ORKAMBI

5 WARNINGS AND PRECAUTIONS 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 dosage should be reduced. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension. ( 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 ) Hypersensitivity reactions: Angioedema and anaphylaxis have been reported with ORKAMBI in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. ( 5.3 ) Intracranial hypertension: Intracranial hypertension (IH) has been reported in the postmarketing setting with the use of ORKAMBI. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt ORKAMBI and refer for prompt medical evaluation. ( 5.4 ) Neuropsychiatric events, including suicidal thoughts and behaviors : Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting for ORKAMBI or drugs containing the same or similar active ingredients. Monitor patients closely for new or worsening symptoms. Consider the risks and benefits for the individual patient to determine if therapy with ORKAMBI should be interrupted at the occurrence of neuropsychiatric symptoms. ( 5.5 ) Respiratory events: Chest discomfort, dyspnea, and respiration abnormal were observed more commonly during initiation of ORKAMBI. Clinical experience in patients with percent predicted FEV 1 (ppFEV 1 ) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy. ( 5.6 , 6.1 ) Blood pressure: Increased blood pressure has been observed in some patients. Periodically monitor blood pressure in all patients. ( 5.7 , 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. ( 5.8 , 6.1 , 7 , 12.3 ) Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Baseline and follow-up examinations are recommended in pediatric patients initiating ORKAMBI. ( 5.9 ) 5.1 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 dosage should be reduced [see Dosage and Administration (2.2) and Adverse Reactions (6.1) ] . 5.2 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 >5 × upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 × ULN when associated with bilirubin elevations >2 × ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing [see Adverse Reactions (6.1) ] . 5.3 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2) ] . If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI. 5.4 Intracranial Hypertension Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of ORKAMBI [see Adverse Reactions (6.2) ] . Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt ORKAMBI and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk. 5.5 Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking ORKAMBI or drugs containing the same or similar active ingredients [see Adverse Reactions (6.2) ] . The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances. Consider the benefits and risks for the individual patient to determine if therapy with ORKAMBI should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement. 5.6 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 FEV 1 <40). Clinical experience in patients with ppFEV 1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy [see Adverse Reactions (6.1) ] . 5.7 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 [see Adverse Reactions (6.1) ] . 5.8 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 (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI [see Adverse Reactions (6.1) , Drug Interactions (7.3 , 7.11) , and Clinical Pharmacology (12.3) ] . 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 (e.g., rifampin, St. John's wort [ Hypericum perforatum ]) is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . 5.9 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 [see Use in Specific Populations (8.4) ] . Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ORKAMBI treatment.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Use in Patients with Advanced Liver Disease [see Warnings and Precautions (5.1) ] Liver-related Events [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3) ] Intracranial Hypertension [see Warnings and Precautions (5.4) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.5) ] Respiratory Events [see Warnings and Precautions (5.6) ] Effect on Blood Pressure [see Warnings and Precautions (5.7) ] Cataracts [see Warnings and Precautions (5.9) ] 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of ORKAMBI is based on the pooled data from 1108 patients with CF aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in two double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2). In addition, the following clinical trials have been conducted: A 24-week, open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation. A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation. A 24-week, open-label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV 1 <40). A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation. A 24-week, open-label trial (Trial 7) in 46 patients aged 1 through 2 years homozygous for the F508del - CFTR mutation. Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 patients received placebo. The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with ORKAMBI and 2% for patients who received placebo. 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. Table 3 shows adverse reactions occurring in ≥5% of patients with CF aged 12 years and older treated with ORKAMBI who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials. Table 3: Incidence of Adverse Drug Reactions in ≥5% of ORKAMBI-Treated Patients Aged 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration Adverse Reaction (Preferred Term) ORKAMBI N=369 (%) Placebo N=370 (%) Dyspnea 48 (13) 29 (8) Nasopharyngitis 48 (13) 40 (11) Nausea 46 (13) 28 (8) Diarrhea 45 (12) 31 (8) Upper respiratory tract infection 37 (10) 20 (5) Fatigue 34 (9) 29 (8) Respiration abnormal 32 (9) 22 (6) Blood creatine phosphokinase increased 27 (7) 20 (5) Rash 25 (7) 7 (2) Flatulence 24 (7) 11 (3) Rhinorrhea 21 (6) 15 (4) Influenza 19 (5) 8 (2) The safety profile from two pediatric trials in CF patients aged 6 through 11 years who are homozygous for the F508del-CFTR mutation, a 24-week, open-label, multicenter safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled, clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo), was similar to that observed in Trials 1 and 2. Adverse reactions that are not listed in Table 3, and that occurred in ≥5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥3% higher than placebo included: productive cough (17.5% vs 5.9%), nasal congestion (16.5% vs 7.9%), headache (12.6% vs 8.9%), abdominal pain upper (12.6% vs 6.9%), and sputum increased (10.7% vs 2.0%). In a 