ORKAMBI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ORKAMBI (ORKAMBI).
Orkambi is a combination of lumacaftor and ivacaftor. Lumacaftor is a CFTR corrector that facilitates the cellular processing and trafficking of the F508del-CFTR protein to increase its quantity at the cell surface. Ivacaftor is a CFTR potentiator that enhances the channel open probability of CFTR proteins at the cell surface, including the F508del-CFTR mutant, to improve chloride transport.
| Metabolism | Lumacaftor is primarily metabolized via ester hydrolysis followed by glucuronidation; ivacaftor is primarily metabolized by CYP3A4 and CYP3A5. |
| Excretion | Following oral administration, approximately 80% of the dose is excreted in feces (as unchanged drug and metabolites) and <6% in urine (as unchanged drug). |
| Half-life | Lumacaftor terminal half-life is approximately 26 hours; ivacaftor terminal half-life is approximately 12 hours following multiple doses of Orkambi. Steady state is reached within 7 days. |
| Protein binding | Lumacaftor: ~99% bound to plasma proteins, primarily albumin; ivacaftor: ~99% bound, primarily to alpha-1-acid glycoprotein and albumin. |
| Volume of Distribution | Lumacaftor: approximately 86 L (1.2 L/kg for a 70 kg adult); ivacaftor: approximately 88 L (1.26 L/kg for a 70 kg adult). Indicates extensive tissue distribution. |
| Bioavailability | Absolute bioavailability of lumacaftor is not established; ivacaftor absolute bioavailability is approximately 25% following oral administration with fat-containing food. |
| Onset of Action | Reduction in sweat chloride levels observed within 2 weeks; improvement in lung function (FEV1) typically seen after 4–8 weeks of continuous therapy. |
| Duration of Action | Sweat chloride reduction persists over 24 hours with twice-daily dosing. Continuous treatment required for sustained pulmonary function improvement; effect diminishes after discontinuation. |
Lumacaftor 200 mg/ivacaftor 125 mg orally every 12 hours with fat-containing food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment (eGFR <30 mL/min/1.73 m²) or ESRD; use with caution. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce to one tablet every 12 hours. Child-Pugh Class C: One tablet every 24 hours or less frequently. |
| Pediatric use | For ages 6 to <12 years and weight ≥30 kg: Lumacaftor 200 mg/ivacaftor 125 mg every 12 hours. For ages 2 to <6 years based on weight: 7 to <14 kg: Lumacaftor 100 mg/ivacaftor 62.5 mg every 12 hours; ≥14 kg: Lumacaftor 150 mg/ivacaftor 94.5 mg every 12 hours. |
| Geriatric use | No specific dose adjustments; use with caution due to potential for age-related renal or hepatic impairment. Monitor for adverse effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ORKAMBI (ORKAMBI).
| Breastfeeding | Unknown if excreted in human milk. M/P ratio not available. Consider risk of infant exposure vs benefit of breastfeeding; caution advised. |
| Teratogenic Risk | Pregnancy category B. No evidence of teratogenicity in animal studies at doses up to 4 times the maximum recommended human dose. Limited human data; avoid use in first trimester unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
None
| Serious Effects |
["Known hypersensitivity to lumacaftor or ivacaftor or any component of the formulation"]
| Precautions | ["Hepatic adverse reactions including transaminase elevations; assess liver function tests prior to initiation and every 3 months during first year, then annually.","Respiratory events including chest discomfort, dyspnea, and abnormal respiration, especially in patients with advanced lung disease.","Risk of cataracts in pediatric patients; ophthalmic examinations are recommended.","Drug interactions with strong CYP3A inducers (e.g., rifampin) and moderate/strong CYP3A inhibitors (e.g., ketoconazole); concomitant use with strong CYP3A inducers is not recommended."] |
Loading safety data…
| Monitor lung function, weight gain, and nutritional status. Consider fetal ultrasound for growth assessment if prolonged use. |
| Fertility Effects | No adverse effects on fertility observed in animal studies. Human data insufficient to assess impact. |