Current issues in the use of oseltamivir for influenza

Epidemiology and clinical features of influenza

The whole world continues to fight the pandemic of the new coronavirus infection, which began in our country at the end of February 2022. The medical community is making unprecedented efforts aimed at studying the new viral infection, developing treatment and prevention methods. The rapid spread of COVID-19 and the increase in the number of severe cases of the disease have diverted medical attention from the equally important problem of other acute respiratory viral infections (ARVI). Although, according to WHO data, ARVI accounts for about 90% of all infectious pathologies [1].

The most dynamic infection from this group is influenza. It causes annual epidemics and periodic pandemics due to high susceptibility rates in both children and adults. Every year, influenza affects up to 5 million people in different regions of the globe. The disease is characterized by high mortality rates, reaching 5–10%. Every year, up to 500 thousand people die from influenza [2]. Of course, the prognosis for this viral infection depends on the concomitant pathology [3]. The most vulnerable are patients suffering from pathologies of the cardiovascular system, respiratory organs, obesity, and immunodeficiency conditions. The risk of death in these patients increases 50–100 times compared to healthy people. Last pandemic 2009–2010 showed a high incidence of severe influenza among pregnant women [4]. But influenza also poses a serious danger for people who are not burdened with concomitant pathologies, regardless of age. Thus, each influenza outbreak is characterized by serious medical, social and economic consequences.

Influenza pathogens belong to the orthomyxoviridae family

). These are RNA viruses with a complex organization. The RNA of influenza viruses has a high ability for genetic recombination and, as a result, for changing the antigenic structure. The lipoprotein shell has spines on its surface, which are formed by two complex proteins - glycoproteins: neuraminidase (N) and hemagglutinin (H). The amount of hemagglutinin is approximately 5 times greater than the amount of neuraminidase. The type of virus is determined by a nucleoprotein and matrix protein that is constant in its structure. On this basis, 3 antigenically independent types A, B and C are distinguished. Influenza C virus has the most stable antigenic structure. Isolation of influenza A and B virus subtypes is determined by variants of surface antigens (N and H) [5].

The most significant of the group of influenza viruses is the influenza A virus. Currently, 18 subtypes H (H1-H18) and 11 subtypes N (N1-N11) of influenza A viruses have been described, so 198 different combinations of these proteins are theoretically possible [6]. The extraordinary variability of the influenza A virus is explained by processes called “antigenic shift” and “antigenic drift.” It is important to emphasize that, starting from its discovery in 1901 and to this day, the discovery of new variants of the influenza A virus continues. They play a major role in the development of not only annual epidemics on a national scale, but also pandemics that cover entire continents with lightning speed. Thus, the 1918–1919 pandemic, called the “Spanish flu” or “Spanish flu,” quickly spread throughout the world, affecting about 500 million people and claiming up to 50 million lives [7]. Many researchers rightly call this pandemic the medical and social catastrophe of the twentieth century. According to some statistics, the mortality rate from the Spanish flu was about 3.5% of the world's population, more than twice the human losses in the First World War [8]. The causative agent of the 1957–1959 pandemic. became the H2N2 subtype of influenza A, isolated in Singapore. It was called the "Asian flu". During this pandemic, up to 2 billion people fell ill worldwide, about 2 million died. The “Asian virus” that circulated in the world until 1968 was replaced by the “Hong Kong flu” type A (subtype H3N2) - A/Hong Kong/1 /68, which received its name in accordance with the site of initial isolation of the virus. The Hong Kong flu pandemic lasted a year and a half. More than 1 billion people fell ill, about 1 million people died, of which 34 thousand were in Russia [9]. The next outbreak of influenza in 1977 was first reported by Soviet doctors, so it was called the “Russian” or “red” flu. The new virus A/USSR/90/77 corresponded to the H3N2 subtype and affected mainly young people [10]. Most scientists do not consider the global spread of this virus as a pandemic due to the predominance of mild forms of the disease, low number of complications and low mortality rates. But since 1977, simultaneous circulation of two types of influenza A virus – H3N2 and H1N1 – has been observed in the human population [11]. Influenza pandemic of the 21st century. began in Mexico and then in the United States in 2009. The pathogen, named A/H1N1/California/04/2009, was a triple reassortant of human, swine and avian influenza viruses. The course of the disease was characterized by frequent development of respiratory failure and severe pneumonia [12]. During the 2009–2010 pandemic. influenza was laboratory confirmed in more than 622 thousand patients, the number of deaths was about 20 thousand.

