Ondansetron Oral Solution IP 2mg/5ml (30ml)

Ondansetron Oral Solution IP 2mg/5ml Technical Specifications:

GENERIC NAME OF MEDICINAL PRODUCT:

1. Ondansetron Oral Solution IP 2mg/5ml (30ml)
2. Ondansetron Oral Solution IP 4mg/5ml (30ml)

QUALITATIVE AND QUANTITATIVE COMPOSITION:

1. Ondansetron Oral Solution IP 2mg/5ml
   Each 5ml contains:
   Ondansetron Hydrochloride IP
   Equivalent to Ondansetron…….2mg
   Excipients……………………………….q.s.

2. Ondansetron Oral Solution IP 4mg/5ml
   Each 5ml contains:
   Ondansetron Hydrochloride IP
   Equivalent to Ondansetron…….4mg
   Excipients……………………………….q.s.

THERAPEUTIC INDICATION:

Ondansetron is used to treat nausea and vomiting caused by chemotherapy. It is also used to prevent or treat nausea and vomiting after surgery.

Ondansetron should be considered for infants and children age six months and older who present to the ED with vomiting related to suspected acute gastroenteritis, and who have mild to moderate dehydration or who have failed oral rehydration therapy.

DIRECTION OF USE:

For Oral use only.

Refer package insert for dosage and administration.

CAUTION AND SCHEDULE:

CAUTION: Do not use if any foreign particulate matter is observed inside the bottle.

For Pediatric Use.

Shake well before use.

Keep bottle well closed.

KEEP OUT OF REACH AND SIGHT OF CHILDREN.

SCHEDULE: SCHEDULE ‘H PRESCRIPTION DRUG-CAUTION Not to be sold by retail without the prescription of a Registered Medical Practitioner.

STORAGE AND DOSAGE:

STORAGE: Store at a temperature 20°C to 25°C (68°F to 77°F). Protect from light.

Store bottle upright in a carton.

DOSAGE:  As directed by the Physician.

3. Pharmaceutical form

Syrup

4. Clinical particulars

4.1 Therapeutic indications

Ondansetron Syrup is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

Ondansetron Syrup is also indicated for the prevention of post-operative nausea and vomiting (PONV).

For treatment of established PONV, administration by injection is recommended.

4.2 Posology and method of administration

Chemotherapy and radiotherapy induced nausea and vomiting (CINV and RINV).

CINV and RINV in Adults:

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge.

Emetogenic chemotherapy and radiotherapy: Ondansetron can be given by oral administration.

The recommended oral dose is 10ml (8mg) 1-2 hours before treatment, followed by 10ml (8mg) orally 12 hours later.

For highly emetogenic chemotherapy: a single dose of up to 30ml (24mg) Ondansetron taken with 12mg oral dexamethasone sodium phosphate, 1 to 2 hours before chemotherapy, may be used.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with Ondansetron may be continued for up to 5 days after a course of treatment.

The recommended dose for oral administration is 10ml (8mg) to be taken twice daily.

Paediatric Population:

CINV in children aged ≥ 6 months and adolescents   

The dose for CINV can be calculated based on body surface area (BSA) or weight – see below. In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50mL of saline or other compatible infusion fluid and infused over not less than 15 minutes.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4.).

There are no data from controlled clinical trials on the use of Ondansetron in the prevention of delayed or prolonged CINV. 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 5mg/m². The single intravenous dose must not exceed 8mg.

Oral dosing can commence 12 hours later and may be continued for up to 5 days (Table 1).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32mg.

Table 1: BSA-based dosing for CINV–(aged 6 months to 17 years)

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours must not exceed adult dose of 32 mg

Dosing by bodyweight:

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

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

Two further intravenous doses may be given in 4-hourly intervals.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2). The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32mg.

Table 2: Weight-based dosing for Chemotherapy – Children aged ≥6 months and adolescents

a The intravenous dose must not exceed 8mg.

b The total dose over 24 hours must not exceed adult dose of 32mg.

Elderly:

Ondansetron is well tolerated by patients over 65 years. No alteration of oral dose or frequency of administration is required.

Post operative nausea and vomiting (PONV).

Adults:

For the prevention of PONV: Ondansetron can be administered orally

For oral administration: 20ml (16mg) one hour prior to anaesthesia.

For the treatment of established PONV: Intravenous or intramuscular administration is recommended.

Paediatric population:

PONV in children aged ≥ 1 month and adolescents

Oral formulation:

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; slow IV injection (not less than 30 seconds) is recommended for this purpose.

