Ava-Ondansetron Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Ava-Ondansetron is indicated for:

• Prevention of nausea and vomiting associated with emetogenic chemotherapy, including high dose cisplatin and radiotherapy.
• Prevention and treatment of postoperative nausea and vomiting.

Pediatrics (<18 years of age)

Post-Chemotherapy:

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

Post-Radiotherapy:

Safety and efficacy of ondansetron hydrochloride dihydrate in any age group in this population following radiotherapy has not been established and is therefore not indicated for use in this population.

Postoperative Nausea and Vomiting:

Safety and efficacy of ondansetron hydrochloride dihydrate in any age group in this population for the prevention and treatment of postoperative 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 hydrochloride dihydrate were similar to that observed in younger adults (see DOSAGE AND ADMINISTARTION).

Postoperative Nausea and Vomiting:

Clinical experience in the use of ondansetron hydrochloride dihydrate in the prevention and treatment of postoperative nausea and vomiting is limited and is not indicated for use in this population.

CONTRAINDICATIONS

• Ava-Ondansetron is contraindicated in patients with a history of hypersensitivity to the drug or any components of its formulations. For a complete listing, see 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 POSTMARKET ADVERSE DRUG REACTIONS).

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

HEPATIC

There is no experience in patients who are clinically jaundiced. The clearance of an 8 mg intravenous dose of ondansetron hydrochloride dihydrate 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 dihydrate 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.

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 or 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.

POSTMARKET ADVERSE DRUG REACTIONS

Over 250 million patient treatment days of ondansetron hydrochloride dihydrate have been supplied since the launch of the product worldwide. The following events have been spontaneously reported during post-approval use of ondansetron hydrochloride dihydrate, 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 have 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 mainly 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 postoperative 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 Disorder

Transient episodes of dizziness (<0.01%) have been reported during or upon completion of IV infusion of ondansetron. Rare reports (<0.01%) suggestive of extrapyramidal reactions such as oculogyric crisis/dystonic reactions (e.g. oro-facial dyskinesia, opisthotonos, tremor, etc.) have been reported without definitive evidence of persistent clinical sequelae.

Respiratory, Thoracic and Mediastinal Disorders

There have also been rare reports of hiccups.

DRUG INTERACTIONS

OVERVIEW

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

Ondansetron is metabolised by multiple hepatic cytochrome P-450 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 (i.e. CYP2D6 genetic deficiency) has been identified to date.

DRUG-DRUG INTERACTIONS

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

DRUG-FOOD INTERACTIONS

Interactions with food have not been established.

DRUG-HERB INTERACTIONS

Interactions with herbal products have not been established.

DRUG-LABORATORY TEST INTERACTIONS

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING:

DOSING CONSIDERATIONS

• Ava-0ndansetron 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 dose of ondansetron hydrochloride dihydrate 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 as shown below.

RECOMMENDED DOSE AND DOSAGE ADJUSTMENT

Administration

Use in Adults:

HIGHLY EMETOGENIC CHEMOTHERAPY (e.g. regimens containing cisplatin) Ondansetron hydrochloride dihydrate has been shown to be effective in the following dose schedules for the prevention of emesis during the first 24 hours following chemotherapy:

Post-chemotherapy:

After the first 24 hours, Ava-Ondansetron tablets 8 mg orally every 8 hoursⁱ for up to 5 days.

LESS EMETOGENIC CHEMOTHERAPY (e.g. regimens containing cyclophosphamide, doxorubicin, epirubicin, fluorouracil and carboplatin)

Post-chemotherapy:

Ava-Ondansetron tablets 8 mg orally twice daily for up to 5 days.

Use in Children:

Clinical experience of ondansetron hydrochloride dihydrate in children is currently limited however, ondansetron hydrochloride dihydrate was effective and well tolerated when given to children 4-12 years of age. After therapy, ondansetron tablets 4 mg should be given orally every 8 hoursⁱⁱ 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).

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:

Ava-Ondansetron tablets 8 mg should be given orally 1 to 2 hours before radiotherapy.

Post-radiotherapy:

Ava-Ondansetron tablets 8 mg should be given 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.

POSTOPERATIVE NAUSEA AND VOMITING

Use in Adults:

For prevention of postoperative nausea and vomiting Ava-Ondansetron tablets may be given orally as a single dose of 16 mg one hour prior to anæsthesia.

Use in Children:

There is no experience in the use of ondansetron hydrochloride dihydrate 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 dihydrate in the prevention and treatment of postoperative 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:

The clearance of an 8 mg intravenous dose of ondansetron hydrochloride dihydrate 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.

