Therapeutic / Pharmacologic Class of Drug:
Tamiflu is an antiviral agent. ATC:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Oseltamivir phosphate is a pro-drug of oseltamivir carboxylate (OC), a potent and selective inhibitor of influenza A and B virus neuraminidase enzymes. Viral neuraminidase is primarily important for the release of recently formed virus particles from infected cells, and the further spread of infectious virus. It has also been suggested that neuraminidase can play a role in viral entry into uninfected cells.
Oseltamivir carboxylate inhibits the neuraminidases of influenza viruses of both types A and B. Concentrations of OC required to inhibit the enzyme activity by 50% (IC50
) are in the low nanomolar range. OC also inhibits influenza virus infection and replication in vitro
and inhibits influenza virus replication and pathogenicity in vivo
Clinical / Efficacy 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 b.i.d. 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 children, aged 1-12 (mean age 5.3), who had fever (>100° F/ 37.8°C) 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 vs placebo. 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.
Treatment of influenza in immunocompromised adults: A randomized, double blind study, to evaluate safety and characterize the effects of oseltamivir on the development of resistant influenza virus (primary analysis) in influenza-infected adult immunocompromised patients, included 151 patients evaluable for efficacy of oseltamivir (secondary analysis, not powered). The study included solid organ transplant [SOT] patients, haematopoietic stem cell transplant [HSCT] patients, HIV positive patients with a CD4+ cell count <500 cells/mm3
, patients on systemic immunosuppressive therapy, and those with haematological malignancy. These patients were randomized to be treated, within 96 hours of symptoms onset, with standard dose (73 patients) or double dose (78 patients) of oseltamivir, for a duration of 10 days.
The median time to resolution of symptoms (TTRS) was similar between the standard dose group (103 hours [90% CI 75.4-110.0]) and double dose group (104 hours [90% CI 65.8-131.0]). The proportion of patients with secondary infections in the standard dose group and double dose group was comparable (8.2% vs 5.1%).
The TTRS in all oseltamivir-treated adult immunocompromised patients (combined from both dose groups) was shorter when compared to matched placebo-treated otherwise healthy (reduced by 14 hours) and "at risk" patients (reduced by 60 hours), from previous studies.
Trials for prophylaxis of influenza: Prophylaxis of influenza in adults and adolescents: The efficacy of Tamiflu in preventing naturally occurring influenza A and B has been proven in three separate phase III studies.
In a phase III trial in adult and adolescent contacts of a household case of influenza, Tamiflu, started within 2 days of onset of symptoms in the household case and continued for seven days, significantly reduced the incidence of influenza illness occurring in the contacts by 92%.
In a double-blind placebo-controlled study conducted in unvaccinated otherwise healthy adults 18-65 years of age, Tamiflu significantly reduced the incidence of clinical influenza illness by 76% during a community outbreak of influenza. The subjects in this study received Tamiflu for a period of 42 days.
In a double-blind placebo-controlled study in elderly residents of nursing homes, 80% of whom had received vaccine in the season of the study, Tamiflu significantly reduced the incidence of clinical influenza illness by 92%. In the same study, Tamiflu significantly reduced the incidence of influenza associated bronchitis, pneumonia and sinusitis by 86%. The subjects in this study received Tamiflu for a period of 42 days.
In all three of the clinical trials, approximately 1% of subjects taking Tamiflu for prophylaxis developed influenza during the dosing period.
In these phase III clinical trials Tamiflu also significantly reduced the incidence of virus shedding and successfully prevented virus transmission in families.
Prophylaxis of influenza in children: The efficacy of Tamiflu in preventing naturally occurring influenza illness has been demonstrated in a post exposure 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.
Prophylaxis of influenza in Immunocompromised Patients: A double-blind, placebo controlled study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects, including 18 children 1-12 years of age. Laboratory-confirmed clinical influenza, as defined by RT-PCR plus oral temperature >99.0°F/37.2°C plus cough and/or coryza, all recorded within 24 hours, was evaluated. Among subjects who were not already shedding virus at baseline, Tamiflu reduced the incidence of laboratory-confirmed clinical influenza from 3.0% (7/231) in the group not receiving prophylaxis to 0.4% (1/232) in the group receiving prophylaxis.
Viral resistance: Reduced sensitivity of viral neuraminidase: Treatment of Influenza: Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or resistance to oseltamivir has been examined during Roche-sponsored clinical studies. Patients who were found to carry oseltamivir-resistant virus generally did so transiently and showed no worsening of the underlying symptoms. In some pediatric patients, oseltamivir-resistant virus was detected for a prolonged period compared to patients carrying oseltamivir-sensitive virus; however these patients showed no prolongation of influenza symptoms.
An overall higher incidence of oseltamivir-resistance was observed in adult immunocompromised patients, treated with standard dose or double dose of oseltamivir for a duration of 10 days [14.9% (10/67) in standard dose group and 2.8% (2/71) in double dose group], compared to data from studies with oseltamivir-treated otherwise healthy adult patients. The majority of patients that developed resistance were transplant recipients (8/10 patients in the standard dose group and 2/2 patients in the double dose group). Most of the patients with oseltamivir-resistant virus were infected with influenza type A and had prolonged viral shedding. (See Table 1.)
