Tamiflu Range 30 mg/45 mg/75 mg/6 mg Capsules

Tamiflu is indicated for the treatment of influenza in adults and children including full-term neonates who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within the two days of first onset of symptoms (see Section 4.2 and 4.4).

Tamiflu is indicated for the prophylaxis of influenza in adults and children u2265 1 year of age following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community. Tamiflu is indicated for the prophylaxis of influenza in infants less than 1 year of age during a pandemic influenza outbreak. Tamiflu is not a vaccine.

Tamiflu may be taken with or without food (see section 5.2). However, Tamiflu taken with food may enhance tolerability in some patients.

Posology

Treatment of influenza

Treatment should begin within the first or second day of onset of symptoms of influenza. Efficacy has not been established in patients who begin treatment after 2 days of symptoms.

Adults and adolescents

The recommended oral dose of Tamiflu Capsules in adults and adolescents u2265 13 years is a 75 mg capsule twice daily, for 5 days. Adults and adolescents u2265 13 years of age who are unable to swallow capsules may receive a dose of 75 mg Tamiflu Powder for Oral Suspension twice daily for 5 days.

Children

Children weighing > 40 kg who are able to swallow capsules, may also receive treatment with a 75 mg capsule twice daily or one 30 mg capsule plus one 45 mg capsule twice a day as an alternative to the recommended dose of Tamiflu Powder for Oral Suspension (see below).

The recommended oral dose of Tamiflu Powder for Oral Suspension for children u2265 1 year of age for 5 days:

Body weight Recommended dose for 5 days

• Capsules
• 6 mg/mL Oral Suspension

u2264 15 kg 30 mg twice daily 5.0 mL twice daily

> 15 to 23 kg 45 mg twice daily 7.5 mL twice daily

> 23 kg to 40 kg 60 mg twice daily 10.0 mL twice daily

> 40 kg 75 mg twice daily 12.5 mL twice daily

A 10 mL oral dosing syringe is provided for 6 mg/mL oral suspension, for children u2265 1 year of age. The 75 mg dose can be measured using a combination of 30 mg and 45 mg. It is recommended that Tamiflu Powder for Oral Suspension be constituted by a pharmacist prior to dispensing to the patient.

The recommended oral dose of Tamiflu for children <1 year of age:

The recommended oral dose of Tamiflu for children 0 to 12 months is 3 mg/kg twice daily, for 5 days. These dosing recommendations are not intended for infants who have a post-conceptual age of less than 36 weeks.

The recommended oral dose of Tamiflu for children u02c21 year of age is*:

Body Weight (kg) Tamiflu (mg) Recommended dose for 5 days Amount of 6 mg/mL suspension

3 kg 9 mg twice daily 1.5 mL twice daily

4 kg 12 mg twice daily 2.0 mL twice daily

5 kg 15 mg twice daily 2.5 mL twice daily

6 kg 18 mg twice daily 3.0 mL twice daily

7 kg 21 mg twice daily 3.5 mL twice daily

8 kg 24 mg twice daily 4.0 mL twice daily

9 kg 27 mg twice daily 4.5 mL twice daily

u2265 10 kg 30 mg twice daily 5.0 mL twice daily

* This table is not intended to contain all possible weights for this population. For all patients under the age of 1 year of age, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

Prophylaxis of influenza

Adults and adolescents

The recommended oral dose of Tamiflu for prophylaxis of influenza following close contact with an infected individual is 75 mg once daily for at least 10 days. Therapy should begin within two days of exposure. The recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated for up to six weeks. The duration of protection lasts for as long as dosing is continued. Efficacy has not been established in patients who begin treatment after 2 days of symptoms.

Children u2265 1 year of age

Children weighing > 40 kg, who are able to swallow capsules, may also receive prophylaxis with a 75 mg capsule once daily or one 30 mg capsule plus one 45 mg capsule once a day, for 10 days as an alternative to the recommended dose of Tamiflu 6 mg/mL Powder for Oral Suspension.

The recommended prophylactic oral dose of Tamiflu for children u2265 1 year of age is 10 days:

Body Weight Recommended dose for 10 days

• Capsules
• 6 mg/mL Oral Suspension

u2264 15 kg 30 mg once daily 5.0 mL once daily

> 15 to 23 kg 45 mg once daily 7.5 mL once daily

> 23 kg to 40 kg 60 mg once daily 10.0 mL once daily

> 40 kg 75 mg once daily 12.5 mL once daily

A 10 mL oral dosing syringe is provided for the 6 mg/mL oral suspension. The 75 mg dose can be measured using a combination of 30 mg and 45 mg. It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see Section 6.6).

