Data Sheet
Tamiflu®
Oseltamivir capsule 75 mg and powder for oral suspension 12 mg/mL
Antiviral
Pharmaceutical Form
Hard capsule 75 mg and powder for oral suspension 12 mg/mL.
Qualitative and Quantitative Composition
Active ingredient
Oseltamivir phosphate.
Capsules containing 98.5 mg oseltamivir phosphate equivalent to 75 mg of oseltamivir.
Powder for oral suspension, which when constituted with water to a concentration of 1.2 % contains 12 mg/mL oseltamivir.
Excipients
Capsules
Capsule fill: Polyvidone K30, pre-gelatinised starch, croscarmellose sodium, talc, sodium stearyl fumarate.
Capsule shell: Black iron oxide, red iron oxide, yellow iron oxide, titanium dioxide, gelatin.
Printing ink: Dehydrated alcohol, shellac, n-butyl alcohol, titanium dioxide, FDC Blue 2, SDA-3A alcohol.
Powder for oral suspension
Sorbitol, titanium dioxide, sodium benzoate, xanthan gum, sodium dihydrogen citrate (monosodium citrate), saccharin sodium, flavour - PERMASEAL 11900-31 tutti frutti.
Appearance
Capsules: The hard gelatin capsule consists of a grey opaque body imprinted with "ROCHE" and a light yellow opaque cap imprinted with "75 mg". Imprints are blue.
Powder for oral suspension: The powder is a granulate or clumped granulate with a white to light yellow colour.
Clinical Particulars
Therapeutic Indications
Tamiflu is indicated for the treatment of influenza in adults and children ≥ 1 year of age (see Special Warnings and Special Precautions for Use and Preclinical Safety).
Tamiflu is indicated for the prophylaxis of influenza in adults and children ≥ 1 years of age.
Vaccination is the preferred method of routine prophylaxis against infection with influenza virus.
Dosage and Method of Administration
Tamiflu may be taken with or without food (see Pharmacokinetic Properties). However, Tamiflu taken with food may enhance tolerability in some patients.
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 Tamiflu capsules in adults and adolescents ≥ 13 years is a 75 mg capsule twice daily, for 5 days. Adults and adolescents ≥ 13 years of age that are unable to swallow capsules may receive a dose of 75 mg Tamiflu suspension bid 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 as an alternative to the recommended dose of Tamiflu suspension (see below).
The recommended oral dose of Tamiflu suspension for children ≥1 year of age is:
| Body weight | Recommended dose for 5 days |
|---|---|
| ≤ 15 kg | 30 mg twice daily |
| > 15 to 23 kg | 45 mg twice daily |
| > 23 kg to 40kg | 60 mg twice daily |
| > 40 kg | 75 mg twice daily |
A dosing syringe marked with 30 mg, 45 mg and 60 mg dosing levels is provided.
It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see Special Remarks, Handling and disposal).
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 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
Children weighing > 40 kg, who are able to swallow capsules, may also receive prophylaxis with a 75 mg capsule once daily for 10 days as an alternative to the recommended dose of Tamiflu suspension (see below).
The recommended prophylactic oral dose of Tamiflu suspension for children ≥ 1 year of age is:
| Body weight | Recommended dose for 10 days |
|---|---|
| ≤ 15 kg | 30 mg once daily |
| > 15 to 23 kg | 45 mg once daily |
| > 23 kg to 40kg | 60 mg once daily |
| > 40 kg | 75 mg once daily |
A dosing syringe marked with 30 mg, 45 mg and 60 mg dosing levels is provided
for oral suspension.
It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see Special Remarks, Handling and disposal).
Special dosage instructions
Patients with renal impairment
Treatment of influenza
No dose adjustment is necessary for patients with creatinine clearance above 30 mL/min. In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose is reduced to 75 mg of Tamiflu once daily for 5 days. 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 ≤ 10 mL/min (see Pharmacokinetics in special populations and Special Warnings and Special Precautions for Use).
Prophylaxis of influenza
No dose adjustment is necessary for patients with creatinine clearance above 30 mL/min. In patients with creatinine clearance between 10 and 30 mL/min receiving Tamiflu it is recommended that the dose be reduced to 75 mg of Tamiflu every other day or 30 mg suspension every day. 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 ≤ 10 mL/min (see Pharmacokinetics in special populations and Special Warnings and Special Precautions for Use).
