Can Ivacaftor cause dyspnea?

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 . 6.1 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 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%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%). The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with KALYDECO 150 mg orally or placebo twice daily. Table 2 shows adverse reactions occurring in ≥8% of KALYDECO-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials. Table 2: Incidence of Adverse Drug Reactions in ≥8% of KALYDECO-Treated Patients with a G551D Mutation in the CFTR Gene and Greater than Placebo in 2 Placebo-Controlled Phase 3 Clinical Trials of 48 Weeks Duration Adverse Reaction (Preferred Term) Incidence: Pooled 48-Week Trials KALYDECO N=109 n (%) Placebo N=104 n (%) Headache 26 (24) 17 (16) Oropharyngeal pain 24 (22) 19 (18) Upper respiratory tract infection 24 (22) 14 (14) Nasal congestion 22 (20) 16 (15) Abdominal pain 17 (16) 13 (13) Nasopharyngitis 16 (15) 12 (12) Diarrhea 14 (13) 10 (10) Rash 14 (13) 7 (7) Nausea 13 (12) 11 (11) Dizziness 10 (9) 1 (1) Adverse reactions in the 48-week clinical trials that occurred in the KALYDECO group at a frequency of 4 to 7% where rates exceeded that in the placebo group include: Infections and infestations : rhinitis Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia Nervous system disorders: sinus headache Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing Skin and subcutaneous tissue disorders: acne The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2). Laboratory Abnormalities Transaminase Elevations: In Trials 1, 2, and 3 the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 2%, 2%, and 6% in KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo. Transaminase elevations were more common in patients with a history of transaminase elevations [ see Warnings and Precautions (5.1) ]. During the 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 × ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 × ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient [ see Warnings and Precautions (5.1) ]. During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3, >5, and >8 × ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to ≤5 × ULN. In the cohort of patients aged 4 months to less than 6 months (N=6), no patients had elevated ALT or AST (>3× ULN). In the cohort of patients aged 1 month to les

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