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Ondansetron Hydrochloride Tablets and Oral Solution

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

The active ingredient in Ondansetron Tablets and Ondansetron Oral Solution is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 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 C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9.

Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.

The active ingredient in Ondansetron ODT Orally Disintegrating Tablets is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula:

The empirical formula is C18H19N3O representing a molecular weight of 293.4.

Each 4-mg Ondansetron Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Each 8-mg Ondansetron Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow (8-mg tablet only).

Each 4-mg Ondansetron ODT Orally Disintegrating Tablet for oral administration contains 4 mg ondansetron base. Each 8-mg Ondansetron ODT Orally Disintegrating Tablet for oral administration contains 8 mg ondansetron base. Each Ondansetron ODT Tablet also contains the inactive ingredients aspartame, gelatin, mannitol, methylparaben sodium, propylparaben sodium, and strawberry flavor. Ondansetron ODT Tablets are a freeze-dried, orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing.

Each 5 mL of Ondansetron Oral Solution contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Ondansetron Oral Solution contains the inactive ingredients citric acid anhydrous, purified water, sodium benzoate, sodium citrate, sorbitol, and strawberry flavor.

2. INDICATIONS AND USAGE

1. Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m2.

2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

3. Prevention of 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.

4. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, Ondansetron Tablets, Ondansetron ODT Orally Disintegrating Tablets, and Ondansetron Oral Solution are recommended even where the incidence of postoperative nausea and/or vomiting is low.

3. DOSAGE AND ADMINISTRATION

Instructions for Use/Handling Ondansetron ODT Orally Disintegrating Tablets: Do not attempt to push Ondansetron ODT Tablets through the foil backing. With dry hands, PEEL BACK the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the Ondansetron ODT Tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary.

Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy: The recommended adult oral dosage of ondansetron is 24 mg given as three 8-mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied.

Pediatric Use: There is no experience with the use of a 24 mg dosage in pediatric patients.

Geriatric Use: The dosage recommendation is the same as for the general population.

Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy: The recommended adult oral dosage is one 8-mg Ondansetron Tablet or one 8-mg Ondansetron ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8-mg Ondansetron Tablet or one 8-mg Ondansetron ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.

Pediatric Use: For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg Ondansetron Tablet or one 4-mg Ondansetron ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of Ondansetron Oral Solution given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg Ondansetron Tablet or one 4-mg Ondansetron ODT Tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of Ondansetron Oral Solution should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.

Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen: The recommended oral dosage is one 8-mg Ondansetron Tablet or one 8-mg Ondansetron ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution given 3 times a day.

For total body irradiation, one 8-mg Ondansetron Tablet or one 8-mg Ondansetron ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.

For single high-dose fraction radiotherapy to the abdomen, one 8-mg Ondansetron Tablet or one 8-mg Ondansetron ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen, one 8-mg Ondansetron Tablet or one 8-mg Ondansetron ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.

Pediatric Use: There is no experience with the use of Ondansetron Tablets, Ondansetron ODT Tablets, or Ondansetron Oral Solution in the prevention of radiation-induced nausea and vomiting in pediatric patients.

Postoperative Nausea and Vomiting: The recommended dosage is 16 mg given as two 8-mg Ondansetron Tablets or two 8-mg Ondansetron ODT Tablets or 20 mL (4 teaspoonfuls equivalent to 16 mg of ondansetron) of Ondansetron Oral Solution 1 hour before induction of anesthesia.

Pediatric Use: There is no experience with the use of Ondansetron Tablets, Ondansetron ODT Tablets, or Ondansetron Oral Solution in the prevention of postoperative nausea and vomiting in pediatric patients.

Dosage Adjustment for Patients With Impaired Renal Function: The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron.

Dosage Adjustment for Patients With Impaired Hepatic Function: 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. In such patients, a total daily dose of 8 mg should not be exceeded.

Geriatric Use: The dosage is the same as for the general population.

4. CONTRAINDICATIONS

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.

Ondansetron Tablets, Ondansetron ODT Orally Disintegrating Tablets, and Ondansetron Oral Solution are contraindicated for patients known to have hypersensitivity to the drug.

5. MECHANISM OF ACTION

Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 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 in chemotherapy-induced nausea and vomiting 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-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of vomiting. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

6.2 Nursing Mothers

It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.

6.3 Pediatric Use

Little information is available about dosage in pediatric patients 4 years of age or younger.

6.4 Geriatric Use

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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.

7. WARNINGS AND PRECAUTIONS

WARNINGS

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

ECG changes including QT interval prolongation has been seen in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron 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.

PRECAUTIONS

General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.

Information for Patients: Phenylketonurics: Phenylketonuric patients should be informed that ondansetron ODT (Orally Disintegrating Tablets) contain phenylalanine (a component of aspartame). Each 4-mg and 8-mg orally disintegrating tablet contains < 0.03 mg phenylalanine.

