Tamiflu, 75 mg capsules 10 pcs

Pharmgroup:

an antiviral agent.

Pharmic action:

Mechanism of action

The antiviral drug. Oseltamivir phosphate is a prodrug, its active metabolite (oseltamivir carboxylate, OC) is an effective and selective inhibitor of influenza virus neuraminidase type A and B – the enzyme which catalyzes the release of newly formed virus particles from infected cells, their penetration into respiratory epithelial cells and further spread of the virus in the body.

Inhibits influenza virus growth in vitro and suppresses viral replication and pathogenicity in vivo, reduces release of influenza A and B viruses from the body. Studies of clinical influenza virus isolates have shown that the concentration of OC needed to inhibit neuraminidase by 50% (IC50) is 0.1-1.3 nM for influenza A virus and 2.6 nM for influenza B virus. According to published studies, the median IC50 value for influenza B is slightly higher at 8.5 nM. </Clinical efficacy

The clinical efficacy of Tamiflu® has been demonstrated in experimental influenza studies in humans and in phase III studies on influenza infection that occurred in vivo. In conducted studies Tamiflu® had no effect on influenza antibody formation, including antibody production in response to administration of inactivated influenza vaccine.

Natural influenza infection studies

In phase III clinical trials conducted in the Northern Hemisphere in 1997-1998 during seasonal influenza infection, patients were started on Tamiflu® no later than 40 h after the first symptoms of influenza infection appeared. 97% of patients were infected with influenza A virus and 3% of patients were infected with influenza B virus. Tamiflu® significantly shortened the period of clinical manifestations of influenza infection (by 32 hours). In patients with a confirmed diagnosis of influenza who took Tamiflu®, the severity of illness, expressed as the area under the curve for the total index of symptoms, was 38% less compared to patients who received placebo. Moreover, in young patients without comorbidities, Tamiflu® reduced by approximately 50% the incidence of flu complications requiring antibiotics (bronchitis, pneumonia, sinusitis, otitis media). In these phase III clinical trials, there was clear evidence of efficacy of the drug with respect to secondary efficacy criteria relating to antiviral activity: Tamiflu® caused both a shortening of the time of virus release from the body and a reduction in the area under the “viral titers-time” curve.

The data obtained in a study of Tamiflu® therapy in elderly and senile patients show that Tamiflu® administration at a dose of 75 mg twice daily for 5 days was accompanied by clinically significant reduction in the median period of clinical manifestations of influenza infection, similar to that in adult patients of younger age, but differences did not reach statistical significance. In another study, influenza patients over 13 years of age who had concomitant chronic diseases of the cardiovascular and/or respiratory systems received Tamiflu® in the same dosing regimen or placebo. There were no differences in the median period before clinical manifestations of influenza infection between the Tamiflu® and placebo groups, but the period of fever with Tamiflu® was shorter by about 1 day. The proportion of patients who excreted the virus on days 2 and 4 became significantly lower. The safety profile of Tamiflu® in patients in the risk group did not differ from that in the general population of adult patients.

Treatment of influenza in children

A double-blind, placebo-controlled study was conducted in children aged 1-12 years (mean age 5.3 years) who had fever (≥37.8ºC) and one of the respiratory symptoms (cough or rhinitis) while the influenza virus was circulating in the population. Sixty-seven percent of patients were infected with influenza A virus and 33% of patients were infected with influenza B virus. Tamiflu® (when taken no later than 48 hours after the appearance of the first symptoms of influenza infection) significantly reduced the duration of illness (by 35.8 hours) compared to placebo. Duration of illness was defined as the time until coughing, nasal congestion, disappearance of fever, and return to normal activity. The frequency of acute otitis media was reduced by 40% in the children treated with Tamiflu® compared to the placebo group. Recovery and return to normal activity occurred almost 2 days earlier in children who received Tamiflu® compared to the placebo group.

