Preparations containing oseltamivir

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Oseltamivir

Description current as of 02/18/2017

  • Latin name: Oseltamyvirum
  • ATX code: J05AH02
  • Chemical formula: C 1 6 H 2 8 N 2 O 4
  • CAS code:-0

Chemical name

(3R,4R,5S)-4-(Acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester

Table of contents:

Chemical properties

Oseltamivir is an antiviral agent, a neurominidase inhibitor, a derivative of aminocyclohexenecarboxylic acid. The product was approved for use in 1999. According to physical properties, it is a white crystalline substance. Molecular mass = 312.4 grams per mole. Available in the form of powder and capsules for the preparation of suspension.

pharmachologic effect

Pharmacodynamics and pharmacokinetics

After oral administration, Oseltamivir is hydrolyzed to the active form oseltamivir carboxylate. The substance inhibits neuraminidases of influenza viruses type A and B, preventing their normal replication and the process of penetration into healthy cells. There are 9 subtypes of influenza A virus neuraminidase and 16 hemagglutinin subtypes, their combinations determine different strains of the same virus. The most common strains that pose a threat to human health are H3N2 and H1N1.

However, some types and new strains of influenza are not sensitive to treatment with Oseltamivir. Cross-resistance has been observed between strains resistant to zanamivir and agents resistant to this substance. The medicine does not have carcinogenic, mutagenic properties, does not affect fertility and early embryonic development.

After oral administration, the drug is quickly absorbed in the digestive tract and, under the action of hepatic esterases, is converted to the active metabolite carboxylate. About 75% of the metabolite and 5% of the unchanged substance are found in the blood. The plasma concentration of the drug is directly dependent on the dose taken. Food intake does not affect pharmacokinetic parameters. The degree of binding to blood proteins is about 42% (for metabolites this value does not reach 3%).

The half-life of the drug from blood plasma is from 1 to 3 hours, of metabolites - up to 10 hours. The substance is excreted through the kidneys (glomerular filtration) and in feces. No dosage adjustment is required for those over 12 years of age and in elderly patients.

Indications for use

  • for the treatment of influenza in adults and children over 1 year of age;
  • as a prophylactic for adults and adolescents at increased risk of infection;
  • for the prevention of influenza in children over one year of age.

Contraindications

The medicine is contraindicated for use:

Side effects

The most common symptoms that may occur during treatment with Oseltamivir:

Children were more likely to experience: abdominal pain, hearing impairment, nosebleeds, and conjunctivitis.

Instructions for use (Method and dosage)

The medicine is prescribed orally, regardless of food intake.

Treatment with Oseltamivir is recommended to begin no later than 2 days after the onset of the first symptoms of the disease. The average dosage is 75 mg, twice a day. The course of treatment is 5 days. Increasing the daily dosage is not advisable.

For prevention, use from 75 to 150 mg of the drug per day for 6 weeks.

In case of renal failure, dosage adjustment is carried out. It is recommended to take no more than 75 mg per day.

Overdose

There have been no reported cases of drug overdose. With a single dose of extremely large doses, nausea and vomiting are observed. Treatment is symptomatic.

Interaction

Drugs that block tubular secretion increase the plasma concentration of Oseltamivir and its active metabolite by 3 times. However, no dosage adjustment is required.

special instructions

The medicine is used with extreme caution in pediatric practice.

There is no data on the safety of taking the substance if creatinine clearance is less than 10 ml per minute.

The product is not effective in treating other viral diseases or bacterial infections.

The effectiveness and safety of using Oseltamivir drugs in immunocompromised patients with diseases of the respiratory and cardiovascular systems, 40 hours after the onset of the first symptoms of influenza, has not been established.

During post-marketing studies, cases of severe skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported; abnormal behavior, delirium, hallucinations. Very rarely, the above reactions resulted in death.

For children

Treatment with the drug is carried out in children from one year of age. Caution is required and the daily dosage must be adjusted if necessary.

During pregnancy and lactation

When treating pregnant and lactating women, caution must be exercised.

Drugs containing (Analogs)

Reviews

Some reviews about Oseltamivir:

  • “...During the flu season, everyone in the family got sick. It’s good that we started taking this remedy on time. The disease passed without complications, I did not notice any adverse reactions”;
  • “... I took this medicine about a year ago. I started taking the pills a few hours later when my temperature rose. After 5 days of treatment – ​​no symptoms of the disease. There were no adverse reactions. But the medicine didn’t help me at all for a common ARVI”;
  • “... The doctor prescribed it and gave it to my child, but he almost immediately felt nauseated and vomited. We decided to be treated without this drug.”

Price, where to buy

The cost of Tamiflu is about 1000 rubles for 10 tablets of 75 mg.

Aglaya42: Thank you. Everything turns out to be so simple.

Ivan: We’ve been working for more than half a year. They have proven themselves. Everything is guaranteed. In stock.

Yulia: I have the same symptoms, I thought it was meningitis. I almost didn’t say goodbye at all. Head.

Diets.Guru: If the stage of the disease and the patient’s condition allow the possibility of surgery.

All materials presented on the site are for reference and informational purposes only and cannot be considered a treatment method prescribed by a doctor or sufficient advice.

The site administration and the authors of the articles are not responsible for any losses and consequences that may arise when using the site materials.

