The active ingredient in ondansetron 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-1 H-imidazol-
1-yl)methyl]-4H-carbazol-4-one. It has the following structural formula:
The molecular formula is C18H19N3O representing a molecular weight of
293.4.
USP disintegration test pending.
Each ondansetron orally disintegrating tablet intended for oral
administration contains 4 mg or 8 mg of ondansetron base. In addition, each
ondansetron orally disintegrating tablet 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 are a
orally administered formulation of ondansetron which rapidly disintegrates on
the tongue and does not require water to aid dissolution or swallowing.
Clinical Pharmacology
Pharmacodynamics 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. 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, Cmax, and T½ 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 was 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-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 less than 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.
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 greater than or equal to 50 mg/m2. Steroid administration was excluded from these clinical
trials. More than 90% of patients receiving a cisplatin dose greater than or equal to 50 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 cisplatin greater than or equal to 50 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 cisplatin greater than or equal to 50 mg/m2, 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:
* 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 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 greater than or equal to 80 cm2 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 greater than or equal to 100 cm2 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.
Indications And Usage
1. Prevention of nausea and vomiting associated with highly
emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2.
2. Prevention of nausea and vomiting associated with initial and repeat
courses of moderately emetogenic cancer chemotherapy.
3. Prevention of 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.
4. Prevention of postoperative nausea and/or vomiting. As with other
antiemetics, routine prophylaxis is not recommended for patients in whom there
is little expectation that nausea and/or vomiting will occur postoperatively. In
patients where nausea and/or vomiting must be avoided postoperatively,
ondansetron hydrochloride tablets, ondansetron orally disintegrating tablets,
and ondansetron hydrochloride oral solution are recommended even where the
incidence of postoperative nausea and/or vomiting is low.
Contraindications
Ondansetron orally disintegrating tablets are contraindicated for patients known
to have hypersensitivity to the drug.
Warnings
Hypersensitivity reactions have been reported in patients who have exhibited
hypersensitivity to other selective 5-HT3 receptor
antagonists.
Precautions
General Ondansetron is not a drug that stimulates gastric or intestinal
peristalsis. It should not be used instead of nasogastric suction. The use of
ondansetron in patients following abdominal surgery or in patients with
chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or
gastric distension.
Rarely and predominantly with intravenous ondansetron, transient ECG changes
including QT interval prolongation have been reported. Information for PatientsPhenylketonurics Phenylketonuric patients should be informed that ondansetron
orally disintegrating tablets contain phenylalanine (a component of aspartame).
Each 4-mg and 8-mg orally disintegrating tablet contains 3 mg and 6 mg of
phenylalanine respectively.
Patients should be instructed not to remove ondansetron orally disintegrating
tablets from the buler until just prior to dosing. The tablet should not be
pushed through the foil. With dry hands, the buler backing should be peeled
completely off the buler. The tablet should be gently removed and immediately
placed on the tongue to dissolve and be swallowed with the saliva. Peelable
illustrated stickers are affixed to the product carton that can be provided with
the prescription to ensure proper use and handling of the product. Drug Interactions Ondansetron does not itself appear to induce or inhibit the
cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL
PHARMACOLOGY, Pharmacokinetics ).
Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing
enzymes (CYP3A4, CYP2D6, CYP1A2), 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. Phenytoin, Carbamazepine, and
Rifampicin In patients treated with potent inducers of CYP3 A4 (i.e.,
phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was
significantly increased and ondansetron blood concentrations were decreased.
However, on the basis of available data, no dosage adjustment for ondansetron is
recommended for patients on these drugs.1,3 Tramadol Although no pharmacokinetic drug interaction between ondansetron
and tramadol has been observed, data from 2 small studies indicate that
ondansetron may be associated with an increase in patient controlled
administration of tramadol.4,5 Chemotherapy Tumor response to chemotherapy in the P-388 mouse leukemia model
is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin
do not affect the pharmacokinetics of ondansetron.
In a crossover study in 76 pediatric patients, I.V. ondansetron did not
increase blood levels of high-dose methotrexate. Use in Surgical Patients The coadministration of ondansetron had no effect on the
pharmacokinetics and pharmacodynamics of temazepam. Carcinogenesis, Mutagenesis, Impairment of
Fertility Carcinogenic effects were not seen in 2-year studies in rats and
mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively.
