Granisetron

Granisetron is a potent, highly selective 5-HT3 receptor antagonist with antiemetic activity against nausea and vomiting caused by cytostatic therapy. Radioligand binding studies show negligible affinity for other receptor types, including 5-HT1, 5-HT2, 5-HT4 and dopamine D2 sites.

Mechanism of Action

• Trigger of vomiting: chemotherapy is thought to release serotonin from enterochromaffin cells of the small intestine. Serotonin stimulates 5-HT3 receptors on vagal and splanchnic nerve endings that project to the vomiting centre, and 5-HT3 receptors in the area postrema, starting the vomiting reflex.
• Blockade: granisetron blocks 5-HT3 receptors both peripherally (gut) and centrally (the medullary chemoreceptor trigger zone), interrupting this reflex.
• Selectivity: little or no affinity for other serotonin receptors, adrenoceptors, dopamine D2, histamine H1, benzodiazepine or opioid receptors.
• Patch versus tablets: in a double-blind, double-dummy study of 641 patients on multi-day chemotherapy, a patch worn for 7 days (applied 24 to 48 hours before chemotherapy) was compared with oral granisetron 2 mg daily. Complete control was reached in 60.2% with the patch and 64.8% with oral granisetron in the per-protocol set, and non-inferiority was confirmed.

Pharmacokinetics

• Absorption, patch: granisetron crosses intact skin by passive diffusion and is absorbed slowly, with maximum concentrations at 24 to 48 hours. About 65% of the drug is delivered, an average of 3.1 mg a day. After 7 days of wear, mean peak concentration was 3.9 ng/mL (between-subject variability 77%). Exposure was not increased overall by a heat pad, and consecutive patches showed minimal accumulation.
• Absorption, oral: rapid and complete, with oral bioavailability of about 60% because of first-pass metabolism; food does not affect absorption.
• Distribution: volume of distribution about 3 L/kg; plasma protein binding about 65%; distributes freely between plasma and red blood cells.
• Metabolism: mainly hepatic, by N-demethylation and aromatic ring oxidation followed by conjugation; the main metabolites are 7-hydroxygranisetron and 9’N-desmethylgranisetron. CYP1A1 and CYP3A4 are involved, and oral and transdermal metabolic profiles do not differ. In vitro, granisetron neither stimulates nor inhibits the cytochrome P450 system.
• Elimination: after oral dosing the remainder of the dose leaves as metabolites, about 48% in urine and 38% in faeces. Half-life is 4 to 6 hours in healthy people and 9 to 12 hours in patients with cancer.
• Special populations: no dose adjustment is needed in the elderly or in renal or hepatic impairment, but a degree of caution is advised in renal and hepatic impairment.

• Sancuso transdermal patch (adults): prevention of nausea and vomiting associated with moderately or highly emetogenic chemotherapy, for a planned duration of 3 to 5 consecutive days, where oral antiemetic administration is complicated by factors making swallowing difficult.
• Kytril solution for injection (adults): prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy; prevention and treatment of postoperative nausea and vomiting.
• Kytril solution for injection: prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.
• Kytril solution for injection (children aged 2 years and older): prevention and treatment of acute nausea and vomiting associated with chemotherapy.
• Kytril tablets (adults): prevention and treatment of acute nausea and vomiting associated with chemotherapy and radiotherapy; prevention of delayed nausea and vomiting associated with chemotherapy and radiotherapy.

• Hypersensitivity to granisetron or to any of the excipients (all products).
• Sancuso: also hypersensitivity to other 5-HT3 receptor antagonists.

The most common reaction with the Sancuso patch was constipation (about 8.7% of patients), and most reactions were mild or moderate. With Kytril the most frequent reactions are headache and constipation, which may be transient; ECG changes with QT prolongation have been reported.

Sancuso Transdermal Patch

Common (≥1/100 to <1/10): constipation.

