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ZOFRAN®
Glaxo Wellcome
Ondansetron HCl Dihydrate
Antiemetic
 
Action And Clinical Pharmacology: Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3. Its precise mode of action in the control of chemotherapy-induced nausea and vomiting is not known. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both.

The mechanisms of ondansetron's antiemetic action in post-operative nausea and vomiting are not known.

Pharmacokinetics: Pharmacokinetic studies in human volunteers showed peak plasma levels of 20 to 30 ng/mL at around 1 1/2 hours after an 8 mg oral dose of ondansetron. An 8 mg infusion of ondansetron reached peak plasma levels of 80 to 100 ng/mL. Repeat dosing of an 8 mg tablet every 8 hours for 6 days increased the peak plasma value to 40 ng/mL. A continuous i.v. infusion of 1 mg/hour after the initial 8 mg loading dose of ondansetron maintained plasma levels over 30 ng/mL during the following 24 hour period.

The absolute bioavailability of ondansetron in humans was approximately 60% and the plasma protein binding was approximately 73%.

Following oral or i.v. administration, ondansetron is extensively metabolised and excreted in the urine and feces. In humans, less than 10% of the dose is excreted unchanged in the urine. The major urinary metabolites are glucuronide conjugates (45%), sulfate conjugates (20%) and hydroxylation products (10%).

The half-life of ondansetron after either an 8 mg oral dose or i.v. dose was approximately 3 to 4 hours and may be extended to 6 to 8 hours in the elderly.

Clinical trial results showing the number and percentage of patients exhibiting a complete response to ondansetron (0 emetic episodes) are shown in Tables I, II and III, for both postoperative and chemotherapy induced emesis.

Indications And Clinical Uses: For the prevention of nausea and vomiting associated with emetogenic chemotherapy, including high dose cisplatin, and radiotherapy.

Ondansetron is also indicated for the prevention and treatment of postoperative nausea and vomiting.

Contra-Indications: In patients with a history of hypersensitivity to the drug or any components of its formulations (see Supplied). tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Cross-reactive hypersensitivity has been reported between 5-HT3 antagonists. Patients who have experienced hypersensitivity reactions to one 5-HT3 antagonist have experienced more severe reactions upon being challenged with another drug of the same class. The use of a different 5-HT3 receptor antagonist is not recommended as a replacement in cases in which a patient has experienced even a mild hypersensitivity type reaction to another 5-HT3 antagonist.

Precautions: Ondansetron is not effective in preventing motion-induced nausea and vomiting.

There is no experience in patients who are clinically jaundiced. The clearance of an 8 mg intravenous dose of ondansetron was significantly reduced and the serum half-life significantly prolonged in subjects with severe impairment of hepatic function. In patients with moderate to severe hepatic function, reductions in dosage are therefore recommended and a total daily dose of 8 mg should not be exceeded. This may be given as a single i.v. or oral dose.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

Pregnancy: The safety of ondansetron during pregnancy has not been established. Ondansetron is not teratogenic in animals. However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended.

Lactation: Ondansetron is excreted in the milk of lactating rats. It is not known if it is excreted in human milk, however, nursing is not recommended during treatment with ondansetron.

Children: Insufficient information is available to provide dosage recommendations for children 3 years of age or younger.

Adverse Reactions: Ondansetron has been administered to over 2 500 patients worldwide in controlled clinical trials and has been well tolerated.

The most frequent adverse events reported in controlled clinical trials were headache (11%) and constipation (4%). Other adverse events include sensations of flushing or warmth (<1%).

Metabolic: There were transient increases of AST and ALT of over twice the upper limit of normal in approximately 5% of patients. These increases did not appear to be related to dose or duration of therapy. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. There have been rare reports of hypokalemia.

CNS: There have been rare reports of seizures.

Hypersensitivity: Rare cases of immediate hypersensitivity reactions sometimes severe, including anaphylaxis, bronchospasm, urticaria and angioedema have been reported.

Cardiovascular: There have been rare reports of tachycardia, angina (chest pain), bradycardia, hypotension, syncope and electrocardiographic alterations.