Patients with hepatic impairment
No dose adjustment is required for patients with hepatic dysfunction in the treatment or prophylaxis of influenza (see Pharmacokinetics in special populations).
Elderly
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 Tamiflu in children under 1 year has not been established (see Pharmacokinetics in special populations). Tamiflu should not be used in children under 1 year of age (see Preclinical Safety).
Contraindications
Hypersensitivity to oseltamivir phosphate or any component of the product.
Special Warnings and Special Precautions for Use
Convulsion and delirium like neuropsychiatric events have been reported during Tamiflu administration in patients with influenza, predominately in children and adolescents. In rare cases, these events resulted in accidental injury. The contribution of Tamiflu to those events is unknown and these have also been reported in patients with influenza who were not taking Tamiflu (see Post Marketing experience).
Patients, especially children and adolescents, should be closely 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.
Dose adjustment is recommended for patients with creatinine clearance of 10 - 30 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 ≤ 10mL/min (see Special dosage instructions and Pharmacokinetics in special populations).
A bottle of 30 g Tamiflu powder for oral suspension contains 25.713 g of sorbitol. One dose of 45 mg oseltamivir administered twice daily delivers 2.6 g of sorbitol. For subjects with hereditary fructose intolerance this is above the recommended daily maximum limit of sorbitol. Tamiflu should not be used in children under 1 year of age (see Preclinical safety).
Interactions with other Medical Products and other Forms of Interaction
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 Pharmacokinetic properties). 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 agents 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 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 oseltamivir, its active metabolite, or paracetamol.
No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering oseltamivir with paracetamol, acetyl-salicylic acid, cimetidine or with antacids (magnesium and aluminium hydroxides and calcium carbonates).
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 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.
Pregnancy and Lactation
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 foetal malformations or foetal 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
Adult treatment studies
In a total of 2107 patients (including patients on placebo, 75 mg bid Tamiflu and 150 mg 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 75 mg 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 placebos. The adverse events that occurred the most frequently at the recommended dose, either for treatment or prophylaxis, 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 with an incidence of ≥ 1% and which were reported more frequently in patients taking Tamiflu compared with placebo, irrespective of causality, were nausea, vomiting, abdominal pain and headache.
Table 1: Most frequent adverse events in studies in naturally acquired influenza
| Treatment * | Prophylaxis | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event | Placebo N=1050 |
Oseltamivir 75 mg bid N=1057 |
Placebo N=1434 |
Oseltamivir 75 mg od N=1480 |
||||
| Nausea (without vomiting) | 71 | (6.8%) | 113 | (10.7%) | 56 | (3.9%) | 104 | (7.0%) |
| Vomiting | 32 | (3.0%) | 85 | (8.0%) | 15 | (1.0%) | 31 | (2.1%) |
| Diarrhoea | 84 | (8.0%) | 58 | (5.5%) | 38 | (2.6%) | 48 | (3.2%) |
| Bronchitis | 52 | (5.0%) | 39 | (3.7%) | 17 | (1.2%) | 11 | (0.7%) |
| Abdominal pain | 21 | (2.0%) | 23 | (2.2%) | 23 | (1.6%) | 30 | (2.0%) |
| Dizziness | 31 | (3.0%) | 20 | (1.9%) | 21 | (1.5%) | 24 | (1.6%) |
| Headache | 16 | (1.5%) | 17 | (1.6%) | 251 | (17.5%) | 298 | (20.1%) |
| Insomnia | 10 | (1.0%) | 11 | (1.0%) | 14 | (1.0%) | 18 | (1.2%) |
| Cough** | 12 | (1.1%) | 10 | (0.9%) | 86 | (6.0%) | 83 | (5.6%) |
| Vertigo** | 6 | (0.6%) | 9 | (0.9%) | 3 | (0.2%) | 4 | (0.3%) |
| Fatigue** | 7 | (0.7%) | 8 | (0.8%) | 107 | (7.5%) | 117 | (7.9%) |
* Adverse events included are all events reported the most frequently in the
treatment studies in the oseltamivir 75 mg bid group, and events are ordered
by decreasing incidence in that group.
** These events no longer qualify as among the most frequently recorded events for the treatment group but are included here for completeness as they were included in a previous version of this table which was based on a smaller dataset.
In general the adverse event profile in the "at risk" patients in treatment studies was qualitatively similar to healthy young adults.
