Flumitev 30, 45, 75 30 mg; 45 mg; 75 mg Capsule

Treatment: FLUMITEV is indicated for the treatment of influenza in adults and children u2265 1 year of age (see sections 4.2 and 4.4).

Pandemic use only: FLUMITEV 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 sections 4.4 and 5.2).

Prophylaxis: FLUMITEV is indicated for the prophylaxis of influenza in adults and children u22651 year of age.

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

Treatment of influenza Treatment should begin within the first or second day of onset of symptoms of influenza. Adults and adolescents: The recommended oral dose of FLUMITEV capsules in adults and adolescents u2265 13 years is a 75 mg capsule 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. The recommended oral dose of FLUMITEV for children u2265 1 year of age is:

• Body Weight Recommended treatment dose for 5 days Capsules Pharmacy compounded 6 mg/ml suspension compounded from capsules (see section 6.6 )
• 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

The 75 mg dose can be measured using a combination of 30 mg and 45 mg. The recommended oral dose of FLUMITEV for children 6 - 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 the pharmacy compounded suspension (3 mg/kg body weight) are shown in the table below:

• Body Weight (kg) FLUMITEV (mg) Volume per dose (6 mg/ml) Pharmacy compounded suspension
• 1 ) 6 18 3 ml
• 7 21 3,5 ml
• 8 24 4 ml
• 9 27 4,5 ml
• u2265 10 30 5 ml

1) A pharmacy compounded 6 mg/ml suspension can be prepared from the capsules. See section 6.6: Pharmacy compounding.

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: Special Populations).

Prophylaxis of influenza: Adults and adolescents: The recommended oral dose of FLUMITEV 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.

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 capsules, the pharmacy compounded 6 mg/ml suspension can be prepared from the capsules. See section 6.6: Pharmacy compounding.

The recommended prophylactic oral dose of FLUMITEV for children u2265 1 year of age is:

• Body Weight Recommended treatment dose for 10 days Capsules Pharmacy compounded ( 6 mg/ml) Pharmacy compounded suspension
• 1) 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 2) 12,5 ml twice daily

1) A pharmacy compounded 6 mg/ml suspension can be prepared from the capsules. See section 6.6: Pharmacy compounding.

2) The 75 mg dose can be measured using a combination of 30 mg and 45 mg.

Special populations: Patients with renal impairment: Treatment of influenza: No dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. Dose adjustment is recommended for patients with moderate or severe renal impairment. Recommended doses are detailed in the table below.

• Creatinine clearance Recommended dose for treatment
• > 30 to 60 (mL/min) 30 mg twice daily for 5 days
• > 10 to 30 (mL/min) 30 mg once daily for 5 days

In patients undergoing routine haemodialysis an initial dose of 30 mg FLUMITEV 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 FLUMITEV 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: Special Populations and 4.4). The pharmacokinetics of FLUMITEV 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. Dose adjustment is recommended for patients with moderate or severe renal impairment as detailed in the table below.

• Creatinine clearance Recommended dose for prevention
• > 30 to 60 (mL/min) 30 mg once daily
• > 10 to 30 (mL/min) 30 mg every second day

In patients undergoing routine haemodialysis an initial dose of 30 mg of FLUMITEV 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 FLUMITEV 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: Special Populations and 4.4). The pharmacokinetics of FLUMITEV have not been studied in patients with u201cend-stage renal diseaseu201d (i.e., creatinine clearance < 10 mu2113/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: Special Populations). 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: Special Populations).

Paediatric population: The safety and efficacy of FLUMITEV in children under 1 year has not been established (see section 5.2: Special Populations). FLUMITEV should not be used in children under 1 year of age, other than during a pandemic influenza outbreak.

Method of administration: For oral administration. Patients who are unable to swallow capsules may receive appropriate extemporaneous formulation, see section 6.6 for preparation.

• Hypersensitivity to oseltamivir phosphate or to any excipient of FLUMITEV as listed in section 6.1.

FLUMITEV is effective only against illness caused by influenza viruses. There is no evidence for efficacy of FLUMITEV in any illness caused by agents other than influenza viruses (see section 5.1).

FLUMITEV is not a substitute for influenza vaccination: Use of FLUMITEV must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as FLUMITEV is administered. FLUMITEV should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community.

Susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers should take into account the most recent information available on oseltamivir susceptibility patterns of the currently circulating viruses when deciding whether to use FLUMITEV.

Resistance of influenza viruses to FLUMITEV have been reported. The prevalence of virus resistance and virus strains on subtypes differs between countries and seasons. The resistance of the predominant virus to FLUMITEV 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.

Severe concomitant condition: No information is available regarding the safety and efficacy of FLUMITEV in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation.

Immunocompromised patients: The efficacy of FLUMITEV in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established (see section 5.1).

Cardiac / respiratory disease: Efficacy of FLUMITEV 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 to 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 sections 4.2 and 5.2).

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

Paediatric population: Based on limited pharmacokinetic and safety data, FLUMITEV may only be used in infants 6 u2013 12 months of age for treatment during a pandemic influenza outbreak. The treating medical practitioner 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. FLUMITEV should not be used in children under 1 year of age, other than during a pandemic influenza outbreak.

FLUMITEV contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially u2018sodium-freeu2019.

Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant drug interactions via these mechanisms are unlikely.

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 drug interactions involving competition for renal tubular secretion are unlikely, due to the known safety margin for most of these substances, 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 FLUMITEV in subjects when taking co-excreted medicines with a narrow therapeutic margin (e.g., chlorpropamide, methotrexate, phenylbutazone).

