Ondansetron Pharmc 4 mg/2 mL & 8 mg/4 mL Solution for injection

ONDANSETRON 4 mg/2 mL PHARMC and ONDANSETRON 8 mg/4 mL PHARMC (ONDANSETRON PHARMC) is indicated for the management of nausea and vomiting induced by chemotherapy and radiotherapy. ONDANSETRON PHARMC is also indicated for the prevention and treatment of post-operative nausea and vomiting. Routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and vomiting will occur.

Posology

Chemotherapy and radiotherapy induced nausea and vomiting

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used.

Adults

Emetogenic chemotherapy and radiotherapy: For most patients receiving emetogenic chemotherapy or radiotherapy ONDANSETRON PHARMC, 8 mg should be administered as a slow IV infusion (not less than 2 u2013 3 minutes) or IM injection in not less than 30 seconds, immediately before treatment.

Highly Emetogenic Chemotherapy: A single dose of ONDANSETRON PHARMC, 8 mg by slow IV infusion (not less than 2 u2013 3 minutes) or IM injection in not less than 30 seconds immediately before chemotherapy, has been shown to be effective in many patients. Higher doses may be required in some patients, particularly those on high dose cisplatin, and the doses should be adjusted according to severity of the emetogenic challenge. In these patients the following dose schedules have been shown to be effective: A dose of 8 mg by slow IV infusion or IM injection immediately before chemotherapy, followed by two further IV or IM doses of 8 mg two to four hours apart, or by constant infusion of 1 mg/hour for up to 24 hours. OR ALTERNATIVELY: A single dose of 16 mg diluted in 50 u2013 100 mL of saline or other compatible infusion fluid, infused over not less than 15 minutes immediately before chemotherapy. A single dose greater than 16 mg should not be given due to dose-dependent increased risk of QT prolongation (see section 4.4). The efficacy of ONDANSETRON PHARMC in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone phosphate 20 mg administered 30 u2013 45 minutes prior to the first ONDANSETRON PHARMC dose prior to chemotherapy.

Children

Experience is currently limited, but ONDANSETRON PHARMC was effective and well tolerated in children over the age of 4 years, when given intravenously at a dose of 5 mg/m2 over 15 minutes, immediately before chemotherapy. This dosage should be followed by an appropriate oral dosage form.

Elderly patients

A greater effect on QTcF is predicted in patients u2265 75 years of age compared to young adults. Specific dosing information for intravenous dosing is provided for patients over 65 years of age and over 75 years of age.

• Elderly patients aged 75 years or older: A single dose of intravenous ONDANSETRON PHARMC given for the prevention of chemotherapy induced nausea and vomiting (CINV) must not exceed 8 mg (infused over at least 15 minutes).
• Adult patients aged less than 75 years: A single dose of intravenous ONDANSETRON PHARMC given for the prevention of CINV in adults (aged less than 75 years) must not exceed 16 mg (infused over at least 5 minutes).
• Elderly patients aged 65 years or older: All intravenous doses should be diluted in 50 u2013 100 ml saline or other compatible fluid and infused over at least 15 minutes. Repeat intravenous doses of ONDANSETRON PHARMC should be given no less than 4 hours apart.

Prevention and Treatment of post-operative nausea and vomiting

Adults: Immediately before induction of anaesthesia, or post-operatively if the patient experiences nausea and/or vomiting occurring shortly after surgery, administer 4 mg undiluted intramuscularly or intravenously. If given intravenously, it must be administered by IV infusion over not less than 2 u2013 5 minutes or longer. Repeat dosing for patients who continue to experience nausea and/or vomiting post-operatively has not been studied. While recommended as a fixed dose for all, few patients above 80 kg or below 40 kg have been studied.

Children: For prevention of post-operative nausea and vomiting in paediatric patients two years and older having surgery performed under general anaesthesia, ONDANSETRON PHARMC may be administered by slow intravenous infusion over 2 to 5 minutes or longer at a dose of 0,1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia. For the treatment of established post-operative nausea and vomiting in paediatric patients two years and older, ONDANSETRON PHARMC may be administered by slow intravenous infusion at a dose of 0,1 mg/kg up to a maximum of 4 mg over not less than 2 u2013 5 minutes or preferably longer. Repeat dosing for paediatric patients who continue to experience nausea and/or vomiting has not been studied and should thus not be given.

Elderly: A slight age-related decrease in clearance, and in increase in the half-life of ondansetron is anticipated, presenting as slight, clinically insignificant age-related increases in both oral bioavailability and a prolonged elimination half-life (5 hours) of ondansetron.

Patients with renal/hepatic impairment

Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration is required for mild to moderate renal impairment. There is limited information available on severe renal impairment.

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

Method of administration: Precaution should be taken before manipulating or administering ONDANSETRON PHARMC, see section 6.6. For instructions on dilution of the medicine before administration, see section 6.6.

• Hypersensitivity to ondansetron or to any of the excipients listed in section 6.1.
• Post operative nausea in pregnancy (see section 4.6).
• Pregnancy.
• Concomitant use with apomorphine (see section 4.5).
• Congenital long QT syndrome.

Hepatic impairment: In patients with moderate or severe impairment of hepatic function, clearance of ONDANSETRON PHARMC is significantly reduced and serum half-life significantly prolonged. In such patients, a total daily dose of 8 mg should not be exceeded (see section 4.2).

ONDANSETRON PHARMC prolongs the QT interval in a dose-dependent manner. Transient ECG changes including QT interval prolongation have been reported in patients receiving ONDANSETRON PHARMC. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. ONDANSETRON PHARMC should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with electrolyte abnormalities, with congenital long QT syndrome, or patients taking other medicinal products that lead to QT prolongation. Therefore, caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-dysrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.