Source: http://medside.ru/oseltamivir

OSELTAMIVIR INSTRUCTIONS

It is a prodrug whose active metabolite (oseltamivir carboxylate) selectively inhibits neuraminidase of influenza virus types A and B. Neuraminidase is a glycoprotein that catalyzes the cleavage of the bond between terminal sialic acid and sugar, thereby facilitating the spread of the virus in the respiratory tract (the release of virions from the infected cell and penetration into epithelial cells of the respiratory tract, preventing inactivation of the virus by epithelial mucus). Oseltamivir carboxylate acts outside cells and competitively inhibits viral neuraminidase. Inhibits the growth of the 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.

Does not affect the production of antibodies in response to inactivated influenza vaccine.

The resistance rate of clinical isolates of the virus is 2%.

Oseltamivir is intended for the treatment of influenza types A and B.

Oseltamivir is taken orally, regardless of food intake.

During treatment, administration should be started no later than 2 days from the development of symptoms of the disease at a dose of 75 mg 2 times a day for 5 days. Increasing the dose to more than 150 mg/day does not increase the effect.

For the prevention of influenza types A and B in adults - 75 mg 1-2 times a day for 6 weeks. (during a flu epidemic). The maximum daily dose for adults is 150 mg.

In patients with CC less than 30 ml/min, the dose is reduced to 75 mg 1 time/day for 5 days.

From the digestive system: nausea, vomiting (usually when taken in high doses, or in the first days of treatment); rarely - diarrhea, abdominal pain.

From the side of the central nervous system: insomnia, dizziness, headache.

From the respiratory system: nasal congestion, sore throat, cough.

Other: feeling tired, weak.

Contraindications to the use of the drug Oseltamivir are: chronic renal failure (creatinine clearance less than 10 ml/min), liver failure, hypersensitivity to oseltamivir.

Use Oseltamivir with caution during pregnancy and lactation.

Medicines that block tubular secretion increase the concentration of the active metabolite by 2-3 times (due to inhibition of the process of active tubular secretion in the kidneys), which does not require dose adjustment.

Information obtained from pharmacological and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.

Drug interactions caused by competition with esterases, under the influence of which oseltamivir phosphate is converted into an active substance, are not covered in detail in the literature. The low degree of binding of Oseltamivir carboxylate to proteins suggests that an interaction due to the displacement of drugs from protein binding is unlikely.

Cimetidine, which is a nonspecific inhibitor of isoenzymes of the cytochrome P450 system and a competitor for the renal tubular secretion of bases and cationic drugs, does not affect the plasma levels of oseltamivir and oseltamivir carboxylate.

Concomitant use with probenecid leads to an approximately 2-fold increase in the AUC of the active metabolite (due to a decrease in active anionic tubular secretion in the kidneys), but no dose adjustment is required.

No pharmacokinetic interaction was detected when oseltamivir was taken simultaneously with amoxicillin, paracetamol, antacids (magnesium and aluminum hydroxide, calcium carbonate).

Currently, no cases of overdose with Oseltamivir have been described. Single doses of oseltamivir phosphate have caused nausea and/or vomiting.

Treatment: symptomatic therapy. There is no specific antidote.

Store at a temperature not exceeding 25 ° C out of the reach of children.

Oseltamivir - capsules 30 mg, 45 mg, 75 mg.

10 capsules in a blister, 1 blister in a cardboard box.

1 capsule of Oseltamivir contains 98.5 mg of oseltamivir phosphate, which is equivalent to 75 mg of oseltamivir.

Excipients: corn starch, croscarmellose sodium, povidone, talc, sodium stearyl fumarate.

Use with caution in children.

Oseltamivir is contraindicated in patients with liver failure (in patients with liver failure, the safety and effectiveness of oseltamivir have not been established).

In patients with hepatic impairment, the safety and effectiveness of oseltamivir have not been established.

Contraindicated in chronic renal failure (creatinine clearance less than 10 ml/min). In patients with CC less than 30 ml/min, the dose is reduced to 75 mg 1 time/day for 5 days.

There is no data on the safety of oseltamivir with CC less than 10 ml/min.

Use with caution in children.

Reviews OSELTAMIVIR

Oseltamivir for the treatment of influenza

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Source: http://www.medcentre.com.ua/medicamenty/oseltamivir.html

Oseltamivir

Oseltamivir (oseltamivir) is a drug recommended by the World Health Organization for the treatment and prevention of influenza A and B. This antiviral drug prevents the reproduction and spread of viruses in the body.

In this article we will look at why doctors prescribe Oseltamivir, including instructions for use, analogues and prices for this drug in pharmacies. Real REVIEWS of people who have already used Oseltamivir can be read in the comments.

Release form and composition

This drug is marketed in the form of white-yellow capsules. Oseltamivir is a prodrug. When taken orally, it undergoes hydrolysis and is converted into the active substance - oseltamivir carboxylate.

What does Oseltamivir help with?

Why is the drug Oseltamivir prescribed (pharmaceutical group - antiviral agents)? According to the attached instructions, this medication is used to treat influenza A and B. It is also often used to prevent these viral diseases.

pharmachologic effect

Oseltamivir is a prodrug that, when taken orally, undergoes hydrolysis and is converted into the active form, oseltamivir carboxylate. The mechanism of action of oseltamivir carboxylate is associated with the inhibition of neuraminidase of influenza viruses type A and B. Neuraminidase, a surface glycoprotein of the influenza virus, is one of the key enzymes involved in the replication of influenza A and B viruses.