Additional information: No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering FLUMITEV with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in subjects stable on warfarin and without influenza). 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 FLUMITEV or its active metabolite. Co-administration with paracetamol does not alter plasma levels of FLUMITEV, its active metabolite, or paracetamol. FLUMITEV has been administered with commonly used medicines such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporin, azithromycin, erythromycin and doxycycline), H 2 - 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 FLUMITEV with these compounds.

Animal reproductive studies in rats and rabbits, no teratogenic effect was observed.

Pregnancy: Safety in pregnancy has not been established. No controlled clinical trials have been conducted on the use of FLUMITEV 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 FLUMITEV and on excretion of FLUMITEV 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 FLUMITEV. Mothers on treatment with FLUMITEV should not breastfeed their infants.

Fertility: No human data available.

FLUMITEV has no influence on the ability to drive and use machines.

a. Summary of the safety profile: In adults/adolescents, the most frequently reported adverse reactions (ARs) were nausea and vomiting in the treatment studies, and nausea in the prevention studies. 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 children, the most commonly reported adverse reaction was vomiting. In the majority of patients, these adverse reactions did not lead to discontinuation of FLUMITEV.

The following serious adverse reactions have been less frequently reported since FLUMITEV has been marketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice), angioneurotic 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, adverse reactions that occurred the most frequently at the recommended dose (75 mg bid for 5 days for treatment and 75 mg od for up to 6 weeks for prophylaxis) are shown in Table 1.

Table 1 Adverse reactions reported in the treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

MedDRA system organ class Frequency Adverse reactions Infections and infestations Frequent Bronchitis, herpes simplex, nasopharyngitis, upper respiratory tract infections, sinusitis, influenza Blood and lymphatic system disorders Less frequent Thrombocytopenia Immune system disorders Less frequent Hypersensitivity reactions, anaphylactic reactions, anaphylactoid reactions Psychiatric disorders Less frequent Agitation, abnormal behaviour, anxiety, confusion, delusions, delirium, hallucination, nightmares, self-injury Nervous system disorders Frequent Headache, insomnia Less frequent Altered level of consciousness, convulsion Eye disorders Less frequent Visual disturbance Cardiac disorders Less frequent Cardiac dysrhythmia Respiratory, thoracic and mediastinal disorders Frequent Cough, sore throat, rhinorrhoea, nasal congestion Gastrointestinal disorders Frequent Nausea, vomiting, abdominal pain (incl. upper abdominal pain), dyspepsia, diarrhoea Less frequent Gastrointestinal bleedings, haemorrhagic colitis Musculoskeletal and connective tissue disorders Frequent Back pain, arthralgia, myalgia Reproductive system and breast disorders Frequent Dysmenorrhoea Hepato-biliary disorders Less frequent Elevated liver enzymes, fulminant hepatitis, hepatic failure, hepatitis Skin and subcutaneous tissue disorders Less frequent Eczema, dermatitis, rash, urticaria, angioneurotic oedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis General disorders and administration site conditions Frequent Pain, dizziness (incl. vertigo), fatigue, pyrexia, pain in limb, influenza-like illness

Treatment and prevention of influenza in children: Table 2 Adverse reactions reported in treatment and prevention of influenza in children (age/weight-based dosing [30 mg to 75 mg o.d.])

MedDRA system organ class Frequency Adverse reactions Infections and infestations Frequent Otitis media, bronchitis, pneumonia, sinusitis Blood and lymphatic system disorders Frequent Lymphadenopathy Nervous system disorders Frequent Headache Eye disorders Frequent Conjunctivitis (including red eyes, eye discharge and eye pain) Ear and labyrinth disorders Frequent Earache Less frequent Tympanic membrane disorder Respiratory, thoracic and mediastinal disorders Frequent Cough, nasal congestion, rhinorrhoea, asthma (including aggravated asthma), epistaxis Gastrointestinal disorders Frequent Vomiting, abdominal pain (incl. upper abdominal pain), dyspepsia, nausea, diarrhoea Skin and subcutaneous tissue disorders Less frequent Dermatitis (including allergic and atopic dermatitis)

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 FLUMITEV. Patients, especially paediatric and adolescent patients should therefore be carefully monitored for abnormal behaviour for the first few days. Convulsions and psychiatric symptoms have also been reported in patients with influenza who were not taking FLUMITEV.

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 FLUMITEV.

Gastrointestinal disorders: Gastrointestinal bleedings, in particular, haemorrhagic colitis was reported that subsided when the course of influenza abated or treatment with FLUMITEV was interrupted.

c. Description of selected adverse reactions: Psychiatric disorders and nervous system disorders: Influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. In patients with influenza who were receiving FLUMITEV, there have been post-marketing reports of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few cases resulting in self-injury or fatal outcomes. These events were reported primarily among paediatric and adolescent patients and often had an abrupt onset and rapid resolution. The contribution of FLUMITEV to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking FLUMITEV.

Hepato-biliary disorders: Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

e. Other special populations: Paediatric population (infants less than one year of age): Safety information available on oseltamivir e.g. FLUMITEV administered for treatment of influenza in infants less than 1 year of age from prospective and retrospective observational trials (comprising together more than 2 400 children of that age class), epidemiological database research and postmarketing 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.

Older people and patients with chronic cardiac and/or respiratory disease: The population included in the influenza treatment studies is comprised of otherwise healthy adults/adolescents and patients u201cat risku201d (patients at higher risk of developing complications associated with influenza, e.g. older people 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.

Immunocompromised patients: The safety profile of oseltamivir observed in studies was consistent with that observed in previous clinical trials where oseltamivir was administered for 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 adverse reaction reported in immunocompromised children was vomiting.

Children with pre-existing bronchial asthma: In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitatively similar to that of otherwise healthy children.

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 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. Treatment is supportive and symptomatic. No specific antidote is known.