Prophylaxis studies
A total of 3434 subjects (adolescents, healthy adults and elderly) participated in phase III prophylaxis studies, of whom 1480 received the recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer duration of dosing (Table 1). Events reported more frequently in subjects receiving Tamiflu compared to subjects receiving placebo in prophylaxis studies, and more commonly than in treatment studies, were aches and pains, rhinorrhoea, dyspepsia and upper respiratory tract infections. However, the difference in incidence between Tamiflu and placebo for these events was less than 1 %. There were no clinically relevant differences in the safety profile of the 942 elderly subjects, who received Tamiflu or placebo, compared with the younger population.
Paediatric treatment studies
A total of 1032 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 oseltamivir given for the treatment of influenza. A total of 515 children received treatment with oseltamivir suspension.
Adverse events occurring in > 1% of children receiving oseltamivir are listed in Table 2. The most frequently reported adverse event was vomiting. Other events reported more frequently by oseltamivir treated children included abdominal pain, epistaxis, ear disorder and conjunctivitis. These events generally occurred once, resolved despite continued dosing and did not cause discontinuation of treatment in the vast majority of cases.
Table 2: Most frequent adverse events occurring in children aged 1 to 12 years in studies in naturally acquired influenza. Adverse events occurring on treatment in > 1% of paediatric patients enrolled in Phase III trials of Tamiflu treatment of naturally acquired influenza.
| Treatmenta | Treatmentb | Prophylaxisb | ||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event | Placebo N=517 |
Oseltamivir 2 mg/kg bid N=515 |
Oseltamivir Unit dosec N=158 |
Oseltamivir Unit dosec N=99 |
||||
| Vomiting | 48 | (9.3%) | 77 | (15.0%) | 31 | (19.6%) | 10 | (10.1%) |
| Diarrhoea | 55 | (10.6%) | 49 | (9.5%) | 5 | (3.2%) | 1 | (1.0%) |
| Otitis media | 58 | (11.2%) | 45 | (8.7%) | 2 | (1.3%) | 2 | (2.0%) |
| Abdominal pain | 20 | (3.9%) | 24 | (4.7%) | 3 | (1.9%) | 3 | (3.0%) |
| Asthma (including aggravated) | 19 | (3.7%) | 18 | (3.5%) | - | 1 | (1.0%) | |
| Nausea | 22 | (4.3%) | 17 | (3.3%) | 10 | (6.3%) | 4 | (4.0%) |
| Epistaxis | 13 | (2.5%) | 16 | (3.1%) | 2 | (1.3%) | 1 | (1.0%) |
| Pneumonia | 17 | (3.3%) | 10 | (1.9%) | - | - | ||
| Ear disorder | 6 | (1.2%) | 9 | (1.7%) | - | - | ||
| Sinusitis | 13 | (2.5%) | 9 | (1.7%) | - | - | ||
| Bronchitis | 11 | (2.1%) | 8 | (1.6%) | 3 | (1.9%) | - | |
| Conjunctivitis | 2 | (0.4%) | 5 | (1.0%) | - | - | ||
| Dermatitis | 10 | (1.9%) | 5 | (1.0%) | 1 | (0.6%) | - | |
| Lymphadenopathy | 8 | (1.5%) | 5 | (1.0%) | 1 | (0.6%) | - | |
| Tympanic membrane disorder | 6 | (1.2%) | 5 | (1.0%) | - | - | ||
a Pooled data from Phase III trials of Tamiflu treatment of
naturally acquired influenza.
b Uncontrolled study comparing treatment (twice-daily dosing for 5
days) with prophylaxis (once-daily dosing for 10 days).
c Unit dose = age-based dosing (see Standard dosage).
Adverse events included are: all events reported in the treatment studies with frequency ≥ 1% in the oseltamivir 75 mg bid group.
Paediatric Prophylaxis
Paediatric patients aged 1 to 12 years participated in a post-exposure prophylaxis study in households, both as index cases (n=134) and as contacts (n=222). Gastrointestinal events were the most frequent, particularly vomiting. Tamiflu was well tolerated in this study, the adverse events noted being consistent with those previously observed (see Table 2).
Post-marketing experience
Skin and subcutaneous tissue disorder: rare cases of hypersensitivity reactions such as allergic skin reactions including dermatitis, rash, eczema, urticaria, and very rare cases of erythema multiforme, Stevens-Johnson-Syndrome and toxic epidermal necrolysis are reported. Also, allergy, anaphylactic /anaphylactoid reactions and face oedema are reported rarely.