Another study involved children aged 6-12 years with bronchial asthma; 53.6% of patients had influenza infection confirmed serologically and/or in culture. The median duration of illness in the group of patients receiving Tamiflu® did not decrease significantly. But by the last 6 days of Tamiflu® therapy, forced expiratory volume in 1 second (FEF1) increased by 10.8% compared to 4.7% in patients receiving placebo (p=0.0148).

The prevention of influenza in adults and adolescents

The preventive efficacy of Tamiflu® in natural influenza A and B infection has been proven in 3 separate phase III clinical trials.

In the phase III study, adults and adolescents who were in contact with a sick family member began taking Tamiflu® within two days of the family member’s flu symptoms and continued it for 7 days, which significantly reduced the incidence of flu in contacted individuals by 92%.

In a double-blind, placebo-controlled study in unvaccinated and generally healthy adults aged 18-65 years, taking Tamiflu® during an influenza epidemic significantly reduced the incidence of influenza (by 76%). Participants in this study took the drug for 42 days.

In a double-blind, placebo-controlled study in elderly and seniors in nursing homes, 80% of whom were vaccinated before the season in which the study was conducted, Tamiflu® significantly reduced the incidence of influenza by 92%. In the same study, Tamiflu® significantly (86%) reduced the incidence of flu complications: bronchitis, pneumonia, and sinusitis. Participants in this study took the drug for 42 days.

In all three clinical trials about 1% of patients got influenza while taking Tamiflu®.

In these clinical trials, Tamiflu® also significantly reduced the frequency of virus excretion and prevented transmission of the virus from one family member to another.

The prevention of influenza in children

The preventive efficacy of Tamiflu® in naturally occurring influenza infection was demonstrated in a study in children from 1 to 12 years after contact with a sick family member or someone in the regular environment. The primary efficacy parameter in this study was the rate of laboratory-confirmed influenza infection. In the study, children who received Tamiflu® /powder for oral suspension preparation/ at a dose of 30 to 75 mg once daily for 10 days and who did not excrete the virus at baseline had a reduced rate of laboratory-confirmed influenza to 4% (2/47) compared with 21% (15/70) in the placebo group.

Resistance

Tamiflu® was not observed when administered for post-exposure prophylaxis (7 days), family exposure prophylaxis (10 days), and seasonal prophylaxis (42 days).

The risk of drug resistance when used to treat influenza has been extensively studied. According to all Roche-sponsored clinical trials on the therapy of influenza infection, resistance to oseltamivir was found in 0.32% (4/1245) of adult patients/adolescents by phenotyping and 0.4% (5/1245) by phenotyping and genotyping, and in children 1 to 12 years old in 4.1% (19/464) and 5.4% (25/464), respectively. All patients had a temporary carrier of OC-resistant virus. This did not affect the elimination of the virus and did not cause a worsening of the clinical condition.

A few different subtype-specific viral neuraminidase mutations have been found in in vitro or literature studies. The degree of decrease in sensitivity depended on the type of mutation, so the I222V mutation in N1 reduced sensitivity by a factor of 2, and the R292K mutation in N2 reduced sensitivity by a factor of 30,000. No mutations were found to reduce the sensitivity of influenza virus neuraminidase type B in vitro.
In patients treated with oseltamivir, the reported N1 neuraminidase mutations (including H5N1 viruses) leading to resistance/reduced sensitivity to OC were H274Y, N294S (1 case), E119V (1 case), R292K (1 case), and N2 neuraminidase mutations were N294S (1 case) and SASG245-248del (1 case). The G402S mutation of influenza B virus was found in one case with a 4-fold decrease in sensitivity, and the D198N mutation with a 10-fold decrease in sensitivity in an immunodeficient child was found in one case.

Viruses with a resistant neuraminidase genotype differ in varying degrees of resistance from the natural strain. Viruses with the R292K mutation in N2 in animals (mice and ferrets) are significantly inferior to viruses with the E119V mutation in N2 and D198N mutation in B by infectivity, pathogenicity and infectiousness and differ slightly from the “wild” strain. Viruses with the H274Y mutation in N1 and N294S mutation in N2 occupy an intermediate position.

