Read all of this leaflet carefully before you start taking this
medicine because it contains important information for you.
* Keep this leaflet. You may need to read it again.
* If you have any further questions, ask your doctor or
pharmacist.
* This medicine has been prescribed for you only.
Do not pass it on to others. It may harm them, even if their
signs of illness are the same as yours.
* If you get any side effects talk to your doctor or pharmacist.
This includes any possible side effects not listed in this leaflet.
See section 4.
and the plasma protein binding was approximately 73%. Following
oral or IV administration, ondansetron is extensively metabolised and
excreted in the urine and faeces. In humans, less than 10% of the dose
is excreted unchanged in the urine. The major urinary metabolites are
glucuronide conjugates (45%), sulphate conjugates (20%) and
hydroxylation products (10%). The half-life of ondansetron after either
an 8 mg oral dose or intravenous dose was approximately 3-4 hours
and may be extended to 6-8 hours in the elderly.
SPECIFIC PATIENT POPULATIONS
Pediatrics: (< 3 years of age): Insufficient information is available to
provide dosage recommendations for children 3 years of age or
younger.
Pregnancy: The safety of ondansetron for use in human pregnancy
has not been established. Ondansetron is not teratogenic in animals.
However, as animal studies are not always predictive of human
response, the use of ondansetron in pregnancy is not recommended.
Nursing Women: Ondansetron is excreted in the milk of lactating rats.
It is not known if it is excreted in human milk, however, nursing is not
recommended during treatment with ondansetron.
CONTRAINDICATIONS
• ZONETRON (ondansetron hydrochloride) is contraindicated in
patients with a history of hypersensitivity to the drug or any
components of its formulations.
• The concomitant use of apomorphine with ondansetron is
contraindicated based on reports of profound hypotension and loss
of consciousness when apomorphine was administered with
ondansetron.
DOSAGE AND ADMINISTRATION
Dosing Considerations ZONETRON has a dose dependent QTc
prolongation effect.
Recommended Dose And Dosage Adjustment Chemotherapy
Induced Nausea and Vomiting:
Use in Adults:
Highly Emetogenic Chemotherapy (e.g. regimens containing
cisplatin) Initial Dose for Prevention of Emesis during the First 24 h
Following Chemotherapy: ZONETRON (ondansetron hydrochloride)
should be given as an initial dose prior to chemotherapy, followed by
a dosage regimen tailored to the anticipated severity of emetic
response caused by different cancer treatments.
Post-chemotherapy: Two additional doses of ondansetron 8 mg IV (15
minutes infusions) may be given 4 and 8 hours after the initial dose
of ondansetron.
After the first 24 hours, ZONETRON 8 mg may be taken orally every 8i
hours for up to 5 days.
Less Emetogenic Chemotherapy (e.g. regimens containing
cyclophosphamide, doxorubicin, epirubicin, fluorouracil and
carboplatin) Initial Dose: Ondansetron 8 mg infused intravenously
over 15 minutes, given at least 30 minutes prior to chemotherapy; or
ZONETRON 8 mg orally 1 to 2 hours prior to chemotherapy.
Post-chemotherapy: ZONETRON 8 mg orally twice daily for up to 5
days.
Use in Elderly:
Oral Formulations: Efficacy and tolerance in patients aged over 65
years were similar to that seen in younger adults indicating no need
to alter oral dosage schedules in this population.
Radiotherapy Induced Nausea and Vomiting:
Use in Adults: Initial Dose: ZONETRON 8 mg orally 1 to 2 hours before
radiotherapy.
Post-radiotherapy: ZONETRON 8 mg orally every 8 hoursii for up to 5
days after a course of treatment.
Post-Operative Nausea and Vomiting:
Use in Adults: For prevention of post-operative nausea and vomiting
ZONETRON may be administered as a single dose of 16 mg given
orally one hour prior to anaesthesia. Alternatively, a single dose of 4
mg, undiluted may be injected intravenously preferably over 2-5
minutes, and not less than 30 seconds, at induction of anaesthesia.
For the treatment of established post-operative nausea and
vomiting, a single dose of 4 mg, undiluted injected intravenously
preferably over 2-5 minutes, and not less than 30 seconds, is
recommended.
Patients with Renal/Hepatic Impairment: Use in Patients with
Impaired Renal Function: No alteration of daily dosage, frequency of
dosing, or route of administration is required.
