Tamiflu is one of the top choices to treat infection with the influenza virus. Containing oseltamivir (neuraminidase inhibitor), as its active ingredient, you can stop the flu virus from spreading and infecting other cells with this medicine. Moreover, Tamiflu is also good for other types of flu (seasonal flu, H1N1 influenza (swine flu) and bird flu). The clinical tests performed with Tamiflu (oral form), show a 37% reduction in the duration of influenza. Moreover, it accelerated the process of getting back to their normal health at about 40% faster than the other patients in the placebo group.
The clinical tests with Tamiflu (oral form), presented a 37% reduction in the duration of influenza and assisted patients to return to normal 40 % faster than the patients in the placebo group.
An online doctor consultation means filling out a medical questionnaire. A registered EU doctor assesses your medical questionnaire and analize whether Tamiflu is suitable and safe for you to buy. After approval, a prescription is issued and send to the registered EU pharmacy. You will receive your discretely shipped Tamiflu pills within 3 business days.
One gram of powder for oral suspension contains: active substance: oseltamivir * - 30 mg (in the form of oseltamivir phosphate 39.4 mg);
Excipients: sorbitol - 857.1 mg, titanium dioxide - 15.0 mg, sodium benzoate - 2.5 mg, xanthan gum - 15.0 mg, sodium dihydrocytrate - 55.0 mg, sodium saccharin - 1.0 mg, flavoring Permasil 11900-31 Tutti Frutti - 15.0 mg. The prepared suspension contains oseltamivir 12 mg / 1 ml.
Fine granular powder from white to light yellow in color, with a fruity odor, sometimes crumpled. After recovery, forms an opaque suspension from white to light yellow.
Antiviral drug. Oseltamivir is a prodrug, its active metabolite (oseltamivir carboxylate, OK) is an effective and selective inhibitor of type A and B influenza neuraminidase, an enzyme that catalyzes the release of newly formed virus particles from infected cells, their penetration into uninfected airway epithelial cells and further spread virus in the body. It inhibits the growth of the influenza virus in vitro and inhibits the replication of the virus and its pathogenicity in vivo reduces the release of influenza A and B viruses from the body. The concentration of OK 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. The median IC50 for influenza B virus is slightly higher and is 8.5 nM.
In the studies, Tamiflu® had no effect on the formation of influenza antibodies, including the production of antibodies in response to the administration of an inactivated influenza vaccine.
Studies of natural influenza infection
In clinical trials conducted during seasonal influenza infections, patients started receiving Tamiflu® no later than 40 hours after the onset of the first symptoms of influenza infection. 97% of patients were infected with influenza A virus and 3% of patients with influenza B. Tamiflu® significantly reduced the period of clinical manifestations of influenza infection (by 32 hours). Patients with a confirmed influenza diagnosis who were taking Tamiflu® had a disease severity expressed as the area under the curve for the total symptom index that was 38% less than patients receiving a placebo. Moreover, in young patients without concomitant diseases, Tamiflu® reduced by about 50% the incidence of influenza complications requiring antibiotics (bronchitis, pneumonia, sinusitis, otitis media).
The data obtained in a 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 adult patients younger age, however differences did not reach statistical significance. In another study, patients with influenza over 13 years old 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 of the period before the clinical manifestations of influenza infection decreased in the Tamiflu® and placebo groups, however, the temperature increase period when taking Tamiflu® was reduced by about 1 day. The proportion of patients secreting the virus on the 2nd and 4th day, it became much less. The safety profile of Tamiflu® in patients at risk did not differ from that in the general population of adult patients.
Influenza treatment in children
In children aged 1-12 years (average age 5.3 years) who had a fever (≥37.8ºС) and one of the symptoms of the respiratory system (cough or rhinitis) during the period of influenza virus circulation in the population, a double-blind placebo-controlled study. 67% of patients have infected with influenza A virus and 33% of patients 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 with placebo. The duration of the disease was defined as the time to stop coughing, nasal congestion, the disappearance of fever, and return to normal activity. In the group of children receiving Tamiflu®, the incidence of acute otitis media was reduced by 40% compared with the placebo group.
Another study involved children aged 6-12 years suffering from bronchial asthma; 53.6% of patients had influenza infection confirmed serologically and/or in culture. The median disease duration in the group of patients treated with Tamiflu® did not significantly decrease. But by the last 6th day of Tamiflu® therapy, the forced expiratory volume for 1 sec (FEV1) increased by 10.8% compared with 4.7% in patients receiving placebo (p = 0.0148).
