Ivacaftor


Generic Medicine Info
Indications and Dosage
Oral
Cystic fibrosis
Adult: In patients with G551D or other gating (class III) or R117H-CFTR gene mutation: 150 mg 12 hourly to be taken with fat-containing food.
Child: As granules: 4-<6 months weighing ≥5 kg: 25 mg 12 hourly. 6 months to <6 years weighing 5-<7 kg: 25 mg 12 hourly; 7-<14 kg: 50 mg 12 hourly; ≥14 kg: 75 mg 12 hourly. As tab: ≥6 years Same as adult dose. All doses are to be given with fat-containing food.
Special Patient Group
Patients taking moderate CYP3A inhibitor (e.g. erythromycin, fluconazole): <6 months Not recommended; ≥6 months Administer the usual dose once daily.

Patients taking strong CYP3A inhibitor (e.g. clarithromycin, ketoconazole): <6 months Not recommended; ≥6 months Administer the usual dose twice weekly.

Pharmacogenomics:

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that enhances chloride transport in various mutant CFTR forms. It has been associated with clinical effectiveness in patients with G551D or other CFTR gating (class III) or R117H-CFTR gene variants. Genetic testing for the presence of these variants is required prior to initiating treatment with ivacaftor if the patient's CFTR genotype is unknown. Additionally, the FDA drug label states that genetic test results should include coverage for positions rs75527207 (G551D-CFTR) and rs113993960 and rs199826652 (F508delCFTR) to follow the CPIC guidelines for ivacaftor.

CPIC Recommendations for ivacaftor based on CFTR genotype:
CFTR Genotype Implications Recommendations
Homozygous or heterozygous G551D-CFTR (e.g. G551D/F508del, G551D/G551D, rs75527207 genotype AA or AG) Significant improvement in lung function, body weight, risk of pulmonary exacerbation, patient-reported outcomes, and reduction in sweat chloride concentrations through enhanced CFTR channel activity (increased probability of open channel). Use ivacaftor according to the product label.
Noncarrier of G551D-CFTR (e.g. F508del/R553X, rs75527207 genotype GG) Not studied clinically. In vitro studies show variable effects on CFTR channel activity depending on the genetic variant. The likelihood of response is unknown. Treatment with ivacaftor is not recommended. May consider alternative drug therapy.
Homozygous for F508del-CFTR (F508del/F508del), rs113993960, or rs199826652 genotype del/del No significant reduction in sweat chloride concentrations; no changes in other clinical measurements, including spirometric measurements, pulmonary exacerbations, or body weight. Unlikely to respond to treatment. Treatment with ivacaftor is not recommended. May consider alternative drug therapy.
Homozygous or heterozygous for 1 of the following CFTR variants: E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, S945L, S997F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N, G1349D, 2789+5G‐>A, 3272‐26A‐>G, 3849+10kbC‐>T, 711+1G‐>T and E831X In vitro assays with CFBEo‐ cells expressing S549N‐CFTR showed potentiation of chloride channel function, and a case study showed improved lung function after ivacaftor treatment. Improvement in sweat chloride and CFQ‐R respiratory domain scores in patients with the R117H variant. Use ivacaftor according to the product label.