Ondansetron was not mutagenic in standard tests for mutagenicity. Oral
administration of ondansetron up to 15 mg/kg/day did not affect fertility or
general reproductive performance of male and female rats. Pregnancy Teratogenic Effects Pregnancy Category B. Reproduction studies have been performed in
pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day,
respectively, and have revealed no evidence of impaired fertility or harm to the
fetus due to ondansetron. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if
clearly needed. Nursing Mothers Ondansetron is excreted in the breast milk of rats. It is not
known whether ondansetron is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when ondansetron is
administered to a nursing woman. Pediatric Use Little information is available about dosage in pediatric
patients 4 years of age or younger (see CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION sections for use in pediatric patients 4 to 18 years of
age). Geriatric Use 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
were 65 years of age and over. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and 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. Dosage adjustment is not needed in patients over the age of
65 (see CLINICAL
PHARMACOLOGY).
Adverse Reactions
The following have been reported as adverse events in clinical
trials of patients treated with ondansetron, the active ingredient of
ondansetron hydrochloride tablets, ondansetron orally disintegrating tablets and
ondansetron hydrochloride oral solution. A causal relationship to therapy with
ondansetron has been unclear in many cases. Chemotherapy-Induced Nausea and Vomiting The adverse events in Table 5 have been reported in greater than or equal to 5% of adult
patients receiving a single 24-mg ondansetron hydrochloride tablet in 2 trials.
These patients were receiving concurrent highly emetogenic cisplatin-based
chemotherapy regimens (cisplatin dose greater than or equal to 50 mg/m2).
Table 5. Principal Adverse Events in US Trials: Single Day
Therapy With 24-mg Ondansetron Hydrochloride Tablets (Highly Emetogenic
Chemotherapy)
Event
Ondansetron 24 mg q.d. n = 300
Ondansetron 8 mg b.i.d.
n=124
Ondansetron 32 mg q.d.
n=117
Headache
33 (11%)
16 (13%)
17 (15%)
Diarrhea
13 (4%)
9 (7%)
3 (3%)
The adverse events in Table 6 have been reported in greater than or equal to 5% of adults receiving
either 8 mg of ondansetron hydrochloride tablets 2 or 3 times a day for 3 days
or placebo in 4 trials. These patients were receiving concurrent moderately
emetogenic chemotherapy, primarily cyclophosphamide-based regimens.
Table 6. Principal Adverse Events in US Trials: 3 Days of
Therapy With 8-mg Ondansetron Hydrochloride Tablets (Moderately Emetogenic
Chemotherapy)
Event
Ondansetron 8 mg b.i.d. n = 242
Ondansetron 8 mg t.i.d. n =
415
Placebo
n = 262
Headache
58 (24%)
113 (27%)
34 (13%)
Malaise/fatigue
32 (13%)
37 (9%)
6 (2%)
Constipation
22 (9%)
26 (6%)
1 (less than 1%)
Diarrhea
15 (6%)
16 (4%)
10 (4%)
Dizziness
13 (5%)
18 (4%)
12
(5%)
Central Nervous System There have been rare reports consistent with, but not diagnostic
of, extrapyramidal reactions in patients receiving ondansetron. Hepatic In 723 patients receiving cyclophosphamide-based chemotherapy in
US clinical trials, AST and/or ALT values have been reported to exceed twice the
upper limit of normal in approximately 1% to 2% of patients receiving
ondansetron hydrochloride tablets. The increases were transient and did not
appear to be related to dose or duration of therapy. On repeat exposure, similar
transient elevations in transaminase values occurred in some courses, but
symptomatic hepatic disease did not occur. The role of cancer chemotherapy in
these biochemical changes cannot be clearly determined.
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. Integumentary Rash has occurred in approximately 1% of patients receiving
ondansetron. Other Rare cases of anaphylaxis, bronchospasm, tachycardia, angina
(chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive
events, and grand mal seizures have been reported. Except for bronchospasm and
anaphylaxis, the relationship to ondansetron was unclear. Radiation-Induced Nausea and Vomiting The adverse events reported in patients receiving ondansetron
hydrochloride tablets and concurrent radiotherapy were similar to those reported
in patients receiving ondansetron hydrochloride tablets and concurrent
chemotherapy. The most frequently reported adverse events were headache,
constipation, and diarrhea. Postoperative Nausea and Vomiting The adverse events in Table 7 have been reported in greater than or equal to 5% of
patients receiving ondansetron hydrochloride tablets at a dosage of 16 mg orally
in clinical trials. With the exception of headache, rates of these events were
not significantly different in the ondansetron and placebo groups. These
patients were receiving multiple concomitant perioperative and postoperative
medications.
