Granisetron
5 HT3 antagonist for chemotherapy and radiation induced nausea
Granisetron is a selective antagonist at 5 HT3 receptors, introduced in 1993 by SmithKline Beecham under the brand name Kytril. In Germany oral tablets, injection and infusion solutions and a transdermal patch (Sancuso) are available, and generics are common. Granisetron is approved for the prophylaxis and treatment of nausea and vomiting due to chemotherapy, radiotherapy and surgery in adults, and during chemotherapy in children aged 2 years and older.
5 HT3 antagonists have revolutionised supportive oncology care. Until the late 1980s chemotherapy induced nausea was one of the most feared adverse effects of many regimens. With the introduction of ondansetron, granisetron, tropisetron and later palonosetron, it became possible to deliver highly emetogenic chemotherapies such as cisplatin or the FEC regimen with acceptable quality of life. In the current MASCC and ASCO antiemesis guidelines, 5 HT3 antagonists form one component of triple prophylaxis alongside dexamethasone and an NK1 antagonist (aprepitant, netupitant, rolapitant).
Mechanism of Action
Serotonin (5 hydroxytryptamine, 5 HT) is stored in enterochromaffin cells of the small intestine. Cytotoxic chemotherapeutics and ionising radiation damage these cells, large amounts of serotonin are released and bind to 5 HT3 receptors on afferent vagal fibres of the intestinal wall. The signal is transmitted to the vomiting centre and the chemoreceptor trigger zone in the brainstem, producing nausea and vomiting.
Granisetron blocks 5 HT3 receptors both peripherally (intestinal wall, vagal fibres) and centrally (chemoreceptor trigger zone, nucleus tractus solitarii, area postrema). This dual action interrupts the central trigger pathway for vomiting. Its effect alone against delayed vomiting after chemotherapy (from day two onwards) is limited, which is why dexamethasone and NK1 antagonists are added in this setting.
The half life of granisetron is 5 to 9 hours, justifying once daily dosing. Metabolism is hepatic via CYP3A4, with elimination in roughly equal parts hepatic and renal. The transdermal patch releases the active ingredient at a controlled rate over 7 days, which is particularly advantageous in multi day chemotherapy blocks.
Indications
- Chemotherapy induced nausea and vomiting (CINV) in moderately and highly emetogenic regimens combined with dexamethasone and an NK1 antagonist
- Radiation induced nausea and vomiting during irradiation of the upper abdomen or total body irradiation
- Postoperative nausea and vomiting (PONV) prophylactically in at risk patients (female sex, non smoker, postoperative opioids, history of motion sickness)
- Multi day chemotherapy blocks: transdermal patch (Sancuso 3.1 mg per 24 hours) once before chemotherapy for 7 days
- Children aged 2 years and older for prophylaxis and treatment during chemotherapy
Dosage and Administration
Oral adults: 1 to 2 mg one hour before chemotherapy, continuing with 1 mg once or twice daily for up to 7 days. Intravenous: 1 mg or 3 mg as a short infusion over 5 minutes, 30 minutes before chemotherapy. Subcutaneous: a single 1 mg dose, an option when venous access is poor. Transdermal patch (Sancuso): 34.3 mg per patch over 7 days, applied 24 to 48 hours before the start of the chemotherapy block to dry skin on the upper arm.
Postoperative nausea: 1 mg intravenously at the end of surgery, alternatively 1 mg orally one hour before induction. Children aged 2 years and older: 10 to 40 µg per kg as a short infusion once before chemotherapy, maximum 3 mg per dose.
Renal impairment: no formal dose adjustment. Hepatic impairment: reduce the dose in severe impairment because of slower metabolism. Elderly patients: no dose adjustment, but caution with QT prolonging co medication.
Side Effects
Very common and common: headache (by far the most common adverse effect), constipation, abdominal pain, dizziness, fatigue, insomnia, transient elevation of liver enzymes.
Uncommon: diarrhoea, rash, hot flushes, extrapyramidal reactions (very rare), bradycardia or tachycardia, blood pressure fluctuations, local reactions at the transdermal patch.
