Voxelotor

Voxelotor is an oral haemoglobin S polymerisation inhibitor that was licensed to raise haemoglobin and reduce haemolysis in sickle cell disease. The manufacturer withdrew it from sale worldwide in 2024 after safety and clinical benefit concerns, so this entry applies to patients who remain on it and to supply that still exists.

Classification. Haemoglobin S polymerisation inhibitor.

Mechanism. Binds reversibly to the alpha chain of haemoglobin, increasing oxygen affinity and keeping haemoglobin in the oxygenated state, which delays polymerisation and red cell sickling.

Pharmacokinetics. Peak levels at about 2 hours. It binds almost entirely to red cells, giving a whole-blood half-life of about 2 days. Metabolism is by CYP3A4 with minor CYP2C19, CYP2B6 and CYP2C9 contributions.

Sickle cell disease (adults and children 12 years and over; paediatric forms from 4 years in some regions).

• Dose, adults and adolescents: 1500 mg orally once daily. Maintenance: the same dose. Loading dose: none.
• Children 4 to under 12 years (tablets for suspension): 10 to under 20 kg, 600 mg; 20 to under 40 kg, 900 mg; 40 kg and over, 1500 mg, once daily.
• Maximum: 1500 mg daily (2500 mg with a strong CYP3A4 inducer). Titration: none.
• Severe hepatic impairment (Child-Pugh C): 1000 mg daily.

Interaction adjustments. With a strong or moderate CYP3A4 inducer such as rifampicin, increase to 2500 mg (or avoid). With a strong or moderate CYP3A4 inhibitor or dual CYP3A4 and CYP2C9 inhibitor such as fluconazole, reduce to 1000 mg.

Adjustments. Kidney: no adjustment, but there are no data in severe impairment (eGFR under 15 mL/min). Liver: 1000 mg daily in Child-Pugh C. Pregnancy and breastfeeding: avoid.

Contraindications. Hypersensitivity.

Warnings. Higher rates of vaso-occlusive crises and deaths were seen in follow-up data in the post-licence period, with a rise in haemoglobin that did not translate into proven clinical benefit. Hypersensitivity reactions (rash, urticaria, mild shortness of breath) are possible.

Adverse effects. Headache, diarrhoea, abdominal pain, nausea, fatigue, rash, fever.

Interactions. CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, efavirenz) lower exposure; CYP3A4 inhibitors raise it. Voxelotor raises exposure of sensitive CYP3A4 substrates with a narrow therapeutic index, for example midazolam.

Pregnancy and breastfeeding. Avoid; no adequate data.

Common errors. Interpreting a haemoglobin rise as clinical response; misreading haemoglobin fractions, because voxelotor interferes with chromatographic haemoglobin analysis; not adjusting for rifampicin or fluconazole.

Administration. Oral, with or without food. Tablets are swallowed whole; tablets for suspension are dispersed in water or soft food for children.

Baseline. Full blood count with reticulocytes and bilirubin, liver function, drug history for CYP3A4 interactions.

Monitoring. Crisis frequency, haemoglobin, haemolysis markers, rash and hepatic function every 3 months. Inform the laboratory before haemoglobin electrophoresis or chromatography.

Referral and escalation. Specialist review is advised for any patient still taking voxelotor, with a plan to transition to hydroxyurea or other therapy.