Granisol

WARNINGS Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of granisetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue granisetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if granisetron is used concomitantly with other serotonergic drugs [see Drug Interactions ].

ADVERSE REACTIONS QT prolongation has been reported with granisetron (see PRECAUTIONS and Drug Interactions ). Chemotherapy-Induced Nausea and Vomiting Over 3700 patients have received Kytril tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens. In patients receiving Kytril tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed in Table 4 . Table 4 Principal Adverse Events in Clinical Trials Percent of Patients With Event Kytril 1 Tablets 1 mg twice a day (n=978) Kytril 1 Tablets 2 mg once a day N=1450) Comparator 2 (n=599) Placebo (n=185) Headache 3 21% 20% 13% 12% Constipation 18% 14% 16% 8% Asthenia 14% 18% 10% 45 Diarrhea 8% 9% 10% 4% Abdominal Pain 6% 4% 6% 3% Dyspepsia 4% 6% 5% 4% 1 Adverse events were recorded for 7 days when Kytril tablets were given on a single day and for up to 28 days when Kytril tablets were administered for 7 or 14 days. 2 Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine. 3 Usually mild to moderate in severity. Other adverse events reported in clinical trials were: Gastrointestinal : In single-day dosing studies in which adverse events were collected for 7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24-hour efficacy assessment period. Hepatic : In comparative trials, elevation of AST and ALT (> 2 times the upper limit of normal) following the administration of Kytril tablets occurred in 5% and 6% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%). Cardiovascular : Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope have been observed rarely. Central Nervous System : Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has been reported in a patient treated with Kytril tablets. Hypersensitivity : Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported. Other : Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia (9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%). Over 5000 patients have received injectable Kytril in clinical trials. Table 5 gives the comparative frequencies of the five commonly reported adverse events (≥3%) in patients receiving Kytril injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Kytril injection administration. Table 5 Principal Adverse Events in Clinical Trials - Single-Day Chemotherapy Percent of Patients With Event Kytril Injection 1 40 mcg/kg (n=1268) Comparator 2 (n=422) Headache 14% 6% Asthenia 5% 6% Somnolence 4% 15% Diarrhea 4% 6% Constipation 3% 3% 1 Adverse events were generally recorded over 7 days post-Kytril injection administration. 2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone.

<table width="100%"><caption>Table 4 Principal Adverse Events in Clinical Trials</caption><tbody><tr><td align="center" colspan="5"><content styleCode="bold">Percent of Patients With Event</content></td></tr><tr><td/><td><paragraph><content styleCode="bold">Kytril ¹Tablets </content></paragraph><paragraph><content styleCode="bold">1 mg twice a day</content></paragraph><paragraph><content styleCode="bold">(n=978)</content></paragraph></td><td><paragraph><content styleCode="bold">Kytril ¹Tablets </content></paragraph><paragraph><content styleCode="bold">2 mg once a day</content></paragraph><paragraph><content styleCode="bold">N=1450)</content></paragraph></td><td><paragraph><content styleCode="bold">Comparator ²</content></paragraph><paragraph><content styleCode="bold">(n=599)</content></paragraph></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n=185)</content></paragraph></td></tr><tr><td>Headache ³</td><td>21%</td><td>20%</td><td>13%</td><td>12%</td></tr><tr><td>Constipation</td><td>18%</td><td>14%</td><td>16%</td><td>8%</td></tr><tr><td>Asthenia</td><td>14%</td><td>18%</td><td>10%</td><td>45</td></tr><tr><td>Diarrhea</td><td>8%</td><td>9%</td><td>10%</td><td>4%</td></tr><tr><td>Abdominal Pain</td><td>6%</td><td>4%</td><td>6%</td><td>3%</td></tr><tr><td>Dyspepsia</td><td>4%</td><td>6%</td><td>5%</td><td>4%</td></tr><tr><td colspan="5"><paragraph>¹Adverse events were recorded for 7 days when Kytril tablets were given on a single day and for up to 28 days when Kytril tablets were administered for 7 or 14 days. </paragraph><paragraph>²Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine. </paragraph>³Usually mild to moderate in severity. </td></tr></tbody></table>

<table width="100%"><caption>Table 5 Principal Adverse Events in Clinical Trials - Single-Day Chemotherapy</caption><tbody><tr><td align="center" colspan="3"><content styleCode="bold">Percent of Patients With Event</content></td></tr><tr><td/><td><paragraph><content styleCode="bold">Kytril Injection ¹</content></paragraph><paragraph><content styleCode="bold">40 mcg/kg</content></paragraph><paragraph><content styleCode="bold">(n=1268)</content></paragraph></td><td><paragraph><content styleCode="bold">Comparator ²</content></paragraph><paragraph><content styleCode="bold">(n=422)</content></paragraph></td></tr><tr><td>Headache</td><td>14%</td><td>6%</td></tr><tr><td>Asthenia</td><td>5%</td><td>6%</td></tr><tr><td>Somnolence</td><td>4%</td><td>15%</td></tr><tr><td>Diarrhea</td><td>4%</td><td>6%</td></tr><tr><td>Constipation</td><td>3%</td><td>3%</td></tr><tr><td colspan="3"><paragraph>¹Adverse events were generally recorded over 7 days post-Kytril injection administration. </paragraph>²Metoclopramide/dexamethasone and phenothiazines/dexamethasone. </td></tr></tbody></table>