Ondansetron

DESCRIPTION The active ingredient in ondansetron orally disintegrating tablets, USP is ondansetron base, 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-1 H-imidazol- 1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula: The molecular formula is C 18 H 19 N 3 O representing a molecular weight of 293.4. USP disintegration test pending. Each ondansetron orally disintegrating tablet, USP intended for oral administration contains 4 mg or 8 mg of ondansetron base. In addition, each ondansetron orally disintegrating tablet, USP contains the following inactive ingredients: aspartame, calcium stearate, colloidal silicon dioxide, mannitol, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, strawberry flavor and talc. Ondansetron orally disintegrating tablets, USP are a orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. structural formula

CLINICAL PHARMACOLOGY Pharmacodynamics 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-HIAA (5-hydroxyindoleacetic acid) 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. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT 3 receptor antagonist. In normal volunteers, 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 normal volunteers. Ondansetron has no effect on plasma prolactin concentrations. Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied. Pharmacokinetics Ondansetron is well 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. 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 but unaffected by antacids. Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. 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. 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. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, C max , and T ½ of ondansetron was observed. 1 This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended [ see PRECAUTIONS : Drug Interactions ]. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is 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 levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 1 and 2 taken from 2 studies. Table 1. Pharmacokinetics in Normal Volunteers: Single 8 mg Ondansetron Hydrochloride Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) Systemic Plasma Clearance L/h/kg Absolute Bioavailability 18-40 M F 69 62.7 6 5 26.2 42.7 2 1.7 3.1 3.5 0.403 0.354 0.483 0.663 61-74 M F 77.5 60.2 6 6 24.1 52.4 2.1 1.9 4.1 4.9 0.384 0.255 0.585 0.643 ≥75 M F 78 67.6 5 6 37 46.1 2.2 2.1 4.5 6.2 0.277 0.249 0.619 0.747 Table 2. Pharmacokinetics in Normal Volunteers: Single 24 mg Ondansetron Hydrochloride Tablet Dose Age-group (years) Mean Weight (kg) n Peak Plasma Concentration (ng/mL Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) 18-43 M F 84.1 71.8 8 8 125.8 194.4 1.9 1.6 4.7 5.8 A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh 2 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. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded. Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted. Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes. Four- and 8 mg doses of either ondansetron hydrochloride oral solution or ondansetron orally disintegrating tablets are bioequivalent to corresponding doses of ondansetron hydrochloride tablets and may be used interchangeably. One 24 mg ondansetron hydrochloride tablet is bioequivalent to and interchangeable with three 8 mg ondansetron hydrochloride tablets.

20191101

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Ondansetron Ondansetron ONDANSETRON ONDANSETRON ASPARTAME CALCIUM STEARATE SILICON DIOXIDE MANNITOL MICROCRYSTALLINE CELLULOSE POLACRILIN POTASSIUM SODIUM STARCH GLYCOLATE TYPE A POTATO TALC STRAWBERRY SZ;342 Ondansetron Ondansetron ONDANSETRON ONDANSETRON ASPARTAME CALCIUM STEARATE SILICON DIOXIDE MANNITOL MICROCRYSTALLINE CELLULOSE POLACRILIN POTASSIUM SODIUM STARCH GLYCOLATE TYPE A POTATO TALC STRAWBERRY SZ;343

