Elexacaftor, tezacaftor, and ivacaftor
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Specialty pharmacy: therapy management checklist, storage and cold chain, dosing calendar, Medicare Part D coverage.
Boxed warning
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease taking TRIKAFTA, in both clinical trials and the postmarketing setting [see Adverse Reactions (6) ]. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA . Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA.
Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test elevations at baseline [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) , Adverse Reactions (6) and Use in Specific Populations (8.7) ] . Interrupt TRIKAFTA for significant elevations in liver function tests or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve.
If abnormalities resolve, resume treatment only if the benefit is expected to outweigh the risk. Closer monitoring is advised after resuming TRIKAFTA [see Warnings and Precautions (5.1) ] . TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B). If used, use with caution at a reduced dosage and monitor patients closely [see Dosage and Administration (2.3) , Warnings and Precautions (5.1) , Adverse Reactions (6) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE See full prescribing information for complete boxed warning. TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Liver failure leading to transplantation and death has been reported. ( 5.1 , 6 ) Assess liver function tests (ALT, AST, alkaline phosphatase, bilirubin) in all patients prior to initiating TRIKAFTA. ( 2.1 , 5.1 ) Monitor liver function tests (ALT, AST, alkaline phosphatase, bilirubin) every month for the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually. ( 2.1 , 5.1 ) Interrupt TRIKAFTA for significant elevations in liver function tests or signs or symptoms…
Dosing in kidney impairment
Renal Impairment TRIKAFTA has not been studied in patients with severe renal impairment or end-stage renal disease. No dosage adjustment is recommended in patients with mild (eGFR 60 to <90 mL/min/1.73 m 2 ) or moderate (eGFR 30 to <60 mL/min/1.73 m 2 ) renal impairment. Use with caution in patients with severe (eGFR <30 mL/min/1.73 m 2 ) renal impairment or end-stage renal disease [see Clinical Pharmacology ] .
Dosing in liver impairment
Recommended Dosage for Patients with Hepatic Impairment Severe Hepatic Impairment (Child-Pugh Class C): Should not be used. 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 [see Warnings and Precautions , Adverse Reactions , Use in Specific Populations and Clinical Pharmacology ] .
Moderate Hepatic Impairment (Child-Pugh Class B) : Treatment is not recommended. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, TRIKAFTA should be used with caution at a reduced dose (see Table 2 ) [see Use in Specific Populations and Clinical Pharmacology ] .
Liver function tests should be closely monitored [see Dosage and Administration and Warnings and Precautions ]. Recommended dosage for patients with moderate hepatic impairment (Child-Pugh Class B) is provided in Table 2. [See table below.] 30 kg or more Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg No evening ivacaftor tablet dose. 12 years and older — Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg No evening ivacaftor tablet dose.
Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is recommended [see Use in Specific Populations and Clinical Pharmacology ] . See Table 1 for recommended dosage of TRIKAFTA. Liver function tests should be closely monitored [see Dosage and Administration and Warnings and Precautions ].
| Age | Weight | Oral Morning Dose | Oral Evening Dose |
|---|---|---|---|
| 2 to less than 6 years | Less than 14 kg | Weekly dosing schedule is as follows:Days 1-3: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each dayDay 4: no doseDays 5-6: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each dayDay 7: no dose | No evening dose of ivacaftor oral granules. |
| 14 kg or more | Weekly dosing schedule is as follows:Days 1-3: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each dayDay 4: no doseDays 5-6: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each dayDay 7: no dose | No evening dose of ivacaftor oral granules. | |
| 6 to less than 12 years | Less than 30 kg | Alternating daily dosing schedule is as follows:Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg)Day 2: One tablet of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg | No evening ivacaftor tablet dose. |
| 30 kg or more | Alternating daily dosing schedule is as follows:Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg)Day 2: One tablet of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg | No evening ivacaftor tablet dose. | |
| 12 years and older | — | Alternating daily dosing schedule is as follows:Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg)Day 2: One tablet of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg | No evening ivacaftor tablet dose. |
Drug interactions
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- Elexacaftor, tezacaftor, and ivacaftor
Label text (10 paragraphs)
Strong CYP3A inducers: Avoid concomitant use. ( 5.5 , 7.1 , 12.3 ) Strong or moderate CYP3A inhibitors: Reduce TRIKAFTA dosage when used concomitantly. Avoid food or drink containing grapefruit. ( 2.4 , 5.6 , 7.1 , 12.3 )
7.1 Effect of Other Drugs and Grapefruit on TRIKAFTA Strong CYP3A Inducers Concomitant use of TRIKAFTA with strong CYP3A inducers is not recommended. 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 [see Warnings and Precautions (5.5) ] . Concomitant use 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 concomitant use with strong CYP3A inducers [see Clinical Pharmacology (12.3) ] .
