zofran
Generic Name: (
ondansetron hydrochloride)
Dosage Type: solution zofran
Generic Name: (
ondansetron hydrochloride)
Dosage Type: tablet, film coated zofran
Generic Name: (
ondansetron)
Dosage Type: tablet, orally disintegrating
DESCRIPTION
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
C18H19N3O•HCl•2H2O, 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.
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, followingadministration 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 T˝ 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 ZOFRAN 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
|
69.0
62.7
|
6
5
|
26.2
42.7
|
2.0
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
|
78.0
67.6
|
5
6
|
37.0
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 ZOFRAN 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 <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.
CLINICAL TRIALS
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 cisplatin =50 mg/m2. Steroid administration was excluded from these clinical
trials. More than 90% of patients receiving a cisplatin dose =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 =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 =50 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 Tablets*
|
Placebo
|
p Value
|
|
Number
of patients
|
33
|
34
|
|
|
Treatment
response
0 Emetic episodes
1-2 Emetic episodes
More than 2 emetic episodes/withdrawn
|
20 (61%)
6 (18%)
7 (21%)
|
2 (6%)
8 (24%)
24 (71%)
|
<0.001
<0.001
|
|
Median
number of
emetic episodes
|
0.0
|
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 ZOFRAN 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, 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
|
|
Ondansetron
|
|
|
8-mg b.i.d.
ZOFRAN Tablets*
|
8-mg t.i.d.
ZOFRAN Tablets†
|
|
Number
of patients
|
165
|
171
|
|
Treatment
response
0 Emetic episodes
1-2 Emetic episodes
More than 2 emetic episodes/withdrawn
|
101
(61%)
16 (10%)
48 (29%)
|
99
(58%)
17 (10%)
55 (32%)
|
|
Median
number of emetic episodes
|
0.0
|
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 ZOFRAN 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 ZOFRAN 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 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.
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 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 of =80 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 of =100 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
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. ZOFRAN 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 ZOFRAN Tablets to ZOFRAN 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,
ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating Tablets, and ZOFRAN
Oral Solution are recommended even where the incidence of postoperative
nausea and/or vomiting is low.
CONTRAINDICATIONS
ZOFRAN Tablets, ZOFRAN ODT Orally Disintegrating
Tablets, and ZOFRAN Oral Solution 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 Patients
Phenylketonurics: Phenylketonuric
patients should be informed that ZOFRAN ODT Orally Disintegrating
Tablets contain phenylalanine (a component of aspartame). Each 4-mg
and 8-mg orally disintegrating tablet contains <0.03 mg phenylalanine.
Patients should be instructed not to remove ZOFRAN ODT
Tablets from the blister until just prior to dosing. The tablet should
not be pushed through the foil. With dry hands, the blister backing
should be peeled completely off the blister. 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 CYP3A4 (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 ZOFRAN. A causal relationship to therapy with ZOFRAN
has been unclear in many cases.
Chemotherapy-Induced Nausea and Vomiting
The adverse
events in Table 5 have been reported in =5% of adult patients
receiving a single 24-mg ZOFRAN Tablet in 2 trials. These patients
were receiving concurrent highly emetogenic cisplatin-based chemotherapy
regimens (cisplatin dose =50 mg/m2).
Table 5. Principal Adverse Events in US Trials: Single
Day Therapy With 24-mg ZOFRAN 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 =5% of adults receiving either 8 mg of ZOFRAN 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
ZOFRAN 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 (<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 ZOFRAN 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 ZOFRAN was unclear.
Radiation-Induced Nausea and Vomiting
The adverse
events reported in patients receiving ZOFRAN Tablets and concurrent
radiotherapy were similar to those reported in patients receiving
ZOFRAN 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 =5% of patients
receiving ZOFRAN 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 ZOFRAN 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%)
|
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 ZOFRAN. 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 ZOFRAN.
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 benzodiazepinesin 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 listed 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 ZOFRAN 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 ZOFRAN
ODT Orally Disintegrating Tablets
Do not attempt
to push ZOFRAN ODT Tablets through the foil backing. With dry hands,
PEEL BACK the foil backing of 1 blister and GENTLY remove the
tablet. IMMEDIATELY place the ZOFRAN ODT 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 ZOFRAN is 24 mg given as three 8-mg tablets
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 a 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 ZOFRAN Tablet or one 8-mg ZOFRAN ODT
Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg
of ondansetron) of ZOFRAN 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 ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL
(2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN
Oral Solution should be administered twice a day (every 12 hours)
for 1 to 2 days after completion of chemotherapy.
