capsule composition: red iron oxide (E 172), yellow iron oxide (E 172), black iron oxide (E 172), titanium dioxide (E 171), gelatin, purified water.
Dosage form
The capsules are hard.
Main physicochemical properties:
30 mg: hard gelatin capsules No. 4 with a light yellow cap and body, marked in blue with “30 mg” on the cap and “M 53” on the body, containing white to almost white granules;
45 mg: hard gelatin capsules No. 4 with a gray cap and body, marked in blue with “45 mg” on the cap and “M 54” on the body, containing white to almost white granules;
75 mg: hard gelatin capsules No. 2 with a light yellow cap and a gray body, marked in blue with “75 mg” on the cap and “M 55” on the body, containing white to off-white granules.
Oseltamivir phosphate is a prodrug of the active metabolite (oseltamivir carboxylate), which selectively inhibits influenza virus neuraminidase, an enzyme that catalyzes the process of releasing newly formed viral particles from infected cells, their penetration into uninfected cells, and the subsequent spread of the virus in the body.
Oseltamivir carboxylate inhibits neuraminidase of influenza A and B viruses in vitro. Oseltamivir phosphate inhibits viral replication and pathogenicity in vitro. Oseltamivir when administered orally inhibits the replication of influenza A and B viruses and pathogenicity in animal models of influenza infection in vivo at antiviral exposures achieved in humans at a dose of 75 mg twice daily.
The antiviral activity of oseltamivir has been confirmed against influenza A and B viruses in experimental studies in healthy volunteers.
The IC50 values of oseltamivir for the neuraminidase enzyme of clinical isolates of influenza A viruses ranged from 0.1 to 1.3 nM and for influenza B viruses were 2.6 nM. Published data have reported higher IC50 values for influenza B viruses with a median of 8.5 nM.
Pharmacokinetics.
Absorption
After oral administration, oseltamivir phosphate is readily absorbed from the gastrointestinal tract and is extensively converted to the active metabolite (oseltamivir carboxylate) by hepatic esterases. At least 75% of an oral dose reaches the systemic circulation as the active metabolite, and less than 5% as the parent drug. Plasma concentrations of both the prodrug and the active metabolite are dose-proportional and therefore independent of food intake.
Distribution
In humans, the mean volume of distribution of the active metabolite at steady state is approximately 23 L, a volume equivalent to the volume of extracellular body fluid. Because the neuraminidase activity is extracellular, oseltamivir carboxylate reaches all major sites of influenza infection.
The binding of the active metabolite to human plasma proteins is low (approximately 3%).
Metabolism
Oseltamivir phosphate is extensively converted to oseltamivir carboxylate by esterases, which are predominantly found in the liver. Neither oseltamivir phosphate nor the active metabolite are substrates or inhibitors of cytochrome P450 isoenzymes in in vitro studies. No phase 2 conjugates for either compound were detected in vivo.
Breeding
Absorbed oseltamivir is eliminated primarily (> 90%) by conversion to oseltamivir carboxylate, which is not further transformed and is excreted in the urine. In most patients, the maximum plasma concentration of the active metabolite declines with a half-life of 6–10 hours. The active metabolite is excreted entirely by the kidneys. Renal clearance (18.8 l/h) exceeds glomerular filtration rate (7.5 l/h), indicating that the drug is also excreted by tubular secretion. Less than 20% of the administered radiolabeled drug is excreted in the feces.
Pharmacokinetics in special groups.
The pharmacokinetics of oseltamivir have been studied in children aged 1 to 16 years in a single-dose pharmacokinetic study. Multiple-dose pharmacokinetics have been studied in a small number of children in a clinical efficacy study. In younger children, elimination of the prodrug and active metabolite occurred more rapidly than in adults, resulting in lower exposures on a mg/kg basis. A dose of 2 mg/kg provides the same exposure to oseltamivir carboxylate as that achieved in adults after a single dose of 75 mg (equivalent to approximately 1 mg/kg body weight). The pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to those in adults.
Elderly patients
In elderly patients (65–78 years), the exposure of the active metabolite at steady state is 25–35% higher than in younger patients (< 65 years) when using similar doses of oseltamivir. The half-life of the drug in elderly patients is not significantly different from that in younger patients. Based on drug exposure and tolerability, no dose adjustment is necessary in elderly patients, except in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min) (see section "Method of administration and dosage").
Patients with kidney damage
Administration of oseltamivir phosphate 100 mg twice daily for 5 days in patients with varying degrees of renal impairment demonstrated that oseltamivir carboxylate exposure is inversely proportional to the decrease in renal function. For dosage, see section 4.2.
