Orkambi (Lumacaftor, Ivacaftor)

Orkambi is a CFTR modulator indicated for cystic fibrosis patients with the F508del homozygous genotype. It improves lung function and reduces pulmonary exacerbations.

• Cystic fibrosis (12 years and older, F508del homozygous): Improves lung function and decreases exacerbation frequency.
• Cystic fibrosis (adolescents 12–17 years, F508del homozygous): Enhances pulmonary outcomes and quality of life.
• Cystic fibrosis (adults ≥18 years, F508del homozygous): Slows decline in respiratory function and supports nutritional status.

• Lumacaftor acts as a CFTR corrector, facilitating proper folding and trafficking of the defective CFTR protein to the cell surface, while ivacaftor functions as a CFTR potentiator that increases the channel‑opening probability of the protein once it reaches the membrane. The combined action enhances chloride transport across epithelial cells, improving airway surface liquid hydration and respiratory function.

Common Side Effects

• Respiratory tract infection: mild to moderate upper respiratory symptoms.
• Headache: transient, often resolves without intervention.
• Diarrhea: usually self‑limiting.
• Nausea: may occur after dosing.
• Elevated liver enzymes: asymptomatic increase in ALT/AST.
• Rash: mild skin irritation.

Serious or Rare Side Effects

• Severe liver injury: jaundice, hepatic failure requiring monitoring.
• Pulmonary hemorrhage: coughing up blood, requires urgent care.
• Anaphylaxis: rapid onset of allergic reaction, may be life‑threatening.
• Vision changes: blurred vision or cataract formation.
• Elevated serum creatinine: indicates possible renal impact.
• Cardiac arrhythmias: rare but reported in post‑marketing data.

Before initiating therapy, patients should be evaluated for liver function and potential drug interactions.

• Liver function monitoring: check ALT/AST before treatment and periodically during therapy.
• Drug interaction review: assess concomitant CYP3A4 substrates and inhibitors.
• Pregnancy risk assessment: use only if benefits outweigh potential fetal risks.
• Adherence with meals: take tablets with a high‑fat meal to improve absorption.
• Storage at ambient temperature: keep below 25 °C in the original pack, protect from moisture.

Orkambi may interact with several medications that affect CYP3A4 metabolism.

Major Interactions (Avoid)

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): may markedly reduce lumacaftor/ivacaftor exposure.
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole): may increase drug levels and risk of toxicity.

Moderate Interactions (Monitor Closely):\n- Azole antifungals (e.g., fluconazole): may modestly raise ivacaftor concentrations.

• Macrolide antibiotics (e.g., clarithromycin): can increase exposure to both components.
• HIV protease inhibitors (e.g., ritonavir): may elevate ivacaftor levels.
• St. John’s wort: may lower drug concentrations.
• Oral contraceptives: potential reduced efficacy, consider alternative contraception.