Neuraminidase catalyzes the cleavage of the bond between the terminal sialic acid and the sugar, thereby promoting the spread of the virus in the respiratory tract (the release of virions from the infected cell and penetration into the epithelial cells of the respiratory tract, preventing inactivation of the virus by epithelial mucus).

There are 9 known antigenic subtypes of influenza virus type A neuraminidase - N1, N2 and so on, which, along with 16 antigenic subtypes of hemagglutinin - H1, H2 and so on, determine different strains of the same type of virus. Several strains of influenza A virus with hemagglutinin 1-5 and neuraminidase 1 and 2 are simultaneously circulating in the human population, the main of which are H3N2 and H1N1.

When neuraminidase is inhibited, the ability of viral particles to penetrate into the cell, as well as the release of virions from the infected cell, is impaired, which leads to limited spread of infection through the respiratory tract.

Instructions for use

According to the instructions for use, Oseltamivir should be started no later than 2 days from the onset of flu symptoms;

  1. Adults and children over 12 years old - at a dose of 75 mg 2 times a day for 5 days; increasing the dose to more than 150 mg/day does not increase the effect.
  2. Children from 1 year to 12 years - depending on body weight.
  3. Prevention: adults and children over 12 years of age - 75 mg 1 time per day for 6 weeks (during a flu epidemic).

In patients with creatinine Cl less than 30 ml/min, dose adjustment is necessary (75 mg 1 time per day for 5 days); when Cl creatinine is less than 10 ml/min there is no data on use

Contraindications

It is strictly not recommended to prescribe the drug to patients under 13 years of age, as well as in the presence of individual intolerance to the active substance or other components of the composition.

Side effects

The most common side effects of Oseltamivir are general weakness, headaches and dizziness; catarrhal phenomena (rhinorrhea, swelling of the nasal mucosa, sore throat, cough); nausea, vomiting, diarrhea, abdominal pain; sleep disorders, seizures; allergic reactions (urticaria, bronchospasm, conjunctivitis); nosebleeds, cardiac arrhythmia, increased activity of liver enzymes.

Hallucinations and mental disorders are possible.

Overdose

To date, there have been no reports of excessive dosing of the drug. It has been established that in case of acute overdose, nausea and vomiting may occur, and if they occur, symptomatic treatment is recommended.

special instructions

  1. During post-marketing studies, cases of severe skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported; abnormal behavior, delirium, hallucinations. Very rarely, the above reactions resulted in death.
  2. The effectiveness and safety of using Oseltamivir drugs in immunocompromised patients with diseases of the respiratory and cardiovascular systems, 40 hours after the onset of the first symptoms of influenza, has not been established.
  3. The medicine is used with extreme caution in pediatric practice.
  4. There is no data on the safety of taking the substance if creatinine clearance is less than 10 ml per minute.
  5. The product is not effective in treating other viral diseases or bacterial infections.

Interactions with other drugs

Concomitant use of Oseltamivir with drugs such as methotrexate, phenylbutazone and chlorpropamide is undesirable due to the possible slowdown in the elimination of their metabolites from the body.

Reviews and evaluations of the effectiveness of the drug

According to test results obtained in the United States of America and Mexico, new viruses are sensitive to neuraminidase inhibitors (Zanamivir and Oseltamivir), but they are resistant to another group - adamantanes (Rimantadine, Amantadine). . It should also be noted that experts have not established the effectiveness of this medication in treating influenza in people with chronic heart and respiratory diseases.

According to doctors, this drug reduces the duration of symptoms by 1 day, but this is only if treatment was started in the first few hours after contact with the patient. To date, there is no reliable information about whether taking this drug affects the incidence of complications of viral or infectious diseases.

Analogs

Synonyms of Oseltamivir: Nomides, Oseltamivir Canon, Tamiflu, Oseltamivir phosphate.

Attention: the use of analogues must be agreed with the attending physician.

Average price of Oseltamivir, tablets in pharmacies (Moscow) rubles.

Source: http://instrukciya-po-primeneniyu.com/ozeltamivir/

Tamiflu (oseltamivir) and its analogues - instructions, release forms (capsules and powder for suspensions), use during pregnancy and in children, description and evidence base of the drug. Other neuraminidase inhibitors and reviews

medicine Tamiflu

Release form of the medicine

  • treatment of influenza type A and B in adults and children over 1 year of age

The threshold for effects in case of an overdose is very high; there is simply not enough money and stomach capacity for such an amount of the drug :)

  1. the average duration of the disease is reduced by 37%

The use of Oseltamivir led to a decrease in the concentration of the influenza virus neuraminidase enzyme in cell culture and suppressed its reproduction.

  • nausea, vomiting, diarrhea, abdominal pain;

Agree, the list is impressive, in children it is much more voluminous (for example, recently the annotations have included the possibility of causing disturbances in consciousness, convulsions and self-harm in children after taking Tamiflu, which requires special monitoring of the child when taking the drug), but if you start taking the drug without permission, Oseltamivir, and then present these symptoms to the doctor, then he, not knowing what you are now taking (the doctor did not prescribe this for you), may begin to treat you in a completely wrong way and not at all what you need.

