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Tamiflu Information Tamiflu Information

TAMIFLU^®

Oseltamivir capsule 75 mg

Antiviral

Composition

Active ingredient

Oseltamivir phosphate

Capsules containing 98.5mg oseltamivir phosphate equivalent to 75mg of oseltamivir.

Excipients

Polyvidone K30, pre-gelatinized starch, croscarmellose sodium, talc, sodium stearyl fumarate.

Appearance

Size 2 hard gelatin capsule with a grey opaque body and a light yellow opaque cap, containing a white to yellow-white powder.

Properties and Effects

Mechanism of action

Oseltamivir phosphate is a pro-drug of a potent and selective inhibitor of influenza virus neuraminidase enzymes. Viral neuraminidase is essential for the release of recently formed virus particles from infected cells, and the further spread of infectious virus.

The active metabolite of oseltamivir inhibits neuraminidases of influenza viruses of both types A and B. Concentrations of the active metabolite required to inhibit the enzyme activity by 50% (IC50) are in the low nanomolar range. The active metabolite also inhibits influenza virus growth in-vitro and inhibits influenza virus replication and pathogenicity in-vivo.

The active metabolite reduces shedding of both influenza A and B virus by inhibiting the release of infectious virus from infected cells.

Efficacy

Clinical efficacy of Tamiflu has been demonstrated in human experimental infection studies and phase III studies in naturally occurring influenza.

In studies in naturally acquired and experimental influenza, treatment with Tamiflu did not impair normal humoral antibody response to infection. Antibody response to inactivated vaccine is not expected to be affected by treatment with Tamiflu.

In phase III clinical trials, patients were treated with Tamiflu for up to 40 hours after reported onset of symptoms. In these studies, 97% of patients were infected with influenza A and 3% with influenza B. Tamiflu treatment significantly reduced the duration of clinically relevant signs and symptoms of influenza by 32 hours. Disease severity in patients with confirmed influenza taking Tamiflu was also reduced by 38% compared to placebo. Moreover, Tamiflu reduced the incidence of complications associated with influenza treated with antibiotic therapy in otherwise healthy young adults by approximately 50%. These complications include bronchitis, pneumonia, sinusitis and otitis media. In phase III clinical trials there was clear evidence of efficacy in the secondary endpoints related to antiviral activity in terms of both reduction of duration of virus shedding and reduction in the AUC of viral titres.

Data from a partially recruited study in the elderly population have shown that Tamiflu 75mg bid for five days was associated with a reduction in median duration of illness that was clinically relevant, and similar to that seen in the adult treatment studies. In a separate partially recruited study, patients aged >13 years with influenza and co-existing chronic cardiac and/or respiratory disease received the same regimen of either Tamiflu or placebo. No difference in the median time to alleviation of all symptoms was seen between patients taking Tamiflu or placebo, however the duration of febrile illness was reduced by approximately one day by receipt of Tamiflu. The proportion of patients shedding virus on days 2 and 4 was also markedly reduced by active treatment. There was no difference in the safety profile of Tamiflu in the at-risk populations compared to the general adult population.

Viral Resistance

The risk of emergence of drug resistance in clinical use has been extensively examined. The incidence of resistance to the active metabolite in viral isolates from clinical studies is up to 1.5% in influenza A. Patients with viruses displaying reduced sensitivity, cleared virus normally and showed no clinical deterioration. All resistant genotypes are disadvantaged compared to the corresponding wild-type isolate and are likely to be less contagious in man. There is no evidence for resistance in influenza B in vitro or in clinical isolates.

Pharmacokinetics

Absorption

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to the active metabolite. Plasma concentrations of the active metabolite are measurable within 30 minutes, reach near maximal levels in 2 to 3 hours post dose, and substantially exceed (>20 fold) those of the prodrug. At least 75% of an oral dose reaches the systemic circulation as the active metabolite. Plasma concentrations of active metabolite are proportional to dose and are unaffected by co-administration with food (See Dosage and Administration).

Distribution

The mean volume of distribution (Vss) of the active metabolite is approximately 23 litres in humans.

The active moiety reaches all key sites of influenza infection as shown by studies in the ferret, rat and rabbit. In these studies, anti-viral concentrations of the active metabolite were seen in the lung, bronchioalveolar lavage, nasal mucosa, middle ear and trachea following oral administration of doses of oseltamivir phosphate.

