Ozelet 6 mg Powder for oral suspension

Treatment: OZELET is indicated for the treatment of influenza in adults and children u2265 1 year of age (see section 4.4 and section 4.2). PANDEMIC USE: OZELET is indicated for the treatment of infants 6-12 months of age during a pandemic influenza outbreak only, and not for endemic (seasonal) influenza use, (see section 4.4 and section 5.2) PROPHYLAXIS: OZELET is indicated for the prophylaxis of influenza in adults and children u2265 1 year of age.

Posology Standard Dosage Treatment of influenza Treatment should begin within the first or second day of onset of symptoms of influenza. Adults and adolescents u2265 13 years of age who are unable to swallow capsules may receive a dose of 75 mg OZELET powder for oral suspension twice daily, for 5 days. Children: The recommended oral dose of OZELET powder for oral suspension for children u2265 1 year of age is:

• Body weight Recommended treatment dose for 5 days 6 mg/mL oral suspension
• u2264 15 kg 5.0 mL twice daily
• > 15 kg to 23 kg 7.5 mL twice daily
• > 23 kg to 40 kg 10.0 mL twice daily
• > 40 kg 12.5 mL twice daily

A 10 mL oral dosing syringe is provided for the 6 mg/mL oral suspension for children u2265 1 year of age. It is recommended that OZELET powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient. The recommended oral dose of OZELET for children 6 u2013 12 months of age: Based on limited pharmacokinetic data currently available, a dosage of 3 mg/kg twice daily in children 6 - 12 months of age provides plasma exposure to the active metabolite in the majority of patients similar to that shown to be clinically efficacious in older children and adults. Recommended volumes of reconstituted oral suspension to be drawn up into an oral syringe (3 mg/kg body weight) are shown in the table below:

• Body weight (kg) OZELET (mg) Rounded volume of 6 mg/mL suspension
• 6 18 3 mL
• 7 21 3.5 mL
• 8 24 4 mL
• 9 27 4.5 mL
• u2265 10 30 5 mL

Use the smallest graduated oral syringe that will accurately deliver the appropriate volume. The recommended treatment dose for infants 6 - 12 months is 3 mg/kg twice daily for 5 days, during a pandemic influenza outbreak only, and not for endemic (seasonal) influenza use (see section 5.2) Children u2265 1 year of age The recommended prophylactic oral dose of OZELET for children u2265 1 year of age is:

• Body weight Recommended treatment dose for 10 days 6 mg/mL oral suspension
• u2265 15 kg 5.0 mL once daily
• > 15 kg to 23 kg 7.5 mL once daily
• > 23 kg to 40 kg 10.0 mL once daily
• > 40 kg 12.5 mL once daily

