Granisetron

Granisetron is a selective 5-HT3 receptor antagonist with a longer half-life than ondansetron, allowing once daily dosing. It is used to prevent chemotherapy-induced and postoperative nausea and vomiting, and a transdermal patch and extended-release injection allow multi-day cover.

Classification. 5-HT3 receptor antagonist; antiemetic.

Mechanism. Blocks serotonin at 5-HT3 receptors on vagal afferents and in the chemoreceptor trigger zone and nucleus tractus solitarius, preventing activation of the vomiting reflex.

Pharmacodynamics. Most effective against acute emesis (first 24 hours). It has little effect on motility and no extrapyramidal activity. QT prolongation is small.

Pharmacokinetics. Oral bioavailability about 60%. Half-life about 9 hours (longer in older adults and cancer patients). Protein binding about 65%.

Metabolism. Hepatic via CYP3A and CYP1A1. About 12% is excreted unchanged in urine, and the remainder as metabolites in urine and faeces.

Adult doses unless stated.

Chemotherapy-induced nausea and vomiting.

• IV: 1 mg (or 10 micrograms/kg) over 30 seconds or diluted and infused over 5 minutes, completed before chemotherapy. A 3 mg dose is also used. A second dose may be given within 24 hours if needed.

• Oral: 1 mg twice daily (first dose 1 hour before chemotherapy), or 2 mg once daily, for up to 7 days.

• Maximum 9 mg IV in 24 hours.

• Give with dexamethasone, and with an NK1 antagonist for highly emetogenic regimens.

Transdermal patch. One patch delivering 3.1 mg over 24 hours (containing 34.3 mg) applied 24 to 48 hours before chemotherapy. Keep for up to 7 days. Remove at least 24 hours after chemotherapy finishes.

Extended-release subcutaneous injection. 10 mg given once, at least 30 minutes before chemotherapy, with dexamethasone and an NK1 antagonist. Do not repeat within 14 days. Availability is limited.

Radiotherapy-induced nausea. 2 mg orally once daily, 1 hour before radiotherapy.

Postoperative nausea and vomiting. Prevention 1 mg IV slowly before induction; treatment 1 mg IV, repeated once. Maximum 3 mg in 24 hours.

Paediatric chemotherapy-induced nausea (age 2 years and over). 10 to 40 micrograms/kg IV (maximum 3 mg) over 5 minutes before chemotherapy; may be repeated once in 24 hours.

Kidney and liver adjustment. No adjustment is needed in kidney or liver impairment, but use caution in severe liver disease.

Contraindications. Hypersensitivity to granisetron or other 5-HT3 antagonists. Use with caution in subacute intestinal obstruction.

Common adverse effects. Headache, constipation, diarrhoea, asthenia, somnolence and transient liver enzyme rise.

Serious adverse effects.

• Serotonin syndrome, particularly with other serotonergic drugs.

• Hypersensitivity and anaphylaxis.

• QT prolongation, less than with ondansetron, but still relevant in heart disease or electrolyte disturbance.

• Masking of progressive ileus.

• Application site reactions and photosensitivity with the patch.

Major interactions.

• QT prolonging drugs (antimalarials such as artemether-lumefantrine and quinine, macrolides, fluoroquinolones, haloperidol, methadone): additive risk.

• Serotonergic drugs (SSRIs, SNRIs, tramadol, linezolid): serotonin syndrome.

• Ketoconazole inhibits CYP3A and may raise levels; phenobarbital and rifampicin induce metabolism and may reduce effect.

• Apomorphine: avoid.

Special groups.

• Pregnancy: limited data; use only if the benefit outweighs the risk.

• Breastfeeding: no data; avoid.

• Children: weight-based IV dosing from 2 years; patch and extended-release injection not established.

• Older adults: no dose adjustment; monitor for constipation and QT.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment; use caution in severe impairment.

Formulations. Tablets 1 mg and 2 mg; oral solution 2 mg in 10 mL; injection 1 mg in 1 mL and 3 mg in 3 mL; transdermal patch; extended-release injection in some markets.

IV administration.

• Injection: give 1 mg undiluted over at least 30 seconds, or dilute in 20 to 50 mL sodium chloride 0.9% or glucose 5% and infuse over 5 minutes (up to 30 minutes for a 3 mg infusion).

• Complete the infusion before chemotherapy starts.

Patch administration. Apply to clean, dry skin on the upper outer arm. Do not cut. Cover and avoid sun and heat on the patch site during use and for 10 days after removal.

Baseline. ECG in heart disease or QT-prolonging coprescription. Potassium and magnesium.

Monitoring.

• Control of nausea and vomiting at 24 hours and again during days 2 to 5.

• Bowel function and abdominal distension.

• Skin reaction under the patch.

• ECG when other QT-prolonging drugs are used.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for hypersensitivity, serotonin syndrome or suspected ileus.

Referral and escalation. Escalate to a three-drug regimen (5-HT3 antagonist, dexamethasone and NK1 antagonist) for highly emetogenic regimens or breakthrough emesis.