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Trikafta
elexacaftor/ tezacaftor/ ivacaftor and ivacaftor
Black Box Warnings .
Hepatotoxicity
can cause serious and potentially fatal drug-induced hepatic injury; hepatic failure leading to death or transplantation reported in patients with or without hepatic disease history; hepatic injury reported within 1-15mo of tx start; monitor LFTs before tx start, then qmo x6mo, then q3mo x12mo, then at least q12mo or consider more frequently if hepatic disease history or baseline LFTs elevated; interrupt tx if significant LFT elevations or if hepatic injury signs/symptoms occur, consider hepatologist referral, and monitor closely until resolution; if abnormalities resolve, only restart tx if benefit outweighs risk with closer monitoring; avoid use in patients with severe hepatic impairment; in patients with moderate hepatic impairment, use not recommended or may use at reduced dose with close monitoring
Adult Dosing .
Dosage forms: TAB (pack): elexacaftor/tezacaftor/ivacaftor 100 mg/50 mg/75 mg x56 and ivacaftor 150 mg x28
cystic fibrosis
- [elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg PO qam and ivacaftor 150 mg PO qpm]
- Info: for patients with at least one variant in CFTR gene that is either responsive to elexacaftor/tezacaftor/ivacaftor or results in CFTR protein production; separate doses by approximately 12h; give with fat-containing food
renal dosing
- [see below]
- CrCl >30: no adjustment; CrCl <30: not defined, caution advised
- HD/PD: not defined
hepatic dosing
- [see below]
- Child-Pugh Class B: alternate elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg with elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg at each morning dose, no ivacaftor evening doses; Child-Pugh Class C: avoid use
Peds Dosing .
- Dosage forms: TAB (pack): elexacaftor/tezacaftor/ivacaftor 50 mg/25 mg/37.5 mg x56 and ivacaftor 75 mg x28; TAB (pack): elexacaftor/tezacaftor/ivacaftor 100 mg/50 mg/75 mg x56 and ivacaftor 150 mg x28; GRANULE (pack): elexacaftor/tezacaftor/ivacaftor 80 mg/40 mg/60 mg per packet x28 and ivacaftor 59.5 mg per packet x28; GRANULE (pack): elexacaftor/tezacaftor/ivacaftor 100 mg/50 mg/75 mg per packet x28 and ivacaftor 75 mg per packet x28
cystic fibrosis
- [2-5 yo, <14 kg]
- Dose: elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg PO qam and ivacaftor 59.5 mg PO qpm; Info: for patients with at least one variant in CFTR gene that is either responsive to elexacaftor/tezacaftor/ivacaftor or results in CFTR protein production; separate doses by approximately 12h; give granules before or after fat-containing food
- [2-5 yo, >14 kg]
- Dose: elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg PO qam and ivacaftor 75 mg PO qpm; Info: for patients with at least one variant in CFTR gene that is either responsive to elexacaftor/tezacaftor/ivacaftor or results in CFTR protein production; separate doses by approximately 12h; give granules before or after fat-containing food
- [6-11 yo, <30 kg]
- Dose: elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg PO qam and ivacaftor 75 mg PO qpm; Info: for patients with at least one variant in CFTR gene that is either responsive to elexacaftor/tezacaftor/ivacaftor or results in CFTR protein production; separate doses by approximately 12h; give tabs with fat-containing food
- [6-11 yo, >30 kg]
- Dose: elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg PO qam and ivacaftor 150 mg PO qpm; Info: for patients with at least one variant in CFTR gene that is either responsive to elexacaftor/tezacaftor/ivacaftor or results in CFTR protein production; separate doses by approximately 12h; give tabs with fat-containing food
- [12 yo and older]
- Dose: elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg PO qam and ivacaftor 150 mg PO qpm; Info: for patients with at least one variant in CFTR gene that is either responsive to elexacaftor/tezacaftor/ivacaftor or results in CFTR protein production; separate doses by approximately 12h; give tabs with fat-containing food
renal dosing
- [see below]
- CrCl >30: no adjustment; CrCl <30: not defined, caution advised
- HD/PD: not defined
hepatic dosing
- [2-5 yo, <14 kg]
- Child-Pugh Class B: elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg qam on days 1-3 and 5-6 of weekly dosing schedule, no dose on days 4 or 7; no ivacaftor evening doses; Child-Pugh Class C: avoid use
- [2-5 yo, >14 kg]
- Child-Pugh Class B: elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg qam on days 1-3 and 5-6 of weekly dosing schedule, no dose on days 4 or 7; no ivacaftor evening doses; Child-Pugh Class C: avoid use
- [6-11 yo, <30 kg]
- Child-Pugh Class B: alternate elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg with elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg at each morning dose, no ivacaftor evening doses; Child-Pugh Class C: avoid use
- [6-11 yo, >30 kg]
- Child-Pugh Class B: alternate elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg with elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg at each morning dose, no ivacaftor evening doses; Child-Pugh Class C: avoid use
- [12 yo and older]
- Child-Pugh Class B: alternate elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg PO with elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg at each morning dose, no ivacaftor evening doses; Child-Pugh Class C: avoid use
Contraindications / Cautions .
