Ondansetron 4 mg Tablet, Film Coated, 30-count — NDC 45963-538-30 (Billing 45963-0538-30)

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions including anaphylaxis and bronchospasm: Discontinue ondansetron tablets if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve ( 5.1 ) QT interval prolongation and Torsade de Pointes: Avoid in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, cardiac failure or arrhythmias, or use of other QT prolonging drugs. ( 5.2 ) Serotonin syndrome : Reported with 5-HT 3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs.

If such symptoms occur, discontinue ondansetron tablets and initiate supportive treatment. If concomitant use of ondansetron tablets with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. ( 5.3 ) Masking of progressive ileus and/or gastric distention following abdominal surgery or chemotherapy-induced nausea and vomiting: Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

( 5.4 )

5.1Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. If hypersensitivity reactions occur, discontinue use of ondansetron tablets; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4) ].

5.2QT Prolongation Electrocardiogram (ECG) changes including QT interval prolongation have been seen in patients receiving ondansetron. In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron tablets. Avoid ondansetron tablets in patients with congenital long QT syndrome.

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 [see Clinical Pharmacology (12.2) ].

5.3Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists alone. 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 tablets 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 tablets and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ondansetron tablets and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ondansetron tablets is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1 ), Overdosage (10)].

5.4Masking of Progressive Ileus and Gastric Distension The use of ondansetron tablets in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ile… [Excerpted — this section continues on DailyMed.]

WARNINGS Sumatriptan tablets should only be used where a clear diagnosis of migraine headache has been established. Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS ). It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease.

The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS ). For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan.

Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following sumatriptan tablets, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan. The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan.

Drug-Associated Cardiac Events and Fatalities Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of sumatriptan succinate injection or sumatriptan tablets. Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low. The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug.

In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain. Premarketing Experience With Sumatriptan Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.

Among the more than 1,900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs.… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan succinate injection or tablets. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS ) .

Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension (see WARNINGS ). Incidence in Controlled Clinical Trials Table 2 lists adverse events that occurred in placebo-controlled clinical trials in patients who took at least 1 dose of study drug. Only events that occurred at a frequency of 2% or more in any group treated with sumatriptan tablets and were more frequent in that group than in the placebo group are included in Table 2.

The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 2.

Treatment Emergent Adverse Events Reported by at Least 2% of Patients in Controlled Migraine Trials a Adverse Event Type Percent of Patients Reporting Placebo (N = 309) Sumatriptan 25 mg (N = 417) Sumatriptan 50 mg (N = 771) Sumatriptan 100 mg (N = 437) Atypical sensations 4% 5% 6% 6% Paresthesia (all types) 2% 3% 5% 3% Sensation warm/cold 2% 3% 2% 3% Pain and other pressure sensations 4% 6% 6% 8% Chest - pain/tightness/pressure and/or heaviness 1% 1% 2% 2% Neck/throat/jaw - pain/ tightness/pressure <1% <1% 2% 3% Pain - location specified 1% 2% 1% 1% Other - pressure/tightness/ heaviness 2% 1% 1% 3% Neurological Vertigo <1% <1% <1% 2% Other Malaise/fatigue <1% 2% 2% 3% a Events that occurred at a frequency of 2% or more in the group treated with sumatriptan tablets and that occurred more frequently in that group than the placebo group.

Other events that occurred in more than 1% of patients receiving sumatriptan tablets and at least as often on placebo included nausea and/or vomiting, migraine, headache, hyposalivation, dizziness, and drowsiness/sleepiness. Sumatriptan tablets are generally well tolerated. Across all doses, most adverse reactions were mild and transient and did not lead to long-lasting effects.

The incidence of adverse events in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse events. Other Events Observed in Association With the Administration of Sumatriptan Tablets In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented.

Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used sumatriptane tablets (25, 50, or 100 mg) and reported an event divided by the total number of patients (N = 6,348) exposed to sumatriptan tablets.

All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are those occur… [Excerpted — this section continues on DailyMed.]

Drug Interactions Monoamine Oxidase Inhibitors (MAO) Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS ). Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan. In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan.

Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration x time curve (AUC), corresponding to a 40% increase in elimination half-life. This interaction was not evident with an MAO-B inhibitor. A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25 mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.

Alcohol Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

Drug Interactions Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life‑threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS ). Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided (see CONTRAINDICATIONS ).

Monoamine Oxidase-A Inhibitors MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan tablets in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS ).

7 DRUG INTERACTIONS

7.1Serotonergic 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 selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ondansetron tablets and initiate supportive treatment [see Warnings and Precautions (5.3) ].

7.2Drugs 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 is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].

7.3Tramadol 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.

7.4Chemotherapy 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 methotr… [Excerpted — this section continues on DailyMed.]

Drug/Laboratory Test Interactions Sumatriptan tablets are not known to interfere with commonly employed clinical laboratory tests.

PRECAUTIONS General Chest discomfort and jaw or neck tightness have been reported following use of sumatriptan tablets and have also been reported infrequently following administration of sumatriptan succinate Nasal Spray. Chest, jaw, or neck tightness is relatively common after administration of sumatriptan succinate injection. Only rarely have these symptoms been associated with ischemic ECG changes.

However, because sumatriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following sumatriptan should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of sumatriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following sumatriptan should be evaluated for atherosclerosis or predisposition to vasospasm (see WARNINGS ).

Sumatriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal function. There have been rare reports of seizure following administration of sumatriptan. Sumatriptan should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine headache or who experience a headache that is atypical for them. There have been rare reports where patients received sumatriptan for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion (see WARNINGS ). For a given attack, if a patient does not respond to the first dose of sumatriptan, the diagnosis of migraine should be reconsidered before administration of a second dose.

Overuse: Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Migraine patients should be informed about the risks of medication overuse, and encouraged to record headache frequency and drug use. Information for Patients See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients. Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.

Laboratory Tests No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with sumatriptan. Drug Interactions Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life‑threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS ). Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.

Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided (see CONTRAINDICATIONS ). Monoamine Oxidase-A Inhibitors MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan tablets in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE One clinical study with sumatriptan succinate injection enrolling 12 patients with a history of substance abuse failed to induce subjective behavior and/or physiologic response ordinarily associated with drugs that have an established potential for abuse.

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