There are no data on the use of ondansetron in the treatment of PONV in children below 2 years of age.

Elderly:

There is limited experience in the use of Ondansetron in the prevention and treatment of PONV in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.

For both indications:

Patients with Renal impairment:

No alteration of daily dosage or frequency of dosing, or route of administration are 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 10ml (8mg) 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 drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.

Method of administration:

► Use the 2.5-5ml double-ended spoon supplied in the pack (see below) to measure the required dose.

► Swallow the solution.

► Wash the spoon with clean water after taking every dose.

► Once measured, the solution should be consumed within 3 hours

Double-ended Spoon

4.3 Contraindications

Hypersensitivity to any of the ingredients in the product.

Concomitant use with apomorphine (see section 4.5).

4.4 Special warnings and precautions for use

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

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

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). 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.

Hypokalaemia and hypomagnesaemia 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.

Paediatric Population:

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

CINV: When calculating the dose on an mg/kg basis and administering three doses at 4-hour intervals, the total daily dose will be higher than if one single dose of 5mg/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 indicates similar efficacy for both regimens (section 5.1).

Excipients in the formulation

Ondansetron Syrup contains Sorbitol, liquid (non-crystallising) (E420). Patients with a rare hereditary problem of fructose intolerance should not take this medicine.

Ondansetron Syrup contains sodium benzoate (E211), which may increase jaundice (yellowing of the skin and eyes) in pre-term and full-term jaundiced neonates.

Ondansetron Syrup also contains 14.74mg/5ml propylene glycol as an ingredient necessary for the medicine to work properly.

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 drugs commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising 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.

Caution should be exercised when ondansetron is coadministered with drugs that prolong the QT interval and/or cause electrolyte abnormalities (See section 4.4).

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 trastuzumab), 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 section 4.4).

Serotonergic Drugs (e.g. SSRIs and SNRIs): 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 section 4.4).

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 oral 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.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations when administered during the first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10 000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)).

The available epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

Breast-feeding

Tests have shown that ondansetron passes into the milk of lactating animals. 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 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and very rare (<1/10,000). 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.

The following frequencies are estimated at the standard recommended doses of ondansetron. The adverse event profiles in children and adolescents were comparable to that seen in adults.

⁽¹⁾ Observed without definitive evidence of persistent clinical sequelae.

⁽²⁾ 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.

⁽³⁾ These events were observed commonly in patients receiving chemotherapy with cisplatin.

Paediatric population

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

4.9 Overdose

Symptoms and Signs

There is limited experience of ondansetron overdose. In the majority of cases, symptoms were similar to those already reported in patients receiving recommended doses (see section 4.8). Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second-degree AV block

Ondansetron prolongs the QT interval in a dose-dependent fashion. 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 (5HT₃) antagonist

Mechanism of Action

Ondansetron is a potent, highly selective 5HT₃ receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT 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 5HT3 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.

Ondansetron does not alter plasma prolactin concentrations.

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

QT Prolongation

The effect of ondansetron on the QTc interval was evaluated in a double blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 19.6 (21.5) msec. At the lower tested dose of 8 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 5.8 (7.8) msec. In this study, there were no QTcF measurements greater than 480 msec and no QTcF prolongation was greater than 60 msec.

Paediatric population

CINV

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 (S3AB3006). On the days of chemotherapy, patients received either ondansetron 5 mg/m² intravenous and ondansetron 4 mg orally after 8 to 12 hours or ondansetron 0.45 mg/kg intravenous and placebo orally after 8 to 12 hrs. 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 intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

A double-blind randomised placebo-controlled trial (S3AB4003) 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/m²intravenous together with 2 to 4 mg dexamethasone orally
• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg together with 2 to 4 mg dexamethasone orally on the days of chemotherapy.

Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, non-comparative, single-arm study (S3A40320). All children received three 0.15 mg/kg doses of intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then at 4 and 8 hours after the first dose. Complete control of emesis was achieved in 56% of patients.

Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for children aged < 12 years and 8 mg for children aged ≥ 12 years (total no. of children n= 28). Complete control of emesis was achieved in 42% of patients.

PONV

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).

5.2 Pharmacokinetic properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30ng/mL are attained approximately 1.5 hours after an 8mg dose. For doses above 8mg 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. Mean bioavailability in healthy male subjects, following the oral administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids.

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 140L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.

A 4mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65ng/mL. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25ng/mL are attained within 10 minutes of injection.

Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing. Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30 ng/mL are attained, typically 6 hours after dosing. Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of ondansetron. The absolute bioavailability of ondansetron from the suppository is approximately 60% and is not affected by gender. The half life of the elimination phase following suppository administration is determined by the rate of ondansetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

Ondansetron is not highly protein bound (70-76%). 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 (the debrisoquine polymorphism) has no effect on ondansetron’s pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 h) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

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.

Special Patient Populations

Gender

Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

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 half-life 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 428 subjects (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years following intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4 months. Volume was related to age and was lower in adults than in infants and children. Clearance was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months or simply inherent variability due to the low number of subjects studied in this age group. Since patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is not likely to be clinically relevant.

Elderly

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (< 65 years of age) and elderly subjects (≥ 65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials to support a different dosing recommendation for the elderly.

Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients ≥75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for intravenous dosing.

Renal impairment

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 (5.4 hours). 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.

Hepatic impairment

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 hours) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism. The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

5.3 Preclinical safety data

No additional data of relevance.

6. Pharmaceutical particulars

6.1 List of excipients

Citric acid monohydrate (E330)

Sodium citrate (E331)

Sorbitol, liquid (non-crystallising) (E420)

Sodium benzoate (E211)

Strawberry flavour (contains propylene glycol (E1520))

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months.

Discard 60 days after first opening

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Bottle: Type III Amber glass

Closure: HDPE, EPE wadded, tamper evident, child resistant screw on white plastic polypropylene cap.

Dosing Device: Double ended plastic spoon with 2.5ml and 5ml measuring ends.

Pack size: 50ml, 100ml and 300ml

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 of in accordance with local requirements.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LTD.
Plot No.220, Mahagujarat Industrial Estate,
At & Post: Moraiya, TAL- Sanand,
Dist. Ahmedabad, Gujarat(India)

Package leaflet: Information for the user

a) Ondansetron Oral Solution IP 2mg/5ml
b) Ondansetron Oral Solution IP 4mg/5ml

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

What is in this leaflet

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

Ondansetron 4mg/5ml Syrup belongs to a group of medicines called anti-emetics, also known as serotonin 5HT₃ antagonists (called Ondansetron Syrup throughout the rest of this leaflet).

Ondansetron Syrup is taken if you are feeling sick (nausea) or being sick (vomiting) after you have had chemotherapy, radiotherapy, or an operation.

3.What you need to know before you take Ondansetron Syrup

Do not take Ondansetron Syrup

• if you are allergic to ondansetron or any of the other ingredients of this medicine (listed in section 6).
• if you are taking apomorphine (used to treat Parkinson’s disease).

Warnings and precaution

Talk to your doctor, pharmacist or nurse before taking Ondansetron Syrup

• if you are allergic (hypersensitivity) to medicines similar to ondansetron such as dolasetron, granisetron and palonosetron;
• if you have a blockage in your gut or bowel or if you have constipation;
• if you have ever had heart problems (e.g. congestive heart failure which causes shortness of breath and swollen ankles)
• if you have an uneven heart beat (arrhythmias)
• if you have problems with your liver;
• if you know that the levels of sodium, potassium, magnesium or chloride in your body are very low or very high.

Other medicines and Ondansetron Syrup

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

Make sure your doctor knows if you are taking a medicine listed here:

• Beta blockers(used to treat certain heart or eye problems, anxiety or prevent migraines);
• Atenololto treat high blood pressure or angina (pains in your chest): use with ondansetron may cause a change to your heart rate;
• Anti-arrhythmicssuch as amiodarone to control your heart rate: use with ondansetron may cause a change to your heart rate;
• Phenytoinand carbamazepine to treat epilepsy, or rifampicin to treat tuberculosis: ondansetron may not work as well;
• Tramadola strong painkiller: ondansetron may stop the tramadol working properly;
• Haloperidolor Methadone medicines that affect the heart;
• Antibioticssuch as erythromycin to treat bacterial infections and Antifungals such as ketoconazole to treat fungal infections: use with ondansetron may increase the risk of irregular heartbeats or changes to your heart rate;
• Cardiotoxic drugssuch as some cancer medicines including anthracyclines (e.g. doxorubicin and daunorubicin) and trastuzumab: use with ondansetron may increase the risk of irregular heartbeats or changes to your heart rate;
• SSRIs(selective serotonin re-uptake inhibitors) used to treat depression and/or anxiety including fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram;
• SNRIs(serotonin noradrenaline re-uptake inhibitors) used to treat depression and/or anxiety including venlafaxine, duloxetine: use with ondansetron may cause side effects to get worse.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

You should not use Ondansetron Syrup during the first trimester of pregnancy. This is because Ondansetron Syrup 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). If you are already pregnant, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking Ondansetron Syrup. If you are a woman of childbearing potential you may be advised to use effective contraception.