- hepatic impairment, Child-Pugh Class C
- caution: hepatic impairment, Child-Pugh Class B
- caution: CrCl <30
- caution: baseline LFTs elevated
- caution: hepatic disease history
- caution: hypersensitivity to drug or ingredient
- caution: hypervitaminosis A
Drug Interactions .
Overview
elexacaftor/tezacaftor/ivacaftor
CFTR facilitator/potentiator
- CYP3A4 substrate
- CYP2C9 inhibitor, weak
- OATP1B1 inhibitor, weak
- OATP1B3 inhibitor, weak
- P-gp inhibitor, weak
- drug interactions apply only to Trikafta (elexacaftor/tezacaftor/ivacaftor); see other products for potentially relevant interactions
Contraindicated
- colchicine
- grazoprevir
Avoid/Use Alternative
- apalutamide
- apixaban
- atrasentan
- bosentan
- brincidofovir
- butalbital
- carbamazepine
- cenobamate
- dabigatran
- dabrafenib
- efavirenz
- elagolix
- encorafenib
- ensartinib
- enzalutamide
- etravirine
- fexinidazole
- fosamprenavir
- fosphenytoin
- grapefruit
- ivosidenib
- lopinavir/ritonavir
- lorlatinib
- lumacaftor/ivacaftor
- mavacamten
- methadone
- mitapivat
- mitotane
- modafinil
- nafcillin
- neratinib
- orforglipron
- pacritinib
- pentobarbital
- pexidartinib
- phenobarbital
- phenytoin
- pralsetinib
- primidone
- relugolix
- repotrectinib
- rifabutin
- rifampin
- rifapentine
- rivaroxaban
- sirolimus albumin-bound
- sotorasib
- St. John's wort
- topotecan
- venetoclax
- zavegepant
Monitor/Modify Tx
- adagrasib
- afatinib
- aficamten
- aprepitant
- atazanavir
- atorvastatin
- avacopan
- berotralstat
- celecoxib
- ceritinib
- chloramphenicol
- clarithromycin
- clofazimine
- cobicistat
- conivaptan
- crizotinib
- cyclosporine
- danazol
- darunavir
- deuruxolitinib
- diclofenac
- digoxin
- diltiazem
- dronedarone
- duvelisib
- edoxaban
- eluxadoline
- enfortumab vedotin
- erythromycin
- everolimus
- fedratinib
- fluconazole
- fluvastatin
- glimepiride
- glipizide
- glyburide
- idelalisib
- imatinib
- isavuconazonium
- itraconazole
- ketoconazole
- lefamulin
- lenacapavir
- letermovir
- levoketoconazole
- lonafarnib
- lovastatin
- mavorixafor
- mifepristone
- momelotinib
- morphine
- nateglinide
- nefazodone
- nelfinavir
- netupitant
- nilotinib
- nirogacestat
- pitavastatin
- posaconazole
- pravastatin
- quinidine (antiarrhythmic)
- ranolazine
- red yeast rice
- relacorilant
- repaglinide
- ribociclib
- rilzabrutinib
- ritonavir
- rosuvastatin
- simvastatin
- sirolimus
- tacrolimus
- talazoparib
- tenofovir alafenamide
- tenofovir disoproxil
- tipranavir
- torsemide
- tucatinib
- ubrogepant
- verapamil
- voriconazole
- warfarin
Caution Advised
- armodafinil
- artemether/lumefantrine
- atogepant
- belzutifan
- bexarotene
- brigatinib
- clobazam
- danshen
- darolutamide
- dexamethasone
- dicloxacillin
- echinacea
- elafibranor
- enasidenib
- eslicarbazepine acetate
- felbamate
- garlic
- ginkgo
- ginseng, Asian
- glecaprevir
- glycerol phenylbutyrate