Use in Patients with Impaired Hepatic Function: The clearance of
an 8 mg intravenous dose of ondansetron was significantly
reduced and the serum half-life significantly prolonged in subjects
with severe impairment of hepatic function. In patients with
moderate or severe impairment of hepatic function, reductions in
dosage are therefore recommended and a total daily dose of 8 mg
should not be exceeded. This may be given as a single intravenous
or oral dose.
WARNINGS AND PRECAUTIONS
Immune
Cross-reactive hypersensitivity has been reported between different
5-HT3 antagonists. Patients who have experienced hypersensitivity
reactions to one 5-HT3 antagonist have experienced more severe
reactions upon being challenged with another drug of the same
class. The use of a different 5-HT3 receptor antagonist is not
recommended as a replacement in cases in which a patient has
experienced even a mild hypersensitivity type reaction to another
5-HT3 antagonist.
Cardiovascular
QTc Interval Prolongation: Ondansetron prolongs the QT interval .
The magnitude of QTc prolongation will depend on the dose and
the infusion rate. In addition, post-marketing cases of torsade de
pointes have been reported in patients using ondansetron. Torsade
de pointes is a polymorphic ventricular tachyarrhythmia. Generally,
the risk of torsade de pointes increases with the magnitude of QTc
prolongation produced by the drug. Torsade de pointes may be
asymptomatic or experienced by the patient as dizziness,
palpitations, syncope, or seizures. If sustained, torsade de pointes
can progress to ventricular fibrillation and sudden cardiac death.
Avoid ondansetron in patients with congenital long QT syndrome.
Ondansetron should be administered with caution to patients who
have or may develop prolongation of QTc, including congestive
heart failure, bradyarrhythmias or patients taking other medicinal
products that lead to either QT prolongation or electrolyte
abnormalities . Hypokalemia, hypocalcemia, and hypomagnesemia
should be corrected prior to ondansetron administration.
Additional risk factors for torsade de pointes in the general
population include, but are not limited to, the following:
• Female gender;
• Age 65 years or older;
• Baseline prolongation of the QT/QTc interval;
• Presence of genetic variants affecting cardiac ion channels or
regulatory proteins;
• Family history of sudden cardiac death at <50years.
• Cardiac disease (e.g., myocardial ischemia or infarction, left
ventricular hypertrophy, cardiomyopathy, conduction system
disease);
• History of arrhythmias (especially ventricular arrhythmias, atrial
fibrillation, or recent conversion from atrial fibrillation);
• Bradycardia (<50beats per minute)
• Acute neurological events (e.g., intracranial or subarachnoid
haemorrhage, stroke, intracranial trauma);
• Nutritional deficits (e.g., eating disorders,
extreme diets);
• Diabetes mellitus;
• Autonomic neuropathy.
ZONETRON ODT contains aspartame and
therefore should be taken with caution in
patients with phenylketonuria.
Neurologic
Serotonin syndrome/Neuroleptic Malignant
Syndrome: Cases of life-threatening
serotonin syndrome or neuroleptic
malignant syndrome-like events have been
reported with 5-HT3 receptor antagonist
antiemetics, including ZONETRON ODT,
when given in combination with other
serotonergic and/or neuroleptic drugs.
Serotonin syndrome symptoms may
include mental status changes (e.g.
agitation, hallucinations, coma), autonomic
instability (e.g., tachycardia, labile blood
pressure, hyperthermia), neuromuscular
aberrations (e.g., hyperreflexia,
incoordination) and/or gastrointestinal
symptoms (e.g. nausea, vomiting, diarrhea).
As these syndromes may result in
potentially life-threatening conditions,
treatment should be discontinued if such
events occur and supportive symptomatic
treatment should be initiated.
If concomitant treatment of ZONETRON with
a drug affecting the serotonergic
neurotransmitter system is clinically
warranted, careful observation of the
patient is advised, particularly during
treatment initiation and dose increases.
Hepatic/Biliary/Pancreatic
There is no experience in patients who are
clinically jaundiced. The clearance of an 8
mg intravenous dose of ZONETRON was
significantly reduced and the serum
half-life significantly prolonged in subjects
with severe impairment of hepatic function.
In patients with moderate or severe
impairment of hepatic function, reductions
in dosage are therefore recommended and
a total daily dose of 8 mg should not be
exceeded. This may be given as a single
intravenous or oral dose.
Ondansetron does not itself appear to
induce or inhibit the cytochrome P450 drug
metabolizing enzyme system of the liver.
