Nu-Ondansetron (Nu-Pharm, 4 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

NU-ONDANSETRON (ondansetron hydrochloride) is indicated for:

• the prevention of nausea and vomiting associated with emetogenic chemotherapy, including high dose cisplatin, and radiotherapy.
• the prevention and treatment of post-operative nausea and vomiting.

Pediatrics (<18 years of age)

Post-Chemotherapy

Clinical experience of ondansetron oral solution in children is currently limited, however, ondansetron oral solution was effective and well tolerated when given to children 4-12 years of age (see DOSAGE AND ADMINISTRATION). NU-ONDANSETRON is not indicated for the treatment of children 3 years of age or younger.

Post-Radiotherapy

Safety and efficacy of NU-ONDANSETRON in any age group in this population following radiotherapy has not been established and is therefore not indicated for use in this population.

Post-Operative Nausea and Vomiting

Safety and efficacy of NU-ONDANSETRON in any age group in this population for the prevention and treatment of post-operative nausea and vomiting has not been established and is not indicated for use in this group.

Geriatrics (>65 years of age)

Post-Chemotherapy and Radiotherapy

Efficacy and tolerance of ondansetron oral solution were similar to that observed in younger adults (see DOSAGE AND ADMINISTRATION).

Post-Operative Nausea and Vomiting

Clinical experience in the use of ondansetron oral solution in the prevention and treatment of post-operative nausea and vomiting is limited and is not indicated for use in this population.

CONTRAINDICATIONS

NU-ONDANSETRON (ondansetron hydrochloride) is contraindicated in patients with a history of hypersensitivity to the drug or any components of its formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

WARNINGS AND PRECAUTIONS

General

Cross-reactive hypersensitivity has been reported between different 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.

Rarely, and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported (See Post-Market Adverse Drug Reactions).

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

Hepatic/Biliary/Pancreatic

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 or severe impairment of 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 intravenous 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.

Ondansetron does not itself appear to induce or inhibit the cytochrome P₄₅₀ drug-metabolizing enzyme system of the liver. Because ondansetron is metabolised by hepatic cytochrome P₄₅₀ drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data no dosage adjustment is recommended for patients on these drugs.

Special Populations

Pregnant Women

The safety of ondansetron for use in human 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.

Nursing Women

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.

Pediatrics (<3 years of age)

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

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Ondansetron hydrochloride has been administered to over 2500 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%).

Cardiovascular

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

Central Nervous System

There have been rare reports of seizures. Movement disorders and dyskinesia have been reported in two large clinical trials of ondansetron at a rate of 0.1 - 0.3%.

Dermatological

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

Hypersensitivity

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

Metabolic

There were transient increases of SGOT and SGPT 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.

Other

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

Special Senses

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

Post-Market Adverse Drug Reactions

Over 250 million patient treatment days of ondansetron hydrochloride oral solution have been supplied since the launch of the product worldwide. The following events have been spontaneously reported during post-approval use of ondansetron hydrochloride oral solution, although the link to ondansetron cannot always be clearly established.

General Disorders

Rare cases of hypersensitivity reactions, such as, laryngeal edema, stridor, laryngospasm and cardiopulmonary arrest have also been reported.

Cardiovascular Disorders

There have been rare reports (<0.01%) of myocardial infarction, myocardial ischemia, angina, chest pain with or without ST segment depression, arrhythmias (including ventricular or supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), electrocardiographic alterations (including second degree heart block), palpitations and syncope.

Rarely, and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation hae been reported (see Warnings and Precautions).

Eye Disorder

There have been very rare cases of transient blindness following ondansetron treatment, generally within the recommended dosing range and predominantly during intravenous administration.

The majority of blindness cases reported resolved within 20 minutes. Although most patients had received chemotherapeutic agents, including cisplatin a few cases of transient blindness occurred following ondansetron administration for the treatment of post-operative nausea or vomiting and in the absence of cisplatin treatment. Some cases of transient blindness were reported as cortical in origin.

