[Posted 09/15/2011] ISSUE: FDA notified healthcare professionals and patients of an ongoing safety review and labeling changes for the anti-nausea drug Zofran (ondansetron, ondansetron hydrochloride and generics). Ondansetron may increase the risk of developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm, including Torsade de Pointes. Patients at particular risk for developing Torsade de Pointes include those with underlying heart conditions, such as congenital long QT syndrome, those who are predisposed to low levels of potassium and magnesium in the blood, and those taking other medications that lead to QT prolongation.
BACKGROUND: Ondansetron (Zofran) is in a class of medications called 5-HT3 receptor antagonists. It is used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy and surgery. FDA is requiring GlaxoSmithKline to conduct a thorough QT study to determine the degree to which ondansetron may cause QT interval prolongation.
RECOMMENDATION: The labels are being revised to include a warning to avoid use in patients with congenital long QT syndrome because these patients are at particular risk for Torsade. Recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or in patients taking other medications that can lead to QT prolongation, are being included in the labels. For more information visit the FDA website at: [Web] and [Web].
Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy; may use orally with highly emetogenic chemotherapy (i.e., cisplatin ≥50 mg/m2) or initial and repeat courses of moderately emetogenic chemotherapy, or IV with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin.
Postoperative Nausea and Vomiting
Prevention or treatment of postoperative nausea and vomiting.
Routine prophylaxis not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.
Recommended for patients who, in the clinician’s judgement, must avoid nausea and/or vomiting postoperatively, even when anticipated incidence is low.
Radiation-induced Nausea and Vomiting
Prevention of nausea and vomiting associated with radiation, either total body irradiation or single high-dose fraction or daily fractionated radiation to the abdomen.
Dosage and Administration
Administration
Administer orally, by IV infusion, or by IV or IM injection.
Oral Administration
Administer orally as conventional tablet, orally disintegrating tablet, or oral solution.
Commercially available oral solution and orally disintegrating tablets may be used interchangeably.
Do not remove orally disintegrating tablet from blister until just prior to dosing; do not push through foil. With dry hands, peel open blister package, and gently remove the tablet; place tablet on tongue to dissolve, and swallow with saliva.
Administration of orally disintegrating tablet with liquid is not necessary.
IV Administration
For prevention of cancer chemotherapy-induced nausea/vomiting, administer by IV infusion using diluted injection or premixed injection.
Administer premixed injection by IV infusion only; do not use flexible plastic container in series connections. For preparation and administration instructions for premixed injection, consult manufacturer’s labeling.
For prevention of postoperative nausea and vomiting, administer undiluted by IV injection.
Dilution
For IV infusion, dilute ondansetron hydrochloride injection in 50 mL of 5% dextrose injection or 0.9% sodium chloride injection; the premixed injection does not require further dilution.
For IV injection, no dilution required.
Rate of Administration
IV infusion: Infuse over 15 minutes.
IV injection: Inject over a period of ≥30 seconds, preferably over 2–5 minutes.
IM Administration
For prevention of postoperative nausea and vomiting in adults, may administer undiluted by IM injection as an alternative to IV injection. (See Postoperative Nausea and Vomiting under Dosage and Administration.)
Dosage
Available as ondansetron hydrochloride dihydrate (for oral or IV use) and as ondansetron base (orally disintegrating tablets); dosage expressed in terms of ondansetron.
Pediatric Patients
Cancer Chemotherapy-induced Nausea and Vomiting
Prevention
Oral
Children 4–11 years of age: Initially, 4 mg given 30 minutes before administration of moderately emetogenic chemotherapy, followed by subsequent 4-mg doses given 4 and 8 hours after first dose. Continue with 4 mg every 8 hours for 1–2 days after completion of chemotherapy.
Children ≥12 years of age: Initially, 8 mg given 30 minutes before administration of moderately emetogenic chemotherapy, followed by a subsequent 8-mg dose given 8 hours after first dose. Continue with 8 mg every 12 hours for 1–2 days after completion of chemotherapy.
IV
Pediatric patients 6 months to 18 years of age: 0.15 mg/kg by IV infusion beginning 30 minutes before start of emetogenic chemotherapy, followed by subsequent 0.15-mg/kg doses given 4 and 8 hours after first dose.
Postoperative Nausea and Vomiting
Prevention
IV
Infants and children 1 month to 12 years of age weighing ≤40 kg: 0.1 mg/kg as a single dose by IV injection immediately before or after induction of anesthesia.
