and efficacy of lumacaftor/ivacaftor (LUMA/IVA) in patients aged ≥6 years with CF homozygous for F508del–a phase 3 extension study. Poster and abstract presented at: 31st Annual North American Cystic Fibrosis Conference; Indianapolis, Indiana; November 2-4, 2017. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-20-00333; 2018. 7. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01799; 2017. 8. Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5(7):557-567. 9. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01795(2); 2017. 10. Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Milla CE, Ratjen F, Marigowda G, et al. On behalf of the VX13-809-011 Part B Investigator Group. Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00008(2); 2017. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01794; 2017. 5. Chilvers M, Owen CA, Marigowda G, et al. Safety and efficacy of lumacaftor/ivacaftor (LUMA/IVA) in patients aged ≥6 years with CF homozygous for F508del–a phase 3 extension study. Poster and abstract presented at: 31st Annual North American Cystic Fibrosis Conference; Indianapolis, Indiana; November 2-4, 2017. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-20-00333; 2018. 7. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01799; 2017. 8. Ratjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5(7):557-567. 9. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-US-20-01795(2); 2017. 10. Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00178; 2018. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00180; 2018. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00179(1); 2019.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Wainwright CE, Elborn JS, Ramsey BW, et al. for the TRAFFIC and TRANSPORT Study Groups. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; June 2019. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston. MA. VXR-HQ-88-00201; 2018.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019. 2. Data on file. Boston, MA. Vertex Pharmaceuticals Incorporated; REF-3538 (v1.0); 2019. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed March 9, 2020 4. Xanax [prescribing information]. New York, NY: Pfizer; January 2017. 5. Klonopin [prescribing information]. South San Francisco, CA: Genentech, Inc.; October 2017. 6. Valium [prescribing information]. South San Francisco, CA: Genentech, Inc.; April 2017. 7. Kunze A, Huwyler J, Camenisch G, Poller B. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos. 2014;42(9):1514-1521.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019.
Reference:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; July 2019