Uncommon (≥1/1,000 to <1/100): decreased appetite; headache; vertigo; flushing; dry mouth, nausea, retching; raised alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase; arthralgia; generalised oedema; application site irritation (including itching and skin irritation).

Rare (≥1/10,000 to <1/1,000): dystonia, dyskinesia.

Not known: hypersensitivity reactions; serotonin syndrome; application site reactions (erythema, rash, pain, hypersensitivity, vesicles, burn, urticaria, discolouration).

Kytril Injection and Tablets

Very common (≥1/10): headache; constipation.

Common (≥1/100 to <1/10): insomnia; diarrhoea; raised liver transaminases (with a similar frequency in patients on comparator treatment).

Uncommon (≥1/1,000 to <1/100): hypersensitivity reactions such as anaphylaxis and urticaria; extrapyramidal reactions; serotonin syndrome; QT prolongation; rash.

Important serious reactions are serotonin syndrome (potentially life-threatening), QT prolongation and arrhythmia, and hypersensitivity including anaphylaxis.

• Serotonergic medicines: serotonin syndrome has been reported when 5-HT3 antagonists are used with other serotonergic medicines, including selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and buprenorphine or other opioids. Patients are observed for symptoms.
• QT-prolonging and arrhythmogenic medicines: granisetron can be associated with ECG changes and QT prolongation, which may matter when it is given with such medicines.
• Paracetamol: giving intravenous 5-HT3 antagonists with oral paracetamol has been reported to block the analgesic effect by a pharmacodynamic mechanism.
• CYP1A1 and CYP3A4 inducers or inhibitors: may change the clearance and half-life of granisetron. Phenobarbital increased total plasma clearance by about 25% after intravenous granisetron. In vitro, ketoconazole may inhibit CYP3A metabolism of granisetron; the clinical significance is unknown.
• No interaction found: in healthy subjects with a benzodiazepine, a neuroleptic or cimetidine; with emetogenic cancer chemotherapy; and with aprepitant, which had no clinically important effect on granisetron pharmacokinetics (Sancuso).
• Children: interaction studies have only been performed in adults.

The three products are dosed differently. The Kytril details follow the Spanish (AEMPS) product information and may differ in other countries.

Sancuso Transdermal Patch

• Adults: apply one patch 24 to 48 hours before chemotherapy; a gradual rise in plasma levels means onset can be slower than with oral granisetron 2 mg. Remove the patch at least 24 hours after chemotherapy ends. It can be worn for up to 7 days, depending on the length of the regimen.
• Selection: after routine blood monitoring, apply only when chemotherapy is unlikely to be delayed, to avoid unnecessary exposure.
• Where and how: on clean, dry, intact skin of the outer upper arm, or on the abdomen if the arm is not possible; never on red, irritated or damaged skin. Apply straight after opening the sachet and removing the release liner. Do not cut the patch.
• Detached patch: reattach it in the same position with medical tape if needed; if that is not possible or the patch is damaged, apply a new one in the same position, or on the opposite arm, and remove it at the originally planned time.
• Corticosteroids: guidelines recommend dexamethasone with a 5-HT3 antagonist before chemotherapy, and corticosteroids were allowed in the pivotal study when part of the chemotherapy regimen.
• Elderly and renal or hepatic impairment: dosing as for adults; no adjustment, with caution.
• Children: safety and efficacy under 18 years not established.