Table 7. Frequency of Adverse Events From Controlled Studies
With Ondansetron Hydrochloride Tablets (Postoperative Nausea and
Vomiting)
Adverse Event
Ondansetron 16 mg (n = 550)
Placebo (n = 531)
Wound problem
152 (28%)
162 (31%)
Drowsiness/sedation
112 (20%)
122 (23%)
Headache
49 (9%)
27 (5%)
Hypoxia
49 (9%)
35 (7%)
Pyrexia
45 (8%)
34 (6%)
Dizziness
36 (7%)
34 (6%)
Gynecological disorder
36 (7%)
33 (6%)
Anxiety/agitation
33 (6%)
29 (5%)
Bradycardia
32 (6%)
30 (6%)
Shiver(s)
28 (5%)
30 (6%)
Urinary retention
28 (5%)
18 (3%)
Hypotension
27 (5%)
32 (6%)
Pruritus
27 (5%)
20 (4%)
Preliminary observations in a small number of subjects suggest a higher
incidence of headache when ondansetron orally disintegrating tablets are taken
with water, when compared to without water. Observed During Clinical Practice In addition to adverse events reported from clinical trials, the
following events have been identified during post-approval use of oral
formulations of ondansetron. Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot be made. The events
have been chosen for inclusion due to a combination of their seriousness,
frequency of reporting, or potential causal connection to ondansetron. Cardiovascular Rarely and predominantly with intravenous ondansetron, transient
ECG changes including QT interval prolongation have been reported. General Flushing. Rare cases of hypersensitivity reactions, sometimes
severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm,
shortness of breath, hypotension, laryngeal edema, stridor) have also been
reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during
allergic reactions in patients receiving injectable ondansetron. Hepatobiliary Liver enzyme abnormalities Lower Respiratory Hiccups Neurology Oculogyric crisis, appearing alone, as well as with other
dystonic reactions Skin Urticaria Special Senses: Eye
Disorders Cases of transient blindness, predominantly during intravenous
administration, have been reported. These cases of transient blindness were
reported to resolve within a few minutes up to 48 hours.
Drug Abuse And Dependence
Animal studies have shown that ondansetron is not discriminated as a
benzodiazepine nor does it substitute for benzodiazepines in direct addiction
studies.
Overdosage
There is no specific antidote for ondansetron overdose. Patients
should be managed with appropriate supportive therapy. Individual intravenous
doses as large as 150 mg and total daily intravenous doses as large as 252 mg
have been inadvertently administered without significant adverse events. These
doses are more than 10 times the recommended daily dose.
In addition to the adverse events uled above, the following events have
been described in the setting of ondansetron overdose: "Sudden blindness"
(amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in 1
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 hydrochloride 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 events resolved completely.
Dosage And Administration
Instructions for Use/Handling Ondansetron Orally Disintegrating Tablets Do not attempt to push ondansetron orally disintegrating tablets
through the foil backing. With dry hands, PEEL BACK the foil backing of 1
buler and GENTLY remove the tablet. IMMEDIATELY place the ondansetron orally
disintegrating tablet on top of the tongue where it will dissolve in seconds,
then swallow with saliva. Administration with liquid is not necessary. Prevention of Nausea and Vomiting Associated With
Highly Emetogenic Cancer Chemotherapy The recommended adult oral dosage of ondansetron hydrochloride
tablets is 24-mg administered 30 minutes before the start of single-day highly
emetogenic chemotherapy, including cisplatin ≥ 50 mg/m2.
Multiday, single-dose administration of a 24 mg dosage has not been
studied. Pediatric Use There is no experience with the use of 24-mg dosage in pediatric
patients. Geriatric Use The dosage recommendation is the same as for the general
population. Prevention of Nausea and Vomiting Associated With
Moderately Emetogenic Cancer Chemotherapy The recommended adult oral dosage is one 8-mg ondansetron
hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10
mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron
hydrochloride oral solution given twice a day. The first dose should be
administered 30 minutes before the start of emetogenic chemotherapy, with a
subsequent dose 8 hours after the first dose.