Patients should be instructed not to remove ondansetron ODT tablets from the blister until just prior to dosing. The tablet should not be pushed through the foil. With dry hands, the blister backing should be peeled completely off the blister. The tablet should be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva. Peelable illustrated stickers are affixed to the product carton that can be provided with the prescription to ensure proper use and handling of the product.

8. ADVERSE REACTIONS

Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 1 have been reported in ≥5% of adult patients receiving a single 24-mg Ondansetron Tablet in 2 trials. These patients were receiving concurrent highly emetogenic cisplatin-based chemotherapy regimens (cisplatin dose ≥50 mg/m2).

Table 1. Principal Adverse Events in US Trials: Single Day Therapy With 24-mg Ondansetron Tablets (Highly Emetogenic Chemotherapy)

The adverse events in Table 2 have been reported in ≥5% of adults receiving either 8 mg of Ondansetron Tablets 2 or 3 times a day for 3 days or placebo in 4 trials. These patients were receiving concurrent moderately emetogenic chemotherapy, primarily cyclophosphamide-based regimens.

Table 2. Principal Adverse Events in US Trials: 3 Days of Therapy With 8-mg Ondansetron Tablets (Moderately Emetogenic Chemotherapy)

Postoperative Nausea and Vomiting: The adverse events in Table 3 have been reported in ≥5% of patients receiving Ondansetron Tablets at a dosage of 16 mg orally in clinical trials. With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications.

Table 3. Frequency of Adverse Events From Controlled Studies With Ondansetron Tablets (Postoperative Nausea and Vomiting)

9. OVERDOSAGE

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages (three doses) as large as 252 mg have been administered intravenously without significant adverse events. These doses are more than 10 times the recommended daily dose.

In addition to the adverse events 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 oral ondansetron. 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.

10. DRUG INTERACTIONS

Ondansetron does not itself 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. On the basis of available data, no dosage adjustment is recommended for patients on these drugs.

Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), 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.

Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.

Chemotherapy: Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.

Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

11. PHARMACOKINETICS

Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%.

Ondansetron systemic exposure does not increase proportionately to dose. AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids.

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T1/2 of ondansetron was observed. This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended.

Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important.

A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy was similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly.

In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.

Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.

Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

Four- and 8-mg doses of either Ondansetron Oral Solution or Ondansetron ODT Orally Disintegrating Tablets are bioequivalent to corresponding doses of Ondansetron Tablets and may be used interchangeably. One 24-mg Ondansetron Tablet is bioequivalent to and interchangeable with three 8-mg Ondansetron Tablets.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: ZOFRAN, by GLAXOSMITHKLINE.

b) Generic drugs: Ondansetron hydrochloride, by various manufacturers.

2) How Supplied:

Ondansetron Hydrochloride Tablets (by AUROBINDO PHARM), 4 mg are white to off-white, oval shaped, film-coated tablets debossed with ‘F’ on one side and ‘91’ on the other side.

Bottles of 30 NDC 65862-187-30

Bottles of 500 NDC 65862-187-05

Bottles of 1000 NDC 65862-187-99

1 x 3 Unit-dose Tablets NDC 65862-187-03

10 x 10 Unit-dose Tablets NDC 65862-187-10

Ondansetron Hydrochloride Tablets, 8 mg are yellow colored, oval shaped, film-coated tablets debossed with ‘F’ on one side and ‘92’ on the other side.

Bottles of 30 NDC 65862-188-30

Bottles of 500 NDC 65862-188-05

Bottles of 1000 NDC 65862-188-99

1 x 3 Unit-dose Tablets NDC 65862-188-03

10 x 10 Unit-dose Tablets NDC 65862-188-10

Ondansetron Hydrochloride Tablets, 24 mg are pink colored, oval shaped, film-coated tablets debossed with ‘C’ on one side and ‘71’ on the other side.

Unit-dose Packs of 1 Tablet NDC 65862-189-11

Ondansetron Orally Disintegrating Tablets USP (by AUROBINDO PHARM), 4 mg are white to off-white, round tablets debossed with ‘5’ on one side and ‘E’ on the other side with an embossed circular edge.

Bottles of 10000 NDC 65862-390-19

3 x 10 Unit-dose Tablets NDC 65862-390-10

Ondansetron Orally Disintegrating Tablets USP, 8 mg are white to off-white, round tablets debossed with ‘7’ on one side and ‘E’ on the other side with an embossed circular edge.

Bottles of 6000 NDC 65862-391-66

3 x 10 Unit-dose Tablets NDC 65862-391-10

Ondansetron Oral Solution, USP (by ROXANE LABS), a clear, colorless liquid with a characteristic strawberry odor, contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron per 5 mL in amber glass bottles of 50 mL with child-resistant closures (NDC 0054-0064-47).

3) Storage:

Tablets: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light.

Oral Solution: Store upright between 15° and 30°C (59° and 86°F). Protect from light.

Rx only

Rev 09/11