Breast-feeding

Do not breast-feed if you are taking Ondansetron. This is because small amounts pass into the mother’s milk. Ask your doctor or midwife for advice.

Driving and using machines

Ondansetron Syrup does not affect your ability to drive or use machines.

Ondansetron Syrup contains

This medicine contains 2 mg sodium benzoate in 1 ml, which is equivalent to 2 mg/ml. Benzoic salt may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicine contains Xylitol (E 967) which may have a laxative effect and has a calorific value of 2.4 kcal/g xylitol.

This medicine contains a very small amount of alcohol, less than 3mg per 5ml spoonful dose.

3. How to take Ondansetron Syrup

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Do not mix Ondansetron syrup with anything (not even water) before swallowing it.

The recommended dose is-

Adults and the elderly

During chemotherapy or radiotherapy

• the usual dose is two 5ml spoonfuls (8mg ondansetron);
• this is taken 1 to 2 hours before your therapy starts;
• take two 5ml spoonfuls (8mg ondansetron) 12 hours later;
• take two 5ml spoonfuls (8mg ondansetron) twice a day for up to five days after the day of your chemo- or radiotherapy;
• if your chemotherapy is expected to make you feel, or be, very sick take 6 spoonfuls (24mg ondansetron) before therapy. Your doctor may recommend taking 12mg of dexamethasone at the same time;
• you should not take more than 32mg over a 24 hour period.

If you are having an operation

• eithertake four 5ml spoonfuls (16mg ondansetron) one hour before your anaesthetic or two 5ml spoonfuls (8mg ondansetron) one hour before your anaesthetic followed by two 5ml spoonfuls at 8 hours and 16 hours after your first dose.

Use in children and adolescents (aged 6 months and above)

During chemotherapy or radiotherapy

• The dose depends on the weight or body surface area of the child;
• Your doctor will tell you the actual dose for your child;
• Make sure the child takes the medicine as the doctor says;
• A dose range of half a 5ml spoonful (2mg ondansetron) to two 5 ml spoonfuls (8mg ondansetron) every 12 hours for up to five days is permitted.

If your child is having an operation

• Ondansetron Syrup is not normally given to children before an operation.

Patients with liver disease

• The maximum dose is two 5ml spoonfuls (8mg ondansetron) each day.

If you take more Ondansetron Syrup than you should

If you or your child take more Ondansetron Syrup than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you. In an event of overdose you may experience constipation, difficulty in seeing, low blood pressure, feeling dizzy, feeling sick, loss of consciousness, abnormal changes to ECG.

If you forget to take Ondansetron Syrup

If you forget to take a dose, take another as soon as you remember. Then take your next dose at the normal time.

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, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you have any of the following rare side effects while taking your medicine tell your doctor immediately or go to hospital straight away:

• severe allergic reaction which may include a red and lumpy skin rash (hives), difficulty with breathing, sudden wheezing, swelling of your face, mouth, lips or eyelids, a high temperature (fever) and feeling faint. If the swelling affects your throat and makes breathing and swallowing difficult, go to hospital straight away;
• uneven, fast or slow heartbeat (palpitations);
• chest pain;
• irregular heartbeat.

Other side effects which may occur

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

Common (may affect up to 1 in 10 people)

• constipation;
• flushing or feeling warm.

Uncommon (may affect up to 1 in 100 people)

• fits (seizures);
• muscle weakness;
• problems controlling movement or problems with the movement of your eyes;
• hiccups;
• low blood pressure, which can make you feel faint or dizzy;
• uneven heart beat;
• chest pain;
• changes to liver function test results (if you take Ondansetron syrup with a medicine called cisplatin).

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

• feeling dizzy or light headed (usually when given by injection);
• changes to your vision such as blurred vision (usually when given by injection);
• 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, especially if you are also having chemotherapy (usually when given by injection).

If you need a blood test tell your doctor you are taking this medicine as it may affect the results.

See section 2 of this leaflet for side effects that may be caused by ethanol, one of the ingredients in your medicine (Ondansetron Syrup contains Ethanol).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.