Liver and biliary system disorder: very rare reports of hepatitis and elevated liver enzymes have been reported in patients with influenza like illness receiving oseltamivir.
Psychiatric disorders/nervous system disorders: Convulsion and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares) have been reported during Tamiflu administration in patients with influenza, predominately in children and adolescents. These events often had an abrupt onset and rapid resolution In rare cases, these events resulted in accidental injury, and some resulted in a fatal outcome. The contribution of Tamiflu to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Tamiflu. Patients with influenza should be closely monitored for signs of abnormal behaviour throughout the treatment period.
Gastro-intestinal disorders: In rare cases gastro-intestinal bleedings were observed after the use of Tamiflu. In particular, haemorrhagic colitis was reported that subsided when the course of influenza abated or treatment with Tamiflu was interrupted.
Overdose
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.
Pharmacological Properties and Effects
Pharmacodynamic Properties
Mechanism of action
Oseltamivir phosphate is a pro-drug of oseltamivir carboxylate, a potent and selective inhibitor of influenza virus neuraminidase enzymes. Viral neuraminidase is important both for viral entry into uninfected cells and for the release of recently formed virus particles from infected cells, and the further spread of infectious virus.
Oseltamivir carboxylate inhibits the neuraminidases of influenza viruses of both types A and B. Concentrations of oseltamivir carboxylate required to inhibit the enzyme activity by 50 % (IC50) are in the low nanomolar range. Oseltamivir carboxylate also inhibits influenza virus infection and replication in-vitro and inhibits influenza virus replication and pathogenicity in-vivo.
Oseltamivir carboxylate reduces shedding of both influenza A and B virus by inhibiting the release of infectious virus from infected cells.
Efficacy/ clinical studies
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.
Trials in naturally occurring influenza
In phase III clinical trials conducted in the 1997 - 1998 Northern Hemisphere influenza season, 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 these 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 treatment study in the elderly population have shown that Tamiflu 75 mg 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 younger adult treatment studies. In a separate 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.
Treatment of influenza in children
One double-blind placebo controlled treatment trial was conducted in otherwise healthy children (65% influenza positive) aged 1 - 12 (mean age 5.3), who had fever (≥ 100° F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. In this study 67% of influenza-infected patients were infected with influenza A and 33% with influenza B. Tamiflu treatment, started within 48 hours of onset of symptoms, significantly reduced the duration of illness by 35.8 hours compared to placebo. Duration of illness was defined as time to alleviation of cough, nasal congestion, resolution of fever, and return to normal health and activity. The proportion of patients developing acute otitis media was reduced by 40% in children receiving Tamiflu (29/183) vs placebo (53/200). Children receiving Tamiflu returned to normal health and activity almost 2 days earlier than those receiving placebo.
A second study was completed in 334 asthmatic children aged 6 to 12 years old of which 53.6% were influenza-positive. In the oseltamivir-treated group the median duration of illness was not reduced significantly. By day 6 (the last day of treatment) FEV1 had increased by 10.8% in the oseltamivir-treated group compared to 4.7% on placebo (p = 0.0148) in this population.
Trials for prophylaxis of influenza
Prophylaxis of influenza in adults and adolescents
The efficacy of Tamiflu in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and two post exposure prophylaxis study in households. The primary efficacy parameter for all these studies was the incidence of laboratory confirmed clinical influenza. Laboratory confirmed clinical influenza was defined as oral temperature ≥ 99.0°F/37.2°C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a fourfold increase in virus antibody titers from baseline.
In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 18 to 65 years), Tamiflu 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory confirmed clinical influenza from 4.8% (25/519) for the placebo group to 1.2% (6/520) for the Tamiflu group.
