Adult: Available preparations:
Lumacaftor 200 mg and ivacaftor 125 mg tab
In patients who are homozygous for F508del mutation in the CFTR gene: 2 tabs 12 hourly to be taken with fat-containing food. Child: Available preparations:
Lumacaftor 100 mg and ivacaftor 125 mg tab
Lumacaftor 200 mg and ivacaftor 125 mg tab
Lumacaftor 100 mg and ivacaftor 125 mg granules in sachet
Lumacaftor 150 mg and ivacaftor 188 mg granules in sachet
2-5 years weighing <14 kg As granules: 100 mg/125 mg 12 hourly; ≥14 kg: 150 mg/188 mg 12 hourly. 6-11 years 2 tabs (100 mg/125 mg) 12 hourly; ≥12 years Same as adult dose.
Special Patient Group
Patients taking strong CYP3A inhibitors (e.g. ketoconazole):
Adult: Initially, 1 tab (200 mg/125 mg) once daily for 1 week, then return to usual adult dose thereafter.
Child: 2-5 years weighing <14 kg As granules: Initially, 100 mg/125 mg once daily every other day for 1 week, then return to usual dose thereafter; ≥14 kg As granules: Initially, 150 mg/188 mg once daily every other day for 1 week, then return to usual dose thereafter; 6-11 years Initially, 1 tab (100 mg/125 mg) once daily for 1 week, then return to usual dose thereafter. ≥12 years Initially, 1 tab (200 mg/125 mg) once daily for 1 week, then return to usual adult dose thereafter.
Hepatic Impairment
Moderate (Child-Pugh Class B): 2-5 years weighing <14 kg As granules: 100 mg/125 mg in the morning, then 100 mg/125 mg in the evening every other day; ≥14 kg As granules: 150 mg/188 mg in the morning, then 150 mg/188 mg in the evening every other day; 6-11 years 2 tabs (100 mg/125 mg) in the morning, then 1 tab (100 mg/125 mg) in the evening; ≥12 years 2 tabs (200 mg/125 mg) in the morning, then 1 tab (200 mg/125 mg) in the evening. Severe (Child-Pugh Class C): 2-5 years weighing <14 kg As granules: 100 mg/125 mg daily or less frequently; ≥14 kg As granules: 150 mg/188 mg daily or less frequently; 6-11 years 1 tab (100 mg/125 mg) 12 hourly; ≥12 years 1 tab (200 mg/125 mg) 12 hourly. Alternatively, reduce daily dose.
Reconstitution
Oral granules: Mix contents of sachet with 5 mL of soft food (e.g. pureed fruits, yogurt, pudding) or liquid (e.g. milk, juice).
Special Precautions
Patient with history of elevated hepatic transaminases or bilirubin, advanced lung disease, pre-existing liver cirrhosis with portal hypertension. Not recommended for use in patients with cystic fibrosis (CF) who undergone organ transplantation. Not intended for CF patients who are heterozygous for F508del and have gating Class III CFTR gene mutation. Severe renal (CrCl ≤30 mL/min) including ESRD, and hepatic (Child-Pugh B and C) impairment. Children. Pregnancy and lactation. Concomitant use with strong CYP3A inhibitors.
Adverse Reactions
Significant: Increased hepatic transaminases (with or without elevations of total serum bilirubin), increased blood pressure, respiratory effects (e.g. chest discomfort, dyspnoea, abnormal respiration), non-congenital lens opacities and cataracts (children). Ear and labyrinth disorders: Ear pain or discomfort, tinnitus, vestibular disorder, tympanic membrane hyperaemia. Gastrointestinal disorders: Nausea, diarrhoea, abdominal pain, flatulence, vomiting, oropharyngeal pain, pharyngeal pain. General disorders and admin site conditions: Fatigue. Investigations: Increased blood creatine phosphokinase, bacteria in sputum. Nervous system disorders: Headache, dizziness. Reproductive system and breast disorders: Menstruation irregular, metrorrhagia, dysmenorrhoea, breast mass. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, upper respiratory tract infection, rhinitis, nasal or sinus congestion, productive cough, sputum increased, rhinorrhoea. Skin and subcutaneous tissue disorders: Rash. Potentially Fatal: Liver function decompensation, including liver failure.
