title: High-dose i.v. granisetron for the prevention of chemotherapy-induced emesis: cardiac safety and tolerability.
abstract: This phase II trial assessed the cardiovascular safety and tolerability of high-dose granisetron for the treatment of nausea and vomiting in cancer patients undergoing emetogenic chemotherapy. Forty-one patients were given 30-min infusions of granisetron, 40 or 120 microg/kg i.v., as either a single dose or as split doses, at 6-h intervals. Subsequently, patients had the option of the alternative dosing regimen or to return to conventional antiemetic therapy. Patients were monitored for 24 h following the first granisetron infusion. Electrocardiogram (ECG; lead II and Holter monitoring) measurements were made during the study and blood samples for pharmacokinetic analysis were taken at regular intervals for 48 h after the start of the first granisetron infusion. During the first chemotherapy session, granisetron was administered as: (i) bolus doses of 80 microg/kg (n=3) and 120 microg/kg (n=19) or (ii) split doses of 2x40 microg/kg (n=1) and 3x40 microg/kg (n=18). Crossover therapy was administered to 22 patients, with granisetron doses of 120 microg/kg (n=12), 2x40 microg/kg (n=1) and 3x40 microg/kg (n=9). We conclude that supra-therapeutic doses up to 120 microg/kg granisetron had no clinically significant effect on ECG, pulse rate or blood pressure. The treatment was well tolerated with no significant changes in biochemistry or hematological parameters.
authors.affiliation: Cancer Research UK, Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK. james.carmichael@astrazeneca.com
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000932:Antiemetics / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D017829:Granisetron / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D000932:Antiemetics; D000970:Antineoplastic Agents; D017829:Granisetron