The binding of the active metabolite to human plasma protein is negligible (approximately 3%). The binding of the prodrug to human plasma protein is 42%. These levels are insufficient to cause significant drug interactions.

Metabolism

Oseltamivir phosphate is extensively converted to the active metabolite by esterases located predominantly in the liver. Neither oseltamivir nor the active metabolite are substrates for, or inhibitors of, cytochrome P450 isoforms (See Interactions).

Elimination

Absorbed oseltamivir is primarily (> 90%) eliminated by conversion to the active metabolite. The active metabolite is not further metabolised and is eliminated in the urine. Peak plasma concentrations of the active metabolite decline with a half-life of 6 to 10 hours in most subjects.

The active substance is eliminated entirely (> 99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h) indicating that tubular secretion in addition to glomerular filtration occurs. Less than 20% of an oral radiolabeled dose is eliminated in faeces .

Pharmacokinetics in Special Clinical Situations

Patients with renal impairment

Administration of 100 mg of Tamiflu twice daily for five days to patients with various degrees of renal impairment showed that exposure to the active metabolite is inversely proportional to declining renal function. Dose adjustment is recommended for patients with creatinine clearance below 30 mL/min. There are no data available in patients with renal failure (creatinine clearance < 10 mL/min), therefore caution is advised when administering Tamiflu to those patient populations (See Precautions and Special dosage instructions).

Patients with hepatic impairment

In-vitro studies have shown that exposure to oseltamivir is not expected to be increased significantly nor is exposure to the active metabolite expected to be significantly decreased in patients with hepatic impairment (See Special dosage instructions).

Elderly

Exposure to the active metabolite at steady state was 25-35% higher in elderly (age range 65- 78) compared to young adults who were given comparable doses of Tamiflu. Half-lives observed in the elderly were similar to those seen in young adults. On the basis of active ingredient exposure and tolerability, dosage adjustments are not required for elderly patients (See Special dosage instructions).

Children

The pharmacokinetics of Tamiflu have been evaluated in a small group of children 5 to 18 years of age after administration of a single 2 mg/kg oral dose given as an oral powder for reconstitution. The pharmacokinetic data showed that younger children cleared both the pro-drug and the active metabolite faster than older children resulting in lower exposure for a given mg/kg dose. In children 5- 8 years old, 2 mg/kg gives comparable exposure to that achieved in adults receiving a single 75 mg capsule dose (approximately 1 mg/kg). With advancing age, the difference in exposure between children and adults (per mg/kg dose) became less, such that exposure in children over 12 years of age was similar to that in adults.

Indications

Tamiflu is indicated for the treatment of influenza in adults and children 12 years and older.

Dosage and Administration

Standard Dosage

The recommended oral dose of Tamiflu is 75 mg twice daily, for 5 days. Treatment should begin within the first or second day of onset of symptoms of influenza. Tamiflu may be taken with or without food (See Pharmacokinetics). However, taking with food may enhance tolerability in some patients.

Special Dosage Instructions

Patients with renal impairment

No dose adjustment is necessary for patients with creatinine clearance above 30 mL/min. In patients with a creatinine clearance of less than 30 mL/min, it is recommended that the dose is reduced to 75 mg of Tamiflu once daily for 5 days. Tamiflu has not been studied in patients with renal failure (creatinine clearance below 10 mL/min), therefore caution is advised when administering Tamiflu to those patient populations (See Pharmacokinetics in special clinical situations and Precautions).

Patients with hepatic impairment

No dose adjustment is required for patients with hepatic dysfunction (See Pharmacokinetics in special clinical situations).

Elderly

No dose adjustment is required for elderly patients (See Pharmacokinetics in special clinical situations).

Children

The safety and efficacy of Tamiflu in children under 12 years has not been established. Limited paediatric pharmacokinetic information is available (See Pharmacokinetics in special clinical situations).

Contraindications

Hypersensitivity to oseltamivir phosphate or any of the components of the product.

Warnings

None.

Precautions

There are limited studies in patients older than 65 years of age and in patients at special risk of influenza complications.

Efficacy of Tamiflu in 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. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation.

Dose adjustment is recommended for patients with creatinine clearance below 30 mL/min. There are no data available in patients with renal failure (creatinine clearance below 10 mL/min), therefore caution is advised when administering Tamiflu to those patient populations. (See Pharmacokinetics in special clinical situations and special dosage instructions).