Patient Counseling Information
This drug may cause dizziness, if affected, do not drive or operate machinery.
Monitoring Parameters
Perform CF mutation test prior to treatment initiation if genotype is unknown; ophthalmological exam at baseline and follow-up in paediatric patients. Monitor ALT/AST, and bilirubin at baseline, then every 3 months for the 1st year, and annually thereafter; blood pressure periodically during treatment; signs and symptoms of respiratory effects in patients with percent predictive FEV1 <40.
Overdosage
Symptoms: Headache, generalised rash, and increased transaminase. Management: Symptomatic and supportive treatment. Monitor vital signs and observe clinical status of the patient.
Drug Interactions
May alter exposure of P-glycoprotein (P-gp) substrates (e.g. digoxin, fexofenadine, dabigatran, ranitidine). May decrease exposure and efficacy of montelukast, clarithromycin, telithromycin, erythromycin, posaconazole, ibuprofen, rifabutin, midazolam, triazolam, immunosuppressants (e.g. ciclosporin, tacrolimus), PPIs (e.g. omeprazole, lansoprazole), repaglinide, hormonal contraceptives (e.g. ethinyloestradiol, norethindrone), antidepressants (e.g. citalopram, sertraline, bupropion), systemic corticosteroids (e.g. prednisone, methylprednisolone). May alter the exposure of warfarin, dabigatran, digoxin.
Lumacaftor: Increased plasma concentration with breast cancer resistance protein (BCRP) inhibitors.
Ivacaftor: Increased exposure with CYP3A inhibitors (e.g. itraconazole, ketoconazole, clarithromycin, erythromycin). Decreased exposure with strong CYP3A inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin).
Food Interaction
Increased exposure when taken with fat-containing foods.
Ivacaftor: Increased serum concentrations with grapefruit or grapefruit juice and Seville oranges. Decreased exposure with St. John’s wort.
Lab Interference
May give false-positive urine screening tests for tetrahydrocannabinol.
Action
Description: Mechanism of Action: Lumacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) corrector, which improves F508del-CFTR conformational stability thereby increasing processing and trafficking of mature CFTR protein to the cell surface.
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 the lungs and gastrointestinal tract.
Combined effects of ivacaftor and lumacaftor are increased quantity, stability, and function of F508del-CFTR at the cell surface, thereby increasing chloride ion transport. Pharmacokinetics: Absorption: Increased absorption with fatty foods.
Lumacaftor: Absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 4 hours.
Ivacaftor: Absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 6 hours. Distribution: Lumacaftor: Crosses placenta and enters breast milk. Volume of distribution: 86 ± 69.8 L. Plasma protein binding: Approx 99%, mainly to albumin.
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. Metabolism: Lumacaftor: Not extensively metabolised. Undergoes oxidation and glucuronidation.
Ivacaftor: Extensively metabolised in the liver by CYP3A and CPY3A5 isoenzyme to form major metabolites, M1 (active) and M6 (inactive). Excretion: Lumacaftor: Via faeces (51% as unchanged drug); urine (8.6%; 0.18% as unchanged drug). Elimination half-life: Approx 26 hours.
Ivacaftor: Via faeces (87.5%, approx 65% as metabolites); urine (minimal, as unchanged drug). Elimination half-life: Approx 12 hours.
Chemical Structure
Lumacaftor Source: National Center for Biotechnology Information. PubChem Database. Lumacaftor, CID=16678941, https://pubchem.ncbi.nlm.nih.gov/compound/Lumacaftor (accessed on Jan. 22, 2020)
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.
R07AX30 - ivacaftor and lumacaftor ; Belongs to the class of other respiratory system products.
References
Anon. Lumacaftor and Ivacaftor. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 19/11/2019.Buckingham R (ed). Ivacaftor. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 19/11/2019.Buckingham R (ed). Lumacaftor. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 19/11/2019.Joint Formulary Committee. Lumacaftor with Ivacaftor. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 19/11/2019.Orkambi Tablet, Film Coated; Granule (Vertex Pharmaceuticals Incorporated). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/11/2019.
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