Granisetrone

Selective 5-HT3 antagonists, including granisetron, have been associated with a number of dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT), usually occurring 1 to 2 hours after IV administration. In general, these changes are not clinically relevant, however, when used in conjunction with other agents that prolong these intervals, arrhythmia may occur. When used with agents that prolong the QT interval (eg, Class I and III antiarrhythmics), clinically relevant QT interval prolongation may occur resulting in torsade de pointes. A number of trials have shown that 5-HT3 antagonists produce QT interval prolongation to variable degrees. Use with caution in patients at risk of QT prolongation and/or ventricular arrhythmia; patients with cardiac disease, electrolyte abnormalities, or who are receiving concomitant cardiotoxic chemotherapy are at higher risk. Reduction in heart rate may also occur with the 5-HT3 antagonists. IV formulations of 5-HT3 antagonists have more association with ECG interval changes, compared to oral formulations.

Constipation may occur with all formulations, although a higher incidence is observed with tablets and the extended release subcutaneous injection. Hospitalization due to constipation or fecal impaction has been reported with the extended release subcutaneous injection. Progressive ileus and/or gastric distention may be masked by the extended release subcutaneous injection (assess risks/benefits in patients with recent abdominal surgery). Monitor for development of constipation and for decreased bowel activity, particularly in patients at risk for gastrointestinal obstruction. Granisetron does not stimulate gastric or intestinal peristalsis; do not use it in place of nasogastric suction.

Hypersensitivity reactions (including anaphylaxis) have been reported with granisetron in patients who have experienced hypersensitivity to other 5-HT3 antagonists (cross-reactivity has been reported). Due to the extended release properties of the subcutaneous formulation, granisetron exposure may continue for 5 to 7 days following administration; hypersensitivity reactions may occur up to 7 days or longer following administration and may have an extended course. Monitor for signs/symptoms of hypersensitivity.

Injection site reactions are associated with the subcutaneous extended-release formulation. Injection site infections have been reported (median onset: 9 days); infections were managed with antibiotics and completely resolved. Bruising and/or hematomas occur in over one-third of patients (median onset: 2 days); may be delayed (~5 days or later following administration). Severe bruising has also been reported. Patients receiving anticoagulant or antiplatelet medications are at higher risk for severe bruising/hematoma at the injection site (consider risk/benefit in these patients). Injection site bleeding has also been observed, occasionally lasting >5 days. Injection site pain/tenderness was commonly reported, usually lasting 5 to 7 days. Pain/tenderness interfered with activity or caused significant discomfort at rest (rare); some patients required pain medications. Injection site nodules occurred in less than one-fifth of patients, usually persisting for 15 to 21 days. Monitor for injection site reactions for at least 2 weeks after administration. If injection site reaction is not yet resolved prior to the next dose, rotate injection site with next administration.

Serotonin syndrome has been reported with 5-HT3 receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, SSRIs, SNRIs, MAOIs, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT3 receptor antagonist have occurred in a postanesthesia setting or in an infusion center. Serotonin syndrome has also been reported following overdose of another 5-HT3 receptor antagonist. Monitor patients for signs of serotonin syndrome, including mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonist treatment and begin supportive management. Disease-related concerns:

Use with caution in patients with congenital long QT syndrome or other risk factors for QT prolongation (eg, medications known to prolong QT interval, electrolyte abnormalities [hypokalemia or hypomagnesemia], and cumulative high-dose anthracycline therapy). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Do not apply to red, irritated, or damaged skin. Application-site reactions have occurred with use; local reactions were generally mild and did not require discontinuation. If skin reaction is severe or generalized (allergic rash including erythematous, macular, or papular rash or pruritus), remove patch. Cover patch application site with clothing to protect from natural or artificial sunlight exposure while patch is applied and for 10 days following removal; granisetron may potentially be affected by natural or artificial sunlight. Do not apply heat (eg, heating pad) over or in area of the transdermal patch; avoid prolonged exposure to heat (may increase plasma concentrations). Other warnings/precautions:

Antiemetics are most effective when used prophylactically (Roila 2016). If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease, concurrent morbidities and medications to assure antiemetic regimen is optimized (Basch 2011).