5. How to store Ondansetron Syrup

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

Do not use this medicine after the expiry date stated on the carton and bottle after “Exp”.

The expiry date refers to the last day of that month.

Once opened, use within 28 days.

There are no special storage conditions for your medicine.

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 Syrup contains

• The active substance is ondansetron (as the hydrochloride dihydrate). Each 5ml spoonful contains 4mg of ondansetron.
• The other ingredients are citric acid anhydrous, sodium citrate dihydrate, sodium benzoate (E211), xylitol (E967), strawberry flavour (containing propylene glycol and ethanol) and purified water.

What Ondansetron Syrup looks like and contents of the pack

Ondansetron Syrup is a clear solution in a brown glass bottle containing 50ml of the solution.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LTD.
Plot No.220, Mahagujarat Industrial Estate,
At & Post: Moraiya, TAL- Sanand,
Dist. Ahmedabad, Gujarat(India)

Ondansetron Oral Solution IP 2mg/5ml; 4mg/5ml

Package leaflet: Information for the user

1. a) Ondansetron Oral Solution IP 2mg/5ml
2. b) Ondansetron Oral Solution IP 4mg/5ml

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

What is in this leaflet

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

Ondansetron 4mg/5ml Syrup belongs to a group of medicines called anti-emetics, also known as serotonin 5HT₃ antagonists (called Ondansetron Syrup throughout the rest of this leaflet).

Ondansetron Syrup is taken if you are feeling sick (nausea) or being sick (vomiting) after you have had chemotherapy, radiotherapy, or an operation.

2. What you need to know before you take Ondansetron Syrup

Do not take Ondansetron Syrup

• if you are allergic to ondansetron or any of the other ingredients of this medicine (listed in section 6).
• if you are taking apomorphine (used to treat Parkinson’s disease).

Warnings and precaution

Talk to your doctor, pharmacist or nurse before taking Ondansetron Syrup

• if you are allergic (hypersensitivity) to medicines similar to ondansetron such as dolasetron, granisetron and palonosetron;
• if you have a blockage in your gut or bowel or if you have constipation;
• if you have ever had heart problems (e.g. congestive heart failure which causes shortness of breath and swollen ankles)
• if you have an uneven heart beat (arrhythmias)
• if you have problems with your liver;
• if you know that the levels of sodium, potassium, magnesium or chloride in your body are very low or very high.

Other medicines and Ondansetron Syrup

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

Make sure your doctor knows if you are taking a medicine listed here:

• Beta blockers(used to treat certain heart or eye problems, anxiety or prevent migraines);
• Atenololto treat high blood pressure or angina (pains in your chest): use with ondansetron may cause a change to your heart rate;
• Anti-arrhythmicssuch as amiodarone to control your heart rate: use with ondansetron may cause a change to your heart rate;
• Phenytoinand carbamazepine to treat epilepsy, or rifampicin to treat tuberculosis: ondansetron may not work as well;
• Tramadola strong painkiller: ondansetron may stop the tramadol working properly;
• Haloperidolor Methadone medicines that affect the heart;
• Antibioticssuch as erythromycin to treat bacterial infections and Antifungals such as ketoconazole to treat fungal infections: use with ondansetron may increase the risk of irregular heartbeats or changes to your heart rate;
• Cardiotoxic drugssuch as some cancer medicines including anthracyclines (e.g. doxorubicin and daunorubicin) and trastuzumab: use with ondansetron may increase the risk of irregular heartbeats or changes to your heart rate;
• SSRIs(selective serotonin re-uptake inhibitors) used to treat depression and/or anxiety including fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram;
• SNRIs(serotonin noradrenaline re-uptake inhibitors) used to treat depression and/or anxiety including venlafaxine, duloxetine: use with ondansetron may cause side effects to get worse.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

You should not use Ondansetron Syrup during the first trimester of pregnancy. This is because Ondansetron Syrup 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). If you are already pregnant, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking Ondansetron Syrup. If you are a woman of childbearing potential you may be advised to use effective contraception.

Breast-feeding

Do not breast-feed if you are taking Ondansetron. This is because small amounts pass into the mother’s milk. Ask your doctor or midwife for advice.

Driving and using machines

Ondansetron Syrup does not affect your ability to drive or use machines.

Ondansetron Syrup contains

This medicine contains 2 mg sodium benzoate in 1 ml, which is equivalent to 2 mg/ml. Benzoic salt may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicine contains Xylitol (E 967) which may have a laxative effect and has a calorific value of 2.4 kcal/g xylitol.