Until recently, it was widely believed that, unlike the influenza A virus, the influenza B virus does not have the ability to change its antigenic structure, the disease is characterized by a relatively mild course, and the virus can only spread from person to person. However, data accumulated over the past decade have refuted this point of view. It has been proven that, by analogy with influenza A, the influenza B virus is also capable of changing its antigenic structure. Scientists have also discovered antibodies to the influenza B virus in animals, in particular in the common seal. The isolated strain of the pathogen was closely related to the one that circulated among people several years ago [13]. These discoveries expanded our understanding of the reservoirs of the influenza B virus and did not exclude the possibility of the emergence of reassortants, which in the future could pose a serious threat to humanity.

Two subtypes of influenza B virus, representing different antigenic variants (B/Victoria and B/Yamagata), have recently been circulating in the human population. Since 2000, influenza B viruses of these two lineages have been simultaneously registered almost all over the world [14].

A negative trend in the epidemic process in recent decades has been the increase in outbreaks of influenza B. Thus, before 1988, seasonal increases in incidence were observed every 3–4 years, and epidemic growth every 5–7 years [14]. Since the early 1990s, due to increased activity of the influenza B virus, epidemics in our country began to be recorded much more frequently (every 1–2 years). And since 1993, epidemics caused by the influenza B virus have occurred almost every year. As a rule, they begin after epidemic outbreaks of influenza A and occur in the middle - late spring [15].

In general, incidence rates of influenza A and B vary depending on the season and region. A clear age-related predisposition to certain types of influenza A and B has also been shown. For example, the influenza B virus more often affects children and adolescents. The non-pandemic variant of influenza A (H1N1) virus is predominant among young children. The pandemic strain of influenza A (H1N1) pdm09 virus causes severe pathology in patients 18–64 years of age, and the influenza A (H3N2) virus causes severe pathology in elderly people (over 65 years of age).

The opinion, which was widespread until recently, about the milder course and absence of fatal complications of influenza B, has been refuted by numerous studies. Comparative studies have shown that the severity of the main symptoms of viral infection, the risk of developing serious complications and adverse outcomes for these two types of influenza are practically indistinguishable among both children and adults [16, 17]. And some manifestations, such as vomiting, diarrhea, headache, severe general weakness, rhinitis, pharyngitis and otitis media, are more common with influenza B [18].

What properties does Oseltamivir have?

The drug was recommended by the FDA in 1999 for the treatment of acute respiratory diseases, and in 2009 it was approved by WHO. Oseltamivir is more often prescribed to people at risk of severe complications. The results of several studies have shown that in flu patients without chronic diseases, symptoms decrease faster in the first days than in other categories of patients. However, evidence-based medicine has not confirmed that taking the medicine prevents the transmission of infection between people. Relief comes due to the substance’s ability to effectively reduce acute symptoms, but not kill bacteria. Indications for use: influenza type A and B.

Oseltamivir - instructions for use and dosage

During an epidemic, it is recommended to take:

• for prevention - 75 mg 1-2 times a day for 1.5 months;
• when the first symptoms of flu appear - 2 rubles. 75 mg for 5 days;
• children over 8 years old - 1 time/day.

Only adolescents over 12 years of age, as well as adults, are prescribed, if necessary, to take capsules twice a day - morning and evening. Until the age of eight, doctors recommend a suspension.