Hepatobiliary Disorders

Occasional asymptomatic increases in liver function tests have been reported.

Nervous System Disorders

Transient episodes of dizziness (<0.01%) have been reported during or upon completion of IV infusion of ondansetron.

Uncommon reports (<1%) suggestive of extrapyramidal reactions such as oculogyric crisis/dystonic reactions (e.g. oro-facial dyskinesia, opisthotonos, tremor, etc.) movement disorders and dyskinesia have been reported without definitive evidence of persistent clinical sequelae.

Respiratory, Thoracic and Mediastinal Disorders

There have also been rare reports of hiccups.

Very rare reports have been received for bullous skin and mucosal reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis). These reports have occurred in patients taking other medications that can be associated with bullous skin and mucosal reactions.

DRUG INTERACTIONS

Drug-Drug Interactions

Specific studies have shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepam, frusemide, tramadol or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P₄₅₀ enzymes: CYP3A4, CYP2D6 and CYP1A2. Despite the multiplicity of metabolic enzymes capable of metabolising ondansetron which can compensate for an increase or decrease in enzyme activity, it was found that patients treated with inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin) demonstrated an increase in oral clearance of ondansetron and a decrease in ondansetron blood concentrations. No effect in ondansetron clearance secondary to enzyme inhibition or reduced activity (e.g. CYP2D6 genetic deficiency) has been identified to date.

Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Chemotherapy Induced Nausea and Vomiting

NU-ONDANSETRON (ondansetron hydrochloride) 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 NU-ONDANSETRON should be flexible in the range of 8-32 mg a day. The selection of dose regimen should be determined by the severity of the emetogenic challenge (See Recommended Dose and Dosage Adjustment).

Recommended Dose And Dosage Adjustment

Chemotherapy Induced Nausea and Vomiting

Use in Adults:

Highly Emetogenic Chemotherapy (e.g. regimens containing cisplatin)

Post-chemotherapy: After the first 24 hours, NU-ONDANSETRON 8 mg orally every 8ⁱ 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/h 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 NU-ONDANSETRON in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous 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: NU-ONDANSETRON 8 mg orally 1 to 2 hours prior to chemotherapy.

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

Use in Children:

Clinical experience of NU-ONDANSETRON in children is currently limited however, ondansetron hydrochloride oral solution was effective and well tolerated when given to children 4-12 years of age. After therapy, NU-ONDANSETRON 4 mg should be given orally every 8 hoursⁱ for up to 5 days. For children 3 years of age and younger, there is insufficient information available to make dosage recommendations (see INDICATIONS AND CLINICAL USE).

ⁱ 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 three times daily dosage regimens for other patient groups should be based on an assessment of the needs and responsiveness of the individual patient. Use in Elderly:

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

Use in Adults:

Initial Dose

NU-ONDANSETRON 8 mg orally 1 to 2 hours before radiotherapy.

Post-radiotherapy

NU-ONDANSETRON 8 mg orally every 8 hoursⁱ for up to 5 days after a course of treatment.

Use in Children:

There is no experience in clinical studies in this population.

Use in Elderly:

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.

Post-Operative Nausea and Vomiting

Use in Adults:

For prevention of post-operative nausea and vomiting NU-ONDANSETRON may be administered as a single dose of 16 mg given orally one hour prior to anaesthesia.

Use in Children:

There is no experience in the use of ondansetron oral solution in the prevention and treatment of postoperative nausea and vomiting in children (see INDICATIONS AND CLINICAL USE).

Use in Elderly:

There is limited experience in the use of ondansetron hydrochloride oral solution in the prevention and treatment of post-operative nausea and vomiting in the elderly (see INDICATIONS AND CLINICAL USE).

Patients with Renal/Hepatic Impairment

Use in Patients with Impaired Renal Function:

No alteration of daily dosage, frequency of dosing, or route of administration is required.

Use in Patients with Impaired Hepatic Function:

In patients with moderate or severe impairment of 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 intravenous or oral dose.