Patients with liver damage
Based on in vitro studies, neither a significant increase in oseltamivir exposure nor a significant decrease in the exposure of the active metabolite of oseltamivir is expected in patients with hepatic impairment (see section 4.2).
Pregnant women
A pooled population pharmacokinetic analysis indicates that the dosing regimen described in the Dosage and Administration section results in lower exposure (on average 30% across all trimesters) of the active metabolite in pregnant women compared to non-pregnant women. However, the predicted lower exposure remains above the inhibitory concentrations (IC95 values) and therapeutic influenza strain ranges. In addition, observational data suggest a benefit of the current dosing regimen in this patient population. Therefore, no dose adjustment is recommended for pregnant women for the treatment or prevention of influenza (see Use during pregnancy and lactation).
Indication
Flu treatment
The drug is indicated for adults and children aged 1 year and older who have symptoms of influenza during the period of influenza virus circulation. Efficacy has been demonstrated when treatment is initiated within 2 days of the first onset of symptoms.
Flu prevention
- prevention of influenza in adults and children aged 1 year and older after contact with a person with clinically diagnosed influenza during influenza virus circulation;
- the appropriate use of the drug for the prevention of influenza should be determined on a case-by-case basis, taking into account the circumstances and the patient population requiring protection. In exceptional situations (e.g. in case of discrepancies between the circulating influenza virus and the influenza virus against which vaccination was carried out and during a pandemic), seasonal prophylaxis can be carried out in persons aged 1 year and older.
The use of the drug does not replace vaccination against influenza.
The use of antivirals for the treatment and prevention of influenza should be based on official recommendations. The decision to use oseltamivir for treatment and prevention should take into account the characteristics of circulating influenza viruses, available information on the susceptibility of influenza viruses to drugs in each season, the impact of the disease in different geographical regions and patient groups.
Contraindication
Hypersensitivity to oseltamivir phosphate or to any component of the drug.
Interaction with other medicinal products and other types of interactions
The pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant interactions with other medicinal products are unlikely.
Probenecid
No dose adjustment is required when oseltamivir and probenecid are co-administered in patients with normal renal function. Concomitant administration of probenecid, a potent inhibitor of the anion pathway of renal tubular secretion, approximately doubles the exposure to the active metabolite of oseltamivir.
Amoxicillin
Oseltamivir does not show a kinetic interaction with amoxicillin, which is eliminated by the same pathway as oseltamivir, indicating a weak interaction with oseltamivir via this pathway.
Clinically significant interactions with other drugs involving competition for renal tubular secretion are unlikely due to the known safety margins of most of these drugs, the elimination characteristics of the active metabolites (glomerular filtration and anionic tubular secretion), and the volume of excretion by these routes. However, caution should be exercised when prescribing oseltamivir to patients taking drugs with a similar excretion pathway and a narrow therapeutic index (e.g., chlorpropamide, methotrexate, phenylbutazone).
Additional information
Pharmacokinetic interactions between oseltamivir and its active metabolite when co-administered with paracetamol, acetylsalicylic acid, cimetidine and antacids (magnesium hydroxide and aluminum hydroxide, calcium carbonate), rimantadine or warfarin (in patients on stable doses of warfarin and not sick with influenza) have not been identified.
In phase III clinical trials of oseltamivir for the treatment and prevention of influenza, the drug was administered with commonly used drugs, such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporin, azithromycin, erythromycin and doxycycline), H2-receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine), corticosteroids, inhaled bronchodilators, analgesics (acetylsalicylic acid, ibuprofen and paracetamol). When Seltavir was used together with the listed drugs, no changes in the safety profile and frequency of adverse reactions were recorded.
There is no mechanism of interaction with oral contraceptives.
Application features
Oseltamivir is effective only against diseases caused by influenza viruses. There are no data on the effectiveness of oseltamivir in any diseases caused by pathogens other than influenza viruses.
The use of the drug does not replace vaccination against influenza. The use of the drug should not affect the screening of individuals for annual vaccination against influenza. Protection against influenza lasts only while taking the drug. Seltavir should be used for the treatment and prevention of influenza only when there is reliable epidemiological data indicating the circulation of the virus. It has been demonstrated that the susceptibility of circulating strains of influenza virus to the drug is highly variable, so the doctor should take into account the latest information on the susceptibility of currently circulating viruses to oseltamivir before making a decision on the use of the drug.