When the dosage is increased to 150 mg, no improved effect is observed. Take regardless of food intake.

Pharmacodynamics

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

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.

Tamiflu significantly shortens the period of clinical manifestations of influenza infection, reduces their severity and reduces the incidence of influenza complications requiring the use of antibiotics (bronchitis, pneumonia, sinusitis, otitis media), shortens the time of virus isolation from the body and reduces the area under the “viral titer-time” curve .

In children aged 1 to 12 years, Tamiflu significantly reduces the duration of the disease (by 35.8 hours) and the incidence of acute otitis media. Recovery and return to normal activity occurs almost 2 days earlier.

When taken for the purpose of prevention, Tamiflu significantly (by 92%) reduces the incidence of influenza among contacted persons, by 76% - the frequency of clinically established influenza during an outbreak of the disease, reduces the frequency of virus isolation and prevents the transmission of the virus from one family member to another.

In children aged 1 to 12 years, preventive use of Tamiflu reduces the incidence of laboratory-confirmed influenza from 24 to 4%.

Tamiflu does not affect the formation of anti-influenza antibodies, incl. to produce antibodies in response to the administration of an inactivated influenza vaccine.

Resistance. When taking Tamiflu for the purpose of prophylaxis (7 days), prophylaxis of family contacts (10 days) and seasonal prophylaxis (42 days), no cases of drug resistance were observed.

In adult patients/adolescents, oseltamivir resistance was detected in 0.32% of cases (4/1245) using phenotyping and in 0.4% of cases (5/1245) using phenotyping and genotyping, and in children from 1 year to 12 years in 4.1% (19/464) and 5.4% (25/464) of cases, respectively. All patients had temporary carriage of an OS-resistant virus. This did not affect virus clearance.

Several different subtype-specific viral neuraminidase mutations have been discovered. The degree of sensitivity reduction depended on the type of mutation; for example, with the 1222V mutation in N1, sensitivity decreased by 2 times, and with R292K in N2, by 30,000 times. No mutations were found to reduce the sensitivity of influenza B virus neuraminidase in vitro.

In patients treated with oseltamivir, reported neuraminidase N1 mutations (including H5N1 viruses) leading to resistance/reduced susceptibility to OS were H274Y, N294S (1 case), E119V (1 case), R292K (1 case), and neuraminidase mutations 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 1 case, the D198N mutation was detected with a 10-fold decrease in sensitivity in a child with immunodeficiency.

Viruses with a resistant neuraminidase genotype differ in resistance to varying degrees from the natural strain. 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 natural strain. Viruses with the H274Y mutation in N1 and N294S in N2 occupy an intermediate position.

Side effects

Taking Oseltamivir is sometimes accompanied by negative symptoms:

• nausea;
• vomiting;
• abdominal pain;
• dizziness;
• sore throat;
• nasal congestion;
• increased anxiety;
• general malaise;
• insomnia;
• convulsions.

The drug is prescribed with extreme caution to children. At the first side effects, it is not recommended to take it. Marketing data from 2006 in Japan indicated that psychiatric abnormalities, thought disorders and other neurocognitive changes may occur.

Brand and are there any analogues?

Oseltamivir or oseltamivir is a drug known in Russia under the trade name Tamiflu. The Latin name of the active ingredient is oseltamivir. The crystalline substance is produced in the form of a white powder and capsules for suspension. During periods of widespread illness, children are recommended to make a solution, and adults to take capsules.

Oseltamivir - instructions on how to prepare a solution

It can be drunk at any time, regardless of meals.

1 Lightly tap the closed bottle to distribute the powder evenly.

2 Pour 52 ml of boiled and cooled water into a measuring cup.

3 Add the contents to the bottle, close and shake.

4 After removing the cap, insert the adapter into the neck of the bottle.

5 Tighten as tightly as possible.

It is recommended to mark the expiration date on the bottle. It is stored at room temperature for 10 days, and in the refrigerator for up to 17. Be sure to shake the bottle before taking it. The kit contains instructions for using Oseltamivir. Using a dosing syringe, draw the required amount of liquid: 30.45 or 60 mg.