Special Populations

Geriatric use

No dose adjustment is required for elderly patients in the treatment or prophylaxis of influenza (see section 5.2).

Patients with renal impairment

Treatment of influenza: No dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. In patients with a creatinine clearance of > 30 - 60 mL/min, it is recommended that the treatment dose be reduced to 30 mg of Tamiflu 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 Tamiflu once daily for 5 days. In patients undergoing routine haemodialysis an initial dose of 30 mg Tamiflu 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 Tamiflu administered prior to the start of dialysis followed by further 30 mg doses administered every 5 days is recommended for treatment (see section 4.4 and 5.2). The pharmacokinetics of Tamiflu 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.

Prophylaxis of influenza: No dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. In patients with a creatinine clearance of > 30 - 60 mL/min, it is recommended that the dose be reduced to 30 mg of Tamiflu once daily. In patients with a creatinine clearance between 10 and 30 mL/min receiving Tamiflu, it is recommended that the dose be reduced to 30 mg of Tamiflu every other day. In patients undergoing routine haemodialysis an initial dose of 30 mg of Tamiflu 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 Tamiflu administered prior to the start of dialysis followed by further 30 mg doses administered every 7 days is recommended for prophylaxis (see section 4.4 and 5.2). The pharmacokinetics of Tamiflu 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 section 5.2). The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied.

Immuno-compromised patients

Treatment of Influenza: The recommended duration for immunocompromised patients is 10 days. No dose adjustment is necessary.

Prophylaxis of Influenza: Seasonal prophylaxis in immuno-compromised patients 1 year of age and older is recommended for 12 weeks. No dose adjustment is necessary (see u201cProphylaxis of Influenzau201d).

Paediatric Population

The efficacy of Tamiflu in children under 1 year has not been established (see section 5.2). Pharmacokinetic data indicates that a dosage of 3 mg/kg twice daily in children 0 u2013 12 months of age provides plasma concentrations of the pro-drug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (See section 4.1).

Method of administration

Oral use. Patients who are unable to swallow capsules may receive appropriate doses of Tamiflu suspension.

Tamiflu is contraindicated in patients with known hypersensitivity to oseltamivir phosphate or to any component of Tamiflu (see section 6.1).

General

Neuropsychiatric events such as convulsions, abnormal and inappropriate behaviour, disturbances in consciousness, hallucinations and delirium have been reported during Tamiflu 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 Tamiflu. Patients, and especially paediatric and adolescent patients, taking Tamiflu should be carefully monitored for signs of abnormal behaviour.

There is no evidence for efficacy of Tamiflu in any illness caused by agents other than influenza viruses types A and B. Tamiflu is not a substitute for influenza vaccination.

Resistance

Resistance of influenza viruses to Tamiflu has 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 Tamiflu. The resistance of the predominant virus to Tamiflu 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.

Renal impairment

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 with end-stage renal disease and for patients with creatinine clearance u2264 10 mL/min (see section 4.2).

Sugars

Tamiflu Powder for Oral Suspension contains sorbitol which may have a laxative effect. Patients with the rare hereditary condition of sorbitol intolerance should not take Tamiflu Powder for Oral Suspension.

Sodium benzoate

The medicine contains sodium benzoate. Sodium benzoate (E211) may increase jaundice in newborn babies (up to 4 weeks old).

Information derived from pharmacology and pharmacokinetic studies of Tamiflu suggest that clinically significant medicine interactions are unlikely. Tamiflu 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. Low protein binding of Tamiflu and the active metabolite do not suggest the probability of medicine displacement interactions.

In vitro studies demonstrated that neither Tamiflu 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. Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal tubular secretion of basic or cationic medicines has no effect on plasma levels of Tamiflu or its active metabolite. Clinically important 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. Co-administration of probenecid results in approximate 2-fold increase in exposure to the active metabolite due to a decrease in active tubular secretion in the kidney. However, due to the wide safety margin of the active metabolite, no dose adjustments are required when co-administering with probenecid. Co-administration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic secretion pathway is weak. Co-administration with paracetamol does not alter plasma levels of Tamiflu, its active metabolite, or paracetamol. No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering Tamiflu with paracetamol, acetyl-salicylic acid, cimetidine or with antacids (magnesium and aluminium hydroxides and calcium carbonates), warfarin, or amantadine. In phase III treatment and prophylaxis clinical studies, Tamiflu has been administered with commonly used medicines such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporin, azithromycin, erythromycin and doxycycline), H2-receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine), corticosteroids, inhaled bronchodilators, and analgesic medicines (aspirin, ibuprofen and paracetamol). No change in adverse event profile or frequency has been observed as a result of co-administration of Tamiflu with these compounds.

