Tamiflu, capsules 75mg, 10pcs

Composition

1 capsule contains:

Active ingredient:

75 mg of oseltamivir;

Auxiliary substances:

pregelatinized starch,

povidone K 30,

croscarmellose sodium,

talc,

sodium stearyl fumarate

Pharmacological action

Pharmaceutical group:

antiviral agent.

Pharmaceutical action:  

Mechanism of action

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

Inhibits the growth of influenza virus in vitro and suppresses the replication of the virus and its pathogenicity in vivo, reduces the release of influenza A and B viruses from the body. Studies of clinical isolates of influenza virus have shown that the concentration of OK required to inhibit neuraminidase by 50% (IC50) is 0.1-1.3 nM for influenza A virus and 2.6 nM for influenza B. According to published studies, the median IC50 values for influenza B virus are slightly higher and is 8.5 nM.

Clinical efficacy

The clinical efficacy of Tamiflu® has been demonstrated in human experimental influenza studies and in phase III studies of in vivo influenza infection. In the conducted studies, Tamiflu® did not affect the formation of anti-influenza antibodies, including the production of antibodies in response to the introduction of inactivated influenza vaccine.

Natural flu infection studies

In phase III clinical trials conducted in the Northern Hemisphere in 1997-1998 during seasonal influenza infection, patients started receiving Tamiflu® no later than 40 hours 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. Tamiflu significantly reduced the period of clinical manifestations of influenza infection (by 32 hours). In patients with a confirmed diagnosis of influenza who received Tamiflu®, the severity of the disease, expressed as the area under the curve for the total symptom index, was 38% less compared to patients who received placebo. Moreover, in young patients without concomitant diseases, Tamiflu® reduced by approximately 50% the incidence of complications of influenza requiring the use of antibiotics (bronchitis, pneumonia, sinusitis, otitis media). In these phase III clinical trials, clear evidence was obtained for the efficacy of the drug in relation to secondary efficacy criteria related to antiviral activity: Tamiflu® caused both a shortening of the time of virus release from the body and a decrease in the area under the “viral titers-time”curve.

Data obtained in the study on the treatment of Tamiflu® in elderly and senile patients show that taking Tamiflu® at a dose of 75 mg 2 times a day for 5 days was accompanied by a clinically significant decrease in the median period of clinical manifestations of influenza infection, similar to that in younger adult patients, but the differences did not reach statistical significance. In another study, flu patients over 13 years of age who had concomitant chronic diseases of the cardiovascular and/or respiratory systems received Tamiflu® in the same dosage regimen or placebo. There were no differences in the median period before the decrease in clinical manifestations of influenza infection in the Tamiflu® and placebo groups, but the period of fever increase when taking Tamiflu® was reduced by about 1 day. The proportion of patients who isolated the virus on days 2 and 4 was significantly lower. The safety profile of Tamiflu® in patients at risk did not differ from that in the general population of adult patients.

Treatment of flu in children

A double-blind placebo-controlled study was conducted in children aged 1-12 years (mean age 5.3 years) who had fever (≥37.8 ° C) and one of the symptoms of the respiratory system (cough or rhinitis) during the period of influenza virus circulation in the population. 67% of patients were infected with influenza A virus and 33% of patients were infected with influenza B. Tamiflu® (when taken no later than 48 hours after the first symptoms of influenza infection) significantly reduced the duration of the disease (by 35.8 hours) compared to placebo. The duration of the disease was defined as the time until cough relief, nasal congestion, fever disappearance, and return to normal activity. In the group of children treated with Tamiflu®, the incidence of acute otitis media decreased by 40% compared to the placebo group. Recovery and return to normal activity occurred almost 2 days earlier in children treated with Tamiflu® compared to the placebo group.

Another study included children aged 6-12 years with bronchial asthma; 53.6% of patients had a serologically and/or culturally confirmed flu infection. The median duration of disease in the group of patients treated with Tamiflu® did not significantly decrease. However, by the last day 6 of Tamiflu® therapy, forced expiratory volume per 1 second (FEV 1) increased by 10.8% compared to 4.7% in patients receiving placebo (p=0.0148).

