ORKAMBI

What it is

Orkambi is a combination medicine containing lumacaftor and ivacaftor. Orkambi 100/125 film-coated tablets contain 100 mg of lumacaftor and 125 mg of ivacaftor. Orkambi 200/125 film-coated tablets contain 200 mg of lumacaftor and 125 mg of ivacaftor. Orkambi is also available as granules in three strengths: 75/94 mg, 100/125 mg, and 150/188 mg per sachet. Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve its cellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel open probability of the CFTR protein at the cell surface.

Approved indications

— Cystic fibrosis in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene.

Dosing overview

For patients aged 1 year and older, dosing is based on age and weight, ranging from lumacaftor 75 mg/ivacaftor 94 mg for children aged 1 to less than 2 years weighing 7 kg to less than 9 kg, to lumacaftor 200 mg/ivacaftor 125 mg twice daily for patients aged 12 years and older. A fat-containing meal or snack should be consumed just before or just after dosing. Film-coated tablets should be swallowed whole and not chewed, broken, or dissolved. The granule contents should be mixed with one teaspoon of age-appropriate soft food or liquid, such as puréed fruits or vegetables, flavoured yogurt or pudding, water, milk, breast milk, infant formula or juice, and the mixture completely consumed. Once mixed, the product is stable for one hour and should be ingested during this period. No dose adjustment is necessary for patients with mild to moderate renal impairment. No dose adjustment is necessary for patients with mild hepatic impairment. A dose reduction is recommended for patients with moderate hepatic impairment.

Key safety warnings

Liver function decompensation, including liver failure leading to death, has been reported in cystic fibrosis patients with pre-existing cirrhosis with portal hypertension receiving Orkambi. Assessments of liver function tests (ALT, AST and bilirubin) are recommended before initiating Orkambi, every 3 months during the first year of treatment, and annually thereafter. Respiratory events such as chest discomfort, dyspnoea, and abnormal respiration were observed more commonly in patients during initiation of Orkambi compared to those who received placebo, and these events have led to drug discontinuation and can be serious, particularly in patients with percent predicted FEV1 less than 40. There is no experience of initiating treatment with Orkambi in patients having pulmonary exacerbations and this is not advisable. Increased blood pressure has been observed in some patients treated with Orkambi, and blood pressure should be monitored periodically in all patients during treatment. Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the post-marketing setting, and if signs or symptoms of serious hypersensitivity reactions develop during treatment, Orkambi should be discontinued and appropriate therapy instituted. Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with Orkambi and ivacaftor monotherapy, and although other risk factors were present in some cases, a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with Orkambi.

Contraindications

Orkambi should not be used in cases of hypersensitivity to the active substance or to any component of this medication.

PBS listing

Orkambi granules are listed on the PBS under Section 100 (Highly Specialised Drugs Program) for cystic fibrosis in patients aged 2 years or over who are homozygous for the F508del mutation in the CFTR gene, with Authority Required restriction.

Regulatory history

Orkambi 200/125 film-coated tablets were first registered on the ARTG on 8 March 2016. Orkambi 100/125 film-coated tablets were registered on 13 August 2018. Orkambi 100/125 and 150/188 granules were registered on 21 June 2019. Orkambi 75/94 granules were registered on 16 May 2023. In November 2017, the PBAC recommended an amendment to expand the PBS listing to include patients aged 6 years and older who are homozygous for the F508del mutation. In July 2018, the PBAC recommended new PBS listing for patients aged 6 years and over under a Managed Access Program, noting beneficial treatment but identifying a need for longer-term data, with the sponsor to provide results of long-term studies. In July 2019, the PBAC recommended listing of a new granule presentation for patients aged 2 years or over who are homozygous for the F508del mutation under the Highly Specialised Drugs Program.