Vinca Alkaloids

Vinca alkaloids bind tubulin dimers, inhibit microtubule polymerisation, and arrest cells in metaphase. They are derived from the Madagascar periwinkle and are used in leukaemia, lymphoma, Wilms tumour, rhabdomyosarcoma, germ cell tumour, Kaposi sarcoma, lung and breast cancer.

Classification. Vincristine, vinblastine, vinorelbine and vindesine.

Pharmacokinetics. Hepatic metabolism by CYP3A4 and biliary excretion; large volume of distribution; terminal half life of 20 to 85 hours.

• Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously weekly to every 3 weeks; infants and children under 10 kg 0.05 mg/kg.
• Vinblastine 6 mg/m2 on days 1 and 15 every 28 days in Hodgkin lymphoma (4 to 6 mg/m2 weekly in other regimens).
• Vinorelbine 25 to 30 mg/m2 intravenously weekly; oral 60 mg/m2 weekly for 3 weeks then 80 mg/m2.

Differences. Vincristine: neurotoxicity, minimal marrow suppression. Vinblastine: myelosuppression, less neurotoxicity. Vinorelbine: neutropenia, phlebitis, less neuropathy.

• Lymphoma (including Burkitt lymphoma), acute lymphoblastic leukaemia, Wilms tumour, neuroblastoma, rhabdomyosarcoma: vincristine.
• Hodgkin lymphoma, germ cell tumour, Kaposi sarcoma: vinblastine and vincristine (with bleomycin in Kaposi sarcoma where liposomal drugs are unavailable).
• Non-small cell lung cancer and breast cancer: vinorelbine.
• Prevent constipation: start a laxative (lactulose or senna) from the first dose; review bowel habit before each dose.
• Extravasation: stop the infusion, aspirate the line, apply warm compresses (not cold), and give hyaluronidase locally where available.

Selection. Avoid in patients with Charcot-Marie-Tooth disease; assess neuropathy before each dose.

Contraindications. Intrathecal use; severe liver impairment; demyelinating neuropathy; pregnancy; concurrent strong CYP3A4 inhibitors.

Adverse effects. Peripheral neuropathy (loss of ankle reflexes, paraesthesia, foot drop, jaw pain), constipation and paralytic ileus, autonomic neuropathy with hypotension, syndrome of inappropriate antidiuretic hormone secretion, seizures, neutropenia (vinblastine, vinorelbine), and tissue necrosis on extravasation.

Interactions. Itraconazole, voriconazole, posaconazole, clarithromycin, and ritonavir- or cobicistat-boosted antiretrovirals can cause severe or fatal neurotoxicity; avoid or reduce the dose and monitor; phenytoin lowers vincristine exposure.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: use the maximum 2 mg cap; infants dosed by weight.
• Older adults: neuropathy risk is higher; reduce dose.
• Kidney impairment: no adjustment.
• Liver impairment: bilirubin 1.5 to 3.0 mg/dL, reduce by 50 percent; over 3.0 mg/dL, avoid or give 25 percent of the dose.

Monitoring. Neurological examination each cycle, bowel function, blood pressure, sodium, bilirubin, and full blood count for vinblastine and vinorelbine.

Referral and escalation. Ileus, severe neuropathy, seizures, or any suspicion of intrathecal injection (immediate neurosurgical and intensive care involvement, with cerebrospinal fluid lavage) need emergency care.