Prevention of influenza in adults and adolescents

The prophylactic efficacy of Tamiflu® in natural influenza A and B infections 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 started taking Tamiflu® within two days after the onset of flu symptoms in family members and continued it for 7 days, which significantly reduced the frequency of flu cases in those who were in contact 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 senile individuals in nursing homes,80% of whom were vaccinated before the study season, Tamiflu ® significantly reduced the incidence of influenza by 92%. In the same study, Tamiflu significantly (by 86%) reduced the incidence of influenza complications: bronchitis, pneumonia, and sinusitis. Participants in this study took the drug for 42 days.

In all three clinical trials, about 1% of patients developed flu while taking Tamiflu®.

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

Prevention of flu in children

The preventive effectiveness of Tamiflu® in natural influenza infection was demonstrated in a study in children from 1 to 12 years of age after contact with a sick family member or with someone from a permanent environment. The main parameter of efficacy in this study was the frequency of laboratory-confirmed influenza infection. In a study in children who received Tamiflu® (powder for preparing a suspension for oral use) at a dose of 30 to 75 mg 1 time per day for 10 days, and did not isolate the virus at baseline, the frequency of laboratory-confirmed influenza decreased to 4% (2/47) compared to 21% (15/70) in the placebo group.

Resistance

When taking Tamiflu® for post-exposure prophylaxis (7 days), family contact prophylaxis (10 days), and seasonal prophylaxis (42 days), there were no cases of drug resistance.

The risk of developing resistance to the drug when used for the treatment of influenza was studied comprehensively. According to all Roche-sponsored clinical trials on the treatment of influenza infection with Tamiflu in adult patients / adolescents, resistance to oseltamivir was found in 0.32% of cases (4/1245) by phenotyping and in 0.4% of cases (5/1245) by phenotyping and genotyping, and in children from 1 to 12 years of age in 4.1% (19/464) and 5.4% (25/464) cases, respectively. All patients had a temporary carrier of the OK – resistant virus. This did not affect the elimination of the virus and did not cause a deterioration in the clinical condition.

Several different subtype-specific mutations of viral neuraminidase have been detected in in vitro studies or in the literature. The degree of sensitivity reduction depended on the type of mutation, so with the I222V mutation in N1, the sensitivity decreased by 2 times, and with R292K in N2-by 30,000 times. No mutations were found to reduce the sensitivity of influenza virus type B neuraminidase in vitro. In patients treated with oseltamivir, registered mutations of neuraminidase N1 (including H5N1 viruses) leading to resistance/decreased sensitivity to OK were H274Y, N294S (1 case), E119V (1 case), R292K (1 case), and mutations of neuraminidase N2 – N294S (1 case) and SASG245-248del (1 case). In one case, the G402S mutation of the influenza B virus was detected, which resulted in a 4-fold decrease in sensitivity, and in one case, the D198N mutation with a 10 – fold decrease in sensitivity in a child with immunodeficiency.

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

Patients who did not receive oseltamivir were found to have naturally occurring mutations of the influenza A/H 1N1 virus, which had reduced sensitivity to the drug in vitro. The degree of decreased sensitivity to oseltamivir and the frequency of occurrence of such viruses may vary depending on the season and region.

Preclinical data

Preclinical data obtained on the basis of standard studies on pharmacological safety, genotoxicity and chronic toxicity did not reveal a particular danger to humans.

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

Effect on fertility: oseltamivir at a dose of 1500 mg / kg / day did not affect the generative function of male and female rats.

Teratogenicity: studies on the teratogenicity of oseltamivir at a dose of up to 1500 mg/kg/day (in rats) and up to 500 mg/kg/day (in rabbits) did not show any effect on fetal development. In studies on the antenatal and postnatal periods of development in rats, an increase in the delivery period was observed when oseltamivir was administered at a dose of 1500 mg/kg/day: the safety limit between human exposure and the maximum non-effecting dose in rats (500 mg / kg / day) It is 480 – fold higher for oseltamivir, and 44-fold higher for its active metabolite. Fetal exposure was 15-20% of that of the mother.

Other: oseltamivir and its active metabolite are excreted in the milk of lactating rats.

Approximately 50% of the guinea pigs tested showed skin sensitisation in the form of erythema when the maximum doses of the Active ingredient oseltamivir were administered. Reversible eye irritation was also detected in rabbits.

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

Indications

• prevention of influenza in adults and adolescents over the age of 12 years who are at high risk of infection with the virus (in military units and large industrial groups, in weakened patients);
• treatment of influenza in adults and children over the age of 1 year;
• prevention of influenza in children over 1 year.

