Mylan Ondansetron 4 mg/2 ml, 8 mg/4 ml Injection

MYLAN ONDANSETRON is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. MYLAN ONDANSETRON 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 therapy varies according to the doses and combinations of chemotherapy and radiotherapy regimens used.

Adults: Emetogenic chemotherapy and radiotherapy: For most patients receiving emetogenic chemotherapy and radiotherapy, MYLAN ONDANSETRON 8 mg should be administered as a slow IV infusion (not less than 2-3 minutes) or IM injection in not less than 30 seconds immediately before treatment, followed by 8 mg of an oral formulation of ondansetron twelve hourly. In circumstances where delayed or prolonged emesis is expected after the first 24 hours treatment with an oral formulation of ondansetron may be continued at 8 mg twice daily, for up to five days after a course of treatment.

Highly emetogenic chemotherapy: A single dose of MYLAN ONDANSETRON 8 mg by slow IV (not less than 2-3 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 doses of cisplatin, and the doses of MYLAN ONDANSETRON should be adjusted according to the 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 or IM injection immediately before chemotherapy, followed by two further IV or IM doses of 8 mg two to four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours. OR A single dose of 16 mg diluted in 50-100 ml of 0,9 % sodium chloride 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 MYLAN ONDANSETRON in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone phosphate 20 mg administered 30-45 minutes prior to the first MYLAN ONDANSETRON dose prior to chemotherapy. To protect against delayed or prolonged emesis after the first 24 hours, treatment with an oral formulation of ondansetron may be continued at 8 mg twice daily, for up to 5 days after a course of treatment.

Special Populations: Children: Experience is currently limited, but MYLAN ONDANSETRON 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, followed by oral therapy of 4 mg ondansetron every 12 hours for up to 5 days. Elderly patients: Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients u226575 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 MYLAN ONDANSETRON 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 MYLAN ONDANSETRON 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 50-100 ml saline or other compatible fluid and infused over at least 15 minutes. Repeat intravenous doses of MYLAN ONDANSETRON 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 MYLAN ONDANSETRON undiluted intramuscularly or intravenously. If given intravenously, MYLAN ONDANSETRON must be administered in not less than 30 seconds, preferably over 2-5 minutes. Alternatively, for the prevention of post-operative nausea and vomiting, 16 mg of an oral ondansetron formulation may be given one hour prior to induction of anaesthesia. 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 people above 80 kg or below 40 mg have been studied.

Special populations: Children: For prevention of post-operative nausea and vomiting in paediatric patients two years and older having surgery performed under general anaesthesia, MYLAN ONDANSETRON may be administered by slow intravenous injection 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, MYLAN ONDANSETRON may be administered by slow intravenous injection at a dose of 0,1 mg/kg up to a maximum of 4 mg over not less than 2-5 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: Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients u226575 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. A slight age-related decrease in clearance, and an increase in the half-life of ondansetron is predicted, presenting as slight, clinically insignificant age-related increases in both oral bioavailability (65 %) and a prolonged elimination half-life (5 hours) of ondansetron. Patients with renal/hepatic impairment: There is limited information available on severely impaired renal or hepatic function. Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration is required. There is limited information available on severely impaired renal function. Patients with hepatic impairment: Clearance of MYLAN ONDANSETRON 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 (see section 4.4).

• MYLAN ONDANSETRON is contraindicated in patients known to have hypersensitivity to ondansetron or any of the excipients of the preparation.
• Concomitant use with apomorphine is contraindicated (see section 4.5).
• Concomitant use with medicines prolonging the QT interval (see section 4.5).
• Congenital long QT syndrome.
• The use of MYLAN ONDANSETRON is contraindicated during the first 12 weeks of pregnancy, irrespective of the indication (see section 4.6 and section 4.4).
• The use of MYLAN ONDANSETRON for post-operative nausea and vomiting is contraindicated in pregnancy and lactation (see section 4.6).

Patients with hepatic impairment: In patients with moderate or severe impairment of hepatic function, clearance of MYLAN ONDANSETRON 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). MYLAN ONDANSETRON prolongs the QT interval in a dose-dependent manner. ECG changes including QT interval prolongation and cases of Torsade de Pointes have been reported. Caution is advised if patients have received cardiotoxic agents and in patients with a history or family history of prolonged QT syndrome (see section 4.3 and section 4.5). MYLAN ONDANSETRON should be administered with caution to patients who have or may develop prolongation of QTc. These include patients with diseases/disorders causing QT prolongation, electrolyte abnormalities, congestive heart failure, brady-dysrhythmia or patients taking other medicines that lead to QT prolongation (see section 4.3).

Pregnancy: The use of MYLAN ONDANSETRON during the first 12 weeks of pregnancy increases the risk of developing oral cleft palate and or lip to the foetus and is contraindicated during the first 12 weeks of pregnancy, irrespective of the indication (see section 4.3 and 4.6).

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, as in MYLAN ONDANSETRON, and other serotonergic medicines (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic medicines is clinically warranted, appropriate observation of the patient is advised (see section 4.5).

