Ondansetron

Ondansetron orally disintegrating 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/m²
• 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 orally disintegrating tablets also indicated for the prevention of postoperative nausea and/or vomiting.

• See full prescribing information for the recommended dosage in adults and pediatrics.
  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.

  2.1 Recommended 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 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)]

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  2.3 Administration Instructions for Ondansetron Orally Disintegrating Tablets

  Do not attempt to push ondansetron orally disintegrating tablets through the foil backing. With dry hands, remove the tablet from the bottle or PEEL BACK the foil backing of 1 blister and 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.
• Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg. (
  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)]

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  ,
  8.6 Hepatic Impairment

  No dosage adjustment is needed in patients with mild or moderate hepatic impairment.
  
  
  
  In patients with severe hepatic impairment, clearance is reduced and the apparent volume of distribution is increased, resulting in a significant increase in the half-life of ondansetron. Therefore, do not exceed a total daily dose of 8 mg in patients with severe hepatic impairment (Child-Pugh score of 10 or greater)

  [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]

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  )

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

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 U.S. 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.

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 U.S. 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).

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 maximum recommended human oral dose of 24 mg/day, respectively, based on BSA.

In a pre- and postnatal developmental toxicity study, pregnant rats received oral doses of ondansetron up to 15 mg/kg/day from Day 17 of pregnancy to litter Day 21. With the exception of a slight reduction in maternal body weight gain, there were no effects upon the pregnant rats and the pre- and postnatal development of their offspring, including reproductive performance of the mated F1 generation. At a dose of 15 mg/kg/day in rats, the maternal exposure margin was approximately 6 times the maximum recommended human oral dose of 24 mg/day, based on BSA.

• Hypersensitivity Reactions, Including Anaphylaxis and Bronchospasm
  : Discontinue ondansetron if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. (
  5.1 Hypersensitivity Reactions

  Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT₃receptor 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)]

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• QT Interval Prolongation and Torsade de Pointes
  : Avoid ondansetron 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-HT₃ receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue ondansetron and initiate supportive treatment. If concomitant use of ondansetron with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. (
  5.3 Serotonin Syndrome

  The development of serotonin syndrome has been reported with 5-HT₃receptor 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-HT₃receptor 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)]

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• Myocardial Ischemia
  : Monitor or advise patients for signs and symptoms of myocardial ischemia after oral administration. (
  5.4 Myocardial Ischemia

  Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, monitor or advise patients for signs or symptoms of myocardial ischemia after oral administration of ondansetron

  [see Adverse Reactions (6.2)].
  )
• Masking of Progressive Ileus and/or Gastric Distension Following Abdominal Surgery or Chemotherapy-Induced Nausea and Vomiting
  : Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. (
  5.5 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:
  Patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 4 mg orally disintegrating tablet contains 1.68 mg phenylalanine and 8 mg orally disintegrating tablet contains 3.37 mg phenylalanine. (
  5.6 Phenylketonuria

  Phenylketonuric patients should be informed that ondansetron orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 4 mg orally disintegrating tablet contains 1.68 mg phenylalanine and 8 mg orally disintegrating tablet contains 3.37 mg phenylalanine.
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