Anviatir Capsule

TREATMENT

ANVIATIR is indicated for the treatment of influenza in adults and children u2265 1 year of age (see section 4.4 and Special dosage instructions).

PANDEMIC USE

ANVIATIR is indicated for the treatment of infants 6 u2013 12 months of age during a pandemic influenza outbreak only, and not for endemic (seasonal) influenza use (see section 4.4 and Pharmacokinetics in special populations).

PROPHYLAXIS

ANVIATIR 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: The recommended oral dose of ANVIATIR 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.

Prophylaxis of influenza

Adults and adolescents

The recommended oral dose of ANVIATIR 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.

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 a creatinine clearance of 30 u2013 60 mL/min, it is recommended that the treatment dose be reduced to 30 mg of ANVIATIR twice daily for 5 days. In patients with a creatinine clearance of 10 u2013 30 mL/min, it is recommended that the dose be reduced to 30 mg of ANVIATIR once daily for 5 days. In patients undergoing routine haemodialysis an initial dose of 30 mg ANVIATIR 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 ANVIATIR 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). The pharmacokinetics of ANVIATIR have not been studied in patients with end-stage renal disease (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 u2013 60 mL/min, it is recommended that the dose be reduced to 30 mg of ANVIATIR once daily. In patients with a creatinine clearance between 10 and 30 mL/min receiving ANVIATIR, it is recommended that the dose be reduced to 30 mg of ANVIATIR every other day. In patients undergoing routine haemodialysis an initial dose of 30 mg of ANVIATIR 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 ANVIATIR administered prior to the start of dialysis followed by further 30 mg doses administered every 7 days is recommended for prophylaxis (see Pharmacokinetics in special populations and section 4.4). The pharmacokinetics of ANVIATIR have not been studied in patients with end-stage renal disease (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 Pharmacokinetics in special populations). The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied.

Immunocompromised patients

Seasonal prophylaxis in immunocompromised patients 1 year of age and older is recommended for 12 weeks. No dose adjustment is necessary.

Elderly patients

No dose adjustment is required for elderly patients in the treatment or prophylaxis of influenza (see Pharmacokinetics in special populations).

Children

The safety and efficacy of ANVIATIR in children under 1 year have not been established (see Pharmacokinetics in special populations). ANVIATIR should not be used in children under 1 year of age, other than during a pandemic influenza outbreak.

Method of administration

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

Adults, adolescents or children unable to swallow capsules

Adults, adolescents or children who are unable to swallow capsules may receive appropriate doses of ANVIATIR by opening capsules and pouring the contents of capsules into a suitable, small amount (1 teaspoon [5 mL] maximum) of sweetened food product, such as regular or sugar-free chocolate syrup, honey (only for children two years or older), light brown or table sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yoghurt to mask the bitter taste. The mixture should be stirred, and the entire contents given to the patient. The mixture must be swallowed immediately after its preparation.

Hypersensitivity to oseltamivir or to any of the excipients listed in section 6.1.

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

ANVIATIR is not a substitute for influenza vaccination. The use of ANVIATIR must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as ANVIATIR is administered. ANVIATIR 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 ANVIATIR.

Severe concomitant condition

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

Immunocompromised patients

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

Cardiac/respiratory disease

Efficacy of ANVIATIR in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established.

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. No dosing recommendation is available for patients with end-stage renal disease and for patients with creatinine clearance of u2264 10 mL/min (see section 4.2). 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 oseltamivir administration in patients with influenza, especially in children and adolescents. In some cases, the delirium resulted in accidental self-injury and death. More events were reported in males than in females. These events are also experienced by patients with influenza without oseltamivir administration. Patients, and especially paediatric and adolescent patients, taking ANVIATIR should be closely monitored for behavioural changes.

Paediatric population

No data allowing a dose recommendation for premature children (< 36 weeks post-conceptual age) are currently available.

Based on limited pharmacokinetic and safety data, ANVIATIR may only be used in infants 6 u2013 12 months of age for treatment during a pandemic influenza outbreak.