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Source: http://grippozus.ru/34-lekarstvennyj-preparat-tamiflyu-oseltamivir.html

Oseltamivir

About the drug:

Oseltamivir (oseltamivir) is a drug recommended by the World Health Organization for the treatment and prevention of influenza A and B. This antiviral drug prevents the reproduction and spread of viruses in the body.

Indications and dosage:

Influenza type A and B (treatment and prevention).

The drug should be taken no later than 2 days from the onset of flu symptoms; adults and children over 12 years old - at a dose of 75 mg 2 times a day for 5 days; increasing the dose to more than 150 mg/day does not increase the effect. Children from 1 year to 12 years - depending on body weight.

Prevention: adults and children over 12 years of age - 75 mg 1 time per day for 6 weeks (during a flu epidemic).

In patients with creatinine Cl less than 30 ml/min, dose adjustment is necessary (75 mg 1 time per day for 5 days); when creatinine Cl is less than 10 ml/min, there is no data on use.

Overdose:

Currently, no cases of overdose have been described. Single doses of oseltamivir phosphate have caused nausea and/or vomiting.

Treatment: symptomatic therapy. There is no specific antidote.

Side effects:

Contraindications:

Due to the lack of studies, Oseltamivir is used with caution:

For liver failure.

In childhood up to 1 year.

There is also information that the degree of effectiveness and safety of using the drug to prevent influenza in children under the age of 13 years has not been determined.

During pregnancy and breastfeeding, the drug can be used only in cases where the expected effect of treatment exceeds the possible risk to the fetus or child (also due to the lack of research).

Interaction with other drugs and alcohol:

Information obtained from pharmacological and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.

Drug interactions caused by competition with esterases, under the influence of which oseltamivir phosphate is converted into an active substance, are not covered in detail in the literature. The low degree of binding of oseltamivir carboxylate to proteins suggests that an interaction caused by displacement of the drug from protein binding is unlikely.

Cimetidine, which is a nonspecific inhibitor of isoenzymes of the cytochrome P450 system and a competitor for the renal tubular secretion of bases and cationic drugs, does not affect the plasma levels of oseltamivir and oseltamivir carboxylate.

Concomitant use with probenecid leads to an approximately 2-fold increase in the AUC of the active metabolite (due to a decrease in active anionic tubular secretion in the kidneys), but no dose adjustment is required.

No pharmacokinetic interaction was detected when oseltamivir was taken simultaneously with amoxicillin, paracetamol, antacids (magnesium and aluminum hydroxide, calcium carbonate).

Composition and properties:

Active ingredient: 1 capsule contains 98.5 mg of oseltamivir phosphate, which is equivalent to 75 mg of oseltamivir.

Excipients: pregelatinized starch, croscarmellose sodium, povidone, talc, sodium stearyl fumarate.

Oseltamivir is the international name of the drug; this active substance is also included in the preparations Tamiflu (capsules and powder for suspension), Tamigripp (capsules).

Diazepam should be given at temperatures up to 25 degrees Celsius.

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Source: http://www.likar.info/lekarstva/Ozeltamivir/

Flu medicine Oseltamivir

The flu medicine Oseltamivir (in another transcription - Oseltamavir, trade name - Tamiflu) is an antiviral agent. It is active against influenza strains type A and B. To understand the essence of the drug’s action, you need to understand the structure of the influenza virus particle.

The structure of the influenza virus

The basis of any virus is its genome. In this case, it is represented by a strand of RNA (ribonucleic acid). The influenza virion has 8 RNA chains, each of which is enclosed in a peptide “film” - a nucleoprotein. All genetic material is in turn covered by a protein shell called a capsid. The capsid contains two enzymes - hemagglutinin and neuraminidase. These proteins determine the penetration ability of the virus.

Hemagglutinin ensures adhesion (attachment) of the virus to the host cell, and neuraminidase ensures partial dissolution of the components of the cell membrane for the virus to penetrate into and exit the dead cell after reproduction.

The virion also has a second shell - a supercapsid. This is an additional glycoprotein protective layer, consisting partly of the proteins of the virus itself and components of the membranes of the “killed” host cell. The supercapsid contains additional proteins in its structure - peptides, which ensure the stability and safety of the shell.

Hemagglutinin (abbreviated as H) and neuraminidase (abbreviated as N) constantly mutate and change their protein structure. There are already 10 varieties of N. And this is not the limit.

The environment and survival in the macroorganism contribute to an increase in the “aggressiveness” of the virus - it becomes more invulnerable to immune cells and medications.

Mechanism of action of the drug

The influenza drug Oseltamivir inhibits the activity of the main infective enzyme of the virus, neuraminidase. The active substance, oseltamivir phosphate, is converted into oseltamivir carboxylate in the human body. This organic compound actively binds the neuraminidase protein molecule, disrupting its structure and properties. The microbe can no longer penetrate the cell or leave it (it all depends on at what stage of virus reproduction the drug blocked N) - it faces death.

The first scenario is that the microorganism did not have time to enter the cell. The virus has small energy “reserves”, but they are only enough to move from one cell to another and “break a hole” in its membrane. If neuraminidase is blocked, it is impossible for him to get into the cage! And if the energy needs of the virus are not satisfied by the host cell, then, in the end, protein synthetic processes stop - the virion dies.