In patients who did not receive oseltamivir, naturally occurring influenza A/H1N1 virus mutations were found to have reduced sensitivity to the drug in vitro. The degree of reduced sensitivity to oseltamivir and the frequency of occurrence of such viruses may vary by season and region.

Preclinical data

Preclinical data based on standard pharmacological safety, genotoxicity and chronic toxicity studies showed no particular risk to humans.

Carcinogenicity: the results of 3 studies to detect carcinogenic potential (two 2-year studies in rats and mice for oseltamivir and one 6-month study in Tg:AC transgenic mice for the active metabolite) were negative.
Mutagenicity: standard genotoxicity tests for oseltamivir and the active metabolite were negative.

Impact on fertility: oseltamivir at a dose of 1500 mg/kg/day had no effect on the generative function of male and female rats.

Teratogenicity: In studies examining the teratogenicity of oseltamivir at doses up to 1500 mg/kg/day (in rats) and up to 500 mg/kg/day (in rabbits) no effect on embryo-fetal development was found. In studies of antenatal and postnatal development in rats, when oseltamivir was administered at a dose of 1500 mg/kg/day, an increase in the period of labor was observed: the safety limit between human exposure and the maximum no-effect dose in rats (500 mg/kg/day) was 480 times higher for oseltamivir, and 44 times higher for its active metabolite. Exposure in the fetus was 15-20% of that in the mother.

Other: oseltamivir and its active metabolite penetrate the milk of lactating rats.

In approximately 50% of the guinea pigs tested, skin sensitization in the form of erythema was observed when maximum doses of the active substance oseltamivir were administered. Reversible eye irritation in rabbits was also observed.

While very high oral single doses (657 mg/kg and above) of oseltamivir phosphate had no effect on adult rats, these doses had toxic effects on immature 7-day-old baby rats, including death of the animals. No undesirable effects were observed when chronically administered at a dose of 500 mg/kg/day from days 7 to 21 of the postnatal period.

Indications

Active ingredient

Composition

1 capsule contains:

The active ingredient:

75 mg oseltamivir;

Associates:

Pregelatinized starch,

povidone K30,

croscarmellose sodium,

talc,

sodium stearyl fumarate

How to take, the dosage

Tamiflu is taken orally, with or without a meal. Taking Tamiflu with a meal or with a little milk reduces possible stomach discomfort.

The treatment should be started on the first or second day of flu symptoms.

Adults and children over 12 years of age are prescribed 75 mg twice daily orally for 5 days. Increasing the dose more than 150 mg/day does not increase the effect.

Children over 40 kg or older than 8 years who are able to swallow capsules may also be treated by taking one 75 mg capsule 2 times daily, as an alternative to the recommended dose of Tamiflu suspension.

In children over 1 year of age, oral suspension is recommended for 5 days:

Children weighing less than 15 kg are prescribed 30 mg 2 times a day;
children weighing 15-23 kg – 45 mg 2 times a day;
children weighing 23-40 kg – 60 mg 2 times a day;
children over 40 kg – 75 mg 2 times a day.

Interaction

Clinically significant drug interactions are unlikely. Drug interactions due to competition and binding to the active centers of esterases that convert oseltamivir phosphate into the active substance are not presented. The low degree of binding of oseltamivir and the active metabolite to proteins does not suggest the presence of interactions associated with displacement of the drug from binding to proteins.

In vitro oseltamivir phosphate and the active metabolite are not a preferred substrate for polyfunctional oxidases of the cytochrome P450 system or for glucuronyltransferases (see “Pharmacokinetics”).

There is no reason for interaction with oral contraceptives.

Cimetidine, a non-specific inhibitor of cytochrome P450 system isoenzymes, amoxicillin and paracetamol have no effect on plasma concentrations of oseltamivir and its active metabolite.