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 medicine interactions via these mechanisms are unlikely.

Oral contraceptives

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 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 ANVIATIR in subjects when taking co-excreted medicines with a narrow therapeutic margin (e.g. chlorpropamide, methotrexate, phenylbutazone).

Additional information

No pharmacokinetic interactions between ANVIATIR or its major metabolite have been observed when co-administering ANVIATIR with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine, amantadine or warfarin (in subjects stable on warfarin and without influenza). In treatment and prophylaxis clinical studies, oseltamivir as in ANVIATIR 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 the adverse event profile or frequency has been observed as a result of co-administration of oseltamivir 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

Influenza is associated with adverse pregnancy and fetal outcomes, with a risk of major congenital malformations, including congenital heart defects. No controlled clinical trials have been conducted on the use of ANVIATIR in pregnant women. Safety in pregnancy has not been established.

Lactation

In lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information is available on children breastfed by mothers taking ANVIATIR and on excretion of ANVIATIR in breast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breast milk. Safety in humans has not been demonstrated in children of breastfeeding women using ANVIATIR. Mothers on treatment with ANVIATIR should not breastfeed their infants.

Fertility

There is no evidence that ANVIATIR has an effect on male or female fertility.

ANVIATIR causes side effects, such as dizziness, fatigue and delirium, which may affect the ability to drive and use machinery. Caution is advised before driving a vehicle or operating machinery until the effects of ANVIATIR are known.

Treatment and prevention of influenza in adults and adolescents

Infections and infestations:

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• Frequent: bronchitis, herpes simplex, nasopharyngitis, upper respiratory tract infections, sinusitis
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Blood and lymphatic system disorders:

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• Less frequent: thrombocytopenia
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Immune system disorders:

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• Less frequent: hypersensitivity reaction, anaphylactic reactions, angioedema, anaphylactoid reactions
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Psychiatric disorders:

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• Less frequent: agitation, abnormal behaviour, anxiety, confusion, delusions, delirium, hallucination, nightmares, self-injury (accidental)
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Nervous system disorders:

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• Frequent: headache, insomnia
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• Less frequent: altered level of consciousness, convulsions
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Eye disorders:

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• Less frequent: visual disturbance
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Cardiac disorders:

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• Less frequent: cardiac dysrhythmia
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Respiratory, thoracic and mediastinal disorders:

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• Frequent: cough, sore throat, rhinorrhoea
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Gastrointestinal disorders:

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• Frequent: nausea, vomiting, abdominal pain (incl. upper abdominal pain), dyspepsia
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• Less frequent: gastrointestinal bleedings, haemorrhagic colitis
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Hepatobiliary disorders:

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• Less frequent: elevated liver enzymes, fulminant hepatitis, hepatic failure, hepatitis
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Skin and subcutaneous tissue disorders:

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• Less frequent: eczema, dermatitis, rash, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
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General disorders and administration site conditions:

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• Frequent: pain, dizziness (incl. vertigo), fatigue, pyrexia, pain in limb
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Treatment and prevention of influenza in children

Infections and infestations:

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• Frequent: otitis media, bronchitis, pneumonia, sinusitis
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Nervous system disorders:

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• Frequent: headache
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Eye disorders:

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• Frequent: conjunctivitis (including red eyes, eye discharge and eye pain)
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Ear and labyrinth disorders:

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• Frequent: earache
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• Less frequent: tympanic membrane disorder
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Respiratory, thoracic and mediastinal disorders:

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• Frequent: cough, nasal congestion, rhinorrhoea, asthma (including aggravated asthma), epistaxis
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Gastrointestinal disorders:

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• Frequent: vomiting, abdominal pain (incl. upper abdominal pain), dyspepsia, nausea, diarrhoea
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Skin and subcutaneous tissue disorders:

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• Frequent: dermatitis (including allergic and atopic dermatitis)
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Post-marketing experience

Immune system disorders:

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• Less frequent: face oedema.
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In overdose, symptoms may be the exacerbation or exaggeration of side effects. Treatment is supportive and symptomatic.