The second scenario is that the microbe actively reproduces in the cell. After neuraminidase is blocked, the newly synthesized “hordes” of virions cannot escape. They consume energy substrates of host cells - carbohydrates, lipids, proteins. But the supply of nutrients in the cytoplasm is not endless. When they end, virion metabolism, including the process of RNA replication, fades away. Both the cell and the viruses die along with it.

Advantages of antiviral drugs over influenza vaccines:

  1. Versatility and wide range of action. Flu drugs with Oseltamavir are designed to block any type of neuraminidase, and therefore many strains of influenza. Whereas a vaccine promotes immunity only against a virus with one type N;
  2. Speed ​​of action. After administration of a vaccine preparation with a dose of weakened or split virion, it takes at least two weeks for the production of anti-influenza antibodies. During this time, you can “catch” an infection and become ill as seriously as if you had not received the vaccine. Oseltamivir anti-flu tablets act purposefully within the first hours from the moment they enter the body, and the clinical effect is visible after 1.5 days from the start of use.
  3. Uniqueness. Due to the strong mutational variability of the influenza virus, every year virologists and microbiologists have to develop a new influenza vaccine. Only a new vaccine is ready and put into practice, and the influenza virus has mutated again and formed another strain. A vaccine created against one strain will not help develop immunity against another strain.
  4. Guarantee. It has been clinically proven that using Oseltamivir for the flu, the likelihood of complications is reduced by 60%, the duration of the disease is reduced by one and a half times, and the likelihood of death is reduced by 70%! Of course, vaccination also helps reduce the number of complicated forms of influenza infection and makes its course easier (if a person does get sick), but does not guarantee a reduction in the duration of the disease.

Some features of the use of Oseltamivir

Ideally, before using the medicine, it is necessary to determine the sensitivity of the strain that infected the person to Oseltamivir. It is known, for example, that swine flu is not sensitive to this drug.

An important point: for the flu medicine Oseltamivir to be truly effective, it should be prescribed at the very beginning of the disease, when the virus is actively multiplying and quickly leaves the cells, i.e. in the first two days from the onset of symptoms. In severe and complicated forms of influenza (especially in viral pneumonia with the development of serous-hemorrhagic pulmonary edema), the drug will be useless.

You only need to prescribe Tamiflu! The simultaneous use of two or more antiviral drugs with the same mechanism of action does not lead to an increase in the therapeutic effect, but only increases the side effects.

Dosage

Oseltamivir is available in 75 mg capsules - once a day is enough for both adults and children.

Increasing the dose by 2 times does not lead to increased antiviral activity, but can activate the cellular component of the immune defense.

Source: http://gripptips.ru/preparatyi/lekarstvo-ot-grippa-ozeltamivir.html

Tamiflu (Oseltamivir)

Pharmacological group: antiviral agents

Systematic (IUPAC) name: (3R, 4R, 5S)-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylic acid ethyl ester

Trade names: Tamiflu

Legal status: Available by prescription only

Protein binding: 42% (parent drug), 3% (active metabolite) Metabolism: liver, to Oseltamivir carboxylate

Half-life: 1-3 hours, 6-10 hours (active metabolite)

Excretion: urine (>90% as Oseltamivir carboxylate), feces Formula: C 16 H 28 N 2 O 8 P

Mol. mass: 312.4 g/mol

Oseltamivir, marketed under the brand name Tamiflu, is an antiviral drug used to prevent or slow the spread of influenza A and B viruses in the body's cells by stopping chemical damage to the host cell. The drug is taken orally in the form of capsules or suspension. Tamiflu is a prodrug, a relatively inactive substance that becomes active when metabolized in the body. The drug is the first oral active neuraminidase inhibitor on the market. It was developed by scientists C.U. Kim, W. Lew and X. Chen from the American company Gilead Sciences, and is marketed marketed by Genentech. The benefits of oseltamivir when taken by healthy people do not outweigh the risks associated with the drug's side effects. Randomized trials of people at high risk of developing complications or elderly hospitalized patients did not demonstrate treatment benefit or risk of death The US Centers for Disease Control and Prevention still recommends the use of oseltamivir for people at high risk for complications and older adults and people at lower risk who see a doctor within 48 hours of the first symptoms of infection.Prior to 2013, the effectiveness of oseltamivir was in question because its manufacturer, Roche, initially refused to make its test data available for independent analysis. Published studies show that Oseltamivir reduces the duration of symptoms by 0.5 to 1 day. It is unclear whether the drug affects transmission of influenza in adults. Any positive effects of treatment are balanced by side effects, which include psychiatric symptoms and vomiting. As of December 15, 2010, the World Health Organization (WHO) reported that during testing, 314 samples of the 2009 H1N1 pandemic influenza virus demonstrated resistance to Oseltamivir. However, the predominant strains of influenza A and influenza B active during influenza years in the United States are susceptible to oseltamivir.

Medical use

When used for treatment or prophylaxis in healthy individuals, the drug does not have benefits that outweigh the risks. The standard recommended dose does not completely suppress viral replication in at least some patients with H5N1 avian influenza virus, increasing the risk of viral resistance and reducing the effectiveness of therapy. Therefore, higher doses and longer periods of therapy are recommended for the treatment of patients with H5N1 virus. There is little data on whether the drug reduces the risk of developing influenza by 1-12%. It is unclear whether the drug affects the need for hospitalization or the risk of death. Oseltamivir is used for the treatment and prevention of infections caused by influenza A and B viruses. The predominant strains of influenza A and B are active against influenza strains of the year in the United States and are sensitive to Oseltamivir.

