Ivacaftor


Concise Prescribing Info
Indications/Uses
Cystic fibrosis.
Dosage/Direction for Use
Adult : PO In patients with G551D or other gating (class III) or R117H CFTR gene mutation: 150 mg 12 hourly to be taken with a fat-containing food.
Dosage Details
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 a fat-containing food.
Child: As granules: ≥12 months weighing 7-<14 kg: 50 mg 12 hourly; 14-<25 kg: 75 mg 12 hourly; ≥6 years weighing ≥25 kg: Same as adult dose.
Special Patient Group
Patient taking moderate CYP3A inhibitor (e.g. erythromycin, fluconazole):
Adult: 150 mg once daily.
Child: ≥12 months weighing 7-<14 kg: 50 mg once daily; 14-<25 kg: 75 mg once daily.

Patient taking strong CYP3A inhibitor (e.g. clarithromycin, ketoconazole):
Adult: 150 mg twice weekly.
Child: ≥12 months weighing 7-<14 kg: 50 mg twice weekly; 14-<25 kg: 75 mg twice weekly.

Pharmacogenomics:

Ivacaftor potentiates the actions of CFTR. It has been associated with clinical effectiveness in patients with G551D or other gating (class III) or R117H CFTR gene variants. Genetic testing for the presence of these variants is recommended under current guideline.

Homozygous or heterozygous G551D-CFTR (e.g. G551D/F508del, G551D/G551D, rs75527207 genotype AA or AG)
Patient may have significant improvement in lung function, weight, risk of pulmonary exacerbation, and patient reported outcomes, and reduction in sweat chloride concentrations through enhanced CFTR channel activity (increased probability of open channel). CPIC recommends use of 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. Likelihood of response is unknown. CPIC does not recommend initiation of Ivacaftor therapy. May consider alternative drug therapy.

Homozygous for F508del-CFTR (F508del/F508del), rs113993960, or rs199826652 genotype del/del
Patient may have 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. CPIC does not recommend initiation of Ivacaftor therapy. May consider alternative drug therapy.
Hepatic Impairment
Moderate (Child-Pugh Class B): ≥12 months weighing 7-<14 kg: 50 mg once daily; weighing 14-<25 kg: 75 mg once daily; ≥6 years weighing ≥25 kg: 150 mg once daily. Severe (Child-Pugh Class C): Initially, 150 mg every other day. Adjust dose according to response and tolerability.
Reconstitution
Mix granules with 5 mL of soft food (e.g. pureed fruits or vegetables, yogurt, applesauce) or liquid (e.g. water, milk, juice).
Special Precautions
Patient with history of elevated hepatic transaminases. Severe renal (CrCl ≤30 mL/min) including ESRD and hepatic (Child-Pugh Class B or C) impairment. Children. Pregnancy and lactation.
Adverse Reactions
Significant: Increased hepatic transaminase, dizziness, cataracts or non-congenital lens opacities in children.
Gastrointestinal disorders: Abdominal pain, diarrhoea, nausea.
Infections and infestations: Bacterial infection.
Metabolism and nutrition disorders: Increased serum glucose.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, musculoskeletal chest pain.
Nervous system disorders: Headache, dizziness.
Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infection, nasopharyngitis, rhinitis, oropharyngeal pain, nasal and parasinus congestion, pharyngeal erythema, pleuritic chest pain, wheezing.
Skin and subcutaneous tissue disorders: Rash, acne vulgaris.
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 G551D mutation status is unknown. Monitor ALT/AST at baseline, every 3 months for 1 year, then annually thereafter or as needed; FEV1; baseline and follow up ophthalmological exams in paediatric patients.
Overdosage
Symptoms: Dizziness, diarrhoea. Management: Supportive treatment. Monitor vital signs, LFT and observe clinical status of patient.
Drug Interactions
Increased exposure with CYP3A inhibitors (e.g. ketoconazole, fluconazole). Decreased exposure and loss of efficacy with strong CYP3A inducers (e.g. rifampin, carbamazepine). May increase concentration of CYP3A substrates (e.g. midazolam, diazepam); P-gp substrates (e.g. digoxin, ciclosporin).
Food Interaction
Fatty foods may increase absorption. Increased serum concentrations grapefruit or Seville oranges. Decreased serum concentration 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 lungs and gastrointestinal tract.
Onset: Increased FEV1; decreased sweat Cl: Approx 2 weeks.
Pharmacokinetics:
Absorption: Absorbed from the gastrointestinal tract. Increased absorption with fatty foods. Time to peak plasma concentration: Approx 4 hours.
Distribution: Crosses placenta, enters breast milk. Volume of distribution: 353 ± 122 L. Plasma protein binding: Approx 99% (mainly to α1 acid glycoprotein, albumin).
Metabolism: Extensively metabolised in the liver via CYP3A enzyme to form major metabolites, M1 (active) and M6 (inactive).
Excretion: Via faeces (87.5%, approx 65% as metabolites); urine (minimal, as unchanged drug). Elimination half-life: Approx 12 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)

Storage
Store between 20-25°C.
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.2014.54. Accessed 15/10/2019

Annotation of CPIC Guideline for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2019.

Annotation of EMA Label for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2019.

Annotation of FDA Label for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2019.

Annotation of HCSC Label for Ivacaftor and CFTR. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2019.

Anon. CFTR - Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/10/2019.

Anon. Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/10/2019.

Buckingham R (ed). Ivacaftor. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 15/10/2019.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 15/10/2019.

CPIC Guideline Update on PharmGKB for “Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype”. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 15/10/2019.

Joint Formulary Committee. Ivacaftor. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 15/10/2019.

Kalydeco Tablet, Film Coated and Granule (Vertex Pharmaceuticals Incorporated). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 15/10/2019.

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 © 2020 MIMS. All rights reserved. Powered by MIMS.com
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