Rare and important: anaphylaxis, QT prolongation (in 2012 the EMA issued class wide warnings for the setron antagonists), torsade de pointes in predisposed patients, serotonin syndrome when combined with other serotonergic drugs.
Patch specific side effects: skin redness, pruritus, local irritation, rarely allergic contact dermatitis. With severe irritation remove the patch and do not reapply to the same site. The patch must not be cut, and direct sun exposure increases drug release.
Interactions
- QT prolonging drugs (amiodarone, sotalol, quinidine, methadone, macrolides, quinolones): additive QT prolongation; particular caution, ECG monitoring
- Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, tramadol, linezolid): theoretical risk of serotonin syndrome; clinical cases have been reported
- CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St John’s wort): reduced plasma levels, loss of efficacy
- CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir): slightly increased plasma levels, usually no clinical consequences
- Cardiac drugs associated with bradycardia: combine cautiously because of rare bradycardia episodes on granisetron
Special Notes
Triple antiemesis: in highly emetogenic chemotherapy (cisplatin, AC regimen), granisetron is combined with dexamethasone and an NK1 antagonist such as aprepitant, netupitant or rolapitant. This combination drastically reduces vomiting in phases I and II and is now the guideline standard.
Delayed nausea: 5 HT3 antagonists act mainly in the first 24 hours after chemotherapy. From day two delayed nausea emerges, and dexamethasone, NK1 antagonists or olanzapine are more effective against it. Therapy must be aligned with the time course of the emetogenic stimulus.
Contraindications: known hypersensitivity, congenital long QT syndrome, severe electrolyte disturbance with hypokalaemia or hypomagnesaemia, severe hepatic impairment.
Pregnancy: data on granisetron in pregnancy are limited. In vital indications (severe hyperemesis gravidarum during chemotherapy) an individual benefit risk assessment is required. Ondansetron has literature on a possible risk of oral clefts in the first trimester; for granisetron the evidence is less clear. Breastfeeding: transfer into breast milk is not reliably quantified; breastfeeding during therapy is not recommended.
Monitoring: ECG with QTc measurement before starting therapy in at risk patients, electrolytes regularly. With longer therapy also check liver values. Inform the patient about headache as the main adverse effect and about particular features of transdermal use.
You might also be interested in
- Dexamethasone, glucocorticoid in antiemesis and oncology
- Methylprednisolone, glucocorticoid at higher acute dose
- Cisplatin, highly emetogenic chemotherapeutic
- Carboplatin, moderately emetogenic platinum analogue
- Dimenhydrinate, classic antiemetic for motion sickness
Frequently Asked Questions
Why also dexamethasone and aprepitant?
Chemotherapy induced nausea has several causes. Granisetron acts mainly against the acute serotonergic phase in the first 24 hours. Dexamethasone prolongs the antiemetic action, and aprepitant blocks the substance P pathway and works against delayed vomiting. The triple combination covers all key mechanisms and substantially reduces the rate of acute and delayed vomiting.
What is the Sancuso patch?
Sancuso is a transdermal granisetron patch that evenly releases 34.3 mg of active ingredient over 7 days. It is ideal for multi day chemotherapy regimens because oral or intravenous dosing is avoided. The patch is applied 24 to 48 hours before the start of chemotherapy to dry skin on the upper arm and worn until day seven.
Why do I get headaches?
Headache is the most common adverse effect of all setron antiemetics. The mechanisms are not fully understood, but serotonergic changes and vasodilation are thought to play a role. In most cases the headache eases after the first dose. Paracetamol or ibuprofen on medical advice relieve the symptoms; for very severe headaches a switch to another 5 HT3 antagonist or a different drug class is possible.
Do setron antiemetics cause constipation?
Yes. In addition to their antiemetic action, 5 HT3 antagonists block the serotonin signals in the gut that contribute to peristalsis. Constipation occurs in about 10 percent of patients. A step wise prophylactic approach with macrogol, adequate fluid intake and exercise is often recommended, particularly when opioids are given concurrently.
Sources
- EMA, European Medicines Agency
- MASCC and ASCO antiemesis guidelines
- Gelbe Liste, granisetron drug profile
- BfArM, Federal Institute for Drugs and Medical Devices
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