Ondansetron

• Ondansetron Injection is contraindicated for patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported in patients taking ondansetron [see Adverse Reactions (6.2) ] . The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron.
• Patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. ( 4 )
• Concomitant use of apomorphine. ( 4 , 7.2 )

• Hypersensitivity Reactions :
• Hypersensitivity reactions, including anaphylaxis and bronchospasm have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. ( 5.1 )
• QT prolongation occurs in a dose-dependent manner. Cases of Torsade de Pointes have been reported.
• Avoid ondansetron in patients with congenital long QT syndrome. ( 5.2 )
• Serotonin Syndrome :
• Serotonin syndrome has been reported with 5-HT 3 receptor agonists alone but particularly with concomitant use of serotonergic drugs. ( 5.3 )
• Myocardial Ischemia :
• Do not exceed the recommended infusion rate and monitor patients during and after administration. ( 2.1 , 2.2 , 5.4 )
• Masking of Progressive Ileus and/or Gastric Distension Following Abdominal Surgery or Chemotherapy-Induced Nausea and Vomiting:
• Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. ( 5.5 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. 5.2 QT Prolongation Ondansetron prolongs the QT interval in a dose-dependent manner [see Clinical Pharmacology (12.2) ] . In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron.
• Avoid ondansetron in patients with congenital long QT syndrome. Electrocardiogram (ECG) monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation. 5.3 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists. Most reports have been associated 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 ondansetron alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms:
• 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, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ondansetron and other serotonergic drugs.
• If symptoms of serotonin syndrome occur, discontinue ondansetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ondansetron is used concomitantly with other serotonergic drugs [see Drug Interactions (7.5) , Overdosage (10) ] . 5.4 Myocardial Ischemia Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore,
• do not exceed the recommended infusion rate of ondansetron and monitor patients for signs and symptoms of myocardial ischemia during and after administration [see Dosage and Administration (2.1 , 2.2) and Adverse Reactions (6.2) ] . 5.5 Masking of Progressive Ileus and Gastric Distension The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distension. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.

