Ondansetron Hydrochloride Tablets USP 8mg Taj Pharma

1. Name of the medicinal product

Ondansetron Hydrochloride Tablets USP 4mg Taj Pharma
Ondansetron Hydrochloride Tablets USP 8mg Taj Pharma

2. Qualitative and quantitative composition

a)Ondansetron Hydrochloride Tablets USP 4mg Taj Pharma
Each film-coated tablet contains:
5 mg Ondansetron hydrochloride, USP
Equivalent to 4mg of  Ondansetron

b)Ondansetron Hydrochloride Tablets USP 8mg Taj Pharma
Each film-coated tablet contains:
10 mg Ondansetron hydrochloride, USP
Equivalent to 8mg of  Ondansetron

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

4. Clinical particulars

4.1 Therapeutic indications

Adults:

Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV).

Paediatric population:

Ondansetron is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged ≥ 6 months, and for the prevention and treatment of PONV in children aged ≥ 1 month.

4.2 Posology and method of administration

Posology

Oral use.

Chemotherapy and Radiotherapy induced nausea and vomiting:

Adults:

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of ondansetron should be flexible in the range of 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy:

Ondansetron can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron 8 mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8 mg orally twelve hourly.

For oral administration: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.

Highly emetogenic chemotherapy

For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous administration.

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.

Pediatric population:

Chemotherapy induced nausea and vomiting in children aged ≥6 months and adolescents

The dose for chemotherapy-induced nausea and vomiting can be calculated based on body surface area (BSA) or weight – see below. Weight-based dosing results in higher total daily doses compared to BSA-based dosing – see sections 4.4 and 5.1.

There are no data from controlled clinical trials on the use of ondansetron in the prevention of chemotherapy-induced delayed or prolonged nausea and vomiting. There are no data from controlled clinical trials on the use of ondansetron for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m². The intravenous dose must not exceed 8mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days. See table 1 below.

The total daily dose must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for chemotherapy – Children aged ≥6 months and adolescents

a: The intravenous dose must not exceed 8mg.

b: The total daily dose must not exceed adult dose of 32mg.

Dosing by body weight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing – see sections 4.4. and 5.1.

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. the intravenous dose must not exceed 8mg.

Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days. See table 2 below.

Table2: Weight-based dosing for chemotherapy – children aged ≥6 months and adolescents

a: The intravenous dose must not exceed 8mg.

b: The total daily dose must not exceed adult dose of 32 mg.

Elderly

Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.

Please refer also to “Special populations”.

Post-operative nausea and vomiting (PONV):

Adults

For the prevention of PONV ondansetron may be administered orally or by intravenous injection.

For oral administration:

16 mg one hour prior to anaesthesia.

Alternatively, 8 mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.

Treatment of established PONV

For the treatment of established PONV intravenous administration is recommended.

Pediatric population:

Post-operative nausea and vomiting in children aged ≥ 1 months and adolescents:

Oral formulations:

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post operative nausea and vomiting, slow i.v. injection is recommended for this purpose.

Injection:

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg.

There are no data on the use of ondansetron for the treatment of post-operative vomiting in children under 2 years of age.

Elderly

There is limited experience in the use of ondansetron in the prevention and treatment of post-operative nausea and vomiting (PONV) in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.

Please refer also to ”Special populations”.

Special populations:

Patients with renal impairment

No alteration of daily dosage or frequency of dosing, or route of administration is required.

Patients with hepatic impairment

Clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.

Patients with poor sparteine/debrisoquine metabolism

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients, repeat dosing will give medicinal product exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

4.3 Contraindications

• Hypersensitivity to the ondansetron or to any of the excipients listed in section 6.1.
• Hypersensitivity to other selective 5-HT3 receptor antagonists (e.g. granisetron, dolasetron).
• Concomitant use with apomorphine (see Interactions with other medicinial products).

4.4 Special warnings and precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. 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 patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities.

Hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration.

There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.