Safety in pregnancy and lactation has not been established. In animal reproductive studies in rats and rabbits, no teratogenic effect was observed.

Pregnancy

No controlled clinical trials have been conducted on the use of Tamiflu in pregnant women; however, there is evidence from post-marketing and observational studies showing benefit of the current dosing regimen in this patient population. Results from pharmacokinetic analyses indicate a lower exposure to the active metabolite, however dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza (see section 5.2 Pharmacokinetics in Special Population). Data from pregnant women exposed to Tamiflu (more than 1 000 exposed outcomes during the first trimester) from post-marketing reports and observational studies in conjunction with animal studies indicate no direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development. Pregnant women may receive Tamiflu, after considering the available safety and benefit information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the pregnant woman.

Lactation

In lactating rats, oseltamivir and the active metabolite are excreted in the milk. Limited information is available on infants breastfed by mothers taking Tamiflu and on excretion of Tamiflu in breast milk. Limited data demonstrated that low levels of oseltamivir and the active metabolite were detected in breast milk; however, the levels were low, which would result in a sub-therapeutic dose to the infant. Based on this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the lactating woman, administration of Tamiflu could be considered.

Fertility

Fertility studies have been conducted in rats. There is no evidence of an effect on male and female fertility at any dose of oseltamivir studied.

Tamiflu has negligible or no influence on the ability to drive and use machines.

a. Summary of the safety profile:

The overall safety profile of Tamiflu is based on data from 2646 adult/adolescent, 859 paediatric patients with influenza, 1943 adult/adolescent and 148 paediatric patients receiving Tamiflu for the prophylaxis of influenza in clinical trials. In adult/adolescent treatment studies, the most frequently reported adverse drug reactions (ADRs) were nausea, vomiting and headache. The majority of reported ADRs occurred on either the first or second treatment day and resolved spontaneously within 1 - 2 days. In adult/adolescent prophylaxis studies, the most frequently reported ADRs were nausea, vomiting, headache and pain. In children, the most commonly reported ADR was vomiting. In the majority of patients, these events did not lead to discontinuation of Tamiflu.

b. Tabulated list of adverse reactions

Treatment and prophylaxis of influenza in adults and adolescents

In adult/adolescent treatment and prophylaxis studies, ADRs that occurred most frequently (u2265 1 %) at the recommended dose (75 mg twice daily for 5 days for treatment and 75 mg once daily for up to 6 weeks for prophylaxis), and whose incidence was at least 1 % higher on Tamiflu compared to placebo. The population included in the influenza treatment studies comprised of otherwise healthy adults/adolescents and patients u201cat risku201d (patients at higher risk of developing complications associated with influenza, e.g. elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the patients u201cat risku201d was qualitatively similar to that in otherwise healthy adults/adolescents. The safety profile reported in the subjects that received the recommended dose of Tamiflu for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in treatment studies, despite a longer duration of dosing in the prophylaxis studies. Adverse drug reactions from clinical trials are listed according to the MedDRA system organ class. The corresponding frequency category for each adverse drug reaction (Table 1) is based on the following convention: Frequency categories: very common (u22651/10); common (u22651/100 and <1/10); uncommon (u22651/1 000 and < 1/100); rare (u22651/10 000 and <1/1 000); very rare (u22651/10 000).

Table 1: Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

System Organ Class (SOC) Adverse reactions according to frequency

Very common Common Uncommon Rare

Infections and infestations Bronchitis, Herpes simplex, Nasopharyngitis, Upper respiratory tract infections, Sinusitis

Blood and lymphatic system disorders Thrombocytopenia

Immune system disorders Hypersensitivity reaction Anaphylactic reactions, Anaphylactoid reactions

Psychiatric disorders Agitation, Abnormal behaviour, Anxiety, Confusion, Delusions, Delirium, Hallucination, Nightmares, Self-injury

Nervous system disorders Headache Insomnia Altered level of consciousness, Convulsion

Eye disorders Visual disturbance

Cardiac disorders Cardiac dysrhythmia

Respiratory, thoracic and mediastinal disorders Cough, Sore throat, Rhinorrhea

Gastrointestinal disorders Nausea Vomiting Abdominal pain (incl. upper abdominal pain), Dyspepsia Gastrointestinal bleedings, Haemorrhagic colitis

Hepatobiliary disorders Elevated liver enzymes Fulminant hepatitis, Hepatic failure, Hepatitis

