Zofran 4mg & 8mg (Tablets and Injection)

ZOFRAN is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. ZOFRAN 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. The study population in all trials thus far consisted of mainly women undergoing laparoscopic procedures. While some men were included in some trials with similar results, clearance of the agent is more rapid in men and insufficient numbers of men have been clinically studied to be certain that efficacy and safety have been established. Few patients undergoing major abdominal surgery have been studied.

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, ZOFRAN 8 mg should be administered as a slow IV or IM injection in not less than 30 seconds, immediately before treatment, or orally (as Zydis or tablets) 1-2 hours before treatment, followed by 8 mg orally twelve hourly. In circumstances where delayed or prolonged emesis is expected after the first 24 hours, ZOFRAN may be continued orally, 8 mg twice daily for up to five days after a course of treatment.

Highly Emetogenic Chemotherapy: A single dose of ZOFRAN 8 mg by slow IV 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 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 saline or other compatible infusion fluid and infused over not less than 15 minutes immediately before chemotherapy. A single dose greater than 16 mg should not be given (see WARNINGS AND SPECIAL PRECAUTIONS). The efficacy of ZOFRAN 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 first ZOFRAN dose prior to chemotherapy. To protect against delayed or prolonged emesis after the first 24 hours, ZOFRAN may be continued orally, 8 mg twice daily for up to 5 days after a course of treatment.

Children: Experience is currently limited but ZOFRAN 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 at doses of ZOFRAN 4 mg every 12 hours for up to 5 days.

Elderly patients: Efficacy and tolerance in patients aged over 65 years was similar to that seen in younger adults indicating no need to alter dosage or route of administration in the elderly.

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 in not less than 30 seconds, preferably over 2-5 minutes. Alternatively, for the prevention of post-operative nausea and vomiting, 16 mg may be given orally (as Zydis or tablets) 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 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, ZOFRAN may be administered by slow intravenous injection 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, ZOFRAN may be administered by slow intravenous injection at a dose of 0,1 mg/kg up to a maximum of 4 mg. Repeat dosing for paediatric patients who continue to experience nausea and/or vomiting has not been studied, and should thus not be given.

Elderly: There is limited experience in the use of ZOFRAN in the prevention and treatment of post-operative nausea and vomiting in the elderly.

Patients with renal/hepatic impairment:

Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required. There is limited information available on severe renal impairment. Patients with hepatic impairment: Clearance of ZOFRAN 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.

ZOFRAN is contra-indicated in patients known to have hypersensitivity to any components of the preparation. Concomitant use with apomorphine is contra-indicated (see WARNINGS AND SPECIAL PRECAUTIONS and INTERACTIONS). The use of ZOFRAN for post-operative nausea and vomiting is contra-indicated in pregnancy (see PREGNANCY AND LACTATION). Congenital long QT syndrome.

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT 3 receptor antagonists. As ZOFRAN is known to increase large bowel transit time, patients with signs of sub-acute intestinal obstructions should be monitored following administration. ZOFRAN prolongs the QT interval in a dose-dependent manner (see Pharmacodynamic properties). In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ZOFRAN. Avoid ZOFRAN in patients with congenital long QT syndrome (see CONTRA-INDICATIONS). ZOFRAN should be administered with caution to patients who have or may develop prolongation of QTc, including patients with electrolyte abnormalities, congestive heart failure, bradydysrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalaemia and hypomagnesaemia should be corrected prior to ZOFRAN administration.

Patients with hepatic impairment: Clearance of ZOFRAN 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.

Effects on ability to drive and use machines: ZOFRAN may affect the ability of patients to drive or operate machines and caution is advised until the effects of ZOFRAN in patients on treatment are known (see SIDE EFFECTS).

Excipient warnings: ZOFRAN tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. As ZOFRAN ZYDIS contains aspartame, caution is advised in patients with phenylketonuria.

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 or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) should be compensated for by other enzymes. Caution should be exercised when ZOFRAN is co-administered with agents that prolong the QT interval and/or cause electrolyte abnormalities (see WARNINGS AND SPECIAL PRECAUTIONS).

Apomorphine: Cases of profound hypotension and loss of consciousness when ZOFRAN was administered concomitantly with apomorphine hydrochloride have been reported. Concomitant use of ZOFRAN and apomorphine may intensify QT prolongation (see CONTRA-INDICATIONS and WARNINGS AND SPECIAL PRECAUTIONS).

Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine and rifampicin), the clearance of oral ZOFRAN was increased and ondansetron blood concentrations were decreased.

Tramadol: ZOFRAN may reduce the analgesic effect of tramadol.

Pregnancy: Safety in pregnancy has not been established (see CONTRA-INDICATIONS).

Lactation: Tests have shown that ZOFRAN passes into the milk of lactating animals. It is therefore recommended that mothers receiving ZOFRAN should not breastfeed their babies.

ZOFRAN may affect the ability of patients to drive or operate machines and caution is advised until the effects of ZOFRAN in patients on treatment are known (see SIDE EFFECTS).

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (u2265 1/10), common (u2265 1/100 and < 1/10), uncommon (u2265 1/1 000 and < 1/100), rare (u2265 1/10 000 and < 1/1 000) and very rare (< 1/10 000), including isolated reports. 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.

Immune system disorders:
Rare: immediate hypersensitivity reactions sometimes severe, including anaphylaxis, bronchospasm, shortness of breath, hypotension, shock, angioedema, urticaria

Nervous system disorders:
Very common: headache
Uncommon: movement disorders (including extrapyramidal reactions such as oculogyric crisis, dystonic reactions and dyskinesia have been observed without definitive evidence of persistent clinical sequelae), seizures
Rare: dizziness during rapid intravenous administration

Eye disorders:
Rare: transient visual disturbances (e.g. blurred vision) during intravenous administration
Very rare: transient blindness predominantly during intravenous administration

Cardiac disorders:
Uncommon: dysrhythmias. 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, thoracic and mediastinal disorders:
Uncommon: hiccups

Gastrointestinal disorders:
Common: constipation

Hepatobiliary disorders:
Uncommon: asymptomatic increases in liver function tests

General disorders and administration site conditions:
Common: pain, redness and burning at site of injection.

There is limited experience of ZOFRAN overdose. In the majority of cases symptoms were similar to those already reported in patients receiving recommended doses. See SIDE EFFECTS. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. There is no specific antidote for ondansetron, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate. Ondansetron prolongs QT interval in a dose-dependent fashion. ECG monitoring is recommended in cases of overdose.