Domina

Composition:

Each 2 ml ampoule contains 4 mg Ondansetron(as Hydrochloride dihydrate)

Pharmacodynamic properties:

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.

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

Indications:

Therapeutic indications:

Adults:

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

Paediatric Population:

Cametron 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.

Contraindication:

Concomitant use with apomorphine

Hypersensitivity to any component of the preparation.

Dosage & Method of administration:

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 Cametron should be flexible in the range of 8-32 mg a day.

Emetogenic chemotherapy and radiotherapy:

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

For most patients receiving emetogenic chemotherapy or radiotherapy, Cametron 8 mg should be administered as a slow intravenous injection (in not less than 30 seconds) or intramuscular injection, immediately before treatment, followed by 8 mg orally twelve hourly.

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

Highly emetogenic chemotherapy: For patients receiving highly emetogenic chemotherapy, e.g. high- dose cisplatin, Cametron can be given either by oral, rectal, intravenous or intramuscular administration.

• A single dose of 8 mg by slow intravenous injection (in not less than 30 seconds) or intramuscular injection immediately before chemotherapy.

• A dose of 8 mg by slow intravenous injection (in not less than 30 seconds) or intramuscular injection immediately before chemotherapy, followed by two further intravenous injection (in not less than 30 seconds) or intramuscular doses of 8 mg four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.

• A maximum initial intravenous dose of 16 mg diluted in 50-100 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes immediately before chemotherapy. The initial dose of Cametron may be followed by two additional 8 mg intravenous doses (in not less than 30 seconds) or intramuscular doses four hours apart.

A single dose greater than 16 mg must not be given due to dose dependent increase of QT- prolongation risk.

The selection of dose regimen should be determined by the severity of the emetogenic challenge. The efficacy of Cametron in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.

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

Paediatric Cametron:

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 50 ml 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.

Cametron injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid and infused intravenously over not less than 15 minutes.

Dosing by BSA:

Cametron 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

BSA	Day 1	Days 2-6
< 0.6 m²	5 mg/m² IV plus 2 mg syrup after 12 hrs	2 mg syrup every 12 hrs
≥ 0.6 m² to ≤ 1.2 m²	5 mg/m² IV plus 4 mg syrup or tablet after 12 hrs	4 mg syrup or tablet every 12 hrs
> 1.2 m²	5 mg/m² or 8 mg IV plus 8 mg syrup or tablet after 12 hours	8 mg syrup or tablet every 12 hours

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

Cametron 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

Weight	Day 1	Days 2-6
≤ 10 kg	Up to 3 doses of 0.15 mg/kg IV every 4 hrs	2 mg syrup every 12 hrs
> 10 kg	Up to 3 doses of 0.15 mg/kg IV every 4 hrs	4 mg syrup or tablet every 12 hrs

Elderly:

In patients 65 to 74 years of age, the dose schedule for adults can be followed. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid and infused over 15 minutes.

In patients 75 years of age or older, the initial intravenous dose of Cametron should not exceed 8 mg. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid and infused over 15 minutes. The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg, infused over 15 minutes and given no less than four hours apart.

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 Cametron 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.

Adults:

For the prevention of PONV: Cametron can be administered orally or by intravenous or intramuscular injection.

Cametron may be administered as a single dose of 4 mg given by intramuscular or slow intravenous injection at induction of anaesthesia.

For treatment of established PONV: A single dose of 4 mg given by intramuscular or slow intravenous injection is recommended.

Paediatric population:

PONV in children aged ≥ 1 month and adolescents

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of Cametron 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 either prior to, at or after induction of anaesthesia.

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

Elderly:

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

Patients with Renal Impairment:

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

Patients with Hepatic Impairment:

Overdose:

Symptoms and Signs:

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.

Side effects:

Immune system disorders
Rare:	Immediate hypersensitivity reactions, including anaphylaxis.
Nervous system disorders
Very common:	Headache.
Uncommon:	Seizures, movement disorders (including extrapyramidal reactions)
Rare:	Dizziness predominantly during rapid IV administration.
Eye disorders
Rare:	Transient visual disturbances (e.g. blurred vision) predominantly during IV administration.
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 and thoracic disorders
Uncommon:	Hiccups.
Gastrointestinal disorders
Common:	Constipation.
Hepatobiliary disorders
Uncommon:	Asymptomatic increases in liver function tests ⁽³⁾.
General disorders and administration site conditions
Common:	Local IV injection site reactions.

Precautions:

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, 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 sub-acute 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 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 indicates similar efficacy for both regimens.

Drug Interactions:

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), antifungals (such as 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). (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.

Use during Pregnancy or 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.

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.

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