Trikafta

Trikafta is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 12 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Talk to your doctor to learn if you have an indicated CF gene mutation.

It is not known if Trikafta is safe and effective in children under 12 years of age.

Trikafta can cause serious side effects, including:

• High liver enzymes in the blood is a common side effect in people treated with Trikafta. These can be serious and may be a sign of liver injury. Your doctor will do blood tests to check your liver:
  • before you start Trikafta
  • every 3 months during your first year of taking Trikafta
  • then every year while you are taking Trikafta

Your doctor may do blood tests to check the liver more often if you have had high liver enzymes in your blood in the past.

Call your doctor right away if you have any of the following symptoms of liver problems:

• • pain or discomfort in the upper right stomach (abdominal) area
  • nausea or vomiting
  • yellowing of your skin or the white part of your eyes
  • dark, amber-colored urine
  • loss of appetite
• Abnormality of the eye lens (cataract) in some children and adolescents treated with Trikafta. If you are a child or adolescent, your doctor should perform eye examinations before and during treatment with Trikafta to look for cataracts.

The most common side effects of Trikafta include:

• headache
• diarrhea
• upper respiratory tract infection (common cold) including stuffy and runny nose
• stomach (abdominal) pain
• inflamed sinuses
• increase in liver enzymes
• increase in a certain blood enzyme called creatine phosphokinase
• rash
• flu (influenza)
• increase in blood bilirubin

These are not all the possible side effects of Trikafta.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General Dosing Information

• Swallow the tablets whole.
• Trikafta should be taken with fat-containing food.
• Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats.

Recommended Dosage In Adults And Pediatric Patients Aged 12 Years And Older

• The recommended dosage is two tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg) taken in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken in the evening, administered orally, approximately 12 hours apart.

Information For Missed Doses

• If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule.

If more than 6 hours have passed since:

• the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time.
• the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time. Morning and evening doses should not be taken at the same time.

Recommended Dosage For Patients With Hepatic Impairment

• No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A). See Table 1. Liver function tests should be closely monitored.
• Treatment is not recommended for patients with moderate hepatic impairment (Child-Pugh Class B). Use of Trikafta in patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefit exceeds the risk. If used, Trikafta should be used with caution at a reduced dose (see Table 1). Liver function tests should be closely monitored.
• Trikafta has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. Trikafta should not be used in patients with severe hepatic impairment.

Table 1: Recommended Dosage for use of Trikafta in patients with hepatic impairment

Dosage Adjustment For Patients Taking Drugs That Are CYP3A Inhibitors

• Table 2 describes the recommended dosage modification for Trikafta when co-administered with strong (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin) or moderate (e.g., fluconazole, erythromycin) CYP3A inhibitors.
• Avoid food or drink containing grapefruit during Trikafta treatment.

Table 2: Dosage Adjustment for Concomitant Use of Trikafta with Moderate and Strong CYP3A Inhibitors

Potential for other drugs to affect elexacaftor/tezacaftor/ivacaftor

Inducers Of CYP3A

• Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced Trikafta efficacy.
• Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%.
• Elexacaftor and tezacaftor exposures are expected to decrease during co-administration with strong CYP3A inducers.
• Therefore, co-administration of Trikafta with strong CYP3A inducers is not recommended.
• Examples of strong CYP3A inducers include:
  • rifampin,
  • rifabutin,
  • phenobarbital,
  • carbamazepine,
  • phenytoin, and
  • St. John’s wort (Hypericum perforatum)

Inhibitors Of CYP3A

• Co-administration with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0 to 4.5-fold.
• When co-administered with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively. The dosage of Trikafta should be reduced when co-administered with strong CYP3A inhibitors.
• Examples of strong CYP3A inhibitors include:
  • ketoconazole,
  • itraconazole,
  • posaconazole, and voriconazole
• telithromycin and
• clarithromycin
• Simulations indicated that co-administration with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9 to 2.3-fold and 2.1-fold, respectively.
• Co-administration of fluconazole increased ivacaftor AUC by 2.9-fold. The dosage of Trikafta should be reduced when co administered with moderate CYP3A inhibitors.
• Examples of moderate CYP3A inhibitors include:
  • fluconazole
  • erythromycin
• Co-administration of Trikafta with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with Trikafta.

Ciprofloxacin

• Ciprofloxacin had no clinically relevant effect on the exposure of tezacaftor or ivacaftor and is not expected to affect the exposure of elexacaftor.
• Therefore, no dose adjustment is necessary during concomitant administration of Trikafta with ciprofloxacin.

Potential for Elexacaftor/tezacaftor/ivacaftor to Affect Other Drugs

CYP2C9 Substrates

• Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co administration of Trikafta with warfarin is recommended.
• Other medicinal products for which exposure may be increased by Trikafta include glimepiride and glipizide; these medicinal products should be used with caution.

Transporters

• Co-administration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor.
• Administration of Trikafta may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions.
• When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus, and tacrolimus, caution and appropriate monitoring should be used.
• Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro.
• Co-administration of Trikafta may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide.
• When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used. Bilirubin is an OATP1B1 and OATP1B3 substrate.

Hormonal Contraceptives

• Trikafta has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive.
• Trikafta is not expected to have an impact on the efficacy of oral contraceptives.

• There are limited and incomplete human data from clinical trials on the use of Trikafta or its individual components, elexacaftor, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk.
• There is no information regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production.