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

Patients with Poor Sparteine/Debrisoquine Metabolism

No alteration of daily dosage or frequency of dosing is recommended for patients known to be poor metabolisers of sparteine and debrisoquine.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

At present there is little information concerning overdosage with ondansetron. Individual doses of 84 mg 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 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 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ondansetron hydrochloride 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.

Pharmacodynamics

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P₄₅₀ enzymes, including CYP1A2, CYP2D6 and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolising ondansetron, it is likely that inhibition or loss of one enzyme (e.g. CYP2D6 enzyme deficiency) will be compensated by others and may result in little change in overall rates of ondansetron clearance.

Pharmacokinetics

Pharmacokinetic studies in human volunteers showed peak plasma levels of 20-30 ng/mL at around 1½ hours after an 8 mg oral dose of ondansetron. An 8 mg infusion of ondansetron resulted in peak plasma levels of 80-100 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 intravenous 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 IV 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%), sulphate conjugates (20%) and hydroxylation products (10%).

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

In a pharmacokinetic study of 16 epileptic patients maintained chronically on carbamazepine or phenytoin, reduction in AUC, C_max and T_1/2 of ondansetron was observed. This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment is recommended (see WARNINGS AND PRECAUTIONS).

STORAGE AND STABILITY

Store NU-ONDANSETRON Oral Solution at room temperature, 15° - 30°C (59° - 86°F). Protect from light. Store upright. Do not refrigerate.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms, Composition and Packaging

NU-ONDANSETRON Oral Solution contains 4 mg/5 mL of ondansetron base in the form of ondansetron hydrochloride dihydrate. NU-ONDANSETRON Oral Solution also contains the following excipients: citric acid, hydroxyethyl cellulose, purified water, sodium citrate dihydrate, sodium benzoate and strawberry flavour. NU-ONDANSETRON Oral Solution is sweetened with fructose.

Ondansetron 4 mg/5 mL (as ondansetron hydrochloride dihydrate) is supplied in 50 mL bottles.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ondansetron Hydrochloride USP

Chemical name(s): 1) 4H-Carbazol-4-one,1,2,3,9-tetrahydro-9-methyl-3-(2-methyl- 1H-imidazol-1-yl) methyl-, monohydrochloride (±)-, dihydrate;

1. 2) (±)-2,3-Dihydro-9-methyl-3-(2-methylimidazol-1-yl)methyl- carbazol-4(1H)-one monohydrochloride dihydrate;
2. 3) (3RS)-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]- 1,2,3, 9-tetrahydro-4H-carbazol-4- one hydrochloride dihydrate (EP) Molecular formula and

molecular mass: C₁₈H₁₉N₃O·HCl₂•H₂O; 365.86

Structural formula:

Physicochemical Properties:

Physical description: White to off white powder

Solubility: Sparingly soluble in water and in alcohol, soluble in methanol, slightly soluble in isopropyl alcohol and in dichloromethane, very slightly soluble in acetone, in chloroform and in ethyl acetate. pH: 4.5 – 4.6

pKa: 7.4

Melting range/point: 178.5°C - 179.5°C

CLINICAL TRIALS

Bioavailability Study Results

A standard, randomized, two-way crossover study was conducted in healthy, adult, male volunteers, under fasting conditions, to evaluate the relative bioavailability of single 8 mg oral doses of NU-ONDANSETRON Oral Solution and Zofran^® Oral Solution (10 mL of the 4 mg/ 5 mL solution). The rate and extent of absorption of ondansetron was measured and compared in the eighteen (18) subjects who completed the study. The results from measured data are summarized as follows:

N

N

N

O

H₃C

H

H₃C

HCl 2H₂O

* Arithmetic means (CV%).

**Based on the least squares estimate.

† Zofran^® is manufactured by GlaxoSmithKline, and was purchased in USA.

Clinical Trial Study Results

Clinical trial results showing the number and percentage of patients exhibiting a complete response to ondansetron (0 emetic episodes) are shown in the tables below for both post-operative and chemotherapy induced emesis.

*Results are from an initial study using a different dosing regimen.