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

PATIENTS WITH POOR SPARTEINE/DEBRISOQUINE METABOLISM The elimination half-life and plasma levels of a single 8 mg intravenous dose of ondansetron did not differ between subjects classified as poor and extensive metabolisers of sparteine and debrisoquine. No alteration of daily dosage or frequency of dosing is recommended for patients known to be poor metabolisers of sparteine and debrisoquine.

____________________________________________________________________________ ⁱⁱ 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.

OVERDOSAGE

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 who was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient who 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 dihydrate 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 postoperative nausea and vomiting are not known.

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 postoperative and chemotherapy induced emesis.

*The majority of patients included in the prevention and treatment of postoperative nausea and vomiting studies using ondansetron have been adult women receiving balanced anaesthesia for gynæcological surgery.

PHARMACOKINETICS

Absorption: 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.

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

Metabolism: 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.

In a pharmacokinetic study of 16 epileptic patients maintained chronically on carbamazepine or phenytoin, reduction in AUC, C_max and T_½ 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).

Excretion: Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and fæces. 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.

STORAGE AND STABILITY

Ava-Ondansetron tablets should be stored between 15 and 30ºC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Ava-Ondansetron tablets contain 8 mg of ondansetron base, in the form of ondansetron hydrochloride dihydrate. Ava-Ondansetron tablets also contain the following excipients: cellulose microcrystalline, lactose monohydrate, maize starch (pregelatinised), magnesium stearate, hypromellose, titanium dioxide, ferric oxide yellow.

Ava-Ondansetron 8 mg tablets

Yellow, film-coated tablet, formed like a bean with an embossment “O” on one side and “8" on the other side. Each tablet contains 8 mg ondansetron (as hydrochloride dihydrate). Available in blister packs of 10 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ondansetron hydrochloride dihydrate

Chemical name: (±)-2,3-Dihydro-9-methyl-3-[(2-methylimidazol-1-

yl)methyl]carbazol-4(1 H)-one monohydrochloride dihydrate. Structural formula:

Molecular formula: C₁₈H₁₉N₃O·HCl·2H₂O (hydrochloride dihydrate) Molecular mass: 365.9 g/mol

Physicochemical properties:

Description and Solubility:

Ondansetron hydrochloride dihydrate is a white to off-white powder.

Hydrochloride dihydrate

Sparingly soluble in water and in alcohol, soluble in methanol, slightly soluble in methylene chloride. The melting point of ondansetron hydrochloride dihydrate is about 177° C. pKa is 7.4 and pH of 1% w/v solution in water is approximately 4.6. The distribution coefficient between n-octanol and water is pH dependent:

log D = 2.2 at a pH of 10.60

log D = 0.6 at a pH of 5.95

CLINICAL TRIALS

Please find below the results of the open, randomized, 2 periods, 2-way crossover, bioequivalence study of ondansetron hydrochloride dihydrate (equivalent to 8 mg ondansetron) film-coated tablets (Hexal AG, Germany) and Zofran® 8 mg film-coated tablets (Glaxo

Wellcome GmbH & Co., Germany) administered as a single oral dose of 8 mg in 24 healthy adult male volunteers under fasting conditions.

Summary Table of Comparative Bioavailability Data for a Single-Dose Fasting Study of Ondansetron Hydrochloride (1 x 8 mg) Tablets

* expressed as median (range) only.

** expressed as arithmetic mean (CV%) only.

*** Zofran^®, manufactured by Glaxo Wellcome Gmbh & Co.

Country where Zofran^® was purchased: Germany.

Please find below the results of the open, randomized, 2 periods, 2-way crossover, bioequivalence study of ondansetron hydrochloride dihydrate (equivalent to 4 mg ondansetron) film-coated tablets and Zofran® 4 mg film-coated tablets (Glaxo Wellcome GmbH & Co., Germany) administered as a single oral dose of 4 mg in 26 healthy adult male volunteers under fasting conditions.

Summary Table of Comparative Bioavailability Data for a Single-Dose Fasting Study of Ondansetron Hydrochloride (1 x 4 mg) Tablets

* expressed as median (range) only.

** expressed as arithmetic mean (CV%) only.

*** Zofran^®, manufactured by Glaxo Wellcome Gmbh & Co.

Country where Zofran^® was purchased: Germany.

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, 250kV). 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 5HT₃ 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 oesophagus in some subjects.

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

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 foetal and postnatal development were detected in rats and no fœtal 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 fœtal 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 fœtal exposure to low levels of ondansetron and its metabolites. Ondansetron is retained in the fœtal 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 postnatal development and mating of the F1 generation. Fœtal development of the F2 generation was comparable to controls; however, the number of implantations and viable fœtuses was reduced in the highest dosage group when compared with controls.

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