Cases of myocardial ischaemia have been reported in patients treated with ondansetron. In some patients, especially in the case of intravenous administration, symptoms appeared immediately after administration of ondansetron. Patients should be alerted to the signs and symptoms of myocardial ischaemia.

Hypocalcaemia and hypomagnesaemia: Hypocalcaemia and hypomagnesaemia should be corrected before ONDANSETRON PHARMC administration.

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

Subacute intestinal obstructions: Patients with subacute intestinal obstructions should be monitored following administration, as ONDANSETRON PHARMC is known to increase large bowel transit time.

Dizziness and transient visual disturbances: Dizziness and transient visual disturbances (e.g., blurred vision) have been reported during or shortly after rapid intravenous administration of ONDANSETRON PHARMC (see section 4.7 and 4.8).

Serotonin syndrome: Post-marketing reports describe patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ONDANSETRON PHARMC and other serotonergic medicines (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ONDANSETRON PHARMC and other serotonergic medicines is clinically warranted, appropriate close observation of the patient is advised (see section 4.8).

Adenotonsillar surgery: In patients with adenotonsillar surgery prevention of nausea and vomiting with ONDANSETRON PHARMC may mask occult bleeding. Therefore, such patients should be carefully monitored after ONDANSETRON PHARMC.

Paediatric population: The daily dose should not exceed 4 mg in patients with hepatic impairment. Paediatric patients receiving ONDANSETRON PHARMC with hepatotoxic chemotherapeutic agents should be closely monitored for impaired hepatic function.

Excipients with known effects: ONDANSETRON PHARMC contains 3,61 mg sodium per 1 mL which is less than 1 mmol sodium (23 mg) per 1 mL, that is to say essentially u2018 sodium free u2019. At maximum dose (16 mL) ONDANSETRON PHARMC contains 57 mg of sodium. This is equivalent to approximately 2,85 % of the recommended maximum daily dietary intake of sodium for an adult.

The cytochrome P450 isoenzyme system: ONDANSETRON PHARMC does not appear to induce or inhibit the cytochrome P450 isoenzyme system, but it is itself metabolised by multiple hepatic isoenzymes, including CYP3A4, CYP2D6, and CYP1A2. Inducers or inhibitors of these isoenzymes may change the clearance and half-life of ondansetron, but on the basis of available data, no dose adjustments are recommended.

Potent inducers of CYP3A4, such as phenytoin, carbamazepine, and rifampicin, have been reported to increase ondansetron clearance and reduce ondansetron plasma concentrations.

QT prolonging medicines: Use of ONDANSETRON PHARMC with QT prolonging medicines may result in additional QT prolongation. Concomitant use of ONDANSETRON PHARMC with cardiotoxic medicines (e.g., anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab), antibiotics (such as erythromycin), antifungals (such as ketoconazole), antidysrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of dysrhythmias.

Apomorphine: Cases of profound hypotension and loss of consciousness when ondansetron was administered concomitantly with apomorphine have been reported. Concomitant use of ONDANSETRON PHARMC and apomorphine may intensify QT prolongation. Concomitant administration of ONDANSETRON PHARMC and apomorphine is contraindicated (see section 4.3).

Tramadol: ONDANSETRON PHARMC may reduce the analgesic effect of tramadol.

Serotonergic Medicines (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 PHARMC and other serotonergic medicines (including SSRIs and SNRIs) (see section 4.4).

Other medicines: There is no evidence that ONDANSETRON PHARMC either induces or inhibits the metabolism of other medicines commonly co-administered with it. Specific studies have shown that there are no interactions when ONDANSETRON PHARMC is administered with alcohol, temazepam, furosemide, alfentanil, morphine, lidocaine, thiopental, or propofol.

Women of childbearing potential / Contraception in males and females: Women of childbearing potential being treated with ONDANSETRON PHARMC should not become pregnant as ONDANSETRON PHARMC is contraindicated in pregnancy, irrespective of the cause of the nausea and vomiting (see section 4.3). Women of childbearing potential to use contraception while taking ONDANSETRON PHARMC and for 2 days after stopping treatment.

Pregnancy: ONDANSETRON PHARMC is contraindicated in pregnancy (see section 4.3). The use of ONDANSETRON PHARMC during the first 12 weeks of pregnancy can be associated with an increased risk of developing oral cleft palate and/or lip to the foetus.

Breastfeeding: Tests have shown that ondansetron as in ONDANSETRON PHARMC passes into the milk of lactating animals. It is therefore recommended that mothers receiving ONDANSETRON PHARMC should not breast feed their babies.

It is not always possible to predict to what extent ONDANSETRON PHARMC may interfere with the daily activities of a patient. Patients should ensure that they do not engage in the above activities until they are aware of the measure to which ONDANSETRON PHARMC affects them.

a. Summary of the safety profile: The following frequencies are estimated at the standard recommended doses of ONDANSETRON PHARMC.

b. Tabulated summary of adverse reactions:

c. Description of selected adverse reactions:

Blindness: 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.

Hepatobiliary disorders: These events were commonly observed in patients receiving cancer chemotherapy with cisplatin.

d. Paediatric population: The adverse event profiles in children and adolescents were comparable to those seen in adults.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAH PRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

See section 4.8. Manifestations that have been reported include severe constipation, visual disturbances, hypotension, and vasovagal episode with transient second-degree AV block, in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate, as there is no specific antidote for ondansetron. 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. In all cases of suspected overdose, treatment is symptomatic and supportive as appropriate. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

Additional information on special populations:

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.