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Prophylaxis of Influenza: There has been no evidence for emergence of drug 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) prevention of influenza in immunocompetent subjects. There was no resistance observed during a 12 week prophylaxis study in immunocompromised subjects.
Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivir in vitro
have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. For example, in 2008 the oseltamivir resistance-associated substitution H275Y was found in >99 % of circulating 2008 H1N1 influenza isolates in Europe, while the 2009 H1N1 influenza ("swine flu") was almost uniformly susceptible to oseltamivir. Resistant strains have also been isolated from both immunocompetent and immunocompromised patients treated with oseltamivir. The susceptibility to oseltamivir and the prevalence of such viruses appears to vary seasonally and geographically. Oseltamivir resistance has also been reported in patients with pandemic H1N1 influenza in connection with both therapeutic and prophylactic regimens.
The rate of emergence of resistance may be higher in the youngest age groups, and in immunocompromised patients. Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific.
Prescribers should consider available information on influenza virus drug susceptibility patterns for each season when deciding whether to use Tamiflu.
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 & Administration).
The mean volume of distribution (Vss
) of the active metabolite is approximately 23 liters 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, antiviral 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 drug interactions.
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).
Absorbed oseltamivir is primarily (>90%) eliminated by conversion to the active metabolite. The active metabolite is not further metabolized 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 drug 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 radio labeled dose is eliminated in feces.
Pharmacokinetics in Special Populations:
Pediatric Population: Children ≥ 1 year of age: The pharmacokinetics of Tamiflu have been evaluated in 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. The rate of clearance of the active metabolite, corrected for bodyweight, was faster in younger children, than in adults, resulting in lower exposure in these children for a given mg/kg dose. Doses of 2 mg/kg and unit doses of 30 and 45 mg, administered to children in the appropriate categories according to the recommendation in Dosage & Administration yield 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.
Children <1 year of age: The pharmacokinetics, pharmacodynamics and safety of Tamiflu have been evaluated in two open-label studies including influenza infected children less than one year of age (n=124). The rate of clearance of the active metabolite, corrected for body-weight, decreases with ages below one year. Metabolite exposures are also more variable in the youngest infants. The available data indicates that the exposure following a 3 mg/kg dose in children 0-12 months of age provides pro-drug and metabolite exposures anticipated to be efficacious with a safety profile comparable to that seen in older children and adults using the approved dose. The reported adverse events were consistent with the established safety profile in older children.
Geriatric Population: 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 drug exposure and tolerability, dosage adjustments are not required for elderly patients for either the treatment or prophylaxis of influenza (see Special Dosage Instructions under Dosage & Administration).
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. For dosage information, see Special Dosage Instructions under Dosage & Administration.
Hepatic impairment: Based on in-vitro
and animal studies, significant increases in exposure to oseltamivir or its active metabolite are not expected and this has been confirmed in clinical studies in patients with mild or moderate hepatic impairment (see Special Dosage Instructions under Dosage & Administration). The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied.
Pregnant Women: A pooled population pharmacokinetic analysis indicates that the Tamiflu dosage regimen described in Dosage & Administration results in lower exposure (30% on average across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. The lower predicted exposure however, remains above inhibitory concentrations (IC95 values) and at a therapeutic level for a range of influenza virus strains. In addition, there is evidence from observational studies showing benefit of the current dosing regimen in this patient population. Therefore, dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza.
Immunocompromised Patients: Population pharmacokinetic analysis indicates that treatment of adult immunocompromised patients with oseltamivir (as described in Dosage & Administration) results in an increased exposure (of up to 50%) to the active metabolite when compared to adult non-immunocompromised patients. However, due to the wide safety margin of the active metabolite, no dose adjustments are required in adult immunocompromised patients.
Toxicology: Nonclinical Safety:
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Carcinogenicity: 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.
Genotoxicity: Oseltamivir and the active metabolite were negative in the standard battery of genotoxicity assays.
Impairment of Fertility: A rat fertility study up to a dose of 1500 mg/kg/day demonstrated no adverse effects on either sex.
Reproductive Toxicity: 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-fetal development were observed. 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. Fetal exposure in the rats and rabbits was approximately 15 to 20% of that of the mother.
Other: In lactating rats, oseltamivir and the active metabolite are excreted in the milk. Limited data indicate that oseltamivir and the active metabolite are excreted in human milk. 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 sensitization to oseltamivir was observed in a "maximization" 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.
Whereas very high oral single doses of oseltamivir phosphate had no effect in adult rats, such doses resulted in toxicity in juvenile 7-day-old rat pups, including death. These effects were seen at doses of 657 mg/kg and higher. At 500 mg/kg, no adverse effects were seen, including upon chronic treatment (500 mg/kg/day administered from 7 to 21 days post partum).