Since there is little experience to date of the use of ondansetron in cardiac patients, caution should be exercised if ondansetron is co-administered with anaesthetics to patients with arrhythmias or cardiac conduction disorders or to patients who are being treated with antiarrhythmic agents or beta-blockers.

Very rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Caution is advised if patients have received cardiotoxic agents and in patients with a history of prolonged QT syndrome.

Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.

Pediatric population:

Pediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.

Chemotherapy-induced nausea and vomiting: When calculating the dose on an mg/kg basis and administering three doses at 4-hourly intervals, the total daily dose will be higher than if one single dose of 5 mg/m2 followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross-trial comparison indicate similar efficacy for both regimens (see section 5.1).

This product contains 38.274 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

There is no evidence that ondansetron either induces or inhibits the metabolism of other medicinal products commonly co-administered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lignocaine, propofol and thiopental.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolizing ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.

There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including SSRIs and SNRIs). (See Special warnings and precautions for use)

Apomorphine

Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was increased and ondansetron blood concentrations were decreased.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines such as doxorubicin, daunorubicin or trastuzimab), antibiotics (such as erythromycin or ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias. (See Special warnings and precautions for use).

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or fetus, the course of gestation and peri- and post-natal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.

BreastfeedingTests have shown that ondansetron passes into the milk of lactating animals (see section 5.3). It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.

4.7 Effects on ability to drive and use machines

In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of ondansetron.

4.8 Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000) not known (cannot be estimated from the available data)

Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.

Very rarely transient ECG changes including QT interval prolongation have been reported

The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.

Immune system disorders

Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.

There may be cross-sensitivity with other selective 5-HT3- antagonists.

Nervous system disorders

Very common: Headache.

Uncommon: Extrapyramidal reactions (such as oculogyric crisis, dystonic reactions and dyskinesia) have been observed without definitive evidence of persistent clinical sequelae; seizures.

Rare: Dizziness during rapid IV administration.

Eye disorders

Rare: Transient visual disturbances (e.g. blurred vision) predominantly during rapid intravenous administration.

Very rare: Transient blindness predominantly during intravenous administration.

The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.

Cardiac disorders

Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.

Rare: QTc prolongation (including Torsade de pointes)

Vascular disorders

Common: Sensation of warmth or flushing.

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups.

Gastrointestinal disorders

Common: Ondansetron is known to increase the large bowel transit time and may cause constipation in some patients. Local burning sensation following insertion of suppositories.

Hepatobiliary disorders

Uncommon: Asymptomatic increases in liver function tests.

These events were observed commonly in patients receiving chemotherapy with cisplatin.

General disorders and administration site conditions

Common: Local IV injection site reactions.

Paediatric population

The adverse event profile in children and adolescents was comparable to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Symptoms and Signs

Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. In the majority of cases symptoms were similar to those already reported in patients receiving recommended doses (see section 4.8 Undesirable Effects). Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second-degree AV block.

Ondansetron prolongs QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.

Treatment

There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

The use of ipecacuanha to treat overdose with Ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of Ondansetron itself.

Paediatric population

Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT₃) antagonists.

Mechanism of action

Ondansetron is a potent, highly selective 5-HT₃ receptor-antagonist.

Its precise antiemetic and antinauseal mechanism of action is not known. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors.

Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5-HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5-HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

In a pharmaco-psychological study in volunteers ondansetron has not shown a sedative effect.

Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in opiate-induced emesis is not yet established.

Paediatric population:

Chemotherapy -induced nausea and vomiting:

The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years. On the days of chemotherapy, patients received either ondansetron 5 mg/m2 i.v. + after 8-12 hrs ondansetron 4 mg p.o. or ondansetron 0.45 mg/kg i.v. + after 8-12 hrs placebo p.o. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2 i.v. + ondansetron 4 mg p.o.) and 41% (0.45 mg/kg i.v. + placebo p.o.). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.

A double-blind randomised placebo-controlled trial in 438 patients aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m2 i.v. together with 2-4 mg dexamethasone p.o. and in 71% of patients when ondansetron was administered as syrup at a dose of 8mg + 2- 4 mg dexamethasone p.o. on the days of chemotherapy. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in open-label, non-comparative, single-arm study. All children received three 0.15 mg/kg doses of intravenous ondansetron, administered at 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients.