Kytril Solution for Injection

• Chemotherapy and radiotherapy, prevention (acute and delayed): 1 to 3 mg (10 to 40 µg/kg) as a slow intravenous injection or a diluted intravenous infusion, given 5 minutes before chemotherapy starts. The solution is diluted in about 5 mL per mg.
• Treatment of acute nausea: 1 to 3 mg (10 to 40 µg/kg) as a slow intravenous injection or diluted infusion over 5 minutes. Further doses may follow at least 10 minutes apart, up to a maximum of 9 mg in 24 hours.
• With a corticosteroid: efficacy may be increased by intravenous dexamethasone 8 to 20 mg before cytostatic treatment, or methylprednisolone 250 mg before chemotherapy and again just after it ends.
• Postoperative nausea and vomiting (adults): 1 mg (10 µg/kg) as a slow intravenous injection, up to 3 mg in 24 hours. For prevention, give it before induction of anaesthesia.
• Children aged 2 years and older (chemotherapy): 10 to 40 µg/kg body weight (maximum 3 mg) as an intravenous infusion in 10 to 30 mL of infusion fluid, over 5 minutes before chemotherapy. One further dose may be given within 24 hours, at least 10 minutes after the first. No dose is recommended for postoperative nausea in children.
• Method: slow intravenous injection (over 30 seconds), or a diluted infusion in 20 to 50 mL of compatible fluid over 5 minutes.
• Elderly and renal impairment: no special precautions. Hepatic impairment: no adjustment, but use with some caution.

Kytril Tablets

• Adults: 1 mg twice daily or 2 mg once daily, for one week after radiotherapy or chemotherapy. The first dose is taken one hour before the treatment starts. Oral dexamethasone, up to 20 mg once daily, has been used together.
• Swallow the tablets whole with water.
• Children: safety and efficacy not established. Elderly and renal impairment: no special precautions. Hepatic impairment: no adjustment, but use with some caution.

Sancuso Patch: Skin, Sunlight, Heat and Water

• Application site reactions were generally mild. If a severe or generalised skin reaction occurs (such as allergic rash or itching), remove the patch.
• Sunlight: cover the application site, for example with clothing, if there is a risk of exposure to natural or artificial sunlight during wear and for 10 days after removal.
• Heat: avoid external heat, such as hot water bottles or heat pads, on the patch.
• Water and activity: normal showering or washing is fine; avoid swimming, strenuous exercise and saunas.

Gut, Heart and Serotonin Syndrome

• Bowel: granisetron may mask a progressive ileus or gastric distension and may reduce lower bowel motility. Patients with signs of sub-acute intestinal obstruction are monitored.
• Heart rhythm: 5-HT3 antagonists may be associated with arrhythmias or ECG changes including QT prolongation. Caution applies with existing arrhythmia or conduction disorders, antiarrhythmics or beta blockers, cardiac comorbidity, cardiotoxic chemotherapy and electrolyte abnormalities.
• Serotonin syndrome: observe for symptoms such as altered mental state, autonomic instability, neuromuscular abnormalities and gastrointestinal symptoms.
• Cross-hypersensitivity has been reported between 5-HT3 antagonists (for example dolasetron and ondansetron).
• Abuse and dependence: granisetron has no known potential for abuse and dependence.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: data are limited (under 300 pregnancy outcomes for Sancuso) and animal studies show no direct or indirect harm to reproduction. As a precaution, avoid granisetron in pregnancy.
• Breastfeeding: it is unknown whether granisetron passes into breast milk. Breastfeeding should be stopped during Sancuso treatment and is not recommended during Kytril treatment.
• Fertility: no human data for Sancuso; Kytril caused no harm to reproductive capacity or fertility in rats.

Excipients

• Kytril tablets contain lactose: patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.
• Kytril solution for injection contains less than 1 mmol (23 mg) of sodium per dose, that is, it is essentially sodium-free.

Effect on Driving

The effect of Sancuso on the ability to drive or operate machinery has not been studied. For Kytril, see the national SmPC.

• Sancuso patch: store in the original package to protect from light. Each patch is in a heat-sealed sachet; a carton holds one patch.
• Kytril solution for injection: store below 30 °C and protect from light. Once diluted, use immediately; storage before use is the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.
• Kytril tablets: no special storage conditions.

• Sancuso patch: 3 years.
• Kytril solution for injection: 3 years unopened.
• Kytril tablets: 5 years.

Prescription only (Rx).

• Sancuso patch and Kytril tablets: supplied to the patient or the treating clinic on prescription.
• Kytril solution for injection: given intravenously, so it is supplied to the hospital or clinic that administers it.