Use during pregnancy and lactation

Category B. During preclinical studies, oseltamivir and its active metabolite were absorbed into the milk of lactating rats. Whether oseltamivir or the active metabolite is excreted in human milk is unknown, but their amount 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 be prescribed during pregnancy or to nursing mothers only if the possible benefits of its use outweigh the potential risk to the fetus or infant.

Contraindications

Hypersensitivity to oseltamivir phosphate or any component of Tamiflu; chronic renal failure (continuous hemodialysis, chronic peritoneal dialysis, creatinine clearance <10 ml / min).

With caution: pregnancy; breast-feeding period.

Side effects

Adults. The most frequent symptoms are nausea and vomiting (usually after taking the first dose; they are transient in nature and in most cases do not require discontinuation of the drug).

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

Children. The most common is vomiting. Abdominal pain, nosebleeds, 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.

Post-marketing surveillance

From the skin and subcutaneous tissue: rarely-hypersensitivity reactions: dermatitis, skin rash, eczema, urticaria, very rarely — erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, anaphylactic and anaphylactoid reactions, angioedema.

From the liver: very rarely — hepatitis, increased liver enzymes.

Neuropsychiatric disorders: seizures and delirium (including symptoms such as impaired consciousness, disorientation in time and space, abnormal behavior, delusions, hallucinations, agitation, anxiety, and nightmares) have been reported in patients (mainly children and adolescents) taking Tamiflu for the treatment of influenza. These cases were rarely accompanied by life-threatening actions. The role of Tamiflu in the development of these phenomena is unknown. Similar neuropsychiatric disorders were also reported in patients with flu who did not receive Tamiflu.

From the gastrointestinal tract: cases of gastrointestinal bleeding were rarely observed during treatment with Tamiflu (in particular, the link between the phenomena disappeared both after the patient recovered from the flu and after discontinuation of the drug).

Interaction

Clinically significant drug interactions are unlikely. Drug interactions due to competition and binding to the active sites of esterases that convert oseltamivir phosphate to the Active ingredient 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 the displacement of drugs from protein binding.

In vitro, oseltamivir phosphate and the active metabolite are not preferred substrates for polyfunctional cytochrome P450 oxidases or for glucuronyltransferases (see Pharmacokinetics).

There are no grounds for interaction with oral contraceptives.

Cimetidine, a non-specific inhibitor of cytochrome P450 isoenzymes, amoxicillin, and paracetamol did not affect plasma concentrations of oseltamivir and its active metabolite.

Probenecid increases the AUC of the active metabolite of oseltamivir 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-blockers (propranolol), xanthines (theophylline), sympathomimetics No changes in the nature or frequency of adverse events were observed with opiates (codeine), corticosteroids, inhaled bronchodilators, and analgesics (aspirin, ibuprofen, and paracetamol).

How to take, course of use and dosage

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

Treatment should begin on the first or second day of flu symptoms.

Adults and children over 12 years of age are prescribed 75 mg 2 times a day inside for 5 days. An increase in the dose of more than 150 mg / day does not lead to an increase in the effect.

Children over 40 kg or over 8 years of age who can swallow capsules can also receive treatment by taking one 75 mg capsule twice daily, as an alternative to the recommended dose of Tamiflu suspension.

Children over 1 year of age are recommended to take an oral suspension 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.

Overdose

Currently, no overdose cases have been described.

Suspected symptoms of acute overdose: nausea with or without vomiting.

Single doses of Tamiflu up to 1000 mg were well tolerated, with the exception of nausea and vomiting.

Special instructions

Seizures and delirium-like neuropsychiatric disorders have been reported in patients (mainly children and adolescents) taking Tamiflu for the treatment of influenza. These cases were accompanied by life-threatening actions. The role of Tamiflu in the development of these phenomena is unknown. Similar neuropsychiatric disorders were also reported in patients with flu who did not receive Tamiflu.

Careful monitoring of the behavior of patients, especially children and adolescents, is recommended in order to detect signs of abnormal behavior.

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

In the treatment and prevention of influenza in patients with creatinine clearance from 10 to 30 ml/min, dose adjustment is required. There are no recommendations for dose adjustment in patients receiving hemodialysis or peritoneal dialysis, and in patients with creatinine clearance < 10 ml/min.

Form of production

Capsules.

Storage conditions

At a temperature not exceeding 25 °C

Shelf

life 7 years

Active ingredient

Oseltamivir

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Indications

Flu Prevention, Flu