Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/493
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Ondansetron Hydrochloride and Dextrose (Injection, Solution)
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Prevention of Chemotherapy-Induced
Nausea and Vomiting: Adult Dosing: The recommended I.V. dosage of ondansetron for adults
is a single 32 mg dose or three 0.15 mg/kg doses. A single 32 mg dose
is infused over 15 minutes beginning 30 minutes before the start of
emetogenic chemotherapy. The recommended infusion rate should not
be exceeded (see OVERDOSAGE). With the three-dose (0.15 mg/kg) regimen,
the first dose is infused over 15 minutes beginning 30 minutes before
the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg)
are administered 4 and 8 hours after the first dose of ondansetron. Ondansetron injection should not be mixed with solutions
for which physical and chemical compatibility have not been established.
In particular, this applies to alkaline solutions as a precipitate
may form. Flexible Plastic Container: Ondansetron in 5% Dextrose
Injection, 32 mg/50 mL (0.64 mg/mL), REQUIRES
NO DILUTION. Pediatric Dosing: On the basis
of the available information (see CLINICAL TRIALS: Pediatric Studies
and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in pediatric
cancer patients 4 to 18 years of age should be three 0.15 mg/kg doses.
The first dose is to be administered 30 minutes before the start of
moderately to highly emetogenic chemotherapy, subsequent doses (0.15
mg/kg) are administered 4 and 8 hours after the first dose of ondansetron.
The drug should be infused intravenously over 15 minutes. Little information
is available about dosage in pediatric cancer patients younger than
6 months of age. Dosing information for
pediatric cancer patients 6 months to 48 months of age is approved
for GlaxoSmithKline Corporation's ondansetron injection. However,
due to GlaxoSmithKline's marketing exclusivity rights, this
drug product is not labeled for use in this subpopulation of pediatric
patients. Flexible Plastic Container: Ondansetron in 5% Dextrose
Injection, 32 mg/50 mL (0.64 mg/mL), REQUIRES
NO DILUTION. Geriatric Dosing: The dosage recommendation
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-Pughscore
of 10 or greater), a single maximal daily dose of 8 mg to be infused
over 15 minutes beginning 30 minutes before the start of the emetogenic
chemotherapy is recommended. There is no experience beyond first-day
administration of ondansetron. Ondansetron in 5% Dextrose Injection in Flexible
Plastic Containers: Instructions
for Use: ToOpen: Tear outer wrap at notch
and remove solution container. Check for minute leaks by squeezing
container firmly. If leaks are found, discard unit as sterility may
be impaired. Preparation for Administration: Use aseptic technique. Caution: Ondansetron in 5% dextrose injection in flexible plastic containers
is to be administered by I.V. drip infusion only. Ondansetron in 5%
dextrose injection should not be mixed with solutions for which physical
and chemical compatibility have not been established. In particular,
this applies to alkaline solutions as a precipitate may form. If used
with a primary I.V. fluid system, the primary solution should be discontinued
during ondansetron in 5% dextrose injection infusion. Do not administer unless solution is clear and container
is undamaged. Warning: Do not use flexible plastic container in series
connections. Note: Parenteral drug products should be inspected visually for particulate
matter and discoloration before administration whenever solution and
container permit.
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The active ingredient in ondansetron in 5% dextrose
injection is ondansetron hydrochloride (HCl), the racemic form of
ondansetron and a selective blocking agent of the serotonin 5-HTreceptor 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
CHNO���HCl���2HO, representing a molecular weight of 365.9. Ondansetron HCl is a white to off-white powder that
is soluble in water and normal saline. Sterile Ondansetron in 5% Dextrose Solution for Intravenous
Administration in Single-Dose, Flexible Plastic Containers: Each 50 mL contains ondansetron 32 mg (as the hydrochloride dihydrate);
dextrose 2,500 mg; and citric acid 26 mg and sodium citrate 11.5 mg
as buffers in Water for Injection, USP. It contains no preservatives.
The osmolarity of this solution is 270 mOsm/L (approx.), and the pH
is 3.0 to 4.0. The flexible
plastic container is fabricated from a specially formulated polyvinylchloride.
Water can permeate from inside the container into the overwrap but
not in amounts sufficient to affect the solution significantly. Solutions
inside the plastic container also can leach out certain chemical components
in very small amounts before the expiration period is attained. However,
the safety of the plastic has been confirmed by tests in animals according
to USP biological standards for plastic containers.
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Pharmacodynamics: Ondansetron is a selective 5-HTreceptor antagonist.
While ondansetron's mechanism of action has not been fully characterized,
it is not a dopamine-receptor antagonist. Serotonin receptors of the
5-HTtype 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
in chemotherapy-induced nausea and vomiting 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 vomiting. The released serotonin may stimulate the
vagal afferents through the 5-HTreceptors 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-HTreceptor
antagonist. In normal volunteers, single I.V.