Flu Prevention in Adults and Adolescents
The prophylactic efficacy of Tamiflu® for natural influenza infection A and B has been proven in 3 separate clinical trials of phase III. About 1% of patients fell ill with Tamiflu® flu. Tamiflu® also significantly reduced the frequency of virus isolation and prevented the transmission of the virus from one family member to another.
Adults and adolescents who were in contact with a sick family member started taking Tamiflu® for two days after the onset of flu symptoms in family members and continued for 7 days, which significantly reduced the incidence of influenza in contactees by 92%.
In unvaccinated and generally healthy adults aged 18-65 years, taking Tamiflu® during an influenza epidemic significantly reduced the incidence of influenza (by 76%). Patients took the drug for 42 days.
In elderly and elderly people in nursing homes, 80% of whom were vaccinated before the season when the study was conducted, Tamiflu® significantly reduced the incidence of influenza by 92%. In the same study, Tamiflu® significantly (by 86%) reduced the frequency of influenza complications: bronchitis, pneumonia, sinusitis. Patients took the drug for 42 days.
Influenza Prevention in Children
The prophylactic effectiveness of Tamiflu® for natural influenza infection has been demonstrated in children from 1 year to 12 years after contact with a sick family member or someone from a permanent environment. The main parameter of effectiveness was the frequency of laboratory-confirmed influenza infection. In children who received Tamiflu® / powder for suspension for oral administration / in a dose of 30 to 75 mg once daily for 10 days and did not isolate the virus initially, the frequency of laboratory-confirmed influenza decreased to 4% (2/47) compared with 21% (15/70) in the placebo group.
Influenza Prevention in Immunocompromised Persons
In immunocompromised individuals with seasonal influenza infection and in the absence of virus isolation, the initial prophylactic use of Tamiflu® reduced the incidence of laboratory-confirmed influenza infection accompanied by clinical symptoms to 0.4% (1/232) compared with 3% (7/231) in the placebo group. Laboratory-confirmed influenza infection accompanied by clinical symptoms was diagnosed if there was an oral temperature above 37.2 ° C, cough and/or acute rhinitis (all recorded on the same day while taking the drug/placebo), as well as a positive result of reverse transcriptase-polymerase chain reaction to RNA of influenza virus.
The risk of developing influenza viruses with reduced sensitivity or drug resistance has been studied in clinical trials sponsored by Roche. In all patients carrying OK-resistant virus, a carriage was temporary, did not affect the elimination of the virus, and did not cause a worsening of the clinical condition.
Oseltamivir is easily absorbed in the gastrointestinal tract and extensively turns into an active metabolite under the influence of hepatic and intestinal esterases. The concentration of the active metabolite in plasma is determined within 30 minutes, the time to reach the maximum concentration of 2-3 hours, and more than 20 times the concentration of the prodrug. At least 75% of the ingested dose enters the systemic circulation as an active metabolite, less than 5% - in the form of the starting drug. Plasma concentrations of both the prodrug and the active metabolite are proportional to the dose and are independent of food intake.
The distribution volume (Vss) of the active metabolite is 23 liters. According to animal studies, after ingestion of oseltamivir, its active metabolite was found in all major foci of infection (lungs, lavage water of the bronchi, nasal mucosa, middle ear, and trachea) in concentrations that provide an antiviral effect.
The relationship of the active metabolite with plasma proteins is 3%. The relationship of the prodrug with plasma proteins is 42%, which is not enough to cause significant drug interactions.
Oseltamivir extensively turns into an active metabolite under the influence of esterases, which are mainly in the liver. Neither oseltamivir nor the active metabolites are substrates or inhibitors of isoenzymes of the cytochrome P450 system.
It is excreted (> 90%) as an active metabolite mainly by the kidneys. The active metabolite does not undergo a further transformation and is excreted by the kidneys (> 99%) by glomerular filtration and tubular secretion. Renal clearance (18.8 l / h) exceeds the glomerular filtration rate (7.5 l / h), which indicates that the drug is also excreted by tubular secretion. Less than 20% of the drug taken through the intestines is excreted. The half-life of the active metabolite is 6-10 hours.
Pharmacokinetics in special patient groups: Patients with kidney damage
When using Tamiflu® (100 mg twice a day for 5 days) in patients with various degrees of kidney damage, the area under the curve “active plasma metabolite concentration-time” (AUC of oseltamivir carboxylate) is inversely proportional to a decrease in renal function.
The pharmacokinetics of oseltamivir in patients with end-stage renal failure (with creatinine clearance ≤10 ml/min) who are not on dialysis have not been studied.
