Orkambi (Lumacaftor, Ivacaftor)

Orkambi is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator used in patients with the F508del mutation.

• Cystic fibrosis (F508del homozygous, ≥12 years): improves lung function and reduces pulmonary exacerbations.
• Cystic fibrosis (F508del homozygous, ≥12 years): lowers sweat chloride concentrations, reflecting enhanced CFTR activity.
• Cystic fibrosis (F508del homozygous, ≥12 years): contributes to better nutritional status and weight gain.

• Lumacaftor acts as a corrector that assists the misfolded CFTR protein to reach the cell surface, while ivacaftor functions as a potentiator that enhances the opening probability of the CFTR channel once it is present at the membrane. Together they increase chloride transport across epithelial cells, addressing the underlying defect in cystic fibrosis caused by the F508del mutation.

Orkambi may cause a range of adverse reactions, most of which are mild to moderate.

Common Side Effects

• Headache: mild to moderate intensity.
• Upper respiratory tract infection: symptoms of congestion or sore throat.
• Nausea: occasional stomach upset.
• Diarrhea: loose stools, generally self‑limiting.
• Elevated liver enzymes: transient increase in ALT/AST.
• Rash: mild skin irritation or erythema.

Serious or Rare Side Effects

• Hepatotoxicity: significant elevation of liver enzymes requiring monitoring.
• Severe respiratory events: bronchospasm or worsening of pulmonary status.
• Allergic reactions: anaphylaxis or severe skin reactions such as Stevens‑Johnson syndrome.
• Vision changes: rare reports of cataract formation.
• Cardiac arrhythmias: QT prolongation in susceptible individuals.

Before initiating Orkambi, consider the following precautions.

• Liver function monitoring: assess baseline ALT/AST and repeat periodically.
• Drug–enzyme interactions: review concomitant CYP3A4 substrates or inhibitors.
• Pregnancy and lactation: weigh potential benefits against unknown fetal risks; consult specialist.
• Respiratory status: monitor for worsening symptoms, especially in severe disease.
• Age restriction: approved for patients aged 12 years and older with the specified genotype.

Store at ambient temperature below 25°C: keep in the original container, protect from moisture and direct sunlight.

Orkambi can interact with several medicines, requiring careful management.

Major Interactions (Avoid)

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): may markedly reduce exposure.
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): can increase systemic levels and toxicity.

Moderate Interactions (Monitor Closely)

• Moderate CYP3A4 inhibitors (e.g., fluconazole): may modestly raise concentrations.
• Medications affecting gastric pH (e.g., proton pump inhibitors): could alter absorption.
• Anticoagulants (e.g., warfarin): monitor INR as changes in liver metabolism may occur.