Another open-label, non-comparative, single-arm study investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4mg for children aged < 12 yrs and 8 mg for children aged ≥ 12 yrs (total no. of children n= 28). Complete control of emesis was achieved in 42% of patients.

Prevention of post-operative nausea and vomiting:

The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670 children aged 1 to 24 months (post-conceptual age ≥44 weeks, weight ≥ 3 kg). Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status ≤ III. A single dose of ondansetron 0.1 mg/kg was administered within five minutes following induction of anaesthesia. The proportion of subjects who experienced at least one emetic episode during the 24-hour assessment period (ITT) was greater for patients on placebo than those receiving ondansetron ((28% vs. 11%, p <0.0001).

Four double-blind, placebo-controlled studies have been performed in 1469 male and female patients (2 to 12 years of age) undergoing general anaesthesia. Patients were randomised to either single intravenous doses of ondansetron (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for paediatric patients weighing more than 40 kg; number of patients = 735)) or placebo (number of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarised in Table 3.

Table Prevention and treatment of PONV in Paediatric Patients – Treatment response over 24 hours

CR = no emetic episodes, rescue or withdrawal

5.2 Pharmacokinetic properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (bioavailability is about 60%). Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) 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.)

The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a terminal half life of about 3 hours and steady state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.

The protein binding of ondansetron is 70-76%. A direct effect of plasma concentration and anti-emetic effect has not been established. Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 has no effect on ondansetron’s pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

In a study of 21 paediatric patients aged between 3 and 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2mg (3-7 years old) or 4mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300mL/min at 12 years of age to 100mL/min at 3 years. Volume of distribution fell from about 75L at 12 years to 17L at 3 years. Use of weight-based dosing (0.1mg/kg up to 4mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.

In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron’s pharmacokinetics to be essentially unchanged following IV administration.

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron’s systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.

Special Patient Populations

Children and Adolescents (aged 1 month to 17 years)

In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The halflife in the patient population aged 1 to 4 month was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron.

In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults. When clearance and volume of distribution values were normalised by body weight, the values for these parameters were similar between the different age group populations. Use of weight-based dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.

Population pharmacokinetic analysis was performed on 74 paediatric cancer patients aged 6 to 48 months and 41 surgery patients aged 1 to 24 months following intravenous administration of ondansetron. Based on the population pharmacokinetic parameters for patients aged 1 month to 48 months, administration of the adult weight based dose (0.15 mg/kg intravenously every 4 hours for 3 doses) would result in a systemic exposure (AUC) comparable to that observed in paediatric surgery patients (aged 5 to 24 months), paediatric cancer patients (aged 4 to 18 years), and surgical patients (aged 3 to 12 years), at similar doses, as shown in Table C. This exposure (AUC) is consistent with the exposure-efficacy relationship described previously in paediatric cancer subjects, which showed a 50% to 90% response rate with AUC values ranging from 170 to 250 ng.h/mL.

Table. Pharmacokinetics in Paediatric Patients 1 Month to 18 Years of Age

¹ Ondansetron single intravenous dose: 0.1 or 0.2 mg/kg

² Population PK patients: 64% cancer patients and 36% surgery patients.

³ Population estimates shown; AUC based on dose of 0.15 mg/kg.

⁴ Ondansetron single intravenous dose: 2 mg (3 to 7 years) or 4 mg (8 to 12 years)

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential.

Ondansetron and its metabolites accumulate in the milk of rats with a milk: plasma ratio of 5.2:1.

A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core: Lactose anhydrous, Cellulose, microcrystalline, Starch, pregelatinised, Magnesium stearate.