- griseofulvin
- meropenem
- mobocertinib
- naldemedine
- nevirapine
- odevixibat
- olutasidenib
- omaveloxolone
- oxcarbazepine
- perampanel
- pibrentasvir
- pioglitazone
- prednisone
- rufinamide
- sarilumab
- seladelpar
- stiripentol
- sunvozertinib
- suzetrigine
- tazemetostat
- tecovirimat
- telotristat ethyl
- tocilizumab
- topiramate
- tovorafenib
- vaborbactam
- vamorolone
- vemurafenib
- vinblastine
- vorasidenib
- voxilaprevir
- zanubrutinib
Adverse Reactions .
Serious Reactions
- hepatotoxicity
- hepatic failure
- hepatic impairment
- hypersensitivity reaction
- anaphylaxis
- angioedema
- intracranial HTN
- neuropsychiatric disorders
- suicidality
- cataracts (peds patients)
Common Reactions
- rash
- headache
- URI
- abdominal pain
- diarrhea
- ALT incr.
- rhinitis
- nasal congestion
- CPK incr.
- AST incr.
- influenza
- constipation
- rhinorrhea
- sinusitis
- bilirubin incr.
- flatulence
- abdominal distension
- conjunctivitis
- pharyngitis
- tonsillitis
- UTI
- hypoglycemia
- CRP incr.
- dizziness
- dysmenorrhea
- acne
- eczema
- pruritus
- BP incr.
Safety/Monitoring .
Monitoring Parameters
LFTs before tx start, then qmo x6mo, then q3mo x12mo, then at least q12mo, or if hepatic disease history or elevated baseline LFTs then consider monitoring more frequently; ophthalmic exam at baseline, then periodically in peds patients; signs/symptoms of neuropsychiatric events including anxiety, depression, suicidality, sleep disturbances
Pregnancy/Lactation .
Pregnancy
Clinical Summary
weigh risk/benefit during pregnancy; possible risk of neonatal LFT elevations or cataracts based on limited or conflicting human data; no known risk of teratogenicity based on animal data at 0.2-14x MRHD
Lactation
Clinical Summary
weigh risk/benefit while breastfeeding; possible risk of infant LFT elevations or cataracts based on limited or conflicting human data; no known adverse effects on milk production based on limited human data
Pharmacology .
Metabolism: for elexacaftor/tezacaftor/ivacaftor: liver extensively; CYP450: 3A4/5 substrate; Info: active metabolite
Excretion: for elexacaftor: feces 87.3% (minimally unchanged), urine 0.23%; Half-life: 27.4h; for tezacaftor: feces 72%, urine 14% (<1% unchanged); Half-life: 25.1h; for ivacaftor: feces 87.8% (35% unchanged), urine 6.6%; Half-life: 15h
Subclass: Cystic Fibrosis
Mechanism of Action
for elexacaftor: facilitates cellular processing of mutant CFTR protein, including F508del-CFTR, increasing amount of functional CFTR protein delivered to cell surfaces; for tezacaftor: facilitates cellular processing of mutant CFTR protein, including F508del-CFTR, increasing amount of functional CFTR protein delivered to cell surfaces; for ivacaftor: potentiates mutant CFTR protein, increasing chloride channel open probability and chloride transport
Formulary .
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