Skin and subcutaneous tissue disorders Eczema, Dermatitis, Rash, Urticaria Angioneurotic oedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis

General disorders and administration site conditions Pain Dizziness (incl. vertigo), Fatigue, Pyrexia, Pain in limb

Treatment and prophylaxis of influenza in children u2265 1 year of age

A total of 1 481 children aged 1 - 12 years (including 698 otherwise healthy children aged 1 - 12 and 334 asthmatic children aged 6 - 12) participated in phase III studies of Tamiflu given for the treatment of influenza. A total of 859 children received treatment with Tamiflu suspension. The ADRs that occurred in u2265 1 % of children aged 1 to 12 years receiving Tamiflu in clinical trials for treatment of naturally acquired influenza (N = 859), and whose incidence was at least 1 % higher on Tamiflu compared to placebo (N = 622), was vomiting (16 % on Tamiflu vs. 8 % on placebo). Amongst the 148 children who received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study in households (N = 99), and in a separate 6-week paediatric prophylaxis study (N = 49), vomiting was the most frequent ADR (8 % on Tamiflu vs. 2 % in the no prophylaxis group). The adverse events noted were consistent with those previously observed in paediatric treatment studies.

Treatment and prophylaxis of Influenza in Children under 1 Year of Age

In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of oseltamivir therapy in 124 influenza infected children less than one year of age, the safety profile was similar among age cohorts with vomiting, diarrhoea and diaper rash being the most frequently reported AEs (see section 5.2). Insufficient data are available for infants who have a post conceptual age of less than 36 weeks. Safety information available on Tamiflu administered for treatment of influenza in children less than 1 year of age from prospective and retrospective observational trials (comprising together more than 2400 children of that age class), epidemiological database research and post-marketing reports suggest that the safety profile in children less than 1 year of age is similar to the established safety profile of children aged 1 year and above.

Treatment and prophylaxis of influenza in Geriatric patients

There were no clinically relevant differences in the safety profile of the 942 elderly subjects (65 years of age and older), who received Tamiflu or placebo, compared with the younger population (aged up to 65 years).

Treatment and Prophylaxis of influenza in immuno-compromised subjects

The treatment of influenza in immunocompromised patients were evaluated in two studies receiving standard dose or high dose regimens (double dose or triple dose) of Tamiflu. The safety profile of Tamiflu observed in these studies was consistent with that observed in previous clinical trials where Tamiflu was administered for the treatment of influenza in non-immunocompromised patients across all age groups (otherwise healthy patients or u201cat risku201d patients [i.e., those with respiratory and/or cardiac co-morbidities]). The most frequent ADR reported in immunocompromised children was vomiting (28 %). In a 12-week prophylaxis study in 475 immuno-compromised subjects, including 18 children 1 - 12 years of age, the safety profile in the 238 subjects receiving Tamiflu was consistent with that previously observed in Tamiflu prophylaxis clinical trials.

Post-Marketing Experience

Psychiatric disorders/Nervous system disorders: Neuropsychiatric events such as convulsions, abnormal and inappropriate behaviour, including abnormal motor behaviour, disturbances in consciousness, hallucinations and delirium have been reported. In some cases, the delirium resulted in accidental self-injury and death. More events were reported in males than in females. These neuropsychiatric events occurred mostly within the first few days of administration of Tamiflu. Patients, especially paediatric and adolescent patients should therefore be carefully monitored for abnormal behaviour for the first few days of treatment.

Convulsions and psychiatric symptoms have also been reported in patients with influenza who were not taking Tamiflu.

Immune system disorders: allergy, anaphylactic/anaphylactoid reactions and face oedema have been reported.

Skin and subcutaneous tissue disorders: Cases of hypersensitivity reactions such as allergic skin reactions including dermatitis, rash, eczema, urticaria, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis have been reported.

Hepato-biliary disorders: Hepatitis and elevated liver enzymes have been reported in patients with influenza-like illness receiving Tamiflu.

Gastrointestinal disorders: Gastrointestinal bleedings, in particular, haemorrhagic colitis has been reported and subsided when the course of influenza abated or treatment with Tamiflu was interrupted.

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. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who - umc.org) found on SAHPRA website.

In overdose, symptoms may be the exacerbation or exaggeration of side effects. Reports of overdoses with Tamiflu have been received from clinical trials and during post-marketing experience. In the majority of cases reporting overdose, no adverse events were reported. Adverse events reported following overdose were similar in nature and distribution to those observed with therapeutic doses of Tamiflu (see section 4.8). Treatment is supportive and symptomatic.