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

Special Senses: Rare cases of transient visual distrubances (e.g., blurred vision) have been reported during or shortly after i.v. administration of ondansetron, particularly at rates equal to or greater than 30 mg in 15 minutes.

Local Reactions: Pain, redness and burning at the site of injection have been reported.

Other: There have been reports of abdominal pain, weakness and xerostomia.

Post-Market Experience: Over 9.5 million patient courses of Zofran (1 patient course defined as 3 i.v. injections followed by 6 oral doses) have been supplied since the launch of the product worldwide. The following are events which have been reported spontaneously. Transient episodes of dizziness (<0.01%) have been reported during or upon completion of i.v. infusion of ondansetron. Rare reports (<0.01%) suggestive of involuntary movement disorders (e.g., oro-facial dyskinesia, opisthotonos, dystonia, tremor, etc.) have been reported without definitive evidence of persistent clinical sequelae. There have been rare reports (<0.01%) of arrhythmias and hiccups. The link to ondansetron cannot be clearly established for spontaneously reported events.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: At present there is little information concerning overdosage with ondansetron. Individual doses of 84 and 145 mg and total daily doses as large as 252 mg have been administered with only mild side effects. There is no specific antidote for ondansetron, therefore, in cases of suspected overdosage, symptomatic and supportive therapy should be given as appropriate.

The use of Ipecac to treat overdosage with ondansetron is not recommended as patients are unlikely to respond due to the antiemetic action of ondansetron itself.

"Sudden blindness" (amaurosis) of 2 to 3 minutes duration plus severe constipation occurred in 1 patient that was administered 72 mg of ondansetron i.v. as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. 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.

Dosage And Administration: Chemotherapy Induced Nausea and Vomiting: Ondansetron should be given as an initial dose prior to chemotherapy, followed by a dosage regimen tailored to the anticipated severity of emetic response caused by different cancer treatments. The route of administration and dose of ondansetron should be flexible in the range of 8 to 32 mg a day. The selection of dose regimen should be determined by the severity of the emetogenic challenge as shown below.

Adults: Highly Emetogenic Chemotherapy (e.g., regimens containing cisplatin): Ondansetron has been shown to be effective in the following dose schedules for the prevention of emesis during the first 24 hours following chemotherapy:

Initial Dose: 8 mg infused i.v. over 15 minutes given 30 minutes prior to chemotherapy; or 8 mg infused i.v. over 15 minutes, given 30 minutes prior to chemotherapy, followed by 1 mg/h by continuous infusion for up to 24 hours; or 32 mg diluted in 50 to 100 mL of saline or other compatible infusion fluid and infused over not less than 15 minutes**, given 30 minutes prior to chemotherapy.

Post-chemotherapy: After the first 24 hours, 8 mg orally every 8 hours* for up to 5 days.

No significant differences in terms of emesis control or grade of nausea have been demonstrated between the 32 mg single dose, the 8 mg single dose, or the 8 mg dose followed by the 24 hour 1 mg/hour continuous infusion.

However, in some studies conducted in patients receiving medium or high doses of cisplatin chemotherapy, the 32 mg single dose has demonstrated a statistically significant superiority over the 8 mg single dose with regard to control of emesis.

The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by the addition of a single i.v. dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.

Less Emetogenic Chemotherapy (e.g., regimens containing cyclophosphamide, doxorubicin, epirubicin, fluorouracil and carboplatin): Initial Dose: 8 mg infused i.v. over 15 minutes, given 30 minutes prior to chemotherapy; or 8 mg tablet orally 1 to 2 hours prior to chemotherapy.

Post-chemotherapy: 8 mg orally twice daily for up to 5 days.

Children: Clinical experience of ondansetron in children is currently limited, however, ondansetron was effective and well tolerated when given to children 4 to 12 years of age. Ondansetron injection should be given i.v. at a dose of 3 to 5 mg/mover 15 minutes immediately before chemotherapy. After therapy, one ondansetron 4 mg tablet should be given orally every 8 hours* for up to 5 days.

Geriatrics: Efficacy and tolerance in patients aged over 65 years were similar to that seen in younger adults indicating no need to alter dosage schedules in this population.