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. In another study in six normal male volunteers, a 16
mg dose infused over 5 minutes showed no effect of the drug on cardiac
output, heart rate, stroke volume, blood pressure, or electrocardiogram
(ECG). Multiday administration of ondansetron has been shown to slow
colonic transit in normal volunteers. Ondansetron has no effect on
plasma prolactin concentrations. In a gender-balanced
pharmacodynamic study (n = 56), ondansetron 4 mg administered intravenously
or intramuscularly was dynamically similar in the prevention of nausea
and vomiting using the ipecacuanha model of emesis. 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 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 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, Cand
Tof ondansetron was observed.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. In normal adult volunteers, the following mean pharmacokinetic
data have been determined following a single 0.15 mg/kg I.V. dose. A reduction in clearance and increase in elimination
half-life are seen in patients over 75 years of age. In clinical trials
with cancer patients, safety and efficacy were similar in patients
over 65 years of age and those under 65 years of age; there was an
insufficient number of patients over 75 years of age to permit conclusions
in thatage group. No dosage adjustment is recommended in the elderly. In patients with mild-to-moderate hepatic impairment,
clearance is reduced twofold and mean half-life is increased to 11.6
hours compared to 5.7 hours in normals. In patients with severe hepatic
impairment (Child-Pughscore of 10 or greater), clearance
is reduced twofold to threefold 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 mean plasma clearance was reduced
by about 41% 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. In adult cancer patients, the mean elimination half-life
was 4 hours, and there was no difference in the multidose pharmacokinetics
over a 4 day period. In a study of 21 pediatric cancer patients (4
to 18 years of age) who received three I.V. doses of 0.15 mg/kg of
ondansetron at 4 hour intervals, patients older than 15 years of age
exhibited ondansetron pharmacokinetic parameters similar to those
of adults. Patients 4 to 12 years of age generally showed higher clearance
and somewhat larger volume of distribution than adults. Most pediatric
patients younger than 15 years of age with cancer had a shorter (2.4
hours) ondansetron plasma half-life than patients older than 15 years
of age. It is not known whether these differences in ondansetron plasma
half-life may result in differences in efficacy between adults and
some young pediatric patients (see CLINICAL TRIALS: Pediatric Studies). Pharmacokinetic information for pediatric cancer patients
6 months to 48 months of age is approved for GlaxoSmithKline Corporation's
ondansetron injection. However, due to GlaxoSmithKline's marketing
exclusivity rights, this drug product is not labeled for use in this
subpopulation of pediatric patients. In a study
of 21 pediatric patients (3 to 12 years of age) who were undergoing
surgery requiring anesthesia for a duration of 45 minutes to 2 hours,
a single I.V. dose of ondansetron, 2 mg (3 to 7 years) or 4 mg (8
to 12 years), was administered immediately prior to anesthesia induction.
Mean weight-normalized clearance and volume of distribution values
in these pediatric surgical patients were similar to those previously
reported for young adults. Mean terminal half-life was slightly reduced
in pediatric patients (range, 2.5 to 3 hours) in comparison with adults
(range, 3 to 3.5 hours). In general, surgical and cancer pediatric patients
younger than 18 years tend to have a higher ondansetron clearance
compared to adults leading to a shorter half-life in most pediatric
patients. In patients 1 month to 4 months of age, a longer half-life
was observed due to the higher volume of distribution in this age
group. Pharmacokinetic information for pediatric
surgical patients 1 month to 24 months of age is approved for GlaxoSmithKline
Corporation's ondansetron injection. However, due to GlaxoSmithKline's
marketing exclusivity rights, this drug product is not labeled for
use in this subpopulation of pediatric patients. In normal volunteers (19 to 39 years old, n = 23), the peak plasma
concentration was 264 ng/mL following a single 32 mg dose administered
as a 15 minute I.V. infusion. The mean elimination half-life was 4.1
hours. Systemic exposure to 32 mg of ondansetron was not proportional
to dose as measured by comparing dose-normalized AUC values to an
8 mg dose. This is consistent with a small decrease in systemic clearance
with increasing plasma concentrations. A study
was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics
of a single 4 mg dose administered as a 5 minute infusion compared
to a single intramuscular injection. Systemic exposure as measured
by mean AUC was equivalent, with values of 156 [95% CI 136, 180] and
161 [95% CI 137, 190] ng���h/mL for I.V. and I.M. groups, respectively.
Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL
at 10 minutes after I.V. infusion and 31.9 [95% CI 26.3, 38.6] ng/mL
at 41 minutes after I.M. injection. The mean elimination half-life
was not affected by route of administration. Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding
constant over the pharmacologic concentration range (10 to 500 ng/mL).
Circulating drug also distributes into erythrocytes. A positive lymphoblast transformation test to ondansetron has been
reported, which suggests immunologic sensitivity to ondansetron.