Because ondansetron is metabolised by
hepatic cytochrome P450 drug-metaboliz-
ing enzymes, 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.
Gastrointestinal As ondansetron is known
to increase large bowel transit time,
patients with signs of subacute intestinal
obstruction should be monitored following
administration.
SPECIAL POPULATIONS
Nursing Women: Ondansetron is excreted in the milk of lactating rats.
It is not known it
is excreted in human milk, however, nursing is not recommended
during treatment with ondansetron.
Pediatrics (< 3 years of age): Insufficient information is available to
provide dosage recommendations for children 3 years of age or
younger.
Pregnant Women: The safety of ondansetron for use in human
pregnancy has not been established. Ondansetron is not teratogenic
in animals. However, as animal studies are not always predictive of
human response, the use of ondansetron in pregnancy is not
recommended.
DRUG INTERRACTIONS
Specific studies have shown that there are no pharmacokinetic
interactions when ondansetron is administered with alcohol,
temazepam, furosemide, tramadol or propofol.
Ondansetron is metabolised by multiple hepatic cytochrome P450
enzymes: CYP3A4, CYP2D6 and CYP1A2. Despite the multiplicity of
metabolic enzymes capable of metabolising ondansetron which can
compensate for an increase or decrease in enzyme activity, it was
found that patients treated with inducers of CYP3A4 (i.e. phenytoin,
carbamazepine, and rifampicin) demonstrated an increase in oral
clearance of ondansetron and a decrease in ondansetron blood
concentrations. No effect in ondansetron clearance secondary to
enzyme inhibition or reduced activity (e.g. CYP2D6 genetic
deficiency) has been identified to date.
QTc-Prolonging Drugs: The concomitant use of ZONETRON with
another QTc prolonging drug should be carefully considered to
determine that the therapeutic benefit
The concomitant use of ZONETRON outweighs the potential risk. Drugs
that have been associated with QTc interval prolongation and/or
torsade de pointes include, but are not limited to, the examples in the
following list. Chemical/pharmacological classes are listed if some,
although not necessarily all, class members have been implicated in
QTc prolongation and/or torsade de pointes:
• Class IA antiarrhythmics (e.g., quinidine, procainamide,
disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide,
dronedarone);
• Class 1C antiarrhythmics (e.g., flecainide, propafenone);
• antiemetics (e.g., dolasetron, droperidol, chlorpromazine,
prochlorperazine); • tyrosine kinase inhibitors (e.g., vandetanib,
sunitinib, nilotinib, lapatinib);
• antipsychotics (e.g., chlorpromazine, pimozide, haloperidol,
ziprasidone);
• antidepressants (e.g., citalopram, fluoxetine, venlafaxine,
tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine,
maprotiline);
• opioids (e.g., methadone);
• domperidone
• macrolide antibiotics and analogues (e.g., erythromycin,
clarithromycin, telithromycin, tacrolimus);
• quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
• antimalarials (e.g., quinine, chloroquine);
• azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
• histone deacetylase inhibitors (e.g., vorinostat);
• beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol)
Drugs that Cause Electrolyte Abnormalities: The use of ZONETRON
with drugs that can disrupt electrolyte
levels should be avoided.
Such drugs include, but not limited to, the following:
• Loop, thiazide, and related diuretics;
• Laxatives and enemas;
• Amphotericin B;
• High dose corticosteroids. The above lists of potentially interacting
drugs are not comprehensive. Current information sources should be
consulted for newly approved drugs that prolong the QTc interval or
cause electrolyte disturbances, as well as for older drugs for which
these effects have recently been established.
Tramadol: Data from small studies indicate that ondansetron may
reduce the analgesic effect of tramadol.
Apomorphine: Based on reports of profound hypotension and loss of
consciousness when ondansetron was administered with
apomorphine hydrochloride, concomitant use with apomorphine is
contraindicated.
Serotonergic Drugs: As with other serotonergic agents, serotonin
syndrome, a potentially life-threatening condition, may occur with
5-HT3 receptor antagonist antiemetic treatment when given in
combination with other agents that may affect the serotonergic
neurotransmitter system (including triptans, SSRIs, SNRIs, lithium,
sibutramine, fentanyl and its analogues, dextromethorphan,
tramadol, tapentadol, meperidine, methadone, and pertazocine or
St. John’s Wort (Hypericum perforatum), and with drugs which impair
metabolism of serotonin (such as MAOIs, including linezolid (an
antibiotic which is a reversible non-selective MAOI), and methylene
blue; See WARNINGS AND PRECAUTIONS, Neurologic.