Radiotherapy Induced Nausea and Vomiting: Adults: Initial Dose: 8 mg orally 1 to 2 hours before radiotherapy.

Post-radiotherapy: 8 mg orally every 8 hours* for up to 5 days after a course of treatment.

Children: There is no experience in clinical studies in this population.

Geriatrics: Efficacy and tolerance in patients aged over 65 years were similar to that seen in younger adults indicating no need to alter dosage schedules in this population.

* Note: The efficacy of twice daily dosage regimens for the treatment of post-chemotherapy emesis has been established only in adult patients receiving less emetogenic chemotherapy. The appropriateness of twice versus 3 times daily dosage regimens for other patient groups should be based on an assessment of the needs and responsiveness of the individual patient.

** Infusion of 32 mg ondansetron injection should take place over a period of not less than 15 minutes, because of increased risk of blurred vision.

Postoperative Nausea and Vomiting: Adults: For prevention of post-operative nausea and vomiting ondansetron may be administered as a single dose of 16 mg given orally 1 hour prior to anesthesia. Alternatively, a single dose of 4 mg may be given by slow i.v. injection at induction of anesthesia.

For the treatment of established postoperative nausea and vomiting, a single dose of 4 mg given by slow i.v. injection is recommended.

Children: There is no experience in the use of ondansetron in the prevention and treatment of postoperative nausea and vomiting in children.

Geriatrics: There is limited experience in the use of ondansetron in the prevention and treatment of postoperative nausea and vomiting in the elderly.

Impaired Renal Function: No alteration of daily dosage, frequency of dosing, or route of administration is required.

Impaired Hepatic Function: The clearance of an 8 mg i.v. dose was significantly reduced and the serum half-life significantly prolonged in subjects with severe impairment of hepatic function. In patients with moderate to severe hepatic function, reductions in dosage are therefore recommended and a total daily dose of 8 mg should not be exceeded. This may be given as a single i.v. or oral dose.

No studies have been conducted to date in patients with jaundice.

Poor Sparteine/Debrisoquine Metabolism: The elimination half-life and plasma levels of a single 8 mg i.v. dose of ondansetron did not differ between subjects classified as poor and extensive metabolizers of sparteine and debrisoquine. No alteration of daily dosage or frequency of dosing is recommended for patients known to be poor metabolizers of sparteine and debrisoquine.

Administration of I.V. Infusion Solutions: Compatibility with I.V. Solutions: The injection is compatible with the following solutions: for ampuls, 0.9% w/v Sodium Chloride Injection; 5% w/v Dextrose Injection; 10% w/v Mannitol Injection; Ringers Injection; 0.3% w/v Potassium Chloride and 0.9% w/v Sodium Chloride Injection; 0.3% w/v Potassium Chloride and 5% w/v Dextrose Injection. For vials, 5% w/v Dextrose Injection; 0.9% w/v Sodium Chloride Injection; 5% w/v Dextrose and 0.9% w/v Sodium Chloride Injection; 5% w/v Dextrose and 0.45% w/v Sodium Chloride Injection; 3% w/v Sodium Chloride Injection.

Compatibility with Other Drugs: The injection should not be administered in the same syringe or infusion with any other medication with the exception of dexamethasone (see below). Ondansetron may be administered by i.v. infusion at 1 mg/hour, e.g., from an infusion bag or syringe pump.

The following drugs may be administered via the Y-site of the administration set, for ondansetron concentration of 16 to 160 µg/mL. If the concentrations of cytotoxic drugs required are higher than indicated below, they should be administered through a separate i.v. line.

For Ampuls and Vials: Cisplatin: Concentrations up to 0.48 mg/mL administered over 1 to 8 hours.

Dexamethasone: Admixtures containing 8 mg of ondansetron and 20 mg of dexamethasone phosphate, in 50 mL of 5% dextrose infusion fluid stored in 50 mL polyvinyl chloride infusion bags, have been shown to be physically and chemically stable for up to 2 days at room temperature or up to 7 days at 2 to 8°C. In addition, these same admixtures have demonstrated compatibility with Continu-Flo administration sets.