A 10 mL oral dosing syringe is provided for the 6 mg/mL oral suspension. It is recommended that OZELET powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see section 6.6) Special Dosage Instructions Patients with renal impairment Treatment of influenza: No dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. In patients with creatinine of > 30 u2013 60 mL/min, it is recommended that the treatment dose be reduced to 30 mg of OZELET twice daily for 5 days. In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose be reduced to 30 mg of OZELET once daily for 5 days. In patients undergoing routine haemodialysis an initial dose of 30 mg OZELET can be administered prior to the start of dialysis if influenza symptoms develop during the 48 hours between dialysis sessions. To maintain plasma concentrations at a therapeutic level, a dose of 30 mg should be administered after every haemodialysis session. For peritoneal dialysis an initial dose of 30 mg of OZELET administered prior to the start of dialysis followed by further 30 mg doses administered every 5 days is recommended for treatment (see section 5.2 and 4.4). The pharmacokinetics of OZELET have not been studied in patients with u201cend-stage renal diseaseu201d (i.e. creatinine clearance 30 - 60 mL/min, it is recommended that the dose be reduced to 30 mg of OZELET once daily. In patients with a creatinine clearance between 10 and 30 mL/min receiving OZELET, it is recommended that the dose be reduced to 30 mg of OZELET every other day. In patients undergoing routine haemodialysis an initial dose of 30 mg of OZELET can be administered prior to the start of dialysis. To maintain plasma concentrations at a therapeutic level, a dose of 30 mg should be administered after every alternate haemodialysis session. For peritoneal dialysis an initial dose of 30 mg of OZELET administered prior to the start of dialysis followed by further 30 mg doses administered every 7 days is recommended for prophylaxis (see section 5.2 and 4.24). The pharmacokinetics of OZELET have not been studied in patients with u201cend-stage renal diseaseu201d (i.e., creatinine clearance < 10 mL/min) not undergoing dialysis Hence, dosing recommendation cannot be provided for this group. Patients with hepatic impairment No dose adjustment is required for patients with mild or moderate hepatic dysfunction in the treatment or prophylaxis of influenza (see 5.2). The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied. Immuno-compromised patients Seasonal prophylaxis in immuno-compromised patients 1 year of age and older is recommended for 12 weeks. No dose adjustment is necessary. Elderly No dose adjustment is required for elderly patients in the treatment or prophylaxis of influenza (see section 5.2). Children The safety and efficacy of OZELET in children under 1 year has not been established (see section 5.2). OZELET should not be used in children under 1 year of age, other than during a pandemic influenza outbreak. Method of administration For oral use OZELET may be taken with or without food. (see section 5.2). However, OZELET taken with food may enhance tolerability in some patients.

Hypersensitivity to any of the ingredients of OZELET, including the excipients listed in section 6.1.

Neuropsychiatric events such as convulsions, abnormal and inappropriate behaviour, disturbances in consciousness, hallucinations and delirium have been reported during oseltamivir administration in patients with influenza. In some cases, the delirium resulted in accidental self-injury and death. These events occurred mostly within the first few days of taking oseltamivir. Patients, and especially paediatric and adolescent patients, taking oseltamivir should be carefully monitored for signs of abnormal behaviour, and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8). OZELET is effective only against illness caused by influenza viruses. There is no evidence for efficacy of OZELET in any illness caused by medicines other than influenza viruses types A and B (see section 5.1). OZELET is not a substitute for influenza vaccination. Resistance of influenza viruses to oseltamivir have been reported. The prevalence of virus resistance and virus strains on subtypes differs between countries and seasons. In South Africa where H1N1 viruses predominated among circulating strains, 100 % [225/225] of H1N1 viruses tested in 2008 were resistant to oseltamivir. The resistance of the predominant virus to oseltamivir generally changes from season to season. Updated local surveillance data from the National Institute for Communicable Diseases (NICD) should be consulted for information on seasonal prevalence of medicine resistant viruses. Based on limited pharmacokinetic and safety data, OZELET may only be used in infants 6 u2013 12 months of age for treatment during a pandemic influenza outbreak. The treating doctor should take into account the pathogenicity of the circulating strain and the underlying condition of the patient to ensure that there is a potential benefit to the child. Severe concomitant condition No information is available regarding the safety and efficacy of oseltamivir in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation. Immunocompromised patients The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established (see section 5.1). Cardiac / respiratory disease Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population (see section 5.1). Severe renal impairment Dose adjustment is recommended for both treatment and prevention in adolescents (13-17 years of age) and adults with severe renal impairment. There is insufficient clinical data available in infants and children (1 year of age or older) with renal impairment to be able to make any dosing recommendation (see section 4.2). Dose adjustment is recommended for patients with creatinine clearance of 10 - 60 mL/min for the treatment of influenza and the prophylaxis of influenza. No dosing recommendation is available for patients undergoing routine haemodialysis and continuous peritoneal dialysis with end stage renal disease and for patients with creatinine clearance of u2264 10 mL/min (see section 4.2). OZELET should not be used in children under 1 year of age, other than during a pandemic influenza outbreak. Excipients OZELET contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take OZELET. Sorbitol may cause gastrointestinal discomfort and mild laxative effect. This medicine contains sodium benzoate. Sodium benzoate may increase jaundice in newborn babies (up to 4 weeks old). Paediatric population No data allowing a dose recommendation for premature children (<36 weeks post-conceptual age) are currently available.

Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems suggest that clinically significant medicine interactions are unlikely. Oseltamivir is extensively converted to the active compound by esterases, located predominantly in the liver. Interactions involving competition for esterases have not been extensively reported in the literature. In vitro studies demonstrated that neither oseltamivir nor the active metabolite is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases, see section 5.2 There is no mechanistic basis for an interaction with oral contraceptives. Probenecid No dose adjustment is required when co-administering with probenecid in patients with normal renal function. Co-administration of probenecid, a potent inhibitor of the anionic pathway of renal tubular secretion, results in an approximate 2-fold increase in exposure to the active metabolite of oseltamivir. Amoxicillin Oseltamivir has no kinetic interaction with amoxicillin, which is eliminated via the same pathway, suggesting that oseltamivir Interaction with this pathway is weak. Renal elimination Clinically important medicine interactions involving competition for renal tubular secretion are unlikely, due to the known safety margin for most of these medicines, the elimination characteristics of the active metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. However, care should be taken when prescribing OZELET in patients when taking co-excreted medicines with a narrow therapeutic margin (e.g. chlorpropamide, methothrexate, phenylbutazone). Additional information No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering OZELET with paracetamol, acetyl-salicylic acid, cimetidine or with antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in patients stable on warfarin and without influenza).

Pregnancy Safety in pregnancy has not been established. No teratogenic effect was not observed in animal reproductive studies. No studies have been conducted with the use of OZELET in pregnant women. Breastfeeding Safety in lactation has not been established. In lactating rats, oseltamivir and the active metabolite are excreted in the milk. Limited information is available on infants breastfed by mothers taking oseltamivir and on excretion of oseltamivir in breast milk. Limited data demonstrated that low levels of oseltamivir and the active metabolite were detected in breast milk. Safety in humans has not been demonstrated in children of breastfeeding women using OZELET. Mothers on treatment with OZELET should not breastfeed their infants. Fertility No fertility data are available.

It is not known whether OZELET could affect the ability to drive a car or operate machinery. However, if symptoms such as delirium or fever are experienced while taking OZELET, patients should be advised not drive or use machines until the symptoms disappear.

a) Summary of the safety profiles In adults/ adolescents, treatment studies the most frequently reported adverse reactions (ARs) were nausea and vomiting and headache. The majority of these ARs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. In adult/adolescent prophylaxis studies, the most frequently reported adverse reaction were vomiting nausea headache and pain. In children the most frequently reported ADR was vomiting.

The following serious adverse reactions have been reported anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice) angioneutotic oedema, stevens-johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders. (Regarding neuropsychiatric disorders, see section 4.4).

b. Tabulated summary of adverse reactions Treatment and prevention of influenza in adults and adolescents: In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently at the recommended dose (75 mg twice a day for 5 days for treatment and 75 mg once daily for up to 6 weeks for prophylaxis) are shown in Table 1. The safety profile reported in subjects who received the recommended dose of OZELET for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies, despite a longer duration of dosing in the prophylaxis studies. Table 1 Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance Infections and infestations Frequency unknown: Bronchitis, Herpes simplex, Nasopharyngitis, Upper respiratory tract infections, Sinusitis, Influenza Blood and lymphatic system disorders Less frequent: Thrombocytopenia.

In overdose symptoms may be the exacerbation or exaggeration of side effects Treatment is supportive and symptomatic No specific antidote is known. Paediatric population Overdose has been reported more frequently for children than adults and adolescents. Caution should be exercised when preparing OZELET oral suspension and when administering OZELET to children.