Efficiency

A 2012 Cochrane review indicated that a large proportion of clinical trials continue to be unavailable for public scrutiny, and that available data are inconclusive whether taking oseltamivir reduces the risk of hospitalization, complications or transmission of influenza-like illness. On April 10, 2014, Cochrane published a systematic review using all previously unpublished data, concluding that taking the drug did not reduce the risk of hospitalization, and that there was no evidence to reduce complications from influenza (eg, pneumonia), or the spread of the virus. The scientists concluded that the guidelines should be revised to take into account the evidence of all, even subtle, positive effects and the increased risk of side effects. In addition, the authors stated that their findings were similar to those of the US FDA at the time of approval; that data from randomized clinical trials support the use of Tamiflu for the prevention and treatment of influenza symptoms only, and do not support its effectiveness in preventing infection, viral transmission, or complications. In 2011, Roche conducted an independent reanalysis of its data. One of the authors received income from a previously sponsored organization by Roche, but Roche did not contribute to the funding of this analysis. The authors concluded that early use of oseltamivir for the treatment of influenza-like illness reduces the incidence of “antibiotic-treated lower respiratory tract infections” in healthy adults and children. However, such infections were not a primary or secondary endpoint in the original trials but were a reconstructed endpoint from the database. In patients not suffering from influenza infection, no beneficial effects were observed. The CDC (US Center for Disease Control) still recommends Oseltamivir for a variety of uses. These recommendations are based in part on observational studies showing that neuraminidase inhibitors reduce the risk of mortality in high-risk patients. The CDC says the clinical trials included in the Cochrane Collaboration's meta-analysis and other trials include too few high-risk patients to fully examine the effectiveness of neuraminidase inhibitors in preventing serious complications, and that observational studies show reduced mortality in hospitalized patients patients and other high-risk patients. Specifically, the CDC analysis relies on a large meta-analysis of cohort studies of adult patients hospitalized during the H1N influenza pandemic, which demonstrated a 19% reduction in the risk of mortality overall and a 50% reduction in mortality among adults who took the drug within 48 hours of symptom onset. The study (which was funded by the manufacturer) failed to detect a statistically significant positive effect of the drug on survival in children.

Side effects

Common adverse reactions associated with oseltamivir (seen in more than 1 percent of participants in clinical trials) include: nausea, vomiting, diarrhea, abdominal pain and headache. Rare side effects include: hepatitis and elevated liver enzyme levels, rash, allergic reactions including anaphylactic shock and Stevens-Johnson syndrome. Various other side effects have been reported in a post-marketing review, including: toxic epidermal necrolysis, cardiac arrhythmia, seizures, confusion, exacerbation of diabetes, and hemorrhagic colitis. There are concerns that Oseltamivir may cause dangerous psychological and neuropsychiatric side effects, including self-harm in some users. These dangerous side effects occur more often in children than in adults. Most of these cases have been reported in Japan, where the drug is most popular and accounts for 60 percent of its global production. In March 2007, the Japanese Ministry of Health issued a warning that oseltamivir should not be used in persons aged 10 to 19 years. Earlier, in May 2004, the Ministry decided to change the accompanying documentation of Oseltamivir to include neurological and psychological disorders as possible negative consequences, including impaired consciousness, behavioral abnormalities and hallucinations. According to the Japanese Ministry of Health, between 2004 and March 2007, fifteen people aged 10 to 19 were injured or killed from jumping or falling from high-rise buildings after taking oseltamivir, and one 17-year-old user died while trying to jump in front of by truck. An updated study of the Japanese data was completed in April 2007. It was found that since 2001, data have been received on 128 patients with behavioral abnormalities after taking Oseltamivir. 43 of them were under 10 years of age, 57 patients were between 10 and 19 years of age, and 28 patients were 20 years of age or older. Eight people, including five teenagers and three adults, died as a result of these actions. In October 2006, Shumpei Yokota, a professor of pediatrics at Yokohama City University, published the results of a study of about 2,800 children that found no differences in behavior between those who took oseltamivir and those who did not. Chugai Pharmaceutical Co. (the company that produces Oseltamivir in Japan) paid the Yokota Department 10 million yen (about US$105,000) over five years. To determine whether the 2007 ban should be lifted, a research team from Japan's Ministry of Labor Health and Welfare studied children under the age of 18 who had been diagnosed with influenza since 2006. The study was completed in April 2009. Taking into account all degrees of abnormal behavior, including juvenile behavioral problems such as schizophasia, the study found that children who took Oseltamivir were 54 percent more likely to exhibit abnormal behavior, compared with patients who did not take the drug. When the team limited their analysis to children with severe behavioral problems that resulted in injury or death, it was shown that patients taking Oseltamivir had a 25 percent chance of behavioral problems. In November 2006, the US FDA changed the drug's labeling to include warnings about possible side effects such as delirium, hallucinations, or other associated behavioral effects. This warning was stronger than the previous one issued the year before, that there was insufficient evidence to establish a causal link between the use of Oseltamivir and the deaths of 12 Japanese children (two as a result of neurological problems, but more have since died children). The move to a more cautious position was prompted by 103 new FDA reports concerning delusions, hallucinations, and other psychiatric abnormalities, primarily in Japanese patients, received between August 29, 2005 and July 6, 2006. These figures are more than 126 similar cases reported between the drug's approval in 1999 and August 2005. In April 2007, South Korea issued a warning against the safety of administering oseltamivir to adolescents (except in special cases). A joint study by the British Medical Journal (BMJ) and British Channel 4, published on December 8, 2009 in the BMJ, found that when used in healthy adults, "it is not certain that oseltamivir reduces the risk of complications and hospitalization in patients with influenza" and that the drug should not be used for the symptomatic treatment of seasonal influenza. Concerns have also been raised about the withholding of information about the drug's side effects. However, according to the BMJ, Roche said in its press conference that Oseltamivir reduced the risk of hospitalization by 61 percent; the risk of secondary complications (including bronchitis, pneumonia and sinusitis) by 67 percent in otherwise healthy individuals and the risk of lower respiratory tract infections requiring antibiotics by 55 percent. BMJ editor Dr Fiona Godlee said that “claims that oseltamivir reduces the risk of complications have been a key rationale for promoting widespread use of the drug. Governments around the world have spent billions of pounds on a drug that the scientific community has failed to evaluate."