This medicine contains a very small amount of alcohol, less than 3mg per 5ml spoonful dose.

3. How to take Ondansetron Syrup

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Do not mix Ondansetron syrup with anything (not even water) before swallowing it.

The recommended dose is-

Adults and the elderly

During chemotherapy or radiotherapy

• the usual dose is two 5ml spoonfuls (8mg ondansetron);
• this is taken 1 to 2 hours before your therapy starts;
• take two 5ml spoonfuls (8mg ondansetron) 12 hours later;
• take two 5ml spoonfuls (8mg ondansetron) twice a day for up to five days after the day of your chemo- or radiotherapy;
• if your chemotherapy is expected to make you feel, or be, very sick take 6 spoonfuls (24mg ondansetron) before therapy. Your doctor may recommend taking 12mg of dexamethasone at the same time;
• you should not take more than 32mg over a 24 hour period.

If you are having an operation

• eithertake four 5ml spoonfuls (16mg ondansetron) one hour before your anaesthetic or two 5ml spoonfuls (8mg ondansetron) one hour before your anaesthetic followed by two 5ml spoonfuls at 8 hours and 16 hours after your first dose.

Use in children and adolescents (aged 6 months and above)

During chemotherapy or radiotherapy

• The dose depends on the weight or body surface area of the child;
• Your doctor will tell you the actual dose for your child;
• Make sure the child takes the medicine as the doctor says;
• A dose range of half a 5ml spoonful (2mg ondansetron) to two 5 ml spoonfuls (8mg ondansetron) every 12 hours for up to five days is permitted.

If your child is having an operation

• Ondansetron Syrup is not normally given to children before an operation.

Patients with liver disease

• The maximum dose is two 5ml spoonfuls (8mg ondansetron) each day.

If you take more Ondansetron Syrup than you should

If you or your child take more Ondansetron Syrup than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you. In an event of overdose you may experience constipation, difficulty in seeing, low blood pressure, feeling dizzy, feeling sick, loss of consciousness, abnormal changes to ECG.

If you forget to take Ondansetron Syrup

If you forget to take a dose, take another as soon as you remember. Then take your next dose at the normal time.

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, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you have any of the following rare side effects while taking your medicine tell your doctor immediately or go to hospital straight away:

• severe allergic reaction which may include a red and lumpy skin rash (hives), difficulty with breathing, sudden wheezing, swelling of your face, mouth, lips or eyelids, a high temperature (fever) and feeling faint. If the swelling affects your throat and makes breathing and swallowing difficult, go to hospital straight away;
• uneven, fast or slow heartbeat (palpitations);
• chest pain;
• irregular heartbeat.

Other side effects which may occur

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

Common (may affect up to 1 in 10 people)

• constipation;
• flushing or feeling warm.

Uncommon (may affect up to 1 in 100 people)

• fits (seizures);
• muscle weakness;
• problems controlling movement or problems with the movement of your eyes;
• hiccups;
• low blood pressure, which can make you feel faint or dizzy;
• uneven heart beat;
• chest pain;
• changes to liver function test results (if you take Ondansetron syrup with a medicine called cisplatin).

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

• feeling dizzy or light headed (usually when given by injection);
• changes to your vision such as blurred vision (usually when given by injection);
• 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, especially if you are also having chemotherapy (usually when given by injection).

If you need a blood test tell your doctor you are taking this medicine as it may affect the results.

See section 2 of this leaflet for side effects that may be caused by ethanol, one of the ingredients in your medicine (Ondansetron Syrup contains Ethanol).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.

5. How to store Ondansetron Syrup

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

Do not use this medicine after the expiry date stated on the carton and bottle after “Exp”.

The expiry date refers to the last day of that month.

Once opened, use within 28 days.

There are no special storage conditions for your medicine.

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 Syrup contains

• The active substance is ondansetron (as the hydrochloride dihydrate). Each 5ml spoonful contains 4mg of ondansetron.
• The other ingredients are citric acid anhydrous, sodium citrate dihydrate, sodium benzoate (E211), xylitol (E967), strawberry flavour (containing propylene glycol and ethanol) and purified water.

What Ondansetron Syrup looks like and contents of the pack

Ondansetron Syrup is a clear solution in a brown glass bottle containing 50ml of the solution.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LTD.
Plot No.220, Mahagujarat Industrial Estate,
At & Post: Moraiya, TAL- Sanand,
Dist. Ahmedabad, Gujarat(India)