Ondansetron ODT

Name: Ondansetron ODT

Ondansetron ODT Dosage and Administration

Dosage

The recommended dosage regimens for adult and pediatric patients are described in Table 1 and Table 2, respectively.

Corresponding doses of ondansetron tablets, ondansetron orally disintegrating tablets, and ondansetron oral solution may be used interchangeably.

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/m2.

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 4 and 8 hours after the first dose.

 

Then administer 8 mg three times a day 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.

 

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)].

Administration Instructions for Ondansetron Orally Disintegrating Tablets

With dry hands, gently remove the tablet. IMMEDIATELY place the ondansetron orally disintegrating tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary.

Warnings and Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. If hypersensitivity reactions occur, discontinue use of ondansetron; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4)].

QT 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. 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 [see Clinical Pharmacology (12.2)].

Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 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 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 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 (7.1), Overdosage (10)].

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/or 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.

Phenylketonuria

Phenylketonuric patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 4 mg and 8 mg orally disintegrating tablet contains 0.9 mg and 1.8 mg phenylalanine, respectively.

Ondansetron ODT Description

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

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

Ondansetron, USP is a white to off-white powder.

Each 4 mg ondansetron orally disintegrating tablet for oral administration contains 4 mg ondansetron base. Each 8 mg ondansetron orally disintegrating tablet for oral administration contains 8 mg ondansetron base. Each ondansetron orally disintegrating tablet also contains the inactive ingredients aspartame, crospovidone, mannitol, peppermint flavor, silicon dioxide, sodium stearyl fumarate, and sorbitol. Ondansetron orally disintegrating tablets are an orally administered formulation of ondansetron which disintegrates on the tongue and does not require water to aid dissolution or swallowing.

Ondansetron ODT - Clinical Pharmacology

Mechanism of Action

Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron 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 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-HT3 receptors and initiate the vomiting reflex.

Pharmacodynamics

In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma prolactin concentrations.

Cardiac Electrophysiology

QTc interval prolongation was studied in a double-blind, single intravenous dose, placebo- and positive-controlled, crossover trial in 58 healthy subjects. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 19.5 (21.8) milliseconds and 5.6 (7.4) milliseconds after 15-minute intravenous infusions of 32 mg and 8 mg of ondansetron injection, respectively. A significant exposure-response relationship was identified between ondansetron concentration and ΔΔQTcF. Using the established exposure-response relationship, 24 mg infused intravenously over 15 minutes had a mean predicted (95% upper prediction interval) ΔΔQTcF of 14.0 (16.3) milliseconds. In contrast, 16 mg infused intravenously over 15 minutes using the same model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 (11.2) milliseconds. In this study, the 8 mg dose infused over 15 minutes did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Absorption

Ondansetron is 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. The 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.

Food Effects

Bioavailability is also slightly enhanced by the presence of food.

Distribution

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

Elimination

Metabolism and Excretion

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

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.

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.

Specific Populations

Age

Geriatric Population

A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years compared to younger subjects [see Use in Specific Populations (8.5)].

Sex

Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of absorption are 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 concentrations. These higher plasma concentrations may in part be explained by differences in body weight between men and women. It is not known whether these sex-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 5 and 6.

Table 5: Pharmacokinetics in Male and Female Healthy Subjects after a Single Dose of an Ondansetron 8 mg Tablet

Age- group (years)

Sex (M/F)

Mean

Weight (kg)

N

Peak Plasma Concentration (ng/mL)

Time of Peak Plasma Concentration (h)

Mean Elimination Half-life

(h)

Systemic Plasma Clearance

L/h/kg

Absolute

Bioavailability

18 to 40

M

F

69.0

62.7

6

5

26.2

42.7

2.0

1.7

3.1

3.5

0.403

0.354

0.483

0.663

61 to 74

M

F

77.5

60.2

6

6

24.1

52.4

2.1

1.9

4.1

4.9

0.384

0.255

0.585

0.643

≥ 75

M

F

78.0

67.6

5

6

37.0

46.1

2.2

2.1

4.5

6.2

0.277

0.249

0.619

0.747

Table 6: Pharmacokinetics in Male and Female Healthy Subjects after a Single Dose of an Ondansetron 24 mg Tablet

Age-group (years)

Sex (M/F)

Mean Weight (kg)

N

Peak Plasma Concentration (ng/mL)

Time of

Peak Plasma Concentration

(h)

Mean

Elimination

Half-life

(h)

18 to 43

M

F

84.1

71.8

8

8

125.8

194.4

1.9

1.6

4.7

5.8

 

Renal Impairment

Renal impairment is not expected to significantly influence the total clearance of ondansetron as renal clearance represents only 5% of the overall clearance. However, the mean plasma clearance of ondansetron was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min). The reduction in clearance was variable and not consistent with an increase in half-life [see Use in Specific Populations (8.7)].

Hepatic Impairment

In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in healthy subjects. 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 [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].

Drug Interaction Studies

CYP 3A4 Inducers

Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, Cmax, and t½ of ondansetron was observed. This resulted in a significant increase in the clearance of ondansetron. However, this increase is not thought to be clinically relevant [see Drug Interactions (7.2)].

Chemotherapeutic Agents

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron [see Drug Interactions (7.4)].

Antacids

Concomitant administration of antacids does not alter the absorption of ondansetron.

How Supplied/Storage and Handling

Ondansetron Orally Disintegrating Tablets, USP are available containing 4 mg or 8 mg of ondansetron, USP.

The 4 mg tablets are white to off-white, round, unscored tablets debossed with M on one side of the tablet and 732 on the other side. They are available as follows:

NDC 0378-7732-93
bottles of 30 tablets

The 8 mg tablets are white to off-white, round, unscored tablets debossed with M on one side of the tablet and 734 on the other side. They are available as follows:

NDC 0378-7734-97
bottles of 10 tablets

NDC 0378-7734-93
bottles of 30 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Patient Counseling Information

QT Prolongation: Inform patients that ondansetron orally disintegrating tablets may cause serious cardiac arrhythmias such as QT prolongation. Instruct patients to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Hypersensitivity Reactions: Inform patients that ondansetron orally disintegrating tablets may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider.

Masking of Progressive Ileus and Gastric Distension: Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that ondansetron orally disintegrating tablets may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.

Drug Interactions:

• Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and ondansetron orally disintegrating tablets may cause a significant drop in blood pressure and loss of consciousness. • Advise patients of the possibility of serotonin syndrome with concomitant use of ondansetron orally disintegrating tablets and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.

Administration of Ondansetron Orally Disintegrating Tablets: Instruct patients not to remove ondansetron orally disintegrating tablets from the bottle until just prior to dosing.

• With dry hands, gently remove the tablet. • Immediately place the ondansetron orally disintegrating tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. • Administration with liquid is not necessary.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 4/2017
ONTOD:R6

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