Hypokalaemia and hypomagnesaemia should be corrected prior to MYLAN ONDANSETRON administration. Patients with signs of sub-acute intestinal obstructions should be monitored following administration, as MYLAN ONDANSETRON is known to increase large bowel transit time and cause constipation. Cross-hypersensitivity reactions have been reported in patients who previously exhibited hypersensitivity to other selective 5-HT3 receptor antagonists, e.g. granisetron or dolasetron. Respiratory events should be treated symptomatically and should be given particular attention as they may be precursors to hypersensitivity reactions. In patients that undergo adenotonsillar surgery, prevention of nausea and vomiting with MYLAN ONDANSETRON may mask occult bleeding. Therefore, such patients should be followed carefully after MYLAN ONDANSETRON.

Myocardial ischemia has been reported in patients treated with MYLAN ONDANSETRON. In some patients, especially in the case of intravenous administration, symptoms appeared immediately after administration of MYLAN ONDANSETRON. Patients should be alerted to the signs and symptoms of myocardial ischaemia. MYLAN ONDANSETRON contains sodium, and this should be taken into consideration by patients on a sodium-restricted diet.

• MYLAN ONDANSETRON should not be given to patients who are taking other medicines that cause QT prolongation (see section 4.3) and/or cause electrolyte abnormalities (see section 4.4).
• Concomitant use of MYLAN ONDANSETRON with cardiotoxic medicines (e.g. anthracyclines (such as doxorubicin, daunorubicin or trastuzumab), antibiotics (e.g. erythromycin), antifungals (e.g. ketoconazole), antidysrhythmics (e.g. amiodarone) and beta blockers (e.g. atenolol or timolol) may increase the risk of dysrhythmias (see section 4.3 and section 4.4).
• Apomorphine: Profound hypotension and loss of consciousness were reported when MYLAN ONDANSETRON was administered with apomorphine. Concomitant use of MYLAN ONDANSETRON with apomorphine may intensify QT prolongation (see section 4.3 and section 4.4).
• 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 and other serotonergic medicines (including SSRIs and SNRIs) (see section 4.4).
• Tramadol: MYLAN ONDANSETRON may reduce the analgesic effect of tramadol.
• Ondansetron is metabolised by multiple hepatic cytochrome P450 enzymes CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition of reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is usually compensated for by other enzymes.
• Cyclophosphamide: MYLAN ONDANSETRON may decrease the concentration of cyclophosphamide in the blood (AUC).
• Cisplatin: MYLAN ONDANSETRON may increase or decrease the concentration of cisplatin in the blood (AUC).

Women of childbearing potential/Contraception in males and females: Women of childbearing potential should use contraception while taking MYLAN ONDANSETRON and for 2 days after stopping treatment. Women of childbearing potential being treated with MYLAN ONDANSETRON should not become pregnant as MYLAN ONDANSETRON is contraindicated in the first 12 weeks of pregnancy, irrespective of the cause of the nausea and vomiting (see section 4.3).

Pregnancy: MYLAN ONDANSETRON is contraindicated for post-operative nausea and vomiting during pregnancy, as well as during the first 12 weeks of pregnancy irrespective of the indication due to the risk (see section 4.3). 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: Ondansetron passes into the milk of lactating animals. Mothers receiving MYLAN ONDANSETRON should therefore not breastfeed their babies.

Fertility: No information available.

MYLAN ONDANSETRON causes nervous system and eye disorders which may adversely affect the ability to drive a car or operate machinery. Caution is advised until the effects of MYLAN ONDANSETRON in patients on treatment are known (see section 4.8 Side effects).

Tabulated list of adverse reactions
Body System Undesirable effect Frequent Less frequent Frequency not known
Immune system disorder: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis (e.g. anaphylaxis, bronchospasm, shortness of breath, dyspnoea, hypotension, shock, angioedema, urticarial) There may be cross-hypersensitivity with other selective 5-HT3- antagonists (see section 4.4). Psychiatric disorders: Depression Nervous system disorders: Headache Seizures, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia). Dizziness during or shortly after rapid I.V administration. Eye disorders: Visual disturbances (eg. blurred vision) during or shortly after rapid intravenous administration. Transient blindness predominantly during intravenous administration. Cardiac disorders: Dysrhythmias Chest pain with or without ST segment depression Bradycardia ECG changes including QTc prolongation (and Torsade de Pointes) Myocardial ischemia (see section 4.4) Vascular disorders: Sensation of warmth or flushing. Hypotension Coronary vasospasm Respiratory, thoracic and mediastinal disorders: Hiccups Gastrointestinal disorders: Increase in large bowel transit time Constipation Hepato-biliary disorders: Asymptomatic increases in aminotransferases Skin and subcutaneous tissue disorders: Rashes Urticaria General disorders and administrative site conditions: Pain, redness and burning at site of injection.

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 providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). Manifestations that have been reported include severe constipation, visual disturbances, hypotension and a 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.