Pregnancy, Nursing Mothers

Pregnancy Category C

In animal reproductive studies in rats and rabbits, no teratogenic effect was observed. Fertility and reproductive toxicity studies have been conducted in rats. There was no evidence of an effect on fertility at any dose of oseltamivir studied. Foetal exposure in rats and rabbits was approximately 15- 20% of that of the mother.

At present, insufficient data are available in pregnant women taking Tamiflu to enable an evaluation of the potential for oseltamivir phosphate to cause fetal malformations or fetal toxicity. Tamiflu should therefore be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

In lactating rats, oseltamivir and the active metabolite are secreted in the milk. It is not known whether oseltamivir or the active metabolite are secreted in human milk, but extrapolation of the animal data provides estimates of 0.01 mg/day and 0.3 mg/day for the respective compounds. Tamiflu should therefore be used only if the potential benefit for the lactating mother justifies the potential risk for the nursing infant.

Undesirable Effects

Experience from Clinical Trials

In a total of 1887 patients (including patients on placebo, 75mg bid Tamiflu and 150mg bid Tamiflu) in adult phase III studies in the treatment of influenza, the most frequently reported adverse events were nausea and vomiting. These events were transient and generally occurred with first dosing. These events did not lead to patient discontinuation of study medication in the vast majority of instances. At the recommended dose of 75mg twice daily, three patients withdrew because of nausea and the same number withdrew because of vomiting.

In adult phase III treatment studies, some adverse events occurred more frequently in patients taking Tamiflu compared to those taking placebo. The adverse events that occurred with an incidence of 1%, are shown in Table 1. This summary includes healthy young adults and at risk patients (patients at higher risk of developing complications associated with influenza e.g. elderly patients and patients with chronic cardiac or respiratory disease. Those events reported more frequently, irrespective of causality, in patients taking Tamiflu compared with placebo were nausea, vomiting, bronchitis, insomnia and vertigo.

Table 1: Summary of Adverse Events in the Treatment of Naturally Acquired Influenza with Dose of 75 mg bid Occurring in 1% of Patients.

Placebo Ro 64-0796
75 mg bid

N=716 N=724

Nausea (without vomiting) 40 (5.6 %) 72 (9.9%)

Vomiting* 21 (2.9%) 68 (9.4 %)

Diarrhoea 70 (9.8%) 48 (6.6%)

Bronchitis 15 (2.1%) 17 (2.3%)

Abdominal pain 16 (2.2%) 16 (2.2%)

Dizziness 25 (3.5%) 15 (2.1%)

Headache 14 (2.0%) 13 (1.8%)

Cough 12 (1.7%) 9 (1.2%)

Insomnia 6 (0.8%) 8 (1.1%)

Vertigo 3 (0.4%) 7 (1.0%)

Fatigue 7 (1.0%) 7 (1.0%)

*In this table subjects reporting nausea in association with vomiting are included in the proportions of individuals reporting vomiting.

In general the adverse event profile in the "at risk" patients was qualitatively similar to healthy young adults.

Studies were also conducted in the prophylaxis of influenza in both healthy adults and elderly patients dosing for up to six weeks whilst influenza was circulating in the community. At a dose of 75 mg once or twice daily, adverse events from these studies were qualitatively similar to those seen in the treatment studies.

Interactions

Information derived from pharmacology and pharmacokinetic studies of oseltamivir phosphate suggest that clinically significant interactions with other medicines are unlikely.

Oseltamivir phosphate 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 oseltamivir and the active metabolite do not suggest the probability of displacement interactions.

In-vitro studies demonstrated that neither oseltamivir phosphate nor the active metabolite is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases. (See Pharmacokinetics). 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 substances has no effect on plasma levels of oseltamivir 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 paracetamol does not alter plasma levels of oseltamivir, its active metabolite, or paracetamol.

In phase III clinical studies, Tamiflu has been administered with commonly used medicines such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide) antibiotics (penicillin, cephalosporin, azithromycin, erythromycine and doxycycline), H₂ receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephidrine), opioids (codeine), corticosteroids, inhaled bronchodilators and analgesic agents (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.

Overdosage

At present there has been no experience with overdose, however the anticipated manifestations of acute overdose would be nausea, with or without accompanying emesis. Single doses of up to 1000 mg of Tamiflu have been well tolerated apart from nausea and/or vomiting.