Patients with liver damage
The data obtained in vitro and in animal studies on the absence of a significant increase in the AUC of oseltamivir or its active metabolite in the impaired liver function of mild to moderate severity were also confirmed in clinical studies (see "Dosage in special cases"). The safety and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been studied.
Patients of advanced and senile age
In elderly and senile patients (65-78 years), the exposure of the active metabolite in the equilibrium state is 25-35% higher than in younger patients with the same doses of Tamiflu®. The half-life of the drug in elderly and senile patients did not significantly differ from that in younger patients. Given the data on the exposure of the drug and its tolerability in elderly and senile patients, dose adjustment in the treatment and prevention of influenza is not required.
Children aged 1 to 8 years and adolescents
The pharmacokinetics of Tamiflu® was studied in children from 1 to 16 years old in a pharmacokinetic study with a single dose of the drug and in a clinical study on the study of multiple doses of the drug in a small number of children aged 3-12 years. The rate of excretion of the active metabolite, adjusted for body weight in young children is higher than in adults, which leads to lower AUC in relation to a specific dose. Taking the drug at a dose of 2 mg / kg and single doses of 30 mg or 45 mg in accordance with the dosage recommendations for children given in the section “Dosage and administration” provides the same AUC of oseltamivir carboxylate, which is achieved in adults after a single dose capsules with 75 mg of the drug (equivalent to about 1 mg/kg). The pharmacokinetics of oseltamivir in children over 12 years of age is the same as in adults.
Flu treatment in adults and children over 1-year-old. Influenza prophylaxis in adults and adolescents over the age of 12 who are at high risk of infection with the virus (in military units and large production teams, in debilitated patients). Influenza prophylaxis in children over 1 year old.
Hypersensitivity to oseltamivir or any component of the drug. The terminal stage of renal failure (creatinine clearance ≤10 ml/min). Children's age up to 1 year. Severe liver failure. Carefully. Pregnancy, the period of breastfeeding. Use during pregnancy and during breastfeeding
No controlled studies in pregnant women have been conducted. However, the results of post-marketing and observational studies have demonstrated the benefits of the proposed standard dosage regimen for this patient population. The results of the pharmacokinetic analysis showed a lower exposure of the active metabolite (approximately 30% during all trimesters of pregnancy) in pregnant women compared with non-pregnant women. However, the calculated exposure value remains above the inhibitory concentrations (IC95 value) and therapeutic values for many influenza virus strains. Changing the dosage regimen in pregnant women during therapy or prophylaxis is not recommended (see section "Pharmacokinetics in special patient groups"). No direct or indirect adverse effects of the drug on pregnancy, embryo-fetal or postnatal development were found (see "Preclinical data"). When assigning Tamiflu® to pregnant women, safety data, as well as the course of pregnancy and the pathogenicity of the circulating strain of the influenza virus, should be taken into account.
During preclinical studies, oseltamivir and the active metabolite penetrated into the milk of lactating rats. Data on the excretion of oseltamivir in human milk and the use of oseltamivir in lactating women are limited. Oseltamivir and its active metabolite in small quantities penetrate into breast milk (see "Preclinical data"), creating subtherapeutic concentrations in the blood of an infant. When prescribing oseltamivir to nursing women, the concomitant disease and pathogenicity of the circulating strain of the influenza virus should also be considered. During pregnancy and during breastfeeding, oseltamivir is used only if the intended benefits to the mother outweigh the potential risk to the fetus and the baby.
Impact on the ability to drive vehicles and mechanisms
Studies to study the effect of the drug on the ability to drive vehicles and engage in other potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions have not been conducted. Based on the safety profile, the impact of Tamiflu® on these activities is unlikely.
Inside, with or without food. Tolerance to the drug can be improved if taken with food. It is advisable that a pharmacist or pharmacist be involved in the preparation of the suspension. Suspension preparation:
On the label of the bottle should indicate the expiration date of the prepared suspension. Before use, the vial with the prepared suspension must be shaken. For dosing the suspension, a dosing syringe is attached with labels indicating dose levels of 30 mg, 45 mg, and 60 mg (see section "Release form and packaging").
In cases where Tamiflu® in the dosage form “powder for oral suspension” is absent, capsules may be used. Detailed recommendations are given in the instructions for medical use of Tamiflu® capsules 30 mg, 45 mg, 75 mg in the subsection “Extemporaneous preparation of Tamiflu® suspension”.
The drug should be started no later than 2 days after the development of the symptoms of the disease. Adults and adolescents aged ≥12 years, children weighing> 40 kg or aged 8 to 12 years. 75 mg 2 times a day by mouth for 5 days. Increasing the dose of more than 150 mg/day does not increase the effect.