⁺ The majority of patients included in the prevention and treatment of post-operative nausea and vomiting studies using ondansetron have been adult women receiving balanced anaesthesia for gynaecological surgery.

^Δ The majority of patients included in the prevention and treatment of post-operative nausea and vomiting studies using ondansetron have been adult women receiving balanced anaesthesia for gynaecological surgery.

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

The ferret provides an excellent model for demonstrating the antiemetic action of drugs. Emesis can be induced by antineoplastic drugs or whole body irradiation. Behavioural changes associated with these treatments are noted in these animals and may also provide a parallel for the human experience of nausea.

The antiemetic action of ondansetron has been evaluated in both male and female ferrets given cisplatin (9-10 mg/kg), cyclophosphamide (200 mg/kg) or irradiation (2 and 8 Gy, 250 kV). Intravenous doses of ondansetron (0.1-1 mg/kg) abolished cisplatin-induced emesis for up to 2 hours. In cyclophosphamide-induced emesis, subcutaneous doses of 0.5 mg/kg ondansetron completely eliminated vomiting, significantly reduced retching and delayed the onset of these responses.

The radiation-induced emesis, 0.5 mg/kg ondansetron alone completely and rapidly eliminated retching and vomiting.

The antiemetic effects of ondansetron (0.1 mg/kg) in combination with dexamethasone (2-5 mg/kg) were potentiated in ferrets with cyclophosphamide-induced emesis, compared with ondansetron alone. Ondansetron with dexamethasone produced a significant reduction in retching (65%) and vomiting (72%).

Serotonin receptors of the 5-HT₃ type are present both peripherally and on vagal nerve terminals. Ondansetron probably acts by preventing activation of these receptors or receptors located in other regions of the central nervous system. Both the peripheral and central nervous systems appear to be involved since both abdominal vagotomy and microinjection of ondansetron and other 5-HT₃ antagonists directly into the area postrema eliminate cisplatin-induced emesis, while 5-HT₁-like (methiothepin maleate) and 5-HT₂ (ketanserin) antagonists have no effect.

Ondansetron is highly selective for 5-HT₃ receptors and shows negligible binding to other receptors such as 5-HT₁-like, 5-HT₂, α1 and α2 adrenoceptors, β1 and β2 adrenoceptors, D₁ and D₂ muscarinic, nicotinic, GABA_A, H₁ and H₂ receptors.

The pharmacological specificity of ondansetron may explain the observed lack of extrapyramidal side effects often seen following similar therapy with metoclopramide, which preferentially binds to dopamine receptors of the D₂ subtype.

Among its secondary effects, ondansetron has also been shown to cause a dose-dependent increase in the rate of gastric emptying in the guinea pig which is significant at doses of 0.01-0.1 mg/kg. As gastric stasis is frequently associated with nausea, stimulation of gastric motility may be a beneficial action of ondansetron. In the cat, dog and monkey, ondansetron has little effect on heart rate, blood pressure or ECG at intravenous doses up to 3 mg/kg.

A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. The concentration at which this effect was seen may be attainable with the 32 mg IV dose, however, the clinical relevance of this finding is uncertain.

Pharmacokinetics

In mice, rats, rabbits and dogs dosed at 1 mg/kg orally and/or intravenously, the plasma half-life of ondansetron was less than 1 hour, but the half-lives of its metabolites were significantly longer. Peak plasma concentrations of ondansetron in rats and dogs ranged from 351 to 419 ng/mL for the IV dose and 8 to 15 ng/mL for the oral dose. Plasma levels were linear over a 30 fold dose range. In repeat dose studies there was no apparent accumulation of ondansetron. Ondansetron is almost completely absorbed in animals, and is rapidly metabolized by N-demethylation and hydroxylation of the indole ring, followed by conjugation with glucuronic acid and sulphate. There is significant first-pass metabolism after oral doses.

Ondansetron and its metabolites are rapidly and widely distributed in tissues, reaching higher levels than the corresponding plasma levels. In the rat and dog, ondansetron binds reversibly to tissues containing melanin and elastin. In rats and man, plasma protein binding is about 73%, while it is slightly lower in the dog (60%). Ondansetron and its metabolites cross the blood-brain barrier to only a slight extent.

