Ivacaftor + Tezacaftor


Concise Prescribing Info
Indications/Uses
Cystic fibrosis.
Dosage/Direction for Use
Adult : PO Each tab contains ivacaftor 150 mg and tezacaftor 100 mg: Combined 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.
Dosage Details
Oral
Cystic fibrosis
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.
MonitoringParameters
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.
Drug Interactions
Decreased systemic exposure and reduced therapeutic effect with potent CYP3A4 inducers (e.g. rifampin, carbamazepine, phenobarbital, phenytoin). Increased serum concentration with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin). Increased serum concentration with P-gp substrates (e.g. digoxin, ciclosporin, tacrolimus), CYP2C9 substrates (e.g. glimepiride, glipizide).
Food Interaction
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: 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

Chemical Structure Image
Ivacaftor

Source: National Center for Biotechnology Information. PubChem Database. Ivacaftor, CID=16220172, https://pubchem.ncbi.nlm.nih.gov/compound/Ivacaftor (accessed on Jan. 21, 2020)


Chemical Structure Image
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)

Storage
Store between 20-25°C.
ATC Classification
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.

Disclaimer: This information is independently developed by MIMS based on Ivacaftor + Tezacaftor from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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