The active ingredient in ZOFRAN Tablets and ZOFRAN Oral Solution is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 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 empirical formula is C18H19N3OHCl2H2O, representing a molecular weight of 365.9.
Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline.
The active ingredient in ZOFRAN ODT Orally Disintegrating Tablets is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula:
The empirical formula is C18H19N3O representing a molecular weight of 293.4.
Each 4-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. Each 8-mg ZOFRAN Tablet for oral administration contains ondansetron HCl dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, pregelatinized starch, hypromellose, magnesium stearate, titanium dioxide, triacetin, and iron oxide yellow (8-mg tablet only).
Each 4-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 4 mg ondansetron base. Each 8-mg ZOFRAN ODT Orally Disintegrating Tablet for oral administration contains 8 mg ondansetron base. Each ZOFRAN ODT Tablet also contains the inactive ingredients aspartame, gelatin, mannitol, methylparaben sodium, propylparaben sodium, and strawberry flavor. ZOFRAN ODT Tablets are a freeze-dried, orally administered formulation of ondansetron which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing.
Each 5 mL of ZOFRAN Oral Solution contains 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron. ZOFRAN Oral Solution contains the inactive ingredients citric acid anhydrous, purified water, sodium benzoate, sodium citrate, sorbitol, and strawberry flavor.
Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 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-HT3 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-HT3 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.
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, Cmax, and Tof 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 ZOFRAN Tablet Dose
Age-group (years)Mean Weight (kg)nPeak Plasma Concentration (ng/mL)Time of Peak Plasma Concentration (h)Mean Elimination Half-life (h)Systemic Plasma Clearance L/h/kgAbsolute Bioavailability18-40 M F69.0 62.76 526.2 42.72.0 1.73.1 3.50.403 0.3540.483 0.66361-74 M F77.5 60.26 624.1 52.42.1 1.94.1 4.90.384 0.2550.585 0.64375 M F78.0 67.65 637.0 46.12.2 2.14.5 6.20.277 0.2490.619 0.747
Table 2. Pharmacokinetics in Normal Volunteers: Single 24-mg ZOFRAN Tablet Dose
Age-group (years)Mean Weight (kg)nPeak Plasma Concentration (ng/mL)Time of Peak Plasma Concentration (h)Mean Elimination Half-life (h)18-43 M F84.1 71.88 8125.8 194.41.9 1.64.7 5.8
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-Pugh2 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 ZOFRAN Oral Solution or ZOFRAN ODT Orally Disintegrating Tablets are bioequivalent to corresponding doses of ZOFRAN Tablets and may be used interchangeably. One 24-mg ZOFRAN Tablet is bioequivalent to and interchangeable with three 8-mg ZOFRAN Tablets.
Chemotherapy-Induced Nausea and Vomiting
Highly Emetogenic Chemotherapy
In 2 randomized, double-blind, monotherapy trials, a single 24-mg ZOFRAN Tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose50 mg/m2 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 cisplatin50 mg/m2. 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 cisplatin50 mg/m2, was confirmed.
Moderately Emetogenic Chemotherapy
In 1 double-blind US study in 67 patients, ZOFRAN 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. ZOFRAN TabletsaPlaceboP ValueNumber of patients3334Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn20 (61%) 6 (18%) 7 (21%)2 (6%) 8 (24%) 24 (71%)< 0.001 < 0.001Median number of emetic episodes0.0UndefinedbMedian time to first emetic episode (h)Undefinedc6.5a 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 ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy.
b Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes.
c Median undefined since at least 50% of patients did not have any emetic episodes.
In 1 double-blind US study in 336 patients, ZOFRAN Tablets 8 mg administered twice a day were as effective as ZOFRAN 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
Ondansetron8-mg b.i.d. ZOFRAN Tabletsa8-mg t.i.d. ZOFRAN TabletsbNumber of patients165171Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn101 (61%) 16 (10%) 48 (29%)99 (58%) 17 (10%) 55 (32%)Median number of emetic episodes0.00.0Median time to first emetic episode (h)UndefinedcUndefinedcMedian nausea scores (0-100)d66a 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 ZOFRAN Tablet was administered twice a day for 2 days after completion of chemotherapy.
b 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 ZOFRAN Tablet was administered 3 times a day for 2 days after completion of chemotherapy.
c Median undefined since at least 50% of patients did not have any emetic episodes.
d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ZOFRAN 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.
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 ZOFRAN(ondansetron HCl) 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 ZOFRAN 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 ZOFRAN Tablets 4 mg 3 times a day to be similar to those in patients 12 to 18 years of age who received ZOFRAN 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, ZOFRAN 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, ZOFRAN 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 of80 cm2 to the abdomen. Patients received the first dose of ZOFRAN 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 of100 cm2 to the abdomen. Patients received the first dose of ZOFRAN 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
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 ZOFRAN Tablets to ZOFRAN Injection has been performed.