Human Pharmacology

Pharmacodynamics

In vivo pharmacodynamic studies have investigated the effects of ondansetron on gastric emptying, small bowel transit time and oesophageal motility.

Both oral (16 mg tid) and intravenous (5-10 mg) doses of ondansetron failed to produce a significant effect on gastric emptying in both healthy volunteers and in patients suffering from delayed gastric emptying. However, in one study intravenous doses of 8 mg did increase gastric emptying in over half the volunteers tested.

Intravenous infusion of either 1 mg or 5 mg ondansetron tended to increase small bowel transit times and single intravenous doses of 10 mg ondansetron have been reported to decrease sphincter pressure in the lower esophagus in some subjects.

In psychomotor testing ondansetron does not impair performance nor cause sedation. MICROBIOLOGY

Not applicable.

TOXICOLOGY

Acute Toxicity

Single doses of ondansetron up to the LD₅₀ in mice and in rats were generally well tolerated. Reactions, including tremor and convulsive behaviour, occurred only at near lethal levels.

All deaths resulted from the acute effects of treatment, the observed clinical signs being consistent with the central nervous system effects associated with behavioural depression. These effects were not associated with any apparent histopathological changes in the brain. No target organ toxicity was identified.

Long Term Toxicity

Subacute Toxicity Studies

Maximum daily dose levels in rats were found to be higher when doses were gradually increased. Identical doses were rapidly lethal to rats not previously exposed to ondansetron. Post-dosing reactions, in both rats and dogs, included ataxia, exophthalmia, mydriasis, tremor and respiratory changes. Increases in liver enzymes (SGPT and SGOT) were noted at high dose levels. Dogs dosed at 6.75 mg/kg/day intravenously exhibited vein irritancy in the form of constriction and thickening, creating resistance to needle penetration. The changes were noted after seven days treatment but were reversed by decreasing the dose concentration.

Chronic Toxicity

Carcinogenicity Studies

There was no evidence of a tumourigenic effect of ondansetron in any tissue.

Mutagenicity Studies

No evidence of mutagenicity was observed in microbial mutagen tests using mutant strains of Salmonella typhimurium, Escherichia coli or Saccharomyces cerevisiae, with or without a rat-liver post-mitochondrial metabolizing system.

There was also no evidence of damage to genetic material noted in in vitro V-79 mammalian cell mutation studies, in vitro chromosome aberration tests using human peripheral lymphocytes, or in vivo chromosome aberration assays in mouse bone marrow.

Reproduction and Teratology

Ondansetron was not teratogenic in rats and rabbits at dosages up to the maximum non-convulsive level (rat: 15 mg/kg/day, rabbit: 30 mg/kg/day). No adverse effects on pregnancy or fetal and post-natal development were detected in rats and no fetal abnormalities were observed in rabbits after oral administration of ondansetron.

A slight maternal toxicity was observed at the highest dose level in intravenous organogenesis (4.0 mg/kg/day) studies in the rabbit. Effects included maternal body weight loss and increased incidence of early fetal death. In a rat fertility study, there was a dose-related decrease in the proportion of surviving pups of the F2 generation; however, the significance of this is unclear.

Administration of ondansetron to pregnant rats and rabbits, indicated there was fetal exposure to low levels of ondansetron and its metabolites. Ondansetron is retained in the fetal eye presumably bound to melanin. In rats, the transfer of ondansetron and its metabolites into breast milk was extensive. The concentration of unchanged ondansetron in breast milk was higher than in corresponding plasma samples.

Daily administration of ondansetron at dosages up to 15 mg/kg/day to pregnant rats from day 17 of pregnancy to litter day 22 had no effects on pregnancy of the parental generation or on post-natal development and mating of the F1 generation. Fetal development of the F2 generation was comparable to controls; however, the number of implantations and viable fetuses was reduced in the highest dosage group when compared with controls.

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