Kalydeco ivacaftor 13.4 mg Granule, 56-count

5 WARNINGS AND PRECAUTIONS Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. In patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve.

Interrupt dosing in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing. ( 5.1 , 6 ) Hypersensitivity reactions: Anaphylaxis has been reported with KALYDECO in the postmarketing setting.

Initiate appropriate therapy in the event of a hypersensitivity reaction. ( 5.2 ) Intracranial hypertension : Intracranial hypertension (IH) has been reported in the postmarketing setting with use of drugs containing the same or similar active ingredients as KALYDECO. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt KALYDECO and refer for prompt medical evaluation.

( 5.3 ) 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 KALYDECO or drugs containing the same or similar active ingredient. Monitor patients closely for new or worsening symptoms. Consider the risks and benefits for the individual patient to determine if therapy with KALYDECO should be interrupted at the occurrence of neuropsychiatric symptoms.

( 5.4 ) Use with CYP3A inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) substantially decreases exposure of ivacaftor, which may diminish effectiveness. Therefore, co-administration is not recommended.

( 5.5 , 7.2 , 12.3 ) Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up examinations are recommended in pediatric patients initiating KALYDECO treatment. ( 5.6 )

5.1Transaminase (ALT or AST) Elevations Elevated transaminases have been reported in patients with CF receiving KALYDECO. ALT and AST should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests.

Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO [see Adverse Reactions (6) and Use in Specific Populations (8.6) ] .

5.2Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of 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 KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO .

5.3Intracranial Hypertension Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of drugs containing the same or similar active ingredients as KALYDECO [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 KALYDECO and refer for prompt medical evaluation.

Conside…

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Transaminase Elevations [ see Warnings and Precautions (5.1) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2) ] Intracranial Hypertension [see Warnings and Precautions (5.3) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.6) ] The most common adverse drug reactions to KALYDECO (≥8% of patients with CF who have a G551D mutation in the CFTR gene) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness.

( 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 .

6.1Clinical 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 clinical practice. The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3).

In addition, the following clinical trials have also been conducted [ see Clinical Pharmacology (12) and Clinical Studies (14) ]: An 8-week, crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E , G1349D , G178R , G551S , G970R , S1251N , S1255P , S549N , or S549R mutation in the CFTR gene. A 24-week, placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene. A 24-week, open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age.

Patients eligible for Trial 6 were those with the G551D, G1244E , G1349D , G178R , G551S , G970R , S1251N , S1255P , S549N , or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation. An 8-week, crossover design trial (Trial 7) involving patients between the ages of 12 and 72 years who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be responsive to ivacaftor.

A total of 156 patients were randomized to and received KALYDECO. A 24-week open-label clinical trial in patients with CF aged less than 24 months (Trial 8) including a cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, a cohort of 6 patients aged 4 months to less than 6 months, and a cohort of 7 patients aged 1 month to less than 4 months. Patients with a gating mutation or R117H mutation were eligible for the first three cohorts of this study.

Patients with any ivacaftor-responsive mutation were eligible for the cohort aged 1 to less than 4 months. Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo for 16 to 48 weeks. The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for KALYDECO-treated patients and 5% for placebo-treated patients.

Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in KALYDECO-treated patients, included abdominal pain, increased hepatic enzymes, and hypoglycemia. The most common adverse reactions in the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%),…

7 DRUG INTERACTIONS Potential for other drugs to affect ivacaftor CYP3A inhibitors: Reduce KALYDECO dosage in patients aged 6 months and older when co-administered with strong CYP3A inhibitors (e.g., ketoconazole) or moderate CYP3A inhibitors (e.g., fluconazole). KALYDECO is not recommended in patients aged 1 month to less than 6 months when co-administered with strong or moderate CYP3A inhibitors. Avoid food or drink containing grapefruit. ( 2.4 , 7.1 )

7.1Inhibitors of CYP3A Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin.

KALYDECO is not recommended for patients less than 6 months of age taking strong CYP3A inhibitors [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.

KALYDECO is not recommended for patients less than 6 months of age taking moderate CYP3A inhibitors [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, avoid food or drink containing grapefruit during treatment with KALYDECO [ see Clinical Pharmacology (12.3) ].

7.2Inducers of CYP3A Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended [ see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ].

7.3Ciprofloxacin Co-administration of KALYDECO with ciprofloxacin had no effect on the exposure of ivacaftor. Therefore, no dosage adjustment is necessary during concomitant administration of KALYDECO with ciprofloxacin [ see Clinical Pharmacology (12.3) ]. Potential for ivacaftor to affect other drugs

7.4CYP2C9 Substrates Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of KALYDECO with warfarin is recommended. Other therapeutic products for which exposure may be increased by KALYDECO include glimepiride and glipizide; these therapeutic products should be used with caution [see Clinical Pharmacology (12.3) ] .

7.5CYP3A and/or P-gp Substrates Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with oral midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor.

Administration of KALYDECO may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering KALYDECO with sensitive CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus [ see Clinical Pharmacology (12.3) ].