Patients (mainly children and adolescents) who were taking Tamiflu® for the treatment of influenza had mental disorders, convulsions, and delirium-like neuropsychiatric disorders. These cases were rarely accompanied by life-threatening actions. The role of Tamiflu® in the development of these phenomena is unknown. Similar neuropsychiatric disorders have also been reported in patients with influenza who have not received Tamiflu®.
The risk of developing neuropsychiatric disorders in patients receiving Tamiflu® does not exceed that in patients with influenza who are not receiving antiviral drugs.
Careful monitoring of the condition and behavior of patients, especially children, and adolescents, is recommended in order to identify signs of abnormal behavior and assess the risk of continuing to take the drug with the development of these phenomena.
In adult / adolescent influenza studies, the most common adverse reactions (HP) were nausea, vomiting, and headache. Most HP occurred on the first or second day of treatment and passed on their own within 1-2 days. In influenza prevention studies in adults and adolescents, the most common HPs were nausea, vomiting, headache, and pain. In children, vomiting was most common. The described HP in most cases did not require discontinuation of the drug.
Treatment and prevention of influenza in adults and adolescents
Table 1 presents the HP that occurred most frequently (≥1%) when taking the recommended dose of Tamiflu® in studies on the prevention and treatment of influenza in adults and adolescents (75 mg 2 times a day for 5 days for treatment and 75 mg 1 time per days to 6 weeks for prevention), and the frequency of which is at least 1% higher compared with placebo. Studies on treatment of influenza included adults/adolescents without concomitant pathology and patients at risk, i.e. patients with a high risk of developing complications of influenza (elderly patients, patients with chronic heart or respiratory diseases). In general, the safety profile in patients at risk was consistent with that in adults/adolescent patients without comorbidity.
In influenza prevention studies, the safety profile in patients receiving the recommended dose of Tamiflu® (75 mg once daily for up to 6 weeks) did not differ from that in studies for influenza treatment, despite a longer administration of the drug.
There is no data on the effectiveness of Tamiflu® for any diseases caused by pathogens other than influenza A and B viruses. Tamiflu® is not a substitute for vaccination.
In most cases, an overdose during clinical trials and with the post-marketing use of Tamiflu® was not accompanied by any adverse events. In other cases, the symptoms of an overdose corresponded to the adverse events presented in the section “Side effects”.
Clinically significant drug interactions are unlikely according to pharmacological and pharmacokinetic studies.
Oseltamivir extensively turns into an active metabolite under the influence of esterases, mainly located in the liver. Drug interactions due to competition for binding to the active centers of esterases are not widely represented in the literature. The low degree of binding of oseltamivir and the active metabolite to plasma proteins does not suggest the presence of interactions associated with the displacement of drugs from protein binding.
In vitro studies show that neither oseltamivir nor its active metabolite is the preferred substrate for multifunctional oxidases of the cytochrome P450 system or for glucuronyltransferases (see Pharmacokinetics subsection). There is no reason to interact with oral contraceptives.
Cimetidine, a non-specific inhibitor of isoenzymes of the cytochrome P450 system and competing in the process of tubular secretion with alkaline drugs and cations, does not affect the plasma concentrations of oseltamivir and its active metabolite.
Clinically significant inter-drug interactions associated with competition for tubular secretion are unlikely, given the safety margin for most of these drugs, the pathways for excretion of the active metabolite of oseltamivir (glomerular filtration and anionic tubular secretion), and the excretory capacity of each pathway.
Probenecid leads to an approximately 2-fold increase in the AUC of the active metabolite of oseltamivir (due to a decrease in active tubular secretion in the kidneys). However, dose adjustment with simultaneous use with probenecid is not required, given the safety margin of the active metabolite.
Simultaneous administration with amoxicillin does not affect the plasma concentrations of oseltamivir and its components, demonstrating little competition for excretion by anionic tubular secretion. Concomitant use with paracetamol does not affect plasma concentrations of oseltamivir and its active metabolite or paracetamol.
No pharmacokinetic interactions between oseltamivir, its main metabolite, were observed when taken simultaneously with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminum hydroxide, calcium carbonate), warfarin, rimantadine or amantadine.
When using Tamiflu® with commonly used drugs, such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), H2 receptor blockers, 2-histamine receptors -adrenoblockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), glucocorticosteroids, inhaled bronchodilators and non-narcotic analgesics (acetylsalicylic acid, ibuprofen and paracetamol), changed second nature or frequency of adverse events was observed.
Oseltamivir should be used with caution in combination with drugs that have a narrow breadth of therapeutic effect (for example, chlorpropamide, methotrexate, butadiene).