Mutagenesis

Although the drug was found to be non-mutagenic in the Ames test and the mouse micronucleus test, Oseltamivir demonstrated a positive result in the Syrian hamster embryo cell transformation test.

Resistance

The vast majority of resistance mutations are substitutions of a single amino acid residue (His274Tyr in N1) in the neuraminidase enzyme.

H1N influenza pandemic

As of December 15, 2010, the World Health Organization (WHO) reported that 314 samples of the 2009 H1N1 pandemic virus had demonstrated resistance to oseltamivir in trials worldwide. A study published in a June 2009 Nature Biotechnology review also highlighted the need for increased supplies of oseltamivir, along with additional antiviral drugs including zanamivir (Relenza), based on the evaluation of these drugs if neuraminidase H1Nγ (NA) acquires a resistance mutation to Oseltamivir.

Seasonal flu

Resistance to Oseltamivir was widespread in seasonal influenza. During the influenza epidemic, the US CDC found that 10.9% of H1N1 samples (n=1020) were resistant. During the epidemic, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) did not show any resistance. All Oseltamivir-resistant strains maintain sensitivity to Zanamivir. Resistance to oseltamivir was low during seasonal influenza years. During the influenza epidemic, the US CDC reported that susceptibility to oseltamivir was maintained in 99.1% of H1N1 samples tested (n = 4229), 99.8% of H3N2 (n = 806), and 100% of influenza B samples (n = 723). As of January 2012, US and European CDCs have reported oseltamivir susceptibility for all (n = 103) seasonal influenza specimens tested since October 2011.

Isolates of mutant H3N2 influenza A virus resistant to oseltamivir were found in 18 percent of a group of 50 Japanese children treated with oseltamivir in 2006. Several theories have been proposed by the study authors to explain the higher than expected resistance rates. First, children tend to have a longer period of infection, allowing more time for resistance to develop. Secondly, Kiso et al. claim to have used more stringent detection methods than previous researchers. The development of resistance may also be caused by insufficient dosage of the drug.

Influenza B

In 2007, Japanese researchers discovered strains of influenza B virus that were resistant to neuraminidase in people not taking these drugs. The prevalence was 1.7 percent. According to the CDC, as of October 3, 2009, no strains of influenza B virus tested have shown any resistance to oseltamivir.

Avian influenza H5N1

High resistance was observed in one girl suffering from H5N1 avian influenza in Vietnam. At the time of discovery, she was taking Oseltamivir. De Jong et al (2005) describe the development of resistance in two other Vietnamese patients suffering from H5N1 and compare these cases with six others. They suggest that the emergence of a resistant strain may be associated with clinical deterioration in the patient's condition. They also note that the recommended dosage of Oseltamivir may not always completely suppress viral replication, which may favor the emergence of resistant strains. Moscona (2005) gives a good overview of the issue of resistance, and states that self-administration of Oseltamivir may result in the patient not taking enough of the drug and thus causing the emergence of resistant H5N1 strains. Resistance can develop in pandemic influenza (Wong and Yen, 2005), and is more likely in avian influenza than in seasonal influenza due to the potentially longer duration of infection with new viruses. Kiso et al suggested that “a higher prevalence of resistant viruses should be expected during a pandemic.” The EU has also reported evidence of resistant strains.

Mechanism of action

The prodrug Oseltamivir itself is not virally effective; however, when it enters the liver, it is hydrolyzed into its active metabolite, free oseltamivir carboxylate. Oseltamivir is a neuraminidase inhibitor that acts as a competitive inhibitor of the sialic acid activity of the viral neuraminidase (NA) enzyme on glycoproteins on the surface of normal host cells. By blocking enzyme activity, Oseltamivir prevents the release of new viral particles from infected cells.