ADVERSE REACTIONS
The most frequent adverse events reported in controlled clinical trials
were headache (11%) and constipation (4%). Other adverse events
include sensations of flushing or warmth (< 1%).
Cardiovascular: There have been rare reports of tachycardia, angina
(chest pain), bradycardia, hypotension, syncope and electrocardio-
graphic alterations.
Central Nervous System: There have been rare reports of seizures.
Movement disorders and dyskinesia have been reported in two large
clinical trials of ondansetron at a rate of 0.1 – 0.3%.
Dermatological: Rash has occurred in approximately 1% of patients
receiving ondansetron. Eye Disorder: Rare cases of transient visual
disturbances (e.g. blurred vision) have been reported during or
shortly after intravenous administration of ondansetron, particularly
at rates equal to or greater than 30 mg in 15 minutes.
Hypersensitivity: Rare cases of immediate hypersensitivity reactions
sometimes severe, including anaphylaxis, bronchospasm, urticaria
and angioedema have been reported.
Local Reactions: Pain, redness and burning at the site of injection
have been reported.
Metabolic: There were transient increases of SGOT and SGPT of over
twice the upper limit of normal in approximately 5% of patients. These
increases did not appear to be related to dose or duration of
therapy. There have been reports of liver failure and death in patients
with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic. The etiology of the liver failure is unclear. There
have been rare reports of hypokalemia.
STORAGE CONDITION
Store Below
30°C in a dry dark place.
Keep this medecine out of the sight and reach of children.
Manufacturer:
Hiral Labs Ltd 265, Sisona, Near Bhagwanpur,
Roorkee Uttarakhand- 247661, India
Marketing Authorisation Holder:
Ondansetron oral dispersible tablet
DESCRIPTION: ZONETRON is a white colored, round shape, scored
orally disintegrating tablets. Box of 10 tablets.
COMPOSITION
Each oral dispersible tablet contains: 8mg of Ondansetron
hydrochloride dihydrate.
Each oral dispersible tablet contains: 4mg of Ondansetron
hydrochloride dihydrate.
Excipients: Talc, Magnesium Stearate, Croscarmellose sodium,
Colloidal silicon Dioxide, Neotame, Dry Mix Pineapple Flavour,
Microcristalline Cellulose (Flocel/ Avicel), Ionex QM 101.
THERAPEUTIC INDICATIONS
-Prevention of nausea (feeling of sickness) and vomiting during
treatment for cancer (chemotherapy and radiotherapy).
-Prevention and treatment of nausea and vomiting after surgery.
PHARMACOLOGICAL PROPERTIES
ZONETRON is a 5-HT3 receptor antagonist
MECHANISM OF ACTION AND PHARMACODYNAMIC EFFECTS
Ondansetron is a selective antagonist of the serotonin receptor
subtype, 5-HT3. Its precise mode of action in the control of
chemotherapy induced nausea and vomiting is not known.
Cytotoxic chemotherapy and radiotherapy are associated with the
release of serotonin (5-HT) from enterochromaffin cells of the small
intestine, presumably initiating a vomiting reflex through stimulation
of 5-HT3 receptors located on vagal afferents. Ondansetron may
block the initiation of this reflex. Activation of vagal afferents may
also cause a central release of serotonin from the chemoreceptor
trigger zone of the area postrema, located on the floor of the fourth
ventricle. Thus, the antiemetic effect of ondansetron is probably due
to the selective antagonism of 5-HT3 receptors on neurons located
in either the peripheral or central nervous systems, or both.
The mechanisms of ondansetron's antiemetic action in
post-operative nausea and vomiting are not known.
PHARMACOKINETICS
Pharmacokinetic studies in human volunteers showed peak plasma
levels of 20-30 ng/mL at around 1½ hours after an 8 mg oral dose of
ondansetron. An 8 mg infusion of ondansetron resulted in peak
plasma levels of 80-100 ng/mL. Repeat dosing of an 8 mg tablet
every 8 hours for 6 days increased the peak plasma value to 40
ng/mL. A continuous intravenous infusion of 1 mg/hour after the
initial 8 mg loading dose of ondansetron maintained plasma levels
over 30 ng/mL during the following 24 hour period. The absolute
bioavailability of ondansetron in humans was approximately 60%
This is a medicament:
- A medicament is a product which
affects your health and its consumption
contrary to instructions is dangerous for
you.