Probenecid leads to an increase in the AUC of the active metabolite of oseltamivir by approximately 2-fold, but no dose adjustment is required when used concomitantly with probenecid.

. When prescribing Tamiflu together with ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), H2-receptor blockers to histamine (ranitidine, cimetidine), beta-adrenoblockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), corticosteroids, inhaled bronchodilators and analgesics (aspirin, ibuprofen and paracetamol) no changes in the nature or frequency of adverse events were observed.

Special Instructions

Convulsions and delirium-like neuropsychiatric disorders have been reported in patients (mostly children and adolescents) who have taken Tamiflu to treat influenza. These cases were accompanied by life-threatening activities. The role of Tamiflu in the development of these phenomena is unknown. Similar neuropsychiatric disorders have also been reported in patients with influenza who did not receive Tamiflu.

The careful monitoring of patient behavior is recommended, especially in children and adolescents, in order to detect signs of abnormal behavior.

Tamiflu has no data on the effectiveness of Tamiflu in any disease caused by pathogens other than influenza A and B viruses.

When treating and preventing influenza in patients with Cl creatinine from 10 to 30 ml/min requires dose adjustment. There are no recommendations on dose adjustment in patients receiving hemodialysis or peritoneal dialysis and in patients with creatinine Cl ≤10 ml/min.

Contraindications

Hypersensitivity to oseltamivir phosphate or any component of the drug Tamiflu; chronic renal failure (permanent hemodialysis, chronic peritoneal dialysis, creatinine Cl ≤10 ml/min).

With caution: pregnancy; breast-feeding period.

Side effects

Adults. Nausea and vomiting are most common (usually after the first dose; transient and in most cases do not require drug withdrawal).

Side effects (≥1%): diarrhea, bronchitis, abdominal pain, dizziness, headache, cough, sleep disturbances, weakness; pain of various localization, rhinorrhea, dyspepsia and upper respiratory tract infections.

Children. The most common is vomiting. Abdominal pain, nasal bleeding, hearing disorders, conjunctivitis (occurred suddenly, stopped despite continued treatment, and in the vast majority of cases did not cause discontinuation of treatment), nausea, diarrhea, asthma (including exacerbation), acute otitis media, pneumonia, sinusitis, bronchitis, dermatitis, lymphadenopathy.

Postmarketing monitoring

Skin and subcutaneous tissue: rare – hypersensitivity reactions: dermatitis, skin rash, eczema, urticaria, very rare – erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, anaphylactic and anaphylactoid reactions, Quincke’s edema.

Hepatic disorders: very rare – hepatitis, increased liver enzymes.

Nervous and mental disorders: in patients (mostly children and adolescents) who have taken Tamiflu to treat influenza seizures and delirium (including such symptoms as impaired consciousness, disorientation in time and space, abnormal behavior, delirium, hallucinations, agitation, anxiety, nightmares) have been registered. These cases were rarely accompanied by life-threatening acts. The role of Tamiflu in the development of these phenomena is unknown. Similar neuropsychiatric disorders have also been noted in patients with influenza who did not receive Tamiflu.

Gastrointestinal disorders: cases of gastrointestinal bleeding during treatment with Tamiflu were rarely observed (in particular, the relationship between the phenomena disappeared both after the patient recovered from the flu, as well as after discontinuation of the drug cannot be excluded).

Overdose

There are currently no cases of overdose described.

Presumed symptoms of acute overdose are nausea with or without vomiting.

The single doses of Tamiflu up to 1000 mg were well tolerated, except for nausea and vomiting.

Pregnancy use

Category B. During preclinical studies, oseltamivir and the active metabolite penetrated the milk of lactating rats. Whether oseltamivir or the active metabolite is excreted with milk in humans is unknown, but the amounts in breast milk can be 0.01 and 0.3 mg/day, respectively.

Since there are insufficient data on the use of the drug in pregnant women, Tamiflu should only be prescribed during pregnancy or to nursing mothers if the possible benefits of its use exceed the potential risk to the fetus or the infant.

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