ANDA078050

Ondansetron

Ondansetron

63187-002

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel 63187-002-10

CLINICAL TRIALS Chemotherapy-Induced Nausea and Vomiting Highly Emetogenic Chemotherapy In 2 randomized, double-blind, monotherapy trials, a single 24 mg ondansetron hydrochloride tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m 2 . Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥ 50 mg/m 2 in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy. The first trial compared oral doses of ondansetron 24 mg once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin ≥ 50 mg/m 2 . A total of 66% of patients in the ondansetron 24 mg once a day group, 55% in the ondansetron 8-mg twice a day group, and 55% in the ondansetron 32-mg once a day group completed the 24 hour study period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control. In the same trial, 56% of patients receiving oral ondansetron 24 mg once a day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral ondansetron 8 mg twice a day group ( P = 0.001) and 50% in the oral ondansetron 32 mg once a day group. In a second trial, efficacy of the oral ondansetron 24 mg once a day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m 2 , was confirmed. Moderately Emetogenic Chemotherapy In 1 double-blind US study in 67 patients, ondansetron hydrochloride tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3 : Table 3. Emetic Episodes: Treatment Response Ondansetron 8 mg b.i.d. ondansetron hydrochloride tablets* Placebo P Value Number of patients 33 34 Treatment response 0 Emetic episodes 20 (61%) 2 (6%) < 0.001 1-2 Emetic episodes 6 (18%) 8 (24%) More than 2 emetic episodes/withdrawn 7 (21%) 24(71%) < 0.001 Median number of emetic episodes 0 Undefined † Median time to first emetic episode (h) Undefined ‡ 6.5 * The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8 mg ondansetron hydrochloride tablet was administered twice a day for 2 days after completion of chemotherapy. † Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. ‡ Median undefined since at least 50% of patients did not have any emetic episodes. In 1 double-blind US study in 336 patients, ondansetron hydrochloride tablets 8 mg administered twice a day were as effective as ondansetron hydrochloride tablets 8 mg administered 3 times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4 : Table 4. Emetic Episodes: Treatment Response Ondansetron 8 mg b.i.d. ondansetron hydrochloride tablets* 8 mg t.i.d. ondansetron hydrochloride tablets † Number of patients 165 171 Treatment response 0 Emetic episodes 101 (61%) 99 (58%) 1-2 Emetic episodes 16 (10%) 17 (10%) More than 2 emetic episodes/withdrawn 48 (29%) 55 (32%) Median number of emetic episodes 0 0 Median time to first emetic episode (h) Undefined ‡ Undefined ‡ Median nausea scores (0-100) § 6 6 * The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8 mg ondansetron hydrochloride tablet was administered twice a day for 2 days after completion of chemotherapy. † The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8 mg ondansetron hydrochloride tablet was administered 3 times a day for 2 days after completion of chemotherapy. ‡ Median undefined since at least 50% of patients did not have any emetic episodes. § Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be. Re-treatment In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron hydrochloride tablets 8 mg 3 times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11 %) of the re-treatment courses. Pediatric Studies Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or noncisplatin regimens. In these foreign trials, the initial dose of ondansetron hydrochloride injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the administration of ondansetron hydrochloride tablets ranging from 4 to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ondansetron hydrochloride tablets 4 mg 3 times a day to be similar to those in patients 12 to 18 years of age who received ondansetron hydrochloride tablets 8 mg 3 times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ondansetron hydrochloride tablets were well tolerated in these pediatric patients. Radiation-Induced Nausea and Vomiting Total Body Irradiation In a randomized, double-blind study in 20 patients, ondansetron hydrochloride tablets (8 mg given 1.5 hours before each fraction of radiotherapy for 4 days) were significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on day 4. Single High-Dose Fraction Radiotherapy Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of ≥ 80 cm 2 to the abdomen. Patients received the first dose of ondansetron hydrochloride tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet late afternoon and 1 tablet before bedtime). If radiotherapy was given in the afternoon, patients took only 1 further tablet that day before bedtime. Patients continued the oral medication on a 3 times a day basis for 3 days. Daily Fractionated Radiotherapy Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of ≥ 100 cm 2 to the abdomen. Patients received the first dose of ondansetron hydrochloride tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with 2 subsequent doses on a 3 times a day basis. Patients continued the oral medication on a 3 times a day basis on each day of radiotherapy. Postoperative Nausea and Vomiting Surgical patients who received ondansetron 1 hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 1 foreign) involving 865 patients. Ondansetron hydrochloride tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting. The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ondansetron hydrochloride tablets to ondansetron injection has been performed.