- Follow strictly the doctor's prescription,
the method of use and the instructions of
the pharmacist who sold the
medicament.
- The doctor and the pharmacist are the
experts in medicine, their benefits and
risks.
- Do not by yourself interrupt the period
of treatment prescribed.
- Do not repeat the same prescription
without consulting your doctor.
- Keep all medicaments out of reach of
children.
Council of Arab Health Ministers
Union of Arab pharmacists
and the plasma protein binding was approximately 73%. Following
oral or IV administration, ondansetron is extensively metabolised and
excreted in the urine and faeces. In humans, less than 10% of the dose
is excreted unchanged in the urine. The major urinary metabolites are
glucuronide conjugates (45%), sulphate conjugates (20%) and
hydroxylation products (10%). The half-life of ondansetron after either
an 8 mg oral dose or intravenous dose was approximately 3-4 hours
and may be extended to 6-8 hours in the elderly.
SPECIFIC PATIENT POPULATIONS
Pediatrics: (< 3 years of age): Insufficient information is available to
provide dosage recommendations for children 3 years of age or
younger.
Pregnancy: The safety of ondansetron for use in human pregnancy
has not been established. Ondansetron is not teratogenic in animals.
However, as animal studies are not always predictive of human
response, the use of ondansetron in pregnancy is not recommended.
Nursing Women: Ondansetron is excreted in the milk of lactating rats.
It is not known if it is excreted in human milk, however, nursing is not
recommended during treatment with ondansetron.
CONTRAINDICATIONS
• ZONETRON (ondansetron hydrochloride) is contraindicated in
patients with a history of hypersensitivity to the drug or any
components of its formulations.
• The concomitant use of apomorphine with ondansetron is
contraindicated based on reports of profound hypotension and loss
of consciousness when apomorphine was administered with
ondansetron.
DOSAGE AND ADMINISTRATION
Dosing Considerations ZONETRON has a dose dependent QTc
prolongation effect.
Recommended Dose And Dosage Adjustment Chemotherapy
Induced Nausea and Vomiting:
Use in Adults:
Highly Emetogenic Chemotherapy (e.g. regimens containing
cisplatin) Initial Dose for Prevention of Emesis during the First 24 h
Following Chemotherapy: ZONETRON (ondansetron hydrochloride)
should be given as an initial dose prior to chemotherapy, followed by
a dosage regimen tailored to the anticipated severity of emetic
response caused by different cancer treatments.
Post-chemotherapy: Two additional doses of ondansetron 8 mg IV (15
minutes infusions) may be given 4 and 8 hours after the initial dose
of ondansetron.
After the first 24 hours, ZONETRON 8 mg may be taken orally every 8i
hours for up to 5 days.
Less Emetogenic Chemotherapy (e.g. regimens containing
cyclophosphamide, doxorubicin, epirubicin, fluorouracil and
carboplatin) Initial Dose: Ondansetron 8 mg infused intravenously
over 15 minutes, given at least 30 minutes prior to chemotherapy; or
ZONETRON 8 mg orally 1 to 2 hours prior to chemotherapy.
Post-chemotherapy: ZONETRON 8 mg orally twice daily for up to 5
days.
Use in Elderly:
Oral Formulations: Efficacy and tolerance in patients aged over 65
years were similar to that seen in younger adults indicating no need
to alter oral dosage schedules in this population.
Radiotherapy Induced Nausea and Vomiting:
Use in Adults: Initial Dose: ZONETRON 8 mg orally 1 to 2 hours before
radiotherapy.
Post-radiotherapy: ZONETRON 8 mg orally every 8 hoursii for up to 5
days after a course of treatment.
Post-Operative Nausea and Vomiting:
Use in Adults: For prevention of post-operative nausea and vomiting
ZONETRON may be administered as a single dose of 16 mg given
orally one hour prior to anaesthesia. Alternatively, a single dose of 4
mg, undiluted may be injected intravenously preferably over 2-5
minutes, and not less than 30 seconds, at induction of anaesthesia.
For the treatment of established post-operative nausea and
vomiting, a single dose of 4 mg, undiluted injected intravenously
preferably over 2-5 minutes, and not less than 30 seconds, is
recommended.
Patients with Renal/Hepatic Impairment: Use in Patients with
Impaired Renal Function: No alteration of daily dosage, frequency of
dosing, or route of administration is required.