In a clinical study (Cunningham et al, 1989) ondansetron (standard dosing regimen) was given to patients receiving cisplatin or non-cisplatin chemotherapy. Eight patients who continued to experience nausea and vomiting were given dexamethasone in addition to ondansetron. In every case there was an improvement in the control of emesis and all patients preferred the combination of ondansetron and dexamethasone.

For Ampuls: 5-Fluorouracil: concentrations up to 0.8 mg/mL, administered at rates of at least 20 mL/hour. Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil infusion may contain up to 0.045% w/v magnesium chloride.

Carboplatin: concentrations of 0.18 to 9.9 mg/mL, administered over 10 to 60 minutes.

Ceftazidime: bolus i.v. doses, over approximately 5 minutes, of 250 to 2 000 mg reconstituted with Water for Injections BP.

Cyclophosphamide: bolus i.v. doses over approximately 5 minutes, of 100 to 1 000 mg, reconstituted with Water for Injections BP 5 mL/100 mg cyclophosphamide.

Doxorubicin and Epirubicin: bolus i.v. doses, over approximately 5 minutes, of 10 to 100 mg as a 2 mg/mL solution. Lyophilized powder presentations can be reconstituted with 0.9% Sodium Chloride Injection USP.

Etoposide: concentrations of 0.144 to 0.25 mg/mL, administered over 30 to 60 minutes.

Stability and Storage: Store below 30°C. The oral solution should be stored upright and should not be refrigerated. The injection should not be frozen and should be protected from light. The injection must not be autoclaved.

Stability and Storage of Diluted Solutions: Compatibility studies have been undertaken in polyvinyl chloride infusion bags, polyvinyl chloride administration sets and polypropylene syringes. Dilutions of ondansetron in sodium chloride 0.9% w/v or in glucose 5% w/v have been demonstrated to be stable in polypropylene syringes. It is considered that ondansetron injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.

I.V. solutions should be prepared at the time of infusion. The injection, in ampuls and vials, when diluted with the recommended i.v. solutions, should be used within 24 hours if stored at room temperature or used within 72 hours if stored in a refrigerator, due to possible microbial contamination during preparation.

Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of i.v. solutions, may extend the storage time for ondansetron injection in admixture with 5% dextrose injection and dexamethasone phosphate injection (concentration of 0.34 mg/mL) in Viaflex bags, at a concentration of 0.14 mg/mL, to 7 days when stored under refrigeration at 2 to 8°C.

Note: As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, or discoloration or leakage should not be used.



Availability And Storage: Injection: Each mL contains: ondansetron 2 mg/mL (as hydrochloride dihydrate) for i.v. use. Nonmedicinal ingredients: citric acid monohydrate, methyl- and propylparaben (vials only), sodium citrate and sodium chloride. Ampuls of 2 mL (4 mg) and 4 mL (8 mg). Boxes of 5. Vials of 20 mL (40 mg). Packed in individual cartons.

Oral Solution: Each 5 mL contains: ondansetron 4 mg (as dihydrate HCl). Nonmedicinal ingredients: citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, sorbitol solution and strawberry flavor. Bottles of 50 mL.

Tablets: 4 mg: Each oval-shaped, yellow film-coated tablet, engraved '4' on one face and 'GLAXO' on the other, contains: ondansetron 4 mg (as hydrochloride dihydrate). Nonmedicinal ingredients: lactose, magnesium stearate, methyl hydroxypropyl cellulose, microcrystalline cellulose, Opadry yellow or Opaspray yellow (containing titanium dioxide and iron oxide yellow) and pregelatinized starch. Gluten- and tartrazine-free. Tamper-evident polypropylene containers of 30.

8 mg: Each oval-shaped, yellow, film-coated tablet, engraved '8' on one face and 'GLAXO' on the other, contains: ondansetron 8 mg (as hydrochloride dihydrate). Nonmedicinal ingredients: lactose, magnesium stearate, methyl hydroxypropyl cellulose, microcrystalline cellulose, Opadry yellow or Opaspray yellow (containing titanium dioxide and iron oxide yellow) and pregelatinized starch. Gluten- and tartrazine-free. Tamper-evident polypropylene containers of 10 and 30. (Shown in Product Recognition Section)