TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE

TRIKAFTA is indicated for the treatment of patients ≥2 years who have a clinical diagnosis of cystic fibrosis (CF) and ≥1 variant in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive based on clinical and/or in vitro data or results in CFTR protein production.

If the patient’s genotype is unknown, an FDA-cleared CF genetic test should be used to confirm the presence of ≥1 indicated variant.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Drug-Induced Liver Injury and Liver Failure

• TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Liver failure leading to transplantation and death has been reported in patients with and without a history of liver disease taking TRIKAFTA. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA
• Assess LFTs in all patients prior to initiating TRIKAFTA, then every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or LFT elevations at baseline
• Interrupt TRIKAFTA in the event of signs or symptoms of liver injury, which may include:
  • Significant elevations in LFTs (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
  • Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
• Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved, and if benefit is expected to outweigh risk, resume TRIKAFTA with close monitoring
• TRIKAFTA should not be used in patients with severe hepatic impairment. TRIKAFTA is not recommended in patients with moderate hepatic impairment and should only be considered when there is a clear medical need and benefit outweighs risk. If used, use with caution at a reduced dosage and monitor patients closely

Hypersensitivity Reactions, Including Anaphylaxis

• Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider benefits and risks to determine whether to resume treatment

Intracranial Hypertension (IH)

• IH has been reported in the postmarketing setting with TRIKAFTA. 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 TRIKAFTA and refer for prompt medical evaluation. Consider benefits and risks to determine whether to resume treatment. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk

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 with and without a previous history of neuropsychiatric symptoms taking TRIKAFTA. Symptoms may occur within the first 3 months of treatment. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms. Consider benefits and risks to determine if TRIKAFTA should be interrupted at symptom occurrence or resumed with symptom improvement

Concomitant Use With CYP3A Inducers

• Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by concomitant use of strong CYP3A inducers, which may reduce effectiveness of TRIKAFTA. Concomitant use with strong CYP3A inducers is not recommended

Concomitant Use With CYP3A Inhibitors

• Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when used concomitantly with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

Cataracts

• Non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients

ADVERSE REACTIONS

Serious Adverse Reactions

• Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%)

Most Common Adverse Reactions

• The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA and higher than placebo by ≥1% were headache; upper respiratory tract infection; abdominal pain; diarrhea; rash; increased ALT, blood creatine phosphokinase, AST, and blood bilirubin; nasal congestion; rhinorrhea; rhinitis; influenza; sinusitis; and constipation

USE IN SPECIFIC POPULATIONS

Pediatric Use

• The safety and effectiveness of TRIKAFTA in patients <2