In a seasonal prophylaxis study in elderly residents of nursing homes, Tamiflu 75 mg once daily taken for 42 days reduced the incidence of laboratory confirmed clinical influenza from 4.4% (12/272) for the placebo group to 0.4% (1/276) for the Tamiflu group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders. In a post-exposure prophylaxis study, household contacts (aged ≥ 13 years) who had no laboratory evidence of influenza at baseline, and who were living with an index case subsequently shown to have had influenza infection, were randomized to treatment (the ITTIINAB population). In this population Tamiflu 75 mg administered once daily within 2 days of onset of symptoms in the index case and continued for 7 days, reduced the incidence of laboratory confirmed clinical influenza in the contacts from 12% (24/200) in the placebo group to 1% (2/205) for the Tamiflu group (risk reduction 91.9%, p < 0.001). For the study population as a whole (the ITT population), including contacts of index cases in whom influenza infection was not confirmed, the incidence of laboratory confirmed clinical influenza was reduced from 7.4% (34/462) in the placebo group to 0.8% (4/493) for the Tamiflu group (risk reduction 89%, p < 0.001). Index cases did not receive Tamiflu in the study. In the ITT population 13.9%of contacts in the placebo group and 11.4 % of contacts in the TAMIFLU group had been vaccinated.
The efficacy of Tamiflu in preventing naturally occurring influenza illness in adults and children has also been demonstrated in a post exposure prophylaxis study conducted in households in which index cases with rapid onset of fever, cough and/or coryza received twice daily treatment with Tamiflu for 5 days. The primary efficacy parameter for this study was the percentage of households with at least one secondary case of febrile laboratory confirmed influenza illness. A laboratory confirmed case was defined as a febrile illness (oral/otic temperature ≥ 100.0 °F/37.8 °C) plus cough and/or coryza, confirmed to be influenza by either detection of viral shedding within 2 days before or after the time that the fever was reported, and/or a four fold increase in influenza virus antibody titers from baseline to the day 30 sample. Household contacts were randomized (by household) to receive either once daily prophylaxis with oseltamivir for 10 days (Group P) or to receive treatment for 5 days upon the emergence of influenza-like illness (Group T).
In households with an infected index case and where there was no laboratory evidence of influenza among the contacts at baseline (ITTIINAB), there was a 78.8% (p = 0.0008) reduction in households with infected contacts in Group T 22% (20/89) versus Group P 5% (4/84). In the population as a whole (ITT), including contacts of index cases in whom influenza infection was not confirmed, the prophylactic efficacy protection was 62.7% (p = 0.0042), Group T 20% (27/137) versus Group P 7% (10/137). A significant number of children aged 1 - 12 participated in this study, both as index cases and as contacts. In the ITTIINAB population of paediatric contacts, there was an 80.1% (p = 0.0206) reduction in the incidence of laboratory confirmed influenza in Group T 21% (15/70) versus Group P 4% (2/47). A similar reduction in clinical influenza was seen in the subset of paediatric contacts that also had paediatric index cases.
Prophylaxis of influenza in children
The efficacy of Tamiflu in preventing naturally occurring influenza illness has been demonstrated in a postexposure prophylaxis study in households that included children aged 1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza. In this study, Tamiflu oral suspension 30 mg to 75 mg once daily taken for 10 days among children who were not already shedding virus at baseline reduced the incidence of laboratory-confirmed clinical influenza from 21% (15/70) in the group not receiving prophylaxis to 4% (2/47) in the group receiving prophylaxis.
Viral resistance
There has been no evidence for emergence of resistance associated with the use of Tamiflu in clinical studies conducted to date in post exposure (7 days), post exposure within household groups (10 days) and seasonal (42 days) prophylaxis of influenza.
The risk of emergence of resistance in clinical use in the treatment of influenza has been extensively examined. In all clinical studies in naturally acquired infection, 0.32% (4/1245) of adults and adolescents and 4.1% (19/464) of children aged 1 - 12 were found to transiently carry influenza virus with decreased neuraminidase susceptibility to oseltamivir carboxylate. Patients carrying resistant virus cleared it 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 trials.
Pharmacokinetic Properties
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 pro-drug. 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 Method of 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, bronchoalveolar 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 pro-drug to human plasma protein is 42%. These levels are insufficient to cause significant 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 with other Medical Products and other Forms of Interaction).
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 radiolabelled dose is eliminated in faeces.
Pharmacokinetics in special populations
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.
Treatment of influenza
No dose adjustment is necessary for patients with creatinine clearance above 30 mL/min. In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose be reduced to 75 mg of Tamiflu once daily for 5 days. 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 ≤ 10mL/min (see Special dosage instructions and Special Warnings and Special Precautions for Use).
Prophylaxis of influenza
In patients with creatinine clearance between 10 and 30 mL/min receiving Tamiflu it is recommended that the dose be reduced to 75 mg of Tamiflu every other day or 30 mg suspension every day. 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 ≤ 10 mL/min (see Special dosage instructions and Special Warnings and Special Precautions for Use).