24-week, open-label, multicenter, study in 60 patients aged 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation (Trial 6) the safety profile was similar to that observed in studies in patients aged 6 years and older [see Clinical Pharmacology (12.2) ] . In a 24-week, open-label, multicenter, study in 46 patients aged 1 through 2 years with CF who were homozygous for the F508del-CFTR mutation (Trial 7) the safety profile was similar to that observed in studies in patients aged 2 years and older [see Clinical Pharmacology (12.2) ] . Additional information on selected adverse reactions from trials is detailed below: Description of Selected Adverse Drug Reactions Liver-related Adverse Reactions In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN elevations were similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including two reported as transaminase elevations and one as hepatic encephalopathy, compared to none in the placebo group. Of these three, one had elevated transaminases (>3 × ULN) associated with bilirubin elevation >2 × ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 × ULN. Among six patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within five days of the start of dosing and resolved following discontinuation of ORKAMBI [see Warnings and Precautions (5.1 , 5.2) ] . During the 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years (Trial 3), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN was 5%, 9%, and 19%. No patients had total bilirubin levels >2 × ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except one patient who discontinued treatment permanently. During the 24-week, placebo-controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN was 1%, 5%, and 13% in the lumacaftor/ivacaftor patients, and 2%, 3%, and 8% in the placebo-treated patients. No patients had total bilirubin levels >2 × ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations. During the 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN was 8.3% (5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels >2 × ULN. Three patients discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. During the 24-week, open-label, clinical trial in 46 patients aged 1 through 2 years (Trial 7), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN was 2.2% (1/46), 4.3% (2/46), and 10.9% (5/46), respectively. No patients had total bilirubin levels >2 × ULN. One patient discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. Respiratory Adverse Reactions In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%). The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pre-treatment FEV 1 . In patients treated with ORKAMBI, the majority of the events began during the first week of treatment [see Warnings and Precautions (5.6) ] . During the 24-week, open-label, clinical trial in 46 patients aged 12 years and older (Trial 5) with advanced lung disease (ppFEV 1 <40) [mean ppFEV 1 29.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65% [see Warnings and Precautions (5.6) ] . During the 24-week, open-label, clinical trial (Trial 3) in 58 patients aged 6 through 11 years (mean baseline ppFEV 1 was 91.4), the incidence of respiratory symptom-related adverse reactions was 3% (2/58). During the 24-week, placebo-controlled, clinical trial (Trial 4) in patients aged 6 through 11 years [mean ppFEV 1 89.8 at baseline (range: 48.6 to 119.6)], the incidence of respiratory symptom-related adverse reactions was 11% in lumacaftor/ivacaftor patients and 9% in placebo patients. A decline in ppFEV 1 at initiation of therapy was observed during serial post-dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16. Menstrual Abnormalities In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%) [see Warnings and Precautions (5.8) and Drug Interactions (7.11) ] . Increased Blood Pressure In Trials 1 and 2, adverse reactions related to increases in blood pressure (e.g., hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo. The proportion of patients who experienced a systolic blood pressure value >140 mmHg or a diastolic blood pressure >90 mmHg on at least two occasions was 3.6% and 2.2% in patients treated with ORKAMBI, respectively, compared with 1.6% and 0.5% in patients who received placebo [see Warnings and Precautions (5.7) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ORKAMBI or drugs containing the same or similar active ingredients as ORKAMBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary : liver function decompensation including liver failure leading to death in patients with pre-existing cirrhosis with portal hypertension [see Warnings and Precautions (5.1) ] . Immune System Disorders : anaphylaxis, angioedema Nervous System Disorders : intracranial hypertension Psychiatric Disorders : anxiety, depression, suicidal ideation and behavior, insomnia

<table width="90%" ID="Table3"><caption>Table 3: Incidence of Adverse Drug Reactions in &#x2265;5% of ORKAMBI-Treated Patients Aged 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration</caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reaction (Preferred Term)</th><th styleCode="Rrule" valign="bottom">ORKAMBI N=369 (%)</th><th styleCode="Rrule" valign="bottom">Placebo N=370 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea</td><td styleCode="Rrule">48 (13)</td><td styleCode="Rrule">29 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">48 (13)</td><td styleCode="Rrule">40 (11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">46 (13)</td><td styleCode="Rrule">28 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">45 (12)</td><td styleCode="Rrule">31 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">37 (10)</td><td styleCode="Rrule">20 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">34 (9)</td><td styleCode="Rrule">29 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Respiration abnormal</td><td styleCode="Rrule">32 (9)</td><td styleCode="Rrule">22 (6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blood creatine phosphokinase increased</td><td styleCode="Rrule">27 (7)</td><td styleCode="Rrule">20 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">25 (7)</td><td styleCode="Rrule">7 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flatulence</td><td styleCode="Rrule">24 (7)</td><td styleCode="Rrule">11 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinorrhea</td><td styleCode="Rrule">21 (6)</td><td styleCode="Rrule">15 (4)</td></tr><tr><td styleCode="Lrule Rrule">Influenza</td><td styleCode="Rrule">19 (5)</td><td styleCode="Rrule">8 (2)</td></tr></tbody></table>