Hepatic Impairment
<6 months Not recommended; ≥6 months Moderate (Child-Pugh Class B): Administer the usual dose once daily. Severe (Child-Pugh Class C): Administer the usual dose once daily or less frequently; consider therapy only if the benefits are expected to outweigh the risks.
Reconstitution
Granules: Mix the appropriate amount with 1 tsp (5 mL) of soft food or liquid (e.g. pureed fruits or vegetables, yoghurt, applesauce, water, breast milk, infant formula, milk, juice) and administer with fat-containing food.
Special Precautions
Patient with history of transaminase elevations. Patients taking moderate or strong CYP3A inhibitors. Not recommended in organ transplant patients. Moderate to severe hepatic (Child-Pugh B or C) and severe renal impairment (CrCl ≤30 mL/min), including ESRD. Children. Pregnancy and lactation.
Adverse Reactions
Significant: Elevated transaminases (ALT/AST); non-congenital lens opacities/cataracts in children.
Ear and labyrinth disorders: Ear pain, ear discomfort, tinnitus, tympanic membrane hyperaemia, vestibular disorder.
Gastrointestinal disorders: Abdominal pain, diarrhoea, nausea, vomiting.
General disorders and administration site conditions: Pyrexia.
Investigations: Bacteria in sputum.
Nervous system disorders: Headache, dizziness.
Reproductive system and breast disorders: Breast mass.
Respiratory, thoracic and mediastinal disorders: Oropharyngeal pain, upper respiratory tract infection, nasal congestion, nasopharyngitis, rhinitis, sinus congestion, pharyngeal erythema, cough, rales, haemoptysis.
Vascular disorders: Rash.
Patient Counseling Information
This drug may cause dizziness, if affected, do not drive or operate machinery.
Monitoring Parameters
Perform CF (cystic fibrosis) mutation test prior to initiation of therapy if mutation status is unknown. Assess transaminase) ALT/AST) prior to initiation of therapy, every 3 months for 1 year, and annually thereafter; FEV1. Baseline and follow-up ophthalmological examinations in children.
Overdosage
Symptoms: Dizziness, diarrhoea. Management: Supportive treatment. Monitor vital signs, LFT and observe the clinical status of the patient.
Drug Interactions
Increased exposure with CYP3A inhibitors (e.g. ketoconazole, fluconazole, clarithromycin, erythromycin). Decreased exposure and efficacy with strong CYP3A inducers (e.g. rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin). May increase the exposure of warfarin, glimepiride, glipizide, oral midazolam, digoxin, ciclosporin and tacrolimus.
Food Interaction
Increased exposure with grapefruit or Seville oranges. Decreased exposure with St. John’s wort.
Action
Description: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (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 the lungs and gastrointestinal tract.
Onset: Increased FEV1; decreased sweat Cl: Approx 2 weeks.
Pharmacokinetics:
Absorption: Absorbed from the gastrointestinal tract. Increased absorption with fatty food. Time to peak plasma concentration: Approx 4 hours (range: 3-6 hours).
Distribution: Volume of distribution: 353 ± 122 L. Plasma protein binding: Approx 99% (mainly to α1-acid glycoprotein and albumin).
Metabolism: Extensively metabolised in the liver by CYP3A enzyme to form major metabolites, M1 (active) and M6 (inactive).
Excretion: Mainly via faeces (87.8%, approx 65% as metabolites); urine (minimal amount, as unchanged drug). Elimination half-life: Approx 12 hours.
Chemical Structure

Chemical Structure Image
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.

Storage
Store between 20-25°C.
MIMS Class
Other Drugs Acting on the Respiratory System
ATC Classification
R07AX02 - ivacaftor ; Belongs to the class of other respiratory system products.
References
Clancy JP, Johnson SG, Yee SW et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype. CPIC Guidelines. 2014 Jun;95(6):592-597. doi: 10.1038/clpt.2014.5. Accessed 02/08/2022

Annotation of CFF Guideline for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 02/08/2022.

Annotation of CPIC Guideline for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 02/08/2022.

Annotation of EMA Label for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 04/08/2022.

Annotation of FDA Label for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 04/08/2022.

Anon. CFTR - Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 02/08/2022.

Anon. Ivacaftor. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 02/08/2022.

Anon. Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 02/08/2022.

Buckingham R (ed). Ivacaftor. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/08/2022.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 02/08/2022.

Joint Formulary Committee. Ivacaftor. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/08/2022.

Kalydeco 75 mg and 150 mg Film-coated Tablets (Vertex Pharmaceuticals Ireland Limited). European Medicines Agency [online]. Accessed 02/08/2022.

Kalydeco Tablet, Film Coated and Granule (Vertex Pharmaceuticals Incorporated). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 02/08/2022.

Vertex Pharmaceuticals Incorporated. Kalydeco 150 mg Film-coated Tablets; 50 mg and 75 mg Granules data sheet 17 December 2020. Medsafe. http://www.medsafe.govt.nz. Accessed 02/08/2022.

Disclaimer: This information is independently developed by MIMS based on Ivacaftor 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 © 2024 MIMS. All rights reserved. Powered by MIMS.com
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