Film coating: Hypromellose, Triacetin, Titanium dioxide, Iron oxide yellow.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister (PVC/ Aluminium)

Pack size:

3, 4, 6, 7, 10, 14, 15, 20, 28, 30, 40, 49, 50, 60, 90, 100, 200, 300 & 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed off in accordance with local requirements.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Ondansetron Hydrochloride Tablets USP 8mg Taj Pharma
(Ondansetron)

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, nurse 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, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Ondansetron Tablets are and what they are used for
2. What you need to know before you take Ondansetron Tablets
3. How to take Ondansetron Tablets
4. Possible side effects
5. How to store Ondansetron Tablets
6. Contents of the pack and other information

1. What Ondansetron Tablets are and what they are used for

The active ingredient in your tablets, ondansetron, belongs to a group of medicines called anti-emetics.

Ondansetron Tablets are used for:

preventing nausea and vomiting caused by chemotherapy (in adults and children) or radiotherapy for cancer (in adults only).

preventing nausea and vomiting after surgery (adults only).

Ask your doctor, nurse, or pharmacist if you would like any further explanation about these uses.

2. What you need to know before you take Ondansetron Tablets Do not take Ondansetron Tablets if:

you are taking apomorphine (used to treat Parkinson’s disease).

you are allergic to ondansetron or any of the other ingredients of this medicine (listed in section 6).

If you are not sure, talk to your doctor, nurse, or pharmacist before taking Ondansetron Tablets.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Ondansetron Tablets if:

you are allergic to medicines similar to ondansetron known as 5HT3 antagonists such as granisetron or palonosetron.

you suffer from severe constipation, or have you been told you have a blockage in your gut.

you have ever had heart problems (e.g. congestive heart failure which causes shortness of breath and swollen ankles)

you have an uneven heart beat (arrhythmias)

you suffer from any liver problems.

you have problems with the levels of salts in your blood, such as potassium, sodium and magnesium.

If you are not sure if any of the above apply to you, talk to your doctor, nurse, or pharmacist before taking Ondansetron Tablets.

Children and adolescents

Children receiving Ondansetron Tablets with drugs that are harmful to liver should undergo regular check-up for liver problems.

Other medicines and Ondansetron Tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because ondansetron can affect the way some medicines work. Also some other medicines can affect the way ondansetron works

Ondansetron Tablets may have an effect on other drugs or other drugs may have an effect on Ondansetron Tablets.

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

Anti-arrhythmic medicines such as amiodarone used to treat an uneven heartbeat.

Phenytoin or carbamazepine, used to treat epilepsy.

Rifampicin, an antibiotic used to treat infections.

Antibiotics such as erythromycin or ketoconazole.

Tramadol, a pain relieving medicine.

Beta-blocker medicines used to treat certain heart or eye problems, anxiety or prevent migraines.

Medicines that affect the heart (such as haloperidol or methadone).

Cancer medicines (especially anthracyclines and trastuzumab).

SSRIs (selective serotonin reuptake inhibitors) used to treat depression and/or anxiety including fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram.

SNRIs (serotonin noradrenaline reuptake inhibitors) used to treat depression and/or anxiety including venlafaxine, duloxetine.

Contact your doctor. It may be necessary to adjust the dose.

Ondansetron Tablets with food and drink

You may take Ondansetron tablets with food and drinks. The tablets should be taken with a glass of water.

Pregnancy and breast-feeding

If you are already pregnant or breast -feeding, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. If you are a woman of childbearing potential you may be advised to use effective contraception.

Pregnancy

You should not use Ondansetron Tablets during the first trimester of pregnancy. This is because Ondansetron Tablets can slightly increase the risk of a baby being born with cleft lip and/or cleft palate (openings or splits in the upper lip and/or the roof of the mouth).

Breast-feeding

Do not take Ondansetron Tablet if you are breast-feeding, because it is excreted into the milk.

Driving and using machines

Ondansetron may cause problems with your vision. If affected do not drive or operate machinery. Psychomotor testing (testing of brain and body coordination) does not impair performance nor cause sedation.

Ondansetron Tablets contain lactose monohydrate

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take Ondansetron Tablets

Always take Ondansetron Tablets exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you are not sure.

The dose you have been prescribed will depend on the treatment you are having.