Pharmacokinetics

The bioavailability of the drug when taken orally is more than 80%. Tamiflu is metabolized to its active form on its first pass through the liver. It has a distribution volume of liters. Its half-life is about 1-3 hours, and the half-life of its active metabolite is 6-10 hours. Tamiflu is primarily excreted in the urine as the active carboxylate metabolite (>90% of the oral dose).

Commercial issues

The patent for Oseltamivir is owned by Gilead Sciences and is valid until 2016. In 1996, Gilead transferred exclusive rights to the drug to Roche. The drug does not have patent protection in Thailand, the Philippines, Indonesia and several other countries. Oseltamivir was widely used during the 2005 H5N1 avian influenza epidemic in Southeast Asia. In response to the epidemic, various governments, including those of the UK, Canada, Israel, the US and Australia, have stockpiled oseltamivir in preparation for a possible pandemic. In late October 2005, Roche announced that it was suspending supply of the drug to pharmacies in the United States and Canada prior to the outbreak of North American seasonal influenza in order to address concerns regarding drug stockpiling in individuals and to maintain drug supply to pharmacies during seasonal influenza. Sales were also suspended in Hong Kong, and on November 8, 2005 in China. Roche stated its intention to send all supplies to the Chinese Ministry of Health. On November 9, 2005, Vietnam became the first country to be granted approval by Roche to produce a generic version of the generic version of Oseltamivir. A week earlier, Thai authorities announced the launch of generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand. The first Thai generic version of Oseltamivir was produced in February 2006, and was available for purchase in July 2006. In November 2005, US President George W. Bush asked Congress to fund $1 billion to produce and stockpile oseltamivir, after Congress had already approved $1.8 billion in funding for military use of the drug. Secretary of Defense Rumsfeld has relinquished all authority to make all government decisions regarding the drug. In December 2005, Roche signed a sublicense agreement with the Chinese company Shanghai Pharmaceuticals for the full production of Oseltamivir, and by March 2006 the sublicense was also granted to the Indian company Hetero. In May 2006, WHO asked Roche to be prepared to send, if necessary, an emergency supply of oseltamivir to Indonesia. The warning was issued in response to suspected person-to-person transmission within a family and the dispatch was planned to take place within two weeks. In December 2008, Indian pharmaceutical company Cipla won a case in India that gave it the right to produce a cheaper generic version of Tamiflu called Antiflu. In May 2009, Cipla received approval from the WHO certifying that Antiflu was as effective as Tamiflu, and Antiflu is on the WHO list of prequalified drugs.

Production Deficiency/Shikimic Acid

In early 2005, Roche announced a production shortage. In 2006, however, Roche stated that annual production reached 400 million treatments per year and that it was "far in excess of total government orders available today" and that "supply shortages no longer exist." The total number of government orders between 2005 and 2007 is estimated to be about 200 million doses of treatment. In fact, Roche's chief executive officer, William Burns, said the lack of orders could lead to production cuts in the future. Roche attributes the growth in production to agreements with 15 external contractors in 9 countries.

Personal supplies

Due to the shortage of Oseltamivir, some individuals are stockpiling their own supplies of the drug. Several US states have taken action to condemn the practice. Since then, production has caught up with current demand. In the New England Journal of Medicine, Anne Moscona (2005) argues that the use of personal supplies of oseltamivir may be associated with the use of low doses of the drug, which contributes to the development of resistant viral strains. Many of these users only have ten 75 mg Oseltamivir tablets (the recommended dose for Oseltamivir) in stock, but this may not be enough to treat H5N1 influenza. Another argument against stockpiling a drug is that drugs with limited availability should be stored where they are needed most, that is, in areas where the epidemic is spreading, by people with important social roles (for example, medical and government workers) , and in people vulnerable to seasonal influenza or in people with avian influenza. Questions about whether rich people or nations can have privileged access to antiviral drugs lie in the area of ​​ethics. Illegal imports may be linked to dwindling supplies of the drug in poorer countries, where the risk of bird flu is actually higher. The counterargument is that it is difficult to justify prohibiting personal stockpiling of a drug, since corporate stockpiling, on the contrary, is permitted and even encouraged. The third argument is that it is difficult for home users to determine whether smuggled Tamiflu is counterfeit. In December 2005, 53 packages of counterfeit Tamiflu tablets were intercepted by US Customs Service in South San Francisco. The packages were labeled “Generic Tamiflu.” Roche representatives are aware of only one case of counterfeit Tamiflu products outside the United States: incorrectly labeled tablets were found in the Netherlands. They contained only vitamin C and lactose. The argument for creating individual stocks is that Roche has officially stated that without more orders coming in, they may officially cut production of the drug. Building individual inventories can bring market forces into play, preserving production capacity and allowing overall supply to be higher in the event that demand again outstrips production in the future, such as during a sudden flu outbreak.

Veterinary use

Tamiflu has been reported to reduce disease severity and hospitalization time for parvovirus infection in dogs. The drug may limit the virus's ability to invade small intestinal cells and reduce gastrobacterial colonization and toxin production.

Production

Oseltamivir is marketed by Genentech under the brand name Tamiflu, in capsule form (containing 98.5 mg oseltamivir phosphate, equivalent to 75 mg oseltamivir) and as a powder for oral suspension (oseltamivir phosphate, equivalent to 6 mg/ml oseltamivir).

Availability

Tamiflu (Ozeltamivir) is used to treat and prevent influenza in adults and children. The drug is available with a prescription.

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