ORKAMBI is a combination of lumacaftor and ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, indicated for the treatment of cystic fibrosis (CF) in patients age 12 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. (1)

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. (1)

• Adults and pediatric patients age 12 years and older: two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours. (2.1)
• Reduce dose in patients with moderate or severe hepatic impairment. (2.2, 8.6, 12.3)
• When initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce ORKAMBI dose for the first week of treatment. (2.3, 7.1, 12.3)

• Use in patients with advanced liver disease: ORKAMBI should be used with caution in these patients 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. (2.2, 5.1, 6.1)
• Liver-related events: Elevated transaminases (ALT/AST) have been observed in some cases associated with elevated bilirubin. Measure serum transaminases and bilirubin before 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. Interrupt dosing in patients with ALT or AST >5 × upper limit of normal (ULN), or ALT or AST >3 × ULN with bilirubin >2 × ULN. Following resolution, consider the benefits and risks of resuming dosing. (5.2, 6.1)
• Respiratory events: Chest discomfort, dyspnea, and respiration abnormal were observed more commonly during initiation of ORKAMBI. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy. (5.3, 6.1)
• Drug interactions: Use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products and co-administration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception and their use is associated with increased menstruation-related adverse reactions. Use with strong CYP3A inducers may diminish exposure of ivacaftor, which may diminish its effectiveness; therefore, co-administration is not recommended. (5.4, 6.1, 7, 12.3)
• Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor, a component of ORKAMBI. Baseline and follow-up examinations are recommended in pediatric patients initiating ORKAMBI. (5.5)

The most common adverse reactions to ORKAMBI (occurring in ≥5% of patients with CF homozygous for the F508del mutation in the CFTR gene) were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, influenza. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See Full Prescribing Information for a complete list. (2.3, 7, 12.3)