ZOFRAN® (ondansetron hydrochloride) injection

ZOFRAN® (ondansetron hydrochloride) injection

ZOFRAN® (ondansetron hydrochloride) injection

The active ingredient of ZOFRAN Injection is ondansetron hydrochloride, a selective blocking agent of the serotonin 5-HT3 receptor type. Its chemical name is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4Hcarbazol-4-one, monohydrochloride, dihydrate.

The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9 g/mol.

Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.

ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous use. The pH of the injection solution is 3.3 to 4.0.

INDICATIONS AND USAGE

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.

ZOFRAN is approved for patients aged 6 months and older.

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.

ZOFRAN is approved for patients aged 1 month and older.

Mechanism of Action

Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.

DOSAGE AND ADMINISTRATION

Prevention of Nausea and Vomiting Associated With Initial and Repeat Courses of Emetogenic Chemotherapy

The recommended dosage for adult and pediatric patients 6 months of age and older for prevention of nausea and vomiting associated with emetogenic chemotherapy is 0.15-mg/kg per dose for 3 doses (maximum of 16 mg per dose).

Caution: Dilution of ZOFRAN Injection is required in adult and pediatric patients prior to administration.

Infuse intravenously over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy and then repeat 4 and 8 hours after the first dose.

Prevention of Postoperative Nausea and/or Vomiting

PopulationRecommended Single DoseAdministration InstructionsTiming of Administration
Adults and pediatric patients older than 12 years of age4 mgaMay be administered intravenously or intramuscularly: • Intravenously: infuse undiluted syringe contents (4 mg) over at least 30 seconds and preferably longer (over 2 to 5 minutes). • Intramuscularly: inject undiluted syringe contents (4 mg)Administer 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 b,c
Pediatric patients 1 month to 12 years and more than 40 kg4 mgInfuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes).Administer 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 b,c
Pediatric patients 1 month to 12 years and 40 kg or less0.1 mg/kgInfuse intravenously over at least 30 seconds and preferably longer (over 2 to 5 minutes). Administer 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 b,c

a Few patients above 80 kg have been studied.

b Administration of a second intravenous dose of 4 mg ondansetron postoperatively in adult patients who received a 4 mg prophylactic dose does not provide additional control of nausea and vomiting.

c for pediatric patients (1 month to 12 years) prevention of nausea and vomiting was only studied in patients who had not received prophylactic ondansetron.

Dosage Adjustment for Patients with Hepatic Impairment

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.

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.

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.

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.
  • QT Prolongation and Torsade de Pointes: 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.
  • Serotonin Syndrome: Serotonin syndrome has been reported with 5-HT3 receptor agonists alone but particularly with concomitant use of serotonergic drugs.
  • Myocardial Ischemia: Do not exceed the recommended infusion rate and monitor patients during and after administration.
  • 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.

ADVERSE REACTIONS

Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron, transient ECG changes, including QT/QTc interval prolongation have been reported.

Flushing: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylactic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A positive lymphocyte transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.

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.

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. Transient dizziness during or shortly after intravenous infusion.

Skin: Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Eye Disorders: 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. Transient blurred vision, in some cases associated with abnormalities of accommodation, has also been reported.

DRUG INTERACTIONS

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

Phenytoin, Carbamazepine, and Rifampin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), 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.

Tramadol: Although there are no data on pharmacokinetic drug interactions between ondansetron and tramadol, data from two small trials indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self-administered tramadol more frequently in these trials, leading to an increased cumulative dose in patient-controlled administration of tramadol.

Serotonergic Drugs: Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs.

Chemotherapy: In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase blood levels of high-dose methotrexate.

Temazepam: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

Alfentanil and Atracurium: Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. Available post marketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes.

Lactation: It is not known whether ondansetron is present in human milk. There are no data on the effects of ZOFRAN on the breastfed infant or the effects on milk production. However, it has been demonstrated that ondansetron is present in the milk of rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOFRAN and any potential adverse effects on the breast-fed infant from ZOFRAN or from the underlying maternal condition.

Pediatric Use: Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month. Little information is available about the use of ondansetron in pediatric cancer patients younger

Hepatic Impairment: In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded.

Renal Impairment: Although plasma clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), no dosage adjustment is recommended.

OVERDOSAGE

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.

In addition to the adverse reactions listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children. Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.

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