Use in Patients with Impaired Hepatic Function: The clearance of
an 8 mg intravenous dose of ondansetron was significantly
reduced and the serum half-life significantly prolonged in subjects
with severe impairment of hepatic function. In patients with
moderate or severe impairment of hepatic function, reductions in
dosage are therefore recommended and a total daily dose of 8 mg
should not be exceeded. This may be given as a single intravenous
or oral dose.
WARNINGS AND PRECAUTIONS
Immune
Cross-reactive hypersensitivity has been reported between different
5-HT3 antagonists. Patients who have experienced hypersensitivity
reactions to one 5-HT3 antagonist have experienced more severe
reactions upon being challenged with another drug of the same
class. The use of a different 5-HT3 receptor antagonist is not
recommended as a replacement in cases in which a patient has
experienced even a mild hypersensitivity type reaction to another
5-HT3 antagonist.
Cardiovascular
QTc Interval Prolongation: Ondansetron prolongs the QT interval .
The magnitude of QTc prolongation will depend on the dose and
the infusion rate. In addition, post-marketing cases of torsade de
pointes have been reported in patients using ondansetron. Torsade
de pointes is a polymorphic ventricular tachyarrhythmia. Generally,
the risk of torsade de pointes increases with the magnitude of QTc
prolongation produced by the drug. Torsade de pointes may be
asymptomatic or experienced by the patient as dizziness,
palpitations, syncope, or seizures. If sustained, torsade de pointes
can progress to ventricular fibrillation and sudden cardiac death.
Avoid ondansetron in patients with congenital long QT syndrome.
Ondansetron should be administered with caution to patients who
have or may develop prolongation of QTc, including congestive
heart failure, bradyarrhythmias or patients taking other medicinal
products that lead to either QT prolongation or electrolyte
abnormalities . Hypokalemia, hypocalcemia, and hypomagnesemia
should be corrected prior to ondansetron administration.
Additional risk factors for torsade de pointes in the general
population include, but are not limited to, the following:
• Female gender;
• Age 65 years or older;
• Baseline prolongation of the QT/QTc interval;
• Presence of genetic variants affecting cardiac ion channels or
regulatory proteins;
• Family history of sudden cardiac death at <50years.
• Cardiac disease (e.g., myocardial ischemia or infarction, left
ventricular hypertrophy, cardiomyopathy, conduction system
disease);
• History of arrhythmias (especially ventricular arrhythmias, atrial
fibrillation, or recent conversion from atrial fibrillation);
• Bradycardia (<50beats per minute)
• Acute neurological events (e.g., intracranial or subarachnoid
haemorrhage, stroke, intracranial trauma);
• Nutritional deficits (e.g., eating disorders,
extreme diets);
• Diabetes mellitus;
• Autonomic neuropathy.
ZONETRON ODT contains aspartame and
therefore should be taken with caution in
patients with phenylketonuria.
Neurologic
Serotonin syndrome/Neuroleptic Malignant
Syndrome: Cases of life-threatening
serotonin syndrome or neuroleptic
malignant syndrome-like events have been
reported with 5-HT3 receptor antagonist
antiemetics, including ZONETRON ODT,
when given in combination with other
serotonergic and/or neuroleptic drugs.
Serotonin syndrome symptoms may
include mental status changes (e.g.
agitation, hallucinations, coma), autonomic
instability (e.g., tachycardia, labile blood
pressure, hyperthermia), neuromuscular
aberrations (e.g., hyperreflexia,
incoordination) and/or gastrointestinal
symptoms (e.g. nausea, vomiting, diarrhea).
As these syndromes may result in
potentially life-threatening conditions,
treatment should be discontinued if such
events occur and supportive symptomatic
treatment should be initiated.
If concomitant treatment of ZONETRON with
a drug affecting the serotonergic
neurotransmitter system is clinically
warranted, careful observation of the
patient is advised, particularly during
treatment initiation and dose increases.
Hepatic/Biliary/Pancreatic
There is no experience in patients who are
clinically jaundiced. The clearance of an 8
mg intravenous dose of ZONETRON was
significantly reduced and the serum
half-life significantly prolonged in subjects
with severe impairment of hepatic function.
In patients with moderate or severe
impairment of hepatic function, reductions
in dosage are therefore recommended and
a total daily dose of 8 mg should not be
exceeded. This may be given as a single
intravenous or oral dose.
Ondansetron does not itself appear to
induce or inhibit the cytochrome P450 drug
metabolizing enzyme system of the liver.
Because ondansetron is metabolised by
hepatic cytochrome P450 drug-metaboliz-
ing enzymes, 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.
