ONDANSETRON INPHA-MEDIS

The active ingredient in ondansetron tablets is ondansetron hydrochloride as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT 3 receptor type.

Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate.

It has the following structural formula

The molecular formula is C 18 H 19 N 3 O•HCl•2H 2 O, representing a molecular weight of 365.86 g/mol.

Ondansetron HCl dihydrate

USP is a white to off-white powder that is soluble in methanol, sparingly soluble in purified water and in alcohol, and slightly soluble in isopropyl alcohol, in dichloromethane, very slightly soluble in acetone, in chloroform and in ethyl acetate.

Each 4 mg ondansetron tablets USP for oral administration contains ondansetron HCl dihydrate USP equivalent to 4 mg of ondansetron.

Each 8 mg ondansetron tablets USP for oral administration contains ondansetron HCl dihydrate USP equivalent to 8 mg of ondansetron.

Each 16 mg ondansetron tablets USP for oral administration contains ondansetron HCl dihydrate USP equivalent to 16 mg of ondansetron.

Each 24 mg ondansetron tablets USP for oral administration contains ondansetron HCl dihydrate USP equivalent to 24 mg of ondansetron.

Each tablet also contains the inactive ingredients colloidal silicon dioxide, hypromellose 2910(5cP) (for the 4 mg and 16 mg tablets only) and hypromellose 2910 (6cP) (for the 8 mg and 24 mg tablets only), iron oxide red and iron oxide black (for the 24 mg tablet only), iron oxide yellow (for the 8 mg and 24 mg tablets only), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, and titanium dioxide. structure.

Ondansetron tablets are indicated for the prevention of nausea and vomiting associated with: highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2. initial and repeat courses of moderately emetogenic cancer chemotherapy. radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen Ondansetron tablets are also indicated for the prevention of postoperative nausea and/or vomiting.

Ondansetron tablets are 5-HT 3 receptor antagonist indicated for the prevention of: nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen postoperative nausea and/or vomiting.

Lactation QT space extension Amygdalectomy and adenoidectomy Child between and 18 years Female likely to be pregnant Pregnancy, last 6 months (of) Congestive heart failure Moderate to severe hepatic impairment Newborn exposed in utero to the medicine Intestinal obstruction Subject at risk of QT space prolongation.

Ondansetron is a selective 5-HT 3 receptor antagonist.

While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist.

Serotonin receptors of the 5-HT 3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema.

It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites.

However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine.

In humans, urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis.

The released serotonin may stimulate the vagal afferents through the 5-HT 3 receptors and initiate the vomiting reflex. 12.2 Pharmacodynamics In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time.

Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects.

Ondansetron has no effect on plasma-prolactin concentrations.

QTc interval prolongation was studied in a double-blind, single-intravenous dose, placebo-and positive-controlled, crossover trial in 58 healthy subjects.

The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 19.5 milliseconds and 5.6 milliseconds after 15minute intravenous infusions of 32 mg and 8 mg of ondansetron injection, respectively.

A significant exposure-response relationship was identified between ondansetron concentration and ΔΔQTcF.

Using the established exposure-response relationship, 24 mg infused intravenously over 15 minutes had a mean predicted (95% upper prediction interval) ΔΔQTcF of 14 milliseconds.

In contrast, 16 mg infused intravenously over 15 minutes using the same model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 milliseconds.

In this study, the 8 mg dose infused over 15 minutes did not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Absorption Ondansetron is absorbed from the gastrointestinal tract and undergoes some first-pass metabolism.

Mean bioavailability in healthy subjects, following administration of a single 8 mg tablet, is approximately 56%.

Ondansetron systemic exposure does not increase proportionately to dose.

The area under curve (AUC) from a 16 mg tablet was 24% greater than predicted from an 8 mg tablet dose.

This may reflect some reduction of first-pass metabolism at higher oral doses.

Bioavailability is also slightly enhanced by the presence of food.

Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of to 500 ng/mL.

Circulating drug also distributes into erythrocytes.

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine.

The metabolites are observed in the urine.

The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 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 metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination.

Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.

Geriatric Population: A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years compared to younger subjects.

Gender differences were shown in the disposition of ondansetron given as a single dose.

The extent and rate of absorption are greater in women than men.

Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron concentrations.

These higher plasma concentrations may in part be explained by differences in body weight between men and women.