Description of the dosage form

Capsules: hard, gelatin, size 2. Body - gray, opaque; the lid is light yellow, opaque. The contents of the capsules are white to yellowish powder. The capsule has the inscription “Roche” (on the body) and “75 mg” in light blue (on the cap).

Note: after 5 years of storage of the drug, signs of “aging” of the capsules may be observed, which can lead to their increased fragility or other physical impairments that do not affect the effectiveness and safety of the drug.

Powder for the preparation of a suspension for oral administration: granulate, from white to light yellow in color, with a fruity odor; clumping is allowed. After reconstitution, it forms an opaque suspension from white to light yellow (add about 52 ml of water to the bottle and shake vigorously for 15 seconds).

Analogs

In the pharmacy chain there are drugs whose active ingredient is oseltamivir.

• "Nomides";
• "Influcein".

There are other drugs that differ in composition, but are similar in pharmacological action. The most popular of them:

• "Cycloferon";
• "Ergoferon";
• "Isoprinosine."

Elements of similar drugs have an immunotropic effect. The substances in their composition, acting as a single mechanism, suppress viral activity, improve well-being and accelerate the healing process.

Use during pregnancy and breastfeeding

Category B. During preclinical studies, oseltamivir and the active metabolite were excreted into the milk of lactating rats. Whether oseltamivir or the active metabolite is excreted in human milk is unknown, but their amounts in breast milk may be 0.01 and 0.3 mg/day, respectively.

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

Consumer Opinions

Most buyers are inclined to purchase cheaper analogues, but forget that inexpensive raw materials are used in their manufacture. Such drugs may cause more side symptoms with relatively low effectiveness. The effectiveness of Oseltamivir has been proven over time. It effectively fights severe forms of the disease. With its help, bird flu, swine flu and other strains of viruses are successfully treated.

Patients who took Oseltamivir testify that in the acute form they recovered faster than other patients. People whose treatment began in the first two days after infection did not have any complications.

special instructions

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

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

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

When treating and preventing influenza in patients with creatinine Cl 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 Cl ≤10 ml/min.

A 30 g bottle of Tamiflu with powder for preparing a suspension contains 25.713 g of sorbitol. When taking 45 mg of Tamiflu 2 times a day, 2.6 g of sorbitol enters the body. In patients with congenital fructose intolerance, this amount exceeds the daily norm of sorbitol.

After preparation, store the suspension at a temperature of 2–8 °C for 17 days or at a temperature not exceeding 25 °C for 10 days.

Do not use the suspension after the expiration date.

Other reviews

• During a period of mass illness, the flu struck the entire family. On time, on the doctor’s recommendation, we began taking the antiviral drug Oseltamivir. No adverse reactions or serious complications were observed.
• After the temperature rose, I started taking Tamiflu. 5 days passed and the flu subsided. The condition improved and the symptoms no longer appeared. The treatment took place without side complications.
• The child was given a prescription by his pediatrician, but after the first dose he started vomiting. He felt sick. We were forced to change the drug.

Self-medication is a dangerous activity. Oseltamivir is an effective drug, but its effects are often accompanied by a negative reaction of the body to the substances, so the drug should be used only after approval by the doctor. It is known that Tamiflu does not treat ARVI.

Interaction

Clinically significant drug interactions are unlikely. Drug interactions due to competition and binding to the active sites 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 give reason to assume the presence of interactions associated with the displacement of drugs from binding to proteins.

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

There are no reasons for interaction with oral contraceptives.

Cimetidine, a nonspecific inhibitor of cytochrome P450 isoenzymes, amoxicillin and paracetamol do not affect plasma concentrations of oseltamivir and its active metabolite.

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

When Tamiflu is prescribed together with ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), histamine H2 receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol) no changes in the nature or frequency of adverse events were observed.