Ondansetron Orodispersible Tablets

Ondansetron Orodispersible Tablets

Ondansetron Orodispersible Tablets

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.

Therapeutic indications

Adults:Ondansetron Orodispersible Tablets 4 mg & 8mg is indicated for the management of nauseaand vomiting induced by cytotoxic chemotherapy and radiotherapy.

Ondansetron Orodispersible Tablets 4 mg & 8mg is indicated for the prevention of postoperative nausea and vomiting (PONV).

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

Paediatric Population: Ondansetron Orodispersible Tablets 4 mg & 8mg is indicated for the management ofchemotherapy-induced nausea and vomiting (CINV) in children aged ≥6 months

For the prevention and treatment of PONV in children aged ≥1 month, administration by injection is recommended.

Posology and method of administration

Place the orodispersible Tablets on top of the tongue, where it will disperse within seconds, then swallow.

Chemotherapy and radiotherapy induced nausea and vomiting.

Adults: The emetogenic potential of cancer treatment varies according to the doses and combinationsof chemotherapy and radiotherapy regimens used. The selection of dose regimen should bedetermined by the severity of the emetogenic challenge.

Emetogenic chemotherapy and radiotherapy: Ondansetron Orodispersible Tablets 4 mg can be given either by rectal, oral (as Orodispersible Tablets, tablets or syrup) intravenous or intramuscular administration. For oral administration: 8mg taken 1 to 2 hours before chemotherapy or radiation treatment, followed by 8mg every 12 hours for a maximum of 5 days to protect against delayed or prolonged emesis.

For highly emetogenic chemotherapy: a single dose of up to 24mg Ondansetron Orodispersible

Tablets 4 mg & 8mg 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 Orodispersible Tablets 4 & 8mg mg may be continued for up to 5 days after a course of treatment.

The recommended dose for oral administration is 8mg to be taken twice daily.

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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.

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.

There are no data from controlled clinical trials on the use of Ondansetron Orodispersible

Tablets 4 mg & 8mg in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of Ondansetron Orodispersible Tablets 4 mg & 8mg for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Ondansetron Orodispersible Tablets 4 mg & 8mg should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m2. The single intravenous dose must not exceed 8 mg.

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 32 mg.

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

BSADay 1 (a,b)Days 2-6(b)
< 0.6 m25 mg/m2 IV. plus 2 mg syrup after 12 hours2 mg syrup every 12 hours
0.6 m25 mg/m2 IV plus 4 mg syrup or tablet after 12 hours4 mg syrup or tablet every 12 hours
>1.2m25mg/m2 or 8mg IV plus 8mg syrup or tablet after 12 hours8mg syrup or tablet every 12 hours

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. Ondansetron Orodispersible Tablets 4 mg & 8mg should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The single intravenous dose must not exceed 8 mg. Two further intravenous doses may be given in 4-hourly intervals. Oral dosing can commence 12 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 32 mg.

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

WeightDay 1 (a,b)Days 2-6(b)
≤ 10 kgUp to 3 doses of 0.15 mg/kg every 4 hours2 mg syrup every 12 hours
> 10 kgUp to 3 doses of 0.15 mg/kg every 4 hours4 mg syrup or tablet every 12 hours

a The intravenous dose must not exceed 8mg.

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

Elderly: Ondansetron Orally Disintegrating Tablets 4 mg & 8mg is well tolerated by patients over65 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 Orodispersible Tablets 4 mg & 8mg may beadministered either orally (as orally disintegrating tablets, tablets or syrup) or by intravenous or intramuscular injection.

For oral administration: 16mg taken one hour prior to anesthesia.

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 theprevention or treatment of post-operative nausea and vomiting; slow IV injection (not lessthan 30 seconds) 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 0.1mg/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 Orodispersible Tablets 4 mg & 8mg may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg.

There are no data on the use of Ondansetron Orodispersible Tablets 4 mg & 8mg in the treatment of PONV in children below 2 years of age.

Elderly: There is limited experience in the use of Ondansetron Orodispersible Tablets 4 mg & 8mg inthe prevention and treatment of PONV in the elderly, however Ondansetron OrodispersibleTablets 4 & 8mg mg 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 Orodispersible Tablets 4 mg & 8mg is significantly reduced andserum half life significantly prolonged in subjects with moderate or severe impairment ofhepatic function. In such patients a total daily dose of 8mg should not be exceeded.

Patients with poor sparteine/debrisoquinemetabolism: The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisersof sparteine and debrisoquine. Consequently in such patients repeat dosing will give drugexposure levels no different from those of the general population. No alteration of daily dosageor frequency of dosing is required.

Contraindications

Concomitant use with apomorphine.

Hypersensitivity to any component of the preparation.

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. In addition, postmarketing 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.

Ondansetron Orodispersible Tablets 4 mg & 8mg formulation contains aspartame and therefore should be taken with caution in patients with phenylketonuria.

Neither non-clinical nor clinical data are available to assess aspartame use in infant below 12 weeks of age.

Paediatric Population: Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents shouldbe 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.

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. Use of ondansetron with QT prolonging drugs may result in additional QT prolongation.

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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.

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).

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.

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 the foetus, 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.

Breast-feeding: Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Ondansetron Orodispersible Tablets 4 mg & 8mg should not breast-feed their babies.

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.

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. 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.

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