It is not known whether these sex-related differences were clinically important.

More detailed pharmacokinetic information is contained in Tables and 6.

Table 5: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 8 mg Tablet Age-group (years) Sex (M/F) Mean Weight (kg) N Peak Plasma Concentration (ng/mL) Tine of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability to 40 M 69 6 26.2 2 3.1 0.403 0.483 F 62.7 5 42.7 1.7 3.5 0.354 0.663 61 to 74 M 77.5 6 24.1 2.1 4.1 0.384 0.585 F 60.2 6 52.4 1.9 4.9 0.255 0.643 ≥75 M 78 5 37 2.2 4.5 0.277 0.619 F 67.6 6 46.1 2.1 6.2 0.249 0.747 Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 24 mg Tablet Age-group (years) Sex (M/F) Mean Weight (kg) N Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18 to 43 M F 84.1 71.8 8 8 125.8 194.4 1.9 1.6 4.7 5.8 Renal Impairment: Renal impairment is not expected to significantly influence the total clearance of ondansetron as renal clearance represents only 5% of the overall clearance.

However, the mean plasma clearance of ondansetron was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

The reduction in clearance was variable and not consistent with an increase in half-life.

In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in healthy subjects.

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours.

CYP 3A4 Inducers: Ondansetron elimination may be affected by cytochrome P-450 inducers.

In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, C max, and t½ of ondansetron was observed.

This resulted in a significant increase in the clearance of ondansetron.

However, this increase is not thought to be clinically relevant.

Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

Concomitant administration of antacids does not alter the absorption of ondansetron.

Mechanism of action

Ondansetron is a potent and highly selective antagonist of serotonin 5-HT3 receptors involved in emetic reflex phenomena.

Its precise mode of action allowing control of nausea and vomiting is not known.

Chemotherapy and radiotherapy can lead to 5-HT release into the small intestine triggering a vomiting reflex by stimulation of 5-HT3 receptors located on the afferent fibres of the wave.

Ondansetron blocks the initiation of this reflex.

The afferent fibres of the wave can also cause 5-HT release into the postrema area, located in the floor of the fourth ventricle and this can also promote vomiting through a central mechanism.

The effect of ondansetron in the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy can also cause 5-HT release in the postrema area, located in the floor of the fourth ventricle and this can also promote vomiting through a central mechanism.

The effect of ondansetron in the management of nausea and vomiting induced by cytotoxic chemotherapy and radiation therapy is probably due to an antagonism of the 5-HT3 receptors on both central and peripheral nervous system.

• Liver status (abnormality) (Uncommon)
• Dermatosis (Very rare)
• Lyell's syndrome Toxic epidermal necrolysis
• Stevens-Johnson Syndrome Chest pain (Uncommon)
• Immediate hypersensitivity (Rare)
• Anaphylactic reaction Vision disorder (Rare)
• Transitional blindness (Very rare)
• Cortical blindness
• Feeling dizzy (Rare)
• Vertigo (Rare)
• Arrhythmia (Uncommon)
• Hot flash (Common)
• Congestive puff (Common)
• Bradycardia (Uncommon)
• Hypotension (Uncommon)
• QT space extension (Rare)
• Torsades de pointes
• Myocardial Ischemia ST segment abnormal with electrocardiogram ST-T segment anomaly
• Hoquet (Uncommon)
• Constipation (Common)
• Sensation of anal burn Ileus Intestinal occlusion
• Headache (Very common)
• Convulsions (Uncommon)
• Extrapyramidal syndrome (Uncommon)
• Abnormal movement (Uncommon)
• Oculogy crisis Dyskinesia Dystonia.

There is no specific antidote for ondansetron overdose.

Patients should be managed with appropriate supportive therapy.

In addition to the adverse reactions listed above, the following adverse reactions have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 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 a patient that took 48 mg of ondansetron 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 adverse reactions resolved completely.

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg per 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 to 2 days.

Ondansetron is contraindicated in patients: known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness Patients known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any components of the formulation.

Concomitant use of apomorphine.

See full prescribing information for the recommended dosage in adults and pediatrics Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg 2.1 Dosage The recommended dosage regimens for adult and pediatric patients are described in Table and Table 2, respectively.

Corresponding doses of ondansetron tablets may be used interchangeably.

Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Highly Emetogenic Cancer Chemotherapy A single 24 mg dose administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 Moderately Emetogenic Cancer Chemotherapy 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose.

Then administer 8 mg twice a day (every 12 hours) for to 2 days after completion of chemotherapy.

For total body irradiation: 8 mg administered to 2 hours before each fraction of radiotherapy each day. For single high-dose fraction radiotherapy to the abdomen: 8 mg administered to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the first dose for to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen: 8 mg administered to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the first dose for each day radiotherapy is given.

Postoperative 16 mg administered 1 hour before induction of anesthesia.

Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Moderately Emetogenic Cancer Chemotherapy to 17 years of age: 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose.

Then administer 8 mg twice a day (every 12 hours) for to 2 days after completion of chemotherapy. 4 to 11 years of age: 4 mg administered 30 minutes before the start of chemotherapy, with a subsequent 4 mg dose and 8 hours after the first dose.

Then administer 4 mg three times a day for to 2 days after completion of chemotherapy. 2.2 Dosage in Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg.

Ondansetron Tablets Ondansetron Tablets Ondansetron tablets

USP, 4 mg (ondansetron hydrochloride USP, equivalent to 4 mg of ondansetron) are white, round, biconvex, film coated tablets debossed “R” on one side and “153” on other side and are supplied in blistercards of 30, 15, 10, 12, and 5.

Blistercards of 30 NDC 0615-8185-39 Blistercards of 15 NDC 0615-8185-05 Blistercards of 10 NDC 0615-8185-10 Blistercards of 12 NDC 0615-8185-12 Blistercards of 5 NDC 0615-8185-00 Ondansetron tablets USP, 8 mg (ondansetron hydrochloride USP, equivalent to 8 mg of ondansetron) are yellow, round, biconvex, film coated tablets debossed “R” on one side and “154” on other side.

Ondansetron tablets

USP, 16 mg (ondansetron hydrochloride USP, equivalent to 16 mg of ondansetron) are white, round, biconvex, film coated tablets debossed “R” on one side and “155” on other side.

USP, 24 mg (ondansetron hydrochloride USP, equivalent to 24 mg of ondansetron) are pink, round, biconvex, film coated tablets debossed “R” on one side and “156” on other side.

Store at 20°-25°C (68°-77°F) .

Dispense in tight container as defined in the USP.

Store blisters in cartons.

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 postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes.

Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area (BSA), respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes.

In the

US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders.

Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses.

One large retrospective cohort study examined 1970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.

Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings.

Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54).

A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however, this association was not confirmed in other studies.

Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings.

A retrospective cohort study of 1.8 million pregnancies in the US Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43).

In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93).

Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]).

It is unknown whether ondansetron exposure in utero in the cases of cleft palate occurred during the time of palate formation (the palate is formed between the 6th and 9th weeks of pregnancy).

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ondansetron up to 15 mg/kg/day and 30 mg/kg/day, respectively, during the period of organogenesis.

With the exception of a slight decrease in maternal body weight gain in the rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring.

At doses of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal exposure margin was approximately and 24 times the maximum recommended human oral dose of 24 mg/day, respectively, based on BSA.

In a pre-and postnatal developmental toxicity study, pregnant rats received oral doses of ondansetron up to 15 mg/kg/day from Day of pregnancy to litter Day 21.

With the exception of a slight reduction in maternal body weight gain, there were no effects upon the pregnant rats and the pre-and postnatal development of their offspring, including reproductive performance of the mated F1 generation.

At a dose of 15 mg/kg/day in rats, the maternal exposure margin was approximately 6 times the maximum recommended human oral dose of 24 mg/day, based on BSA.

The safety and effectiveness of orally administered ondansetron have been established in pediatric patients 4 years and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

Use of ondansetron in these age-groups is supported by evidence from adequate and well-controlled studies of ondansetron in adults with additional data from 3 open-label, uncontrolled, non-US trials in 182 pediatric patients aged to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens.

Additional information on the use of ondansetron in pediatric patients may be found in ondansetron Injection prescribing information.

• prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.

• prevention of nausea and vomiting associated with radiotherapy.

• prevention of postoperative nausea and/or vomiting.

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US-and foreign-controlled clinical trials, for which there were subgroup analyses, 938 (19%) were aged 65 years and older.

No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger subjects.

A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects.

There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment is needed in elderly patients.