Ondansetron

RECENT MAJOR CHANGES Warnings and Precautions, Myocardial Ischemia ( 5.4 ) 10/2021

1 INDICATIONS AND USAGE Ondansetron tablets are indicated for the prevention of nausea and vomiting associated with: highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 . initial and repeat courses of moderately emetogenic cancer chemotherapy. radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. Ondansetron tablets are also indicated for the prevention of postoperative nausea and/or vomiting. Ondansetron tablets are a 5-HT 3 receptor antagonist indicated for the prevention of: nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 . ( 1 ) nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. ( 1 ) nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. ( 1 ) postoperative nausea and/or vomiting. ( 1 )

2 DOSAGE AND ADMINISTRATION See full prescribing information for the recommended dosage in adults and pediatrics. ( 2 ) Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. ( 2.2 , 8.6 ) 2.1 Recommended Dosage The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively. Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Highly Emetogenic Cancer Chemotherapy A single 24-mg dose administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin greater than or equal to 50 mg/m 2. . Moderately Emetogenic Cancer Chemotherapy 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose. Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. Radiotherapy For total body irradiation: 8 mg administered 1 to 2 hours before each fraction of radiotherapy each day. For single high-dose fraction radiotherapy to the abdomen: 8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen: 8 mg administered 1 to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the first dose for each day radiotherapy is given. Postoperative 16 mg administered 1 hour before induction of anesthesia. Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Moderately Emetogenic Cancer Chemotherapy 12 to 17 years of age: 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose. Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. 4 to 11 years of age: 4 mg administered 30 minutes before the start of chemotherapy, with a subsequent 4 mg dose 4 and 8 hours after the first dose. Then administer 4 mg three times a day for 1 to 2 days after completion of chemotherapy. 2.2 Dosage in Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg [see Use in Specific Populations (8.6 ), Clinical Pharmacology (12.3 )].

3 DOSAGE FORMS AND STRENGTHS Ondansetron hydrochloride tablets are white, round, film-coated tablets and are available in the following strengths: 4 mg – tablet debossed with “CE” on one side and “6” on the other side. 8 mg – tablet debossed with “CE” on one side and “7” on the other side. Tablets: 4 mg and 8 mg. ( 3 )

4 CONTRAINDICATIONS Ondansetron tablets are contraindicated in patients: known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation [see Adverse Reactions (6.2 )]. receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness. Patients known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any components of the formulation. ( 4 ) Concomitant use of apomorphine. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1 )] QT Prolongation [see Warnings and Precautions (5.2 )] Serotonin Syndrome [see Warnings and Precautions (5.3 )] Myocardial Ischemia [see Warnings and Precautions (5.4 )] Masking of Progressive Ileus and Gastric Distension [ see Warnings and Precautions (5.5 )]. The most common adverse reactions in adults for the: prevention of chemotherapy-induced (≥5%) are: headache, malaise/fatigue, constipation, diarrhea. ( 6.1 ) prevention of radiation-induced nausea and vomiting (≥ 2%) are: headache, constipation, and diarrhea. ( 6.1 ) prevention of postoperative nausea and vomiting (≥ 9%) are: headache and hypoxia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Natco Pharma USA LLC at 1-201-786-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions have been reported in clinical trials of patients treated with ondansetron, the active ingredient of ondansetron tablets. A causal relationship to therapy with ondansetron tablets was unclear in many cases. Prevention of Chemotherapy-Induced Nausea and Vomiting The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a single 24 mg dose of ondansetron tablets orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m 2 ) were: headache (11%) and diarrhea (4%). The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3. Table 3: Most Common Adverse Reactions in Adults 1 for the Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens] Adverse Reaction Ondansetron Tablets 8 mg Twice Daily (n = 242) Placebo (n = 262) Headache 58 (24%) 34 (13%) Malaise/Fatigue 32 (13%) 6 (2%) Constipation 22 (9%) 1 (<1%) Diarrhea 15 (6%) 10 (4%) 1 Reported in greater than or equal to 5% of patients treated with ondansetron tablets and at a rate that exceeded placebo. Less Common Adverse Reactions Central Nervous System: Extrapyramidal reactions (less than 1% of patients). Hepatic : Aspartate transaminase (AST) and/or alanine transaminase (ALT) values exceeded twice the upper limit of normal in approximately 1% to 2% of 723 patients receiving ondansetron tablets and cyclophosphamide-based chemotherapy in US clinical trials. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes is unclear. Liver failure and death has been reported in cancer patients receiving concurrent medications, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. Integumentary : Rash (approximately 1% of patients). Other (less than 2%): Anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures. Except for bronchospasm and anaphylaxis, the relationship to ondansetron tablets is unclear. Prevention of Radiation-Induced Nausea and Vomiting The most common adverse reactions (greater than or equal to 2%) reported in patients receiving ondansetron tablets and concurrent radiotherapy were s …

7 DRUG INTERACTIONS 7.1 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. Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron tablets and initiate supportive treatment [see Warnings and Precautions (5.3)]. 7.2 Drugs Affecting Cytochrome P-450 Enzymes Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver [see Clinical Pharmacology (12.3 )] . 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. 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 tablets are recommended for patients on these drugs [see Clinical Pharmacology (12.3 )]. 7.3 Tramadol Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, ondansetron tablets may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol. 7.4 Chemotherapy Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate. 7.5 Alfentanil and Atracurium Ondansetron tablets do 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.

8 USE 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 during organogenesis at approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/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 oral doses of ondansetron up to 15 mg/kg/day and 30 mg/kg/day, respectively, during the period of organogenesis. With the exception of a slight decrease in maternal body weight gain in the rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring. At doses of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal exposure margin was approximately 6 and 24 times the max …

12.1 Mechanism of Action Ondansetron is a selective 5-HT 3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT 3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT 3 receptors and initiate the vomiting reflex.

11 DESCRIPTION The active ingredient in ondansetron tablets is ondansetron hydrochloride as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT 3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula: The empirical formula is C 18 H 19 N 3 O•HCl•2H 2 O, representing a molecular weight of 365.5. Ondansetron hydrochloride dihydrate is a white to off-white powder that is soluble in water and normal saline. Each 4 mg ondansetron tablet, USP for oral administration contains ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron. Each 8 mg ondansetron tablet, USP for oral administration contains ondansetron hydrochloride dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, titanium dioxide, triacetin, and iron oxide yellow (8 mg tablet only). This product meets USP Dissolution Test 3. structure

10 OVERDOSAGE There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. In addition to the adverse reactions listed above, the following adverse reactions 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 a patient that took 48 mg of ondansetron 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 adverse reactions resolved completely. Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ondansetron Tablets Ondansetron Tablets USP, 4 mg (ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron), are white, oval, film-coated tablets engraved with “4” on one side and “NO” on another side. They are supplied as follows: NDC 69339-171-03 Bottles of 30 Tablets NDC 69339-171-01 Bottles of 100 Tablets NDC 69339-171-05 Bottles of 500 Tablets Ondansetron Tablets USP, 8 mg (ondansetron hydrochloride dihydrate equivalent to 8 mg of ondansetron), are yellow, oval, film-coated tablets engraved with “8” on one side and “NO” on the other side. They are supplied as follows: NDC 69339-172-03 Bottles of 30 Tablets NDC 69339-172-01 Bottles of 100 Tablets NDC 69339-172-05 Bottles of 500 Tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from light. Dispense in tight, light-resistant container as defined in the USP.