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 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 exposure and tolerability, dosage adjustments are not required for elderly patients for either the treatment or prophylaxis of influenza (see Special dosage instructions).
Children
The pharmacokinetics of Tamiflu have been evaluated in a single dose pharmacokinetic studies in children aged 1 to 16 years. Multiple dose pharmacokinetics were studied in a small number of children aged 3 - 12 enrolled in a clinical trial. Younger children cleared both the pro-drug and the active metabolite faster than adults resulting in lower exposure for a given mg/kg dose. Doses of 2 mg/kg give oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75 mg capsule dose (approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children over 12 years of age are similar to those in adults.
Preclinical safety
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Three studies for carcinogenic potential (two year rat and mouse studies with oseltamivir, and a six month transgenic Tg:AC mouse assay performed with the active metabolite) were negative.
Teratology studies have been conducted in rats and rabbits at doses up to 1500 mg/kg/day and 500 mg/kg/day, respectively. No effects on embryo-foetal development were observed. A rat fertility study up to a dose of 1500 mg/kg/day demonstrated no adverse effects on either sex. In pre-/post-natal rat studies, prolonged parturition was noted at 1500 mg/kg/day: the safety margin between human exposure and the highest no effect dose (500 mg/kg/day) in rats is 480-fold for oseltamivir and 44-fold for the active metabolite, respectively. Foetal exposure in the rats and rabbits was approximately 15 to 20 % of that of the mother.
In lactating rats, oseltamivir and the active metabolite are excreted in the milk. It is not known whether oseltamivir or the active metabolite are excreted 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.
A potential for skin sensitisation to oseltamivir was observed in a "maximisation" test in guinea pigs. Approximately 50 % of the animals treated with the unformulated active ingredient showed erythema after challenging the induced animals. Reversible irritancy of the rabbits' eyes was detected.
In a two-week study in unweaned rats a single dose of 1000 mg/kg oseltamivir phosphate to 7-day-old pups resulted in deaths associated with unusually high exposure to the pro-drug. However, at 2000 mg/kg in 14-day-old unweaned pups, there were no deaths or other significant effects. No adverse effects occurred at 500 mg/kg/day administered from 7 to 21 days post partum: this dose level gave an exposure to the brain of approximately 800-fold that estimated for the brains of 1-year-old children.
In a single-dose investigatory study of this observation in 7-, 14-, 24- and 42-day-old rats, a dose of 1000 mg/kg resulted in brain exposure to the pro-drug that indicated respectively 1500-, 650- and 2-fold the exposure found in the brain of adult (42-day-old) rats.
These data suggest that oseltamivir may be safely administered only once the blood-brain-barrier is fully developed.
Pharmaceutical Particulars
Stability
Capsules: Do not store above 30°C.
Powder for oral suspension: After reconstitution, the suspension can be stored at room temperature (below 25°C) for up to 10 days or in a refrigerator (2 – 8°C) for up to 17 days. Tamiflu oral suspension should not be frozen
This medicine should not be used after the expiry date shown on the pack.
Special Remarks
Handling and disposal
Preparation of Tamiflu powder for oral suspension
It is recommended that Tamiflu powder for oral suspension be constituted by the pharmacist prior to dispensing to the patient (see Dosage and Method of Administration):
- Tap the closed bottle several times to loosen the powder.
- Measure 52 mL of water. Use the measuring cup (where provided) and fill it to the indicated level.
- Add all 52 mL of water for constitution to the bottle and shake the closed bottle well for 15 seconds. The final reconstituted volume is 75 mL.
- Remove the child-resistant cap and push bottle adapter into neck of bottle.
- Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
The oral dispenser should be dispensed to the patient. It is recommended that the date of expiration of the constituted suspension be written on the bottle label.
Medicine Classification
Prescription medicine
Packs
Tamiflu capsules 75 mg blister pack of 10 capsules
Tamiflu powder for oral suspension 12 mg/mL bottle pack with 30 g of powder
Name and Address
Roche Products (New Zealand) Limited
P O Box 12-492
Penrose
AUCKLAND
Telephone: (09) 633 0700
Telefax: (09) 633 0722
Toll Free: 0800 656 464
Date of Preparation
20 February 2008
Reference: Core Data Sheet Version 5.0, 20 December 2007.