Gastrointestinal As ondansetron is known
to increase large bowel transit time,
patients with signs of subacute intestinal
obstruction should be monitored following
administration.
SPECIAL POPULATIONS
Nursing Women: Ondansetron is excreted in the milk of lactating rats.
It is not known it
is excreted in human milk, however, nursing is not recommended
during treatment with ondansetron.
Pediatrics (< 3 years of age): Insufficient information is available to
provide dosage recommendations for children 3 years of age or
younger.
Pregnant Women: The safety of ondansetron for use in human
pregnancy has not been established. Ondansetron is not teratogenic
in animals. However, as animal studies are not always predictive of
human response, the use of ondansetron in pregnancy is not
recommended.
DRUG INTERRACTIONS
Specific studies have shown that there are no pharmacokinetic
interactions when ondansetron is administered with alcohol,
temazepam, furosemide, tramadol or propofol.
Ondansetron is metabolised by multiple hepatic cytochrome P450
enzymes: CYP3A4, CYP2D6 and CYP1A2. Despite the multiplicity of
metabolic enzymes capable of metabolising ondansetron which can
compensate for an increase or decrease in enzyme activity, it was
found that patients treated with inducers of CYP3A4 (i.e. phenytoin,
carbamazepine, and rifampicin) demonstrated an increase in oral
clearance of ondansetron and a decrease in ondansetron blood
concentrations. No effect in ondansetron clearance secondary to
enzyme inhibition or reduced activity (e.g. CYP2D6 genetic
deficiency) has been identified to date.
QTc-Prolonging Drugs: The concomitant use of ZONETRON with
another QTc prolonging drug should be carefully considered to
determine that the therapeutic benefit
The concomitant use of ZONETRON outweighs the potential risk. Drugs
that have been associated with QTc interval prolongation and/or
torsade de pointes include, but are not limited to, the examples in the
following list. Chemical/pharmacological classes are listed if some,
although not necessarily all, class members have been implicated in
QTc prolongation and/or torsade de pointes:
• Class IA antiarrhythmics (e.g., quinidine, procainamide,
disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide,
dronedarone);
• Class 1C antiarrhythmics (e.g., flecainide, propafenone);
• antiemetics (e.g., dolasetron, droperidol, chlorpromazine,
prochlorperazine); • tyrosine kinase inhibitors (e.g., vandetanib,
sunitinib, nilotinib, lapatinib);
• antipsychotics (e.g., chlorpromazine, pimozide, haloperidol,
ziprasidone);
• antidepressants (e.g., citalopram, fluoxetine, venlafaxine,
tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine,
maprotiline);
• opioids (e.g., methadone);
• domperidone
• macrolide antibiotics and analogues (e.g., erythromycin,
clarithromycin, telithromycin, tacrolimus);
• quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
• antimalarials (e.g., quinine, chloroquine);
• azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
• histone deacetylase inhibitors (e.g., vorinostat);
• beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol)
Drugs that Cause Electrolyte Abnormalities: The use of ZONETRON
with drugs that can disrupt electrolyte
levels should be avoided.
Such drugs include, but not limited to, the following:
• Loop, thiazide, and related diuretics;
• Laxatives and enemas;
• Amphotericin B;
• High dose corticosteroids. The above lists of potentially interacting
drugs are not comprehensive. Current information sources should be
consulted for newly approved drugs that prolong the QTc interval or
cause electrolyte disturbances, as well as for older drugs for which
these effects have recently been established.
Tramadol: Data from small studies indicate that ondansetron may
reduce the analgesic effect of tramadol.
Apomorphine: Based on reports of profound hypotension and loss of
consciousness when ondansetron was administered with
apomorphine hydrochloride, concomitant use with apomorphine is
contraindicated.
Serotonergic Drugs: As with other serotonergic agents, serotonin
syndrome, a potentially life-threatening condition, may occur with
5-HT3 receptor antagonist antiemetic treatment when given in
combination with other agents that may affect the serotonergic
neurotransmitter system (including triptans, SSRIs, SNRIs, lithium,
sibutramine, fentanyl and its analogues, dextromethorphan,
tramadol, tapentadol, meperidine, methadone, and pertazocine or
St. John’s Wort (Hypericum perforatum), and with drugs which impair
metabolism of serotonin (such as MAOIs, including linezolid (an
antibiotic which is a reversible non-selective MAOI), and methylene
blue; See WARNINGS AND PRECAUTIONS, Neurologic.