Examples of strong CYP3A inducers include: rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort ( Hypericum perforatum ) Strong or Moderate CYP3A Inhibitors The dosage of TRIKAFTA should be reduced when used concomitantly with strong CYP3A inhibitors [see Dosage and Administration (2.4) and Warnings and Precautions (5.6) ] . Concomitant use with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When used concomitantly with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively [see Clinical Pharmacology (12.3) ] .
Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole and voriconazole telithromycin and clarithromycin The dosage of TRIKAFTA should be reduced when used concomitantly with moderate CYP3A inhibitors [see Dosage and Administration (2.4) and Warnings and Precautions (5.6) ]. Simulations indicated that concomitant use with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold and 2.1-fold, respectively. Concomitant use of fluconazole increased ivacaftor AUC by 2.9-fold [see Clinical Pharmacology (12.3) ] .
Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Grapefruit Concomitant use 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 [see Dosage and Administration (2.4) ] .
7.2 Effect of TRIKAFTA on Other Drugs CYP2C9 Substrates Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during concomitant use 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 [see Clinical Pharmacology (12.3) ] . Transporters Concomitant use 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 [see Clinical Pharmacology (12.3) ] . Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Concomitant use 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 [see Clinical Pharmacology (12.3) ] . Bilirubin is an OATP1B1 and OATP1B3 substrate.
7.3 Drugs with No Clinically Significant Interactions 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 [see Clinical Pharmacology (12.3) ] . 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.
Hormonal contraceptives may play a role in the occurrence of rash and cannot be excluded [see Adverse Reactions (6.1) ] . For patients with CF taking hormonal contraceptives who develop rash, consider interrupting TRIKAFTA and hormonal contraceptives. Following the resolution of rash, consider resuming TRIKAFTA without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.
Contraindications
None. None. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
LiverTox has no chapter for elexacaftor, tezacaftor, and ivacaftor. Check the label's hepatic warnings.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary 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. Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with each active component of TRIKAFTA in pregnant rats and rabbits.
In animal embryo fetal development (EFD) studies oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits [based on summed AUCs of elexacaftor and its metabolite (for rat) and AUC of elexacaftor (for rabbit)].
Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 5 and 14 times the exposure at the MRHD, respectively [based on summed AUCs of ivacaftor and its metabolites (for rat) and AUC of ivacaftor (for rabbit)].
No adverse developmental effects were observed after oral administration of elexacaftor, tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 time, approximately 1 time and 3 times the exposures at the MRHD, respectively [based on summed AUCs of parent and metabolite(s)] (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Animal Data Elexacaftor In an EFD study, pregnant rats were administered oral doses of elexacaftor at 15, 25, and 40 mg/kg/day during the period of organogenesis from gestation Days 6-17. Elexacaftor did not cause adverse developmental outcomes at exposures up to 9 times the MRHD (based on summed AUCs for elexacaftor…
Breastfeeding (LactMed)
Elexacaftor and ivacaftor have low levels in the serum of infants exposed in utero that generally decrease during nursing. However, an ivacaftor metabolite and tezacaftor and its metabolites appears to remain in the therapeutic range during breastfeeding. An international survey of cystic fibrosis (CF) centers found no adverse effects in breastfed infants of mothers taking the elexacaftor, tezacaftor and ivacaftor combination. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding. The amounts of the drugs in milk is sometimes sufficient to treat CF in breastfed infants, but not in all cases. Infants exposed to CFTR modulators through breastmilk should have periodic liver function testing and an examination by an ophthalmologist for cataracts.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
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