PediatricUse: 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 ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL
(1 teaspoonful equivalent to 4 mg of ondansetron) of ZOFRAN
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
ZOFRAN Tablet or one 4-mg ZOFRAN ODT Tablet or 5 mL (1 teaspoonful
equivalent to 4 mg of ondansetron) of ZOFRAN 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 ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet
or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron)
of ZOFRAN Oral Solution given 3 times a day.
For total body irradiation, one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT
Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg
of ondansetron) of ZOFRAN 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 ZOFRAN Tablet or
one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent
to 8 mg of ondansetron) of ZOFRAN 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 ZOFRAN Tablet
or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent
to 8 mg of ondansetron) of ZOFRAN 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 ZOFRAN Tablets, ZOFRAN ODT Tablets, or ZOFRAN 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 ZOFRAN Tablets
or two 8-mg ZOFRAN ODT Tablets or 20 mL (4 teaspoonfuls
equivalent to 16 mg of ondansetron) of ZOFRAN Oral Solution 1 hour before induction of anesthesia.
Pediatric Use: There is no experience with the use of ZOFRAN Tablets,
ZOFRAN ODT Tablets, or ZOFRAN 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
ZOFRAN Tablets, 4 mg (ondansetron HCl dihydrate
equivalent to 4 mg of ondansetron), are white, oval, film-coated
tablets engraved with "Zofran" on one side and "4" on the other in
daily unit dose packs of 3 tablets (NDC 0173-0446-04), bottles
of 30 tablets (NDC 0173-0446-00), and unit dose packs of 100 tablets
(NDC 0173-0446-02).
Bottles:Store between 2° and 30°C (36° and
86°F). Protect from light.
Dispense in tight, light-resistant container as defined in the USP.
Unit Dose Packs: Store between 2° and
30°C (36° and 86°F). Protect from light. Store blisters
in cartons.
ZOFRAN Tablets, 8 mg (ondansetron
HCl dihydrate equivalent to 8 mg of ondansetron), are yellow,
oval, film-coated tablets engraved with "Zofran" on one side and "8"
on the other in daily unit dose packs of 3 tablets (NDC 0173-0447-04),
bottles of 30 tablets (NDC 0173-0447-00), and unit dose packs
of 100 tablets (NDC 0173-0447-02).
Bottles:Store
between 2° and 30°C (36° and 86°F). Dispense in tight container as defined in the USP.
Unit Dose Packs: Store between 2° and 30°C
(36° and 86°F).
ZOFRAN ODT Orally
Disintegrating Tablets, 4 mg (as 4 mg ondansetron base)
are white, round and plano-convex tablets debossed with a“Z4”
on one side in unit dose packs of 30 tablets (NDC 0173-0569-00).
ZOFRAN ODT Orally Disintegrating Tablets, 8 mg (as
8 mg ondansetron base) are white, round and plano-convex tablets
debossed with a “Z8” on one side in unit dose packs
of 10 tablets (NDC 0173-0570-04) and 30 tablets (NDC 0173-0570-00).
Store between 2° and 30°C (36° and 86°F).
ZOFRAN Oral Solution, a clear, colorless
to light yellow liquid with a characteristic strawberry odor, contains
5 mg of ondansetron HCl dihydrate equivalent to 4 mg of
ondansetron per 5 mL in amber glass bottles of 50 mL with
child-resistant closures (NDC 0173-0489-00).
Store upright between 15° and 30°C (59° and 86°F). Protect from light. Store bottles upright in
cartons.
REFERENCES
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, Romanň R, et al. Anesth Analg. 2002;94:1553-1557.
GlaxoSmithKline
Research Triangle
Park, NC 27709
ZOFRAN Tablets and Oral Solution:
GlaxoSmithKline
Research Triangle
Park, NC 27709
ZOFRAN ODT Orally Disintegrating
Tablets:
Manufactured for GlaxoSmithKline
Research Triangle Park, NC 27709
by Cardinal Health
Blagrove, Swindon, Wiltshire,
UK SN5 8RU
©2006, GlaxoSmithKline. All
rights reserved.
February 2006 RL-2237
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| ZOFRAN (ondansetron hydrochloride) |
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| ZOFRAN (ondansetron hydrochloride) |
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Revised: 03/2007