ADVERSE REACTIONS
The most frequent adverse events reported in controlled clinical trials
were headache (11%) and constipation (4%). Other adverse events
include sensations of flushing or warmth (< 1%).
Cardiovascular: There have been rare reports of tachycardia, angina
(chest pain), bradycardia, hypotension, syncope and electrocardio-
graphic alterations.
Central Nervous System: There have been rare reports of seizures.
Movement disorders and dyskinesia have been reported in two large
clinical trials of ondansetron at a rate of 0.1 – 0.3%.
Dermatological: Rash has occurred in approximately 1% of patients
receiving ondansetron. Eye Disorder: Rare cases of transient visual
disturbances (e.g. blurred vision) have been reported during or
shortly after intravenous administration of ondansetron, particularly
at rates equal to or greater than 30 mg in 15 minutes.
Hypersensitivity: Rare cases of immediate hypersensitivity reactions
sometimes severe, including anaphylaxis, bronchospasm, urticaria
and angioedema have been reported.
Local Reactions: Pain, redness and burning at the site of injection
have been reported.
Metabolic: There were transient increases of SGOT and SGPT of over
twice the upper limit of normal in approximately 5% of patients. These
increases did not appear to be related to dose or duration of
therapy. There have been reports of liver failure and death in patients
with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic. The etiology of the liver failure is unclear. There
have been rare reports of hypokalemia.
STORAGE CONDITION
Store Below
30°C in a dry dark place.
Keep this medecine out of the sight and reach of children.
Manufacturer:
Hiral Labs Ltd 265, Sisona, Near Bhagwanpur,
Roorkee Uttarakhand- 247661, India
Marketing Authorisation Holder:
Date of Revision: 16 August 2024
PI006/01
10 Oral Dispersible Tablets Reg. N : 116124/1
10 Oral Dispersible Tablets Reg. N : 124324/1
DESCRIPTION: ZONETRON is a white colored, round shape, scored
orally disintegrating tablets. Box of 10 tablets.
COMPOSITION
Each oral dispersible tablet contains: 8mg of Ondansetron
hydrochloride dihydrate.
Each oral dispersible tablet contains: 4mg of Ondansetron
hydrochloride dihydrate.
Excipients: Talc, Magnesium Stearate, Croscarmellose sodium,
Colloidal silicon Dioxide, Neotame, Dry Mix Pineapple Flavour,
Microcristalline Cellulose (Flocel/ Avicel), Ionex QM 101.
THERAPEUTIC INDICATIONS
-Prevention of nausea (feeling of sickness) and vomiting during
treatment for cancer (chemotherapy and radiotherapy).
-Prevention and treatment of nausea and vomiting after surgery.
PHARMACOLOGICAL PROPERTIES
ZONETRON is a 5-HT3 receptor antagonist
MECHANISM OF ACTION AND PHARMACODYNAMIC EFFECTS
Ondansetron is a selective antagonist of the serotonin receptor
subtype, 5-HT3. Its precise mode of action in the control of
chemotherapy induced nausea and vomiting is not known.
Cytotoxic chemotherapy and radiotherapy are associated with the
release of serotonin (5-HT) from enterochromaffin cells of the small
intestine, presumably initiating a vomiting reflex through stimulation
of 5-HT3 receptors located on vagal afferents. Ondansetron may
block the initiation of this reflex. Activation of vagal afferents may
also cause a central release of serotonin from the chemoreceptor
trigger zone of the area postrema, located on the floor of the fourth
ventricle. Thus, the antiemetic effect of ondansetron is probably due
to the selective antagonism of 5-HT3 receptors on neurons located
in either the peripheral or central nervous systems, or both.
The mechanisms of ondansetron's antiemetic action in
post-operative nausea and vomiting are not known.
PHARMACOKINETICS
Pharmacokinetic studies in human volunteers showed peak plasma
levels of 20-30 ng/mL at around 1½ hours after an 8 mg oral dose of
ondansetron. An 8 mg infusion of ondansetron resulted in peak
plasma levels of 80-100 ng/mL. Repeat dosing of an 8 mg tablet
every 8 hours for 6 days increased the peak plasma value to 40
ng/mL. A continuous intravenous infusion of 1 mg/hour after the
initial 8 mg loading dose of ondansetron maintained plasma levels
over 30 ng/mL during the following 24 hour period. The absolute
bioavailability of ondansetron in humans was approximately 60%