One 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally
disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of
ondansetron) of ondansetron hydrochloride oral solution should be administered
twice a day (every 12 hours) for 1 to 2 days after completion of
chemotherapy. Pediatric Use For pediatric patients 12 years of age and older, the dosage is
the same as for adults. For pediatric patients 4 through 11 years of age, the
dosage is one 4-mg ondansetron hydrochloride tablet or one 4-mg ondansetron
orally disintegrating tablet or 5 mL (1 teaspoonful equivalent to 4 mg of
ondansetron) of ondansetron hydrochloride oral solution given 3 times a day. The
first dose should be administered 30 minutes before the start of emetogenic
chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg
ondansetron hydrochloride tablet or one 4-mg ondansetron orally disintegrating
tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ondansetron
hydrochloride oral solution should be administered 3 times a day (every 8 hours)
for 1 to 2 days after completion of chemotherapy. Geriatric Use The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With
Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or
Daily Fractions to the Abdomen The recommended oral dosage is one 8-mg ondansetron hydrochloride
tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2
teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride
oral solution given 3 times a day.
For total body irradiation, one 8-mg ondansetron
hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10
mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron
hydrochloride oral solution should be administered 1 to 2 hours before each
fraction of radiotherapy administered each day.
For single high-dose fraction radiotherapy to the
abdomen, one 8-mg ondansetron hydrochloride tablet or one 8-mg
ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to
8 mg of ondansetron) of ondansetron hydrochloride oral solution should be
administered 1 to 2 hours before radiotherapy, with subsequent doses every 8
hours after the first dose for 1 to 2 days after completion of radiotherapy.
For daily fractionated radiotherapy to the abdomen,
one 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally
disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of
ondansetron) of ondansetron hydrochloride oral solution should be administered 1
to 2 hours before radiotherapy, with subsequent doses every 8 hours after the
first dose for each day radiotherapy is given. Pediatric Use There is no experience with the use of ondansetron hydrochloride
tablets, ondansetron orally disintegrating tablets, or ondansetron hydrochloride
oral solution in the prevention of radiation-induced nausea and vomiting in
pediatric patients. Geriatric Use The dosage recommendation is the same as for the general
population. Postoperative Nausea and Vomiting The recommended dosage is 16 mg given as two 8-mg ondansetron
hydrochloride tablets or two 8-mg ondansetron orally disintegrating tablets or
20 mL (4 teaspoonfuls equivalent to16 mg of ondansetron) of ondansetron
hydrochloride oral solution 1 hour before induction of anesthesia. Pediatric Use There is no experience with the use of ondansetron hydrochloride
tablets, ondansetron orally disintegrating tablets, or ondansetron hydrochloride
oral solution in the prevention of postoperative nausea and vomiting in
pediatric patients. Geriatric Use The dosage is the same as for the general population. Dosage Adjustment for Patients With Impaired Renal
Function The dosage recommendation is the same as for the general
population. There is no experience beyond first-day administration of
ondansetron. Dosage Adjustment for Patients With Impaired Hepatic
Function In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent
volume of distribution is increased with a resultant increase in plasma
half-life. In such patients, a total daily dose of 8 mg should not be exceeded.
How Supplied
Ondansetron Orally Disintegrating Tablets USP,
equivalent to 4 mg of ondansetron base, are white to off white, round,
flat, beveled edged tablets, debossed with “SZ” on one side and “342”
on the other side, and are supplied as follows:
Bottles of 10
NDC 54868-5887-0
Bottles of 15
NDC 54868-5887-1
Ondansetron
Orally Disintegrating Tablets USP, equivalent to 8 mg of ondansetron
base, are white to off white, round, flat, beveled edged tablets,
debossed with “SZ” on one side and “343” on the other side, and are
supplied as follows:
Bottles of 10
NDC 54868-5749-0
Bottles of 15
NDC 54868-5749-1
STORAGE AND HANDLING SECTION
Store at 20° - 25°C (68° - 77°F) (see USP Controlled Room Temperature).
REFERENCE
1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND)
metabolism in humans. Clin Pharmacol Ther 1997;61:228.
2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the
oesophagus for bleeding oesophageal varices. Brit J Surg. 1973; 60:646-649.
3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral
and intravenous ondansetron. Clin Pharmacol Ther 1999;65:377-381.
4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg 2001;92:1319-1321.
5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg 2002;94:1553-1557.
Manufactured in India by Sandoz Private Limited
For Sandoz Inc. Princeton, NJ 08540
Revised October 2008
Relabeling and Repackaging by:
Physicians Total Care, Inc.Tulsa, OK 74146
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