Children ≤12 years of age weighing >40 kg: 4 mg as a single dose by IV injection immediately before or after induction of anesthesia.
Treatment
IV
Infants and children 1 month to 12 years of age weighing ≤40 kg: 0.1 mg/kg as a single dose by IV injection postoperatively, if nausea and/or vomiting occur shortly after surgery.
Children ≤12 years of age weighing >40 kg: 4 mg as a single dose by IV injection postoperatively, if nausea and/or vomiting occur shortly after surgery.
Efficacy of a second dose administered postoperatively after a single, prophylactic, preinduction IV dose has failed to achieve adequate control of postoperative nausea and vomiting has not been evaluated in children; such repeat doses are not effective in adults.
Adults
Cancer Chemotherapy-induced Nausea and Vomiting
Prevention
Oral
Initially, 8 mg given 30 minutes before administration of moderately emetogenic chemotherapy, followed by a subsequent 8-mg dose given 8 hours after first dose. Continue with 8 mg every 12 hours for 1–2 days after completion of chemotherapy.
24 mg as a single dose given 30 minutes before administration of single-day highly emetogenic chemotherapy.
IV
0.15 mg/kg by IV infusion beginning 30 minutes before administration of emetogenic chemotherapy, followed by 0.15 mg/kg infused 4 and 8 hours after first dose.
Alternatively, 32 mg as a single dose by IV infusion beginning 30 minutes before administration of emetogenic chemotherapy.
Postoperative Nausea and Vomiting
Prevention
Oral
16 mg as a single dose given 1 hour before induction of anesthesia.
IV
4 mg as a single dose by IV injection (undiluted) immediately before induction of anesthesia.
Limited information available regarding dosage in patients weighing >80 kg.
IM
4 mg as a single dose by IM injection (undiluted) as an alternative to IV administration.
Limited information available regarding dosage in patients weighing >80 kg.
Treatment
IV
4 mg as a single dose by IV injection (undiluted) postoperatively, if nausea and/or vomiting occur shortly after surgery.
If adequate control of postoperative nausea and vomiting is not achieved after a single, prophylactic, preinduction IV dose, a second IV dose postoperatively does not provide additional control of nausea and vomiting.
Radiation-induced Nausea and Vomiting
Prevention, Usual Dosage
Oral
Usually, 8 mg 3 times daily.
Prevention, for Total Body Irradiation
Oral
8 mg 1–2 hours before each fraction of radiotherapy administered each day.
Prevention, for Single High-dose Fraction Radiation to Abdomen
Oral
8 mg 1–2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1–2 days after completion of radiotherapy.
Prevention, for Daily Fractionated Radiation to Abdomen
Oral
8 mg 1–2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.
Special Populations
Hepatic Impairment
Do not exceed total daily dosage of 8 mg (parenteral or oral) in patients with severe hepatic impairment (Child-Pugh score ≥10); no experience to date with continuation beyond the first day of IV therapy.
Renal Impairment
No dosage adjustment required, but no experience to date with continuation beyond the first day of therapy.
May mask progressive ileus and/or gastric distention in patients undergoing abdominal surgery or in those with chemotherapy-induced nausea and vomiting.
Cardiac Effects
Transient ECG alterations (e.g., QT interval prolongation) reported rarely, generally in patients receiving ondansetron IV.
Phenylketonuria
Each 4- or 8-mg Zofran® ODT® orally disintegrating tablet contains aspartame (Nutrasweet®), which is metabolized in the GI tract to provide <0.03 mg of phenylalanine per tablet.
Specific Populations
Pregnancy
Category B.
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Caution advised if used in nursing women.
Pediatric Use
Safety and efficacy of oral or IV ondansetron for prevention of chemotherapy-induced emesis generally comparable to that in adults.
Little information available on IV use for prevention of postoperative nausea and vomiting in pediatric patients <1 month of age or for prevention of chemotherapy-induced nausea and vomiting in pediatric patients <6 months of age. Little information available on oral dosage in children ≤4 years of age.
Because clearance is reduced in infants 1–4 months of age compared with those >4 to 24 months of age, closely monitor infants <4 months of age. (See Half-life under Pharmacokinetics.)
