Adult: Available preparations:
Ivacaftor 150 mg and Tezacaftor 100 mg
In combination with ivacaftor in patient who are homozygous for the F508del mutation or have at least 1 mutation in the CFTR gene: 1 tab once daily in the morning and ivacaftor 150 mg in the evening, approx 12 hours apart to be taken with fat-containing food. Child: ≥12 years Same as adult dose.
Special Patient Group
Patient taking moderate CYP3A inhibitor (e.g. erythromycin, fluconazole):
Adult:1 tab in the morning every other day and ivacaftor 150 mg in the morning on alternate days. Evening dose of ivacaftor should not be taken on any day.
Child: ≥12 years Same as adult dose.
Patient taking strong CYP3A inhibitor (e.g. clarithromycin, voriconazole, itraconazole, ketoconazole):
Adult: 1 tab in the morning twice weekly, approx 3-4 days apart. Evening dose of ivacaftor should not be taken.
Child: ≥12 years Same as adult dose.
Hepatic Impairment
Moderate (Child-Pugh Class B): 1 tab once daily in the morning. Severe (Child-Pugh Class C): 1 tab once daily in the morning. Modify dosing interval according to response and tolerability.
Administration
film-coated tab: Should be taken with food. Take approx 12 hr apart. Swallow tab whole. Take w/ fat-containing food (eg, butter, oils, eggs, cheese, nuts, whole milk, or meat). Avoid food or drinks containing grapefruit or Seville oranges.
Special Precautions
Patient with history of elevated hepatic transaminases. Severe renal including ESRD and hepatic (Child-Pugh Class B or C) impairment. Children. Pregnancy and lactation. Concomitant use with moderate or strong CYP3A inhibitors and potent CYP3A4 inducers. Not intended for patients who are heterozygous for F508del mutation and have 2nd CFTR mutation.
Adverse Reactions
Significant: Cataract, increase hepatic transaminases. Ear and labyrinth disorders: Ear pain, tinnitus, tympanic membrane hyperaemia, vestibular disorder, ear congestion (ivacaftor). Gastrointestinal disorders: Nausea, diarrhoea, gastrointestinal obstruction. Infections and infestations: Bacterial infection (ivacaftor). Investigations: Increased creatinine phosphokinase, CPK concentrations. Nervous system disorders: Headache, dizziness. Reproductive system and breast disorders: Breast mass, breast inflammation, gynaecomastia, nipple disorder, nipple pain (ivacaftor). Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, increased sputum production, sinus congestion (ivacaftor). Skin and subcutaneous tissue disorders: Rash (ivacaftor).
Patient Counseling Information
This drug may cause dizziness, if affected, do not drive or operate machinery.
Monitoring Parameters
Perform CF mutation test prior to initiation of therapy if unknown genotype. Obtain renal function test, ALT and AST at baseline, every 3 months for 1 year, then annually thereafter or as needed; baseline and follow up ophthalmological exams in paediatric patients.
Increased systemic absorption with fat-containing food. Decreased systemic exposure and reduced therapeutic effect with St. John’s wort. Increased serum concentration with grapefruit, grapefruit juice or Seville orange; avoid use.
Action
Description: Mechanism of Action: Ivacaftor is a CFTR protein potentiator which improves chloride ion transport of CFTR mutated protein across the membrane. This leads to improved regulation of salt and water absorption and secretions in various tissues in lungs and gastrointestinal tract.
Tezacaftor is a selective cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector that improves chloride ion transport by facilitating cellular processing and trafficking of normal and multiple mutant forms of CFTR including F508del-CFTR. Pharmacokinetics: Absorption: Increased absorption with fatty foods.
Ivacaftor: Absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 6 hours.
Tezacaftor: Absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 4 hours. Distribution: Ivacaftor: Crosses placenta, enters breast milk. Volume of distribution: 206 ± 82.9 L. Plasma protein binding: Approx 99%, primarily to α1-acid glycoprotein and albumin.
Tezacaftor: Volume of distribution: 271 ± 157 L. Plasma protein binding: Approx 99%, primarily to albumin. Metabolism: Ivacaftor: Extensively metabolised in the liver by CYP3A and CPY3A5 isoenzyme to form major metabolites, M1 (active) and M6 (inactive).
Tezacaftor: Extensively metabolised by CYP3A and CPY3A5 isoenzyme to form major metabolites M1 and M2 (active), M5 (inactive). Excretion: Ivacaftor: Via faeces (87.5%, approx 65% as metabolites); urine (minimal, as unchanged drug). Elimination half-life: Approx 12 hours.
Tezacaftor: Via faeces (approx 72% as unchanged drug or as M2 metabolite); urine (approx 14%, mostly as M2 metabolite); <1% as unchanged drug. Terminal elimination half-life: Approx 15 hours.
Chemical Structure
Ivacaftor Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 16220172, Ivacaftor. https://pubchem.ncbi.nlm.nih.gov/compound/16220172. Accessed Aug. 26, 2022.
Tezacaftor Source: National Center for Biotechnology Information. PubChem Database. Tezacaftor, CID=46199646, https://pubchem.ncbi.nlm.nih.gov/compound/Tezacaftor (accessed on Jan. 21, 2020)
R07AX31 - ivacaftor and tezacaftor ; Belongs to the class of other respiratory system products.
References
Annotation of EMA Label for Ivacaftor/Tezacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 28/11/2019.Annotation of FDA Label for Ivacaftor/Tezacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 28/11/2019.Anon. CFTR - Tezacaftor and Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 28/11/2019.Anon. Tezacaftor and Ivacaftor. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com/. Accessed 28/11/2019.Anon. Tezacaftor and Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 28/11/2019.Buckingham R (ed). Ivacaftor. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 28/11/2019.Buckingham R (ed). Tezacaftor. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 28/11/2019.Joint Formulary Committee. Tezacaftor With Ivacaftor. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 28/11/2019.Symdeko Kit (Vertex Pharmaceuticals Incorporated). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 28/11/2019.
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