• Risk Summary Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy (see Data ) .
• Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes.
• Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered intravenously during organogenesis at approximately 3.6 and 2.9 times the maximum recommended human intravenous dose of 0.15 mg/kg given three times a day, based on body surface area (BSA), respectively (see Data ) .
• The background risk of major birth defects and miscarriage for the indicated population is unknown.
• All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes.
• In the US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
• Data Human Data Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders.
• Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses.
• One large retrospective cohort study examined 1970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.
• Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings.
• Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54).
• A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however this association was not confirmed in other studies.
• Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings.
• A retrospective cohort study of 1.8 million pregnancies in the US Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43).
• In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93).
• Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]).
• It is unknown whether ondansetron exposure in utero in the cases of cleft palate occurred during the time of palate formation (the palate is formed between the 6th and 9th weeks of pregnancy).
• Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of ondansetron up to 10 mg/kg/day and 4 mg/kg/day, respectively, during the period of organogenesis.
• With the exception of short periods of maternal weight loss and a slight increase in the incidence of early uterine deaths at the high dose level in rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring.
• At doses of 10 mg/kg/day in rats and 4 mg/kg/day in rabbits, the maternal exposure margin was approximately 3.6 and 2.9 times the maximum recommended human oral dose of 0.15 mg/kg given three times a day, respectively, based on BSA.
• No intravenous pre- and post-natal developmental toxicity study was performed with ondansetron.
• In an oral pre- and post-natal development study pregnant rats received oral doses of ondansetron up to 15 mg/kg/day from Day 17 of pregnancy to litter Day 21.
• With the exception of a slight reduction in maternal body weight gain, there were no effects upon the pregnant rats and the pre- and postnatal development of their offspring, including reproductive performance of the mated F1 generation.
• IN SPECIFIC POPULATIONS
• 8.1 Pregnancy Risk Summary Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy (see Data ) .
• Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes.
• Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered intravenously during organogenesis at approximately 3.6 and 2.9 times the maximum recommended human intravenous dose of 0.15 mg/kg given three times a day, based on body surface area (BSA), respectively (see Data ) .
• The background risk of major birth defects and miscarriage for the indicated population is unknown.
• All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes.
• In the US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
• Data Human Data Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders.
• Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses.
• One large retrospective cohort study examined 1970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.
• Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings.
• Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54).
• A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however this association was not confirmed in other studies.
• Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings.
• A retrospective cohort study of 1.8 million pregnancies in the US Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43).
• In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93).
• Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]).
• It is unknown whether ondansetron exposure in utero in the cases of cleft palate occurred during the time of palate formation (the palate is formed between the 6th and 9th weeks of pregnancy).
• Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of ondansetron up to 10 mg/kg/day and 4 mg/kg/day, respectively, during the period of organogenesis.
• With the exception of short periods of maternal weight loss and a slight increase in the incidence of early uterine deaths at the high dose level in rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring.
• At doses of 10 mg/kg/day in rats and 4 mg/kg/day in rabbits, the maternal exposure margin was approximately 3.6 and 2.9 times the maximum recommended human oral dose of 0.15 mg/kg given three times a day, respectively, based on BSA.
• No intravenous pre- and post-natal developmental toxicity study was performed with ondansetron.
• In an oral pre- and post-natal development study pregnant rats received oral doses of ondansetron up to 15 mg/kg/day from Day 17 of pregnancy to litter Day 21.
• With the exception of a slight reduction in maternal body weight gain, there were no effects upon the pregnant rats and the pre- and postnatal development of their offspring, including reproductive performance of the mated F1 generation.
• 8.2 Lactation Risk Summary Ondansetron is unlikely to result in clinically relevant exposures in breastfed infants when administered intravenously at doses up to 4 mg/day to women who are breastfeeding.
• Available data from a lactation study involving pharmacokinetic samples from 80 lactating women and 20 infants indicate that ondansetron is present at low levels in human milk and in the plasma of breastfed infants.
• Both the estimated daily infant dose (DID) of ondansetron (0.002 mg/kg/day), and the relative infant dose (RID) (3.7%) were low (see Data ).
• In the same study, no adverse effects attributed to ondansetron were reported in infants exposed to ondansetron through breast milk.
• There are no data on the effects of ondansetron on milk production.
• Data A pharmacokinetic study utilizing opportunistic sampling of a convenience sample of 80 lactating women receiving intravenous ondansetron for the treatment of post-operative nausea and vomiting and 20 breastfed infants showed that ondansetron was present in breast milk with an average milk to plasma ratio of 0.91 following a median (range) dose of ondansetron of 4 (4 to 8) mg/dose.
• Using the average milk concentration over 24 hours to estimate the DID and the RID, the DID was 0.002 mg/kg/day and the RID was 3.7% of a weight-adjusted single maternal dose of 4 mg.
• Among the 20 infant plasma samples, seven concentrations (35%) were below the limit of quantification.
• Among the 13 infants with a quantifiable plasma concentration, the median (range) concentration was 0.78 (0 to 7.2) ng/mL.
• The highest observed concentration among these 13 infants was approximately 10 times lower than the median maximum concentration (76.6 ng/mL) observed in an open-label, single-dose pharmacokinetic study conducted in pediatric surgical patients aged 1 to 24 months who received a single 0.1 mg/kg dose of intravenous ondansetron.
• 8.4 Pediatric Use Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month [see Clinical Studies (14.2) ] .
• Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months [see Clinical Studies (14.1) , Dosage and Administration (2) ] .
• The clearance of ondansetron in pediatric patients aged 1 month to 4 months is slower and the half-life is ~2.5-fold longer than patients who are aged > 4 to 24 months.
• As a precaution, it is recommended that patients younger than 4 months receiving this drug be closely monitored [see Clinical Pharmacology (12.3) ] .
• 8.5 Geriatric Use Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting US- and foreign-controlled clinical trials, 862 were aged 65 years and older.
• No overall differences in safety or effectiveness were observed between subjects 65 years and older and younger subjects.
• A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3) ] .
• There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group.
• Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
• Dosage adjustment is not needed in patients over the age of 65.
• 8.6 Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life [see Clinical Pharmacology (12.3) ] .
• In such patients, a total daily dose of 8 mg should not be exceeded [see Dosage and Administration (2.3) ] .
• 8.7 Renal Impairment Although plasma clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), no dosage adjustment is recommended [see Clinical Pharmacology (12.3) ] .

• 7.1 Drugs Affecting Cytochrome P-450 Enzymes Ondansetron does not appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver.
• Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron [see Clinical Pharmacology (12.3) ] .
• On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs.
• 7.2 Apomorphine Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with ondansetron is contraindicated [see Contraindications (4) ] .
• 7.3 Phenytoin, Carbamazepine, and Rifampin In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased.
• However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3) ] .
• 7.4 Tramadol Although there are no data on pharmacokinetic drug interactions between ondansetron and tramadol, data from two small trials indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol.
• Patients on concomitant ondansetron self-administered tramadol more frequently in these trials, leading to an increased cumulative dose in patient-controlled administration of tramadol.
• 7.5 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs [see Warnings and Precautions (5.3) ] .
• 7.6 Chemotherapy In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
• In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase blood levels of high-dose methotrexate.
• 7.7 Temazepam The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.
• 7.8 Alfentanil and Atracurium Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium.
• Interactions with general or local anesthetics have not been studied.

• There is no specific antidote for ondansetron overdose.
• Patients should be managed with appropriate supportive therapy.
• Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events.
• These doses are more than 10 times the recommended daily dose.
• In addition to the adverse reactions listed above, the following events have been described in the setting of ondansetron overdose:
• "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single-dose.
• Hypotension (and faintness) occurred in another patient that took 48 mg of ondansetron hydrochloride tablets.
• Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed.
• In all instances, the events resolved completely.
• Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children.
• Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure.
• Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.

Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.