Efficacy of single 24-mg oral dose for prevention of nausea and vomiting induced by highly emetogenic chemotherapy or oral therapy for prevention of radiation-induced or postoperative nausea and vomiting not established in children <18 years of age.
Geriatric Use
No substantial differences in safety or efficacy in patients >65 years of age relative to younger adults, but increased sensitivity cannot be ruled out.
Hepatic Impairment
Clearance is decreased and half-life increased in patients with hepatic impairment. Use with caution and at reduced dosage in patients with severe hepatic impairment. (See Special Populations under Dosage and Administration.)
Substrate of CYP1A2, CYP2D6, and CYP3A4 in vitro; does not appear to induce or inhibit CYP isoenzymes.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or inducers of CYP1A2, CYP2D6, or CYP3A4; potential pharmacokinetic interaction (altered ondansetron metabolism). Based on available data, no dosage adjustment recommended for patients on these drugs.
Specific Drugs
Drug
Interaction
Comments
Alfentanil
No change in respiratory depressant effects of alfentanil
No pharmacokinetic interaction observed, but possible increased tramadol dosage requirements for patient-controlled analgesia
Pharmacokinetics
Absorption
Bioavailability
Well absorbed from GI tract after oral administration. Mean bioavailability after administration of single 8-mg tablet is approximately 56%; increased bioavailability expected with dosages >8 mg.
Peak plasma concentrations are attained approximately 1.5–2.2 hours after oral administration, approximately 25 minutes after IV infusion, or 41 minutes after IM injection.
Commercially available oral solution and orally disintegrating tablets (4- or 8-mg doses) are bioequivalent to corresponding doses of conventional tablets.
Food
Food slightly increases bioavailability.
Special Populations
Extent and rate of absorption are increased in women compared with men; not known whether differences are clinically important.
Distribution
Extent
Circulating drug distributes into erythrocytes.
Distributed into milk in rats; not known whether distributed into human milk.
Plasma Protein Binding
70–76%.
Elimination
Metabolism
Extensively metabolized in the liver via hydroxylation followed by subsequent glucuronide or sulfate conjugation. CYP isoenzymes 1A2, 2D6, and 3A4 are involved.
Exibits nonlinear pharmacokinetics, possibly due to saturation of hepatic metabolism.
Elimination Route
<5% of a dose is excreted unchanged in urine.
Half-life
Adults: Approximately 3–3.5 hours after single 8-mg oral dose; approximately 4 hours after IV administration.
Children and adolescents 3–18 years of age: 2.4–3 hours after IV administration.
Infants 5–24 months of age: 2.9 hours after IV administration.
Infants 1–4 months of age: 6.7 hours after IV administration.
Special Populations
In patients with mild to moderate hepatic impairment, clearance is decreased 2-fold and half-life increased to 11.6 hours. In patients with severe hepatic impairment (Child-Pugh score ≥10), clearance is decreased 2- to 3-fold and half-life increased to 20 hours.
Although renal clearance contributes minimally to overall clearance, mean plasma clearance is reduced by about 50% in patients with severe renal impairment (Clcr <30 mL/minute); reduction in clearance is variable and not consistent with an increase in half-life.
In geriatric patients >75 years of age, clearance is decreased and half-life is increased to 4.5–6.2 hours.
Stability
Storage
Oral
Conventional Tablets
Tight, light resistant containers at 2–30°C; protect from light.
Orally Disintegrating Tablets
2–30°C.
Solution
15–30°C; store bottles upright and protect from light.
Parenteral
Injection
2–30°C; protect from light.
Occasionally precipitates at the stopper/vial interface in vials stored upright; potency and safety not affected. If precipitate is found, vigorously shake vial to resolubilize.
Premixed Injection
2–30°C. Protect from light; do not freeze; avoid excessive heat.
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Do not mix with solutions for which physical and chemical compatibility have not been established, particularly alkaline solutions, as precipitate may form.
Antiemetic activity appears to be mediated both centrally (in medullary chemoreceptor trigger zone) and peripherally (in GI tract) via inhibition of 5-HT3 receptors.
Advice to Patients
For patients taking orally disintegrating tablets, importance of not removing tablet from blister until just before administering dose and of not pushing tablet through foil; importance of opening blister pack with dry hands and of placing tablet on tongue to dissolve and be swallowed with saliva.
Importance of informing patients with phenylketonuria that orally disintegrating tablets contain aspartame.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of advising patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
Sign up with Facebook