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Ondansetron in 5% Dextrose Injection is contraindicated
for patients known to have hypersensitivity to the drug.
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Ondansetron in 5% Dextrose
Injection, 32 mg/50 mL (0.64 mg/mL), contains no preservatives
and is supplied as a sterile solution for I.V. administration in single-dose,
flexible plastic containers (NDC 0409-4760-13) (case of 6). Store at 20 to 25��C
(68 to 77��F). [See USP Controlled Room Temperature.] May be refrigerated.
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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 distention. Rarely and predominantly with intravenous ondansetron, transient
ECG changes including QT interval prolongation have been reported.<br/>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 oflimited 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. 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. 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.<br/>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
per day, respectively. Ondansetron was not mutagenic in standard tests
for mutagenicity. Oral administration of ondansetron up to 15 mg/kg
per day did not affect fertility or general reproductive performance
of male and female rats.<br/>Pregnancy:: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in
pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day 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.<br/>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.<br/>Pediatric Use:: Little information is available about the use of
ondansetron in pediatric surgical patients younger than 1 month of
age. Little information is available about the use of ondansetron
in pediatric cancer patients younger than 6 months of age. The clearance of ondansetron in pediatric patients
1 month to 4 months of age is slower and the half-life is ~2.5 fold
longer than patients who are>4 to 24 months of age. As a precaution,
it is recommended that patients less than 4 months of age receiving
this drug be closely monitored. (See CLINICAL PHARMACOLOGY: Pharmacokinetics). The frequency and type of adverse events reportedin pediatric patients receiving ondansetron were similar to those
in patients receiving placebo.<br/>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, 862 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).
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There is no specific antidote for ondansetron overdose.
Patients should be managed with appropriate supportive therapy. Individual
doses as large as 150 mg and total daily dosages (three doses) as
large as 252 mg have been administered intravenously 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 one
patient that was administered 72 mg of ondansetron intravenously as
a single dose. Hypotension (and faintness) occurred in another patient
that took 48 mg of oral ondansetron. Following infusion of 32 mg over
only a 4 minute period, a vasovagal episode with transientsecond-degree
heart block was observed. In all instances, the events resolved completely.
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Ondansetron Hydrochloride and Dextrose
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Ondansetron Hydrochloride and Dextrose (Injection, Solution)
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Chemotherapy-Induced Nausea
and Vomiting: The adverse events in Table 7 have been reported
in adults receiving ondansetron at a dosage of three 0.15 mg/kg doses
or as a single 32 mg dose in clinical trials. These patients were
receiving concomitant chemotherapy, primarily cisplatin, and I.V.
fluids. Most were receiving a diuretic. The following have been reported during controlled
clinical trials: Cardiovascular: Rare cases of angina (chest pain), electrocardiographic
alterations, hypotension, and tachycardia have been reported. In many
cases, the relationship to ondansetron injection was unclear. Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving
multiday ondansetron. Hepatic: In comparative trials
in cisplatin chemotherapy patients with normal baseline values of
aspartate transaminase (AST) and alanine transaminase (ALT), these
enzymes have been reported to exceed twice the upper limit of normal
in approximately 5% of patients. 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. Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron. Neurological: There have been rare reports consistent with, but not diagnostic
of, extrapyramidal reactions in patients receiving ondansetron injection,
and rare cases of grand mal seizure. The relationship to ondansetron
was unclear. Other: Rare cases of hypokalemia have been reported. The
relationship to ondansetron injection was unclear. Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during post-approval use of
intravenous 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: Arrhythmias
(including ventricular and supraventricular tachycardia, premature
ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic
alterations (including second-degree heart block, QT interval prolongation,
and ST segment depression), palpitations, and syncope. General: Flushing. Rare cases
of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid
reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension,
laryngeal edema, laryngospasm, shock, shortness of breath, stridor)
have also been reported. Hepatobiliary: Liver enzyme
abnormalities have been reported. Liver failure and death have been
reported in patients with cancer receiving concurrent medications
including potentially hepatotoxic cytotoxic chemotherapy and antibiotics.
The etiology of the liver failure is unclear. Local Reactions: Pain, redness, and burning at site of injection. Lower Respiratory: Hiccups Neurological:
Oculogyric crisis, appearing alone, as well as with other
dystonic reactions. Skin: Urticaria Special Senses: Transient dizziness during or shortly after I.V. infusion. Eye Disorders: Transient blurred vision,
in some cases associated with abnormalities of accommodation. 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.
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Hypersensitivity reactions have been reported in
patients who have exhibited hypersensitivity to other selective 5-HTreceptor antagonists.
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Prevention of nausea and vomiting associated with
initial and repeat courses of emetogenic cancer chemotherapy, including
high-dose cisplatin. Efficacy of the 32 mg single dose beyond 24 hours
in these patients has not been established.
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Ondansetron Hydrochloride and Dextrose
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