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ZOFRAN (ondansetron hydrochloride) injection for intravenous
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ZOFRAN safely and effectively. See full prescribing information for ZOFRAN.
ZOFRAN (ondansetron hydrochloride) injection for intravenous use
Initial U.S. Approval: 1991
RECENT MAJOR CHANGES
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Warnings and Precautions, Serotonin Syndrome (5.3)
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09/2014
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INDICATIONS AND USAGE
ZOFRAN Injection is a 5-HT3 receptor antagonist indicated:
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Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy. ( 1.1)
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Prevention of postoperative nausea and/or vomiting. ( 1.2)
DOSAGE AND ADMINISTRATION
Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (2.1):
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Adults and Pediatric patients (6 months to 18 years): Three 0.15 mg/kg doses, up to a maximum of 16 mg per dose, infused intravenously over 15 minutes. The first dose should be administered 30 minutes before the start of chemotherapy. Subsequent doses are administered 4 and 8 hours after the first dose.
Prevention of postoperative nausea and/or vomiting (2.2):
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Population
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Age
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Dosage of ZOFRAN
Injection
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Intravenous Infusion Rate
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Adults
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>12 yrs
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4 mg x 1
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over 2 - 5 min
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Pediatrics
(>40 kg)
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1 mo. – 12 yrs
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4 mg x 1
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over 2 - 5 min
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Pediatrics
(≤40 kg)
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1 mo. – 12 yrs
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0.1 mg/kg x 1
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over 2 - 5 min
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In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. ( 2.4)
DOSAGE FORMS AND STRENGTHS
ZOFRAN Injection (2 mg/mL): 20-mL multidose vials. (3)
CONTRAINDICATIONS
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Patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. ( 4)
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Concomitant use of apomorphine. ( 4)
WARNINGS AND PRECAUTIONS
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Hypersensitivity reactions including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. ( 5.1)
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QT prolongation occurs in a dose-dependent manner. Cases of Torsade de Pointes have been reported. Avoid ZOFRAN in patients with congenital long QT syndrome. ( 5.2)
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Serotonin syndrome has been reported with 5-HT 3 receptor agonists alone but particularly with concomitant use of serotonergic drugs. ( 5.3)
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Use in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention. ( 5.4) ( 5.5)
ADVERSE REACTIONS
Chemotherapy-Induced Nausea and Vomiting –
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The most common adverse reactions (≥7%) in adults are diarrhea, headache, and fever. ( 6.1)
Postoperative Nausea and Vomiting –
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The most common adverse reaction (≥10%) which occurs at a higher frequency compared with placebo in adults is headache. ( 6.1)
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The most common adverse reaction (≥2%) which occurs at a higher frequency compared with placebo in pediatric patients aged 1 to 24 months is diarrhea. ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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Apomorphine – profound hypotension and loss of consciousness. Concomitant use with ondansetron is contraindicated. ( 7.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 9/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Cancer Chemotherapy
ZOFRAN® Injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin [see Clinical Studies (14.1)].
ZOFRAN is approved for patients aged 6 months and older.
1.2 Prevention of Postoperative Nausea and/or Vomiting
ZOFRAN Injection is indicated for the 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 in whom nausea and/or vomiting must be avoided postoperatively, ZOFRAN Injection is recommended even when the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic ZOFRAN Injection and experience nausea and/or vomiting postoperatively, ZOFRAN Injection may be given to prevent further episodes [see Clinical Studies (14.3)].
ZOFRAN is approved for patients aged 1 month and older.
2 DOSAGE AND ADMINISTRATION
2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy
ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Adults
The recommended adult intravenous dosage of ZOFRAN is three 0.15-mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ZOFRAN.
Pediatrics
For pediatric patients aged 6 months through 18 years, the intravenous dosage of ZOFRAN is three 0.15-mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1), Clinical Pharmacology (12.2, 12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ZOFRAN. The drug should be infused intravenously over 15 minutes.
2.2 Prevention of Postoperative Nausea and Vomiting
ZOFRAN Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.
Adults
The recommended adult intravenous dosage of ZOFRAN is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.
Pediatrics
For pediatric patients aged 1 month through 12 years, the dosage is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ZOFRAN.
2.3 Stability and Handling
After dilution, do not use beyond 24 hours. Although ZOFRAN Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.
ZOFRAN Injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.
2.4 Dosage Adjustment for Patients with Impaired Hepatic Function
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)]
3 DOSAGE FORMS AND STRENGTHS
ZOFRAN Injection, 2 mg/mL is a clear, colorless, nonpyrogenic, sterile solution available as a 20-mL multidose vial.
4 CONTRAINDICATIONS
ZOFRAN Injection is contraindicated for patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported in patients taking ondansetron. [See Adverse Reactions (6.2).]
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.
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
5.2 QT Prolongation
Ondansetron prolongs the QT interval in a dose-dependent manner [see Clinical Pharmacology (12.2)]. In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ZOFRAN 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.
5.3 Serotonin Syndrome
The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. 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 ZOFRAN 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 ZOFRAN and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ZOFRAN and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ZOFRAN is used concomitantly with other serotonergic drugs [see Drug Interactions (7.5), Overdosage (10), Patient Counseling Information (17)].
5.4 Masking of Progressive Ileus and Gastric Distension
The use of ZOFRAN in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention.
5.5 Effect on Peristalsis
ZOFRAN is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The following adverse reactions have been reported in clinical trials of adult patients treated with ondansetron, the active ingredient of intravenous ZOFRAN across a range of dosages. A causal relationship to therapy with ZOFRAN (ondansetron) was unclear in many cases.
Chemotherapy-induced Nausea and Vomiting
Cardiovascular:
Rare cases of angina (chest pain), electrocardiographic alterations, hypotension, and tachycardia have been reported.
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 ZOFRAN Injection, and rare cases of grand mal seizure.
Other:
Rare cases of hypokalemia have been reported.
Postoperative Nausea and Vomiting
The adverse reactions in Table 2 have been reported in ≥2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to 5 minutes in clinical trials.
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