ONDANSETRON HYDROCHLORIDE (Page 3 of 4)

INDICATIONS AND USAGE

  1. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in these patients has not been established.
  2. 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 injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic ondansetron injection and experience nausea and/or vomiting postoperatively, ondansetron injection may be given to prevent further episodes (see CLINICAL TRIALS).

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 injection is contraindicated for patients known to have hypersensitivity to the drug.

WARNINGS

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

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 distention.

Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.

Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (See CLINICAL PHARMACOLOGY: Pharmacokinetics). 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 limited available data, no dosage adjustment is recommended for patients on these drugs.

Apomorphine: Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, concomitant use of apomorphine with ondansetron is contraindicated (see CONTRAINDICATIONS).

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. 1,3

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.4,5

Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondensetron. 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg per day did not affect fertility or general reproductive performance of male and female rats.

Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, 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.

Nursing Mothers: Ondansetron is excreted in the breast milk of rats. 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.

Pediatric Use: Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month of age. (See CLINICAL TRIALS section for studies of ondansetron in prevention of postoperative nausea and vomiting in patients 1 month of age and older.) Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months of age. (See CLINICAL TRIALS section for studies of ondansetron in chemotherapy-induced nausea and vomiting in pediatric patients 6 months of age and older.) (See DOSAGE AND ADMINISTRATION.)

The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower and the half-life is ~2.5 fold longer than patients who are >4 to 24 months of age. As a precaution, it is recommended that patients less than 4 months of age receiving this drug be closely monitored. (See CLINICAL PHARMACOLOGY: Pharmacokinetics).

The frequency and type of adverse events reported in pediatric patients receiving ondansetron were similar to those in patients receiving placebo.(See ADVERSE EVENTS.)

Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65 years of age and over. 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 (see CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS

Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 12 have been reported in adults receiving ondansetron at a dosage of three 0.15-mg/kg doses or as a single 32-mg dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily cisplatin, and IV. fluids. Most were receiving a diuretic.

Table 12. Principal Adverse Events in Comparative Trials in Adults
Number of Adult Patients With Event

Ondansetron Injection

0.15 mg/kg x 3

n = 419

Ondansetron Injection

32 mg x 1

n = 220

Metoclopramide

n = 156

Placebo

n = 34
Diarrhea16%8%44%18%
Headache17%25%7%15%
Fever8%7%5%3%
Akathisia0%0%6%0%
Acute dystonic reactions* 0%0%5%0%
* See Neurological.

The following have been reported during controlled clinical trials:

Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations, hypotension, and tachycardia have been reported. In many cases, the relationship to ondansetron injection was unclear.

Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.

Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. 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.

Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.

Neurological: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron injection, and rare cases of grand mal seizure. The relationship to ondansetron was unclear.

Other: Rare cases of hypokalemia have been reported. The relationship to ondansetron injection was unclear.

Postoperative Nausea and Vomiting: The adverse events in Table 13 have been reported in ≥2% of adults receiving ondansetron at a dosage of 4 mg I.V. over 2 to 5 minutes in clinical trials. 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 13. Adverse Events in ≥ 2% of Adults Receiving Ondansetron at a Dosage of 4 mg I.V. over 2 to 5 Minutes in Clinical Trials

Ondansetron Injection

4 mg I.V.

n = 547 patients

Placebo

n = 547 patients
Headache92 (17%)77 (14%)
Dizziness67 (12%)88 (16%)
Musculoskeletal pain57 (10%)59 (11%)
Drowsiness/sedation44 (8%)37 (7%)
Shivers38 (7%)39 (7%)
Malaise/fatigue25 (5%)30 (5%)
Injection site reaction21 (4%)18 (3%)
Urinary retention17 (3%)15 (3%)
Postoperative CO2 -related pain* 12 (2%)16 (3%)
Chest pain (unspecified)12 (2%)15 (3%)
Anxiety/agitation11 (2%)16 (3%)
Dysuria11 (2%)9 (2%)
Hypotension10 (2%)12 (2%)
Fever10 (2%)6 (1%)
Cold sensation9 (2%)8 (1%)
Pruritus9 (2%)3 (<1%)
Paresthesia9 (2%)2 (<1%)
* Sites of pain included abdomen, stomach, joints, rib cage, shoulder.

Pediatric Use: The adverse events in Table 14 were the most commonly reported adverse events in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered intravenously over at least 30 seconds. 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 14. Frequency of Adverse Events From Controlled Studies in Pediatric Patients 2 to 12 Years of Age

Adverse Event

Ondansetron

n = 755 Patients

Placebo

n = 731 Patients
Wound problem80 (11%)86 (12%)
Anxiety/agitation49 (6%)47 (6%)
Headache44 (6%)43 (6%)
Drowsiness/sedation41 (5%)56 (8%)
Pyrexia32 (4%)41 (6%)
Table 15. Frequency of Adverse Events (Greater Than or Equal to 2% in Either Treatment Group) in Pediatric Patients 1 Month to 24 Months of Age

Adverse Event

Ondansetron

n = 336 Patients

Placebo

n = 334 Patients
Pyrexia14 (4%)14 (4%)
Bronchospasm2 (< 1%)6 (2%)
Post-procedural pain4 (1%)6 (2%)
Diarrhea6 (2%)3 (< 1%)
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of intravenous formulations of ondansetron. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron.

Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT interval prolongation, and ST segment depression), palpitations, and syncope.

General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported.

Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.

Local Reactions: Pain, redness, and burning at site of injection.

Lower Respiratory: Hiccups

Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.

Skin: Urticaria

Special Senses: Transient dizziness during or shortly after I.V. infusion.

Eye Disorders: Transient blurred vision, in some cases associated with abnormalities of accommodation. Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

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