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.

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

• ZOFAMED

ODT(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 ZOFAMED

ODT 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: ZOFAMED

ODT (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, ZOFAMED

ODT 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

ZOFAMED

ODT 8 mg orally 1 to 2 hours prior to chemotherapy.

Post-chemotherapy: ZOFAMED

ODT 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: ZOFAMED

ODT 8 mg orally 1 to 2 hours before

radiotherapy.

Post-radiotherapy: ZOFAMED

ODT 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

ZOFAMED

ODT may be administered as a single dose of 16 mg given

orally one hour prior to anaesthesia.

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.

ZOFAMED

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 ZOFAMED

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 ZOFAMED

ODT

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 ZOFAMED

ODT 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 ZOFAMED

ODT with

another QTc prolonging drug should be carefully considered to

determine that the therapeutic benefit

The concomitant use of ZOFAMED

ODT 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 ZOFAMED

ODT 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, PACKED BY:



Ondansetron oral dispersible tablet

DESCRIPTION: ZOFAMED

ODT 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.

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

ZOFAMED

ODT 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%

and the plasma protein binding was approximately 73%. Following

oral or IV administration, ondansetron is extensively metabolised and