To prevent nausea and vomiting from chemotherapy or radiotherapy

On the day of chemotherapy or radiotherapy

the recommended adult dose is 8 mg taken one or two hours before treatment and another 8 mg twelve hours after.

On the following days

the recommended adult dose is 8 mg twice a day

this may be given for up to 5 days.

Children aged over 6 months and adolescents

The doctor will decide the dose depending on the child’s size (body surface area) or weight. Look at the label for more information.

The recommended dose for a child is up to 4 mg twice a day.

This can be given for up to 5 days.

To prevent nausea and vomiting after an operation

The usual adult dose is 16 mg before your operation or

8 mg before the operation, then

8 mg after the operation, then

8 mg after a further eight hours.

Children aged over 1 month and adolescents.

It is recommended that ondansetron is given as an injection.

Patients with moderate or severe liver problems

The total daily dose should not be more than 8 mg.

Ondansetron Tablets should start to work within one or two hours of taking a dose. If you are sick (vomit) within one hour of taking a dose

take the same dose again

otherwise, do not take more Ondanseron Tablets than the label says. If you continue to feel sick, tell your doctor or nurse.

If you take more Ondansetron Tablets than you should

If you or your child take more Ondansetron Tablets than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you.

If you forget to take Ondansetron Tablets

If you miss a dose and feel sick or vomit:

take Ondansetron Tablets as soon as possible, then

take your next tablet at the usual time (as shown on the label)

do not take a double dose to make up for a forgotten dose.

If you miss a dose but do not feel sick

take the next dose as shown on the label

do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Ondansetron Tablets can cause side effects, although not everybody gets them.

Allergic reactions

If you have an allergic reaction, stop taking it and see a doctor straight away. The signs may include:

sudden wheezing and chest pain or chest tightness

swelling of your eyelids, face, lips, mouth, or tongue

skin rash – red spots or lumps under your skin (hives) anywhere on your body

collapse

Other side effects include:

Very common (may affect more than 1 in 10 people)

headache

Common (may affect up to 1 in 10 people)

a feeling of warmth or flushing

constipation

changes to liver function test results (if you take Ondansetron Tablets with a medicine called cisplatin, otherwise this side effect is uncommon)

Uncommon (may affect up to 1 in 100 people)

hiccups

low blood pressure, which can make you feel faint or dizzy

uneven heart beat

chest pain

fits

unusual body movements or shaking

slower heart rate

Rare (may affect up to 1 in 1,000 people)

feeling dizzy or light headed

blurred vision

disturbance in heart rhythm (sometimes causing a sudden loss of consciousness)

Very rare (may affect up to 1 in 10,000 people)

poor vision or temporary loss of eyesight, which usually comes back within 20 minutes

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

5. How to store Ondansetron Tablets

Keep this medicine out of the sight and reach of children.

Do not use Ondansetron Tablets after the expiry date which is stated on the pack after ‘EXP’. The expiry date refers to the last day of that month.

Store in the original package. Keep blister in the outer carton.

If your doctor tells you to stop taking Ondansetron Tablets, it is important to return any which are left over to your pharmacist.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Ondansetron Tablets contain

The active ingredient in Ondansetron Tablets is ondansetron hydrochloride dihydrate. Each Ondansetron film-coated tablet contains ondansetron 4 mg or 8 mg.

The other ingredients are: lactose monohydrate, microcrystalline cellulose, maize starch, magnesium stearate, hypromellose, titanium dioxide E171, macrogol.

What Ondansetron Tablets looks like and contents of the pack

Ondansetron 4 mg Tablets are white, circular, biconvex, film coated tablet marked ‘4’ on one side, plain on the other

Ondansetron 8 mg Tablets are white, circular, biconvex, film coated tablet marked ‘8’ on one side and with a deep breakline on the other.

Ondansetron Tablets come in:

Blister strips comprising PVC/PVdC/Aluminium foil enclosed in an outer carton. Pack sizes of 10, 30, or 100 tablets.

Not all pack sizes may be marketed.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).