Severe skin reactions and hypersensitivity reactions
During post-marketing use, cases of anaphylaxis and severe skin reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, have been reported. Seltavir should be discontinued and appropriate treatment instituted if such reactions are observed or suspected.
Severe comorbidities
There is no information on the safety and efficacy of oseltamivir in patients with severe or unstable illness at imminent risk of hospitalization.
Immunocompromised patients
The safety and efficacy of oseltamivir for the treatment and prevention of influenza in immunocompromised patients have not been established.
Heart/respiratory disease
The efficacy of oseltamivir in the treatment of individuals with chronic heart and/or respiratory disease has not been established. In such patients, no difference in the incidence of complications was observed between the treatment and placebo groups.
Severe renal failure
Dose adjustment of the drug for treatment and prophylaxis is recommended for adults and adolescents (≥13 - <18 years) with severe renal impairment. There are insufficient clinical data on the use of the drug in children aged 1 year and older with renal impairment to make dosage recommendations (see sections "Pharmacokinetics", "Method of administration and dosage").
Neuropsychiatric disorders
Cases of neuropsychiatric disorders have been reported in influenza patients (mainly children and adolescents) using the drug. Such disorders have also been reported in influenza patients who did not use the drug. Patients should be closely monitored for behavioral changes, and the benefits and risks of continued treatment should be carefully assessed for each patient (see section "Adverse reactions").
Disposal of unused and expired medicinal products. Release of medicinal products into the environment should be minimised. The medicinal product should not be disposed of in wastewater or household waste. For disposal, a so-called waste collection system should be used (if available).
Use during pregnancy or breastfeeding
Pregnancy
The data obtained and the results of animal studies indicate no direct or indirect harmful effects on the course of pregnancy, embryonal/fetal development and postnatal development. Pregnant women can use the drug taking into account the available safety information, the pathogenicity of the circulating influenza virus strain and the condition of the pregnant woman after assessing the benefit/risk ratio.
Breastfeeding period
In lactating rats, oseltamivir and its active metabolite are excreted in human milk. There is limited information on breastfeeding in women taking oseltamivir and on the excretion of oseltamivir in human milk. Limited data demonstrate that oseltamivir and its active metabolite have been detected in human milk, but their levels were low, which may result in subtherapeutic doses to the infant. Given these data, as well as the pathogenicity of the circulating influenza virus strain and the condition of the nursing woman, the use of oseltamivir may be considered after assessing the benefit/risk ratio.
Fertility
Based on preclinical data, there is no evidence of an effect of the drug on male or female fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
No effect.
Method of administration and doses
Method of application
For oral use.
Dosage
The drug at a dose of 75 mg can be used as:
– 1 capsule of 75 mg or
– 1 capsule of 30 mg and plus one capsule of 45 mg.
Adults and adolescents aged 13 and over
Treatment. The recommended dosage regimen of the drug is 1 capsule of 75 mg 2 times a day orally for 5 days for adults and adolescents (≥13 - <18 years) with a body weight of more than 40 kg.
Treatment should be started on the first or second day of flu symptoms.
Post-exposure prophylaxis. The recommended dose for post-exposure prophylaxis is 75 mg orally once daily for 10 days for adults and adolescents (≥13–<18 years) weighing more than 40 kg. The drug should be started no later than 2 days after exposure.
Prevention during seasonal influenza epidemics. The recommended dose for prevention during seasonal influenza epidemics is 75 mg once a day for 6 weeks.
Children aged ≥1 – <13 years.
Treatment. Recommended dosage regimen with weight adjustment for the treatment of infants and children aged 1 year and older
Body weight
Recommended dose for 5 days
From 10 kg to 15 kg
30 mg 2 times a day
> 15 kg to 23 kg
45 mg 2 times a day
> 23 kg to 40 kg
60 mg 2 times a day
> 40 kg
75 mg 2 times a day
Treatment should be started as soon as possible, on the first or second day of flu symptoms.
Prevention during seasonal influenza epidemics. Prevention during seasonal influenza epidemics in children under 12 years of age has not been studied.
Dosage in special cases
Patients with liver dysfunction
No dose adjustment is necessary for treatment or prophylaxis in patients with hepatic impairment. The safety and pharmacokinetics of oseltamivir have not been studied in children with hepatic impairment.
Patients with renal impairment
Treatment of influenza: Dose adjustment is required in adults and adolescents (≥13 - <18 years) with moderate or severe renal impairment (see Table 1).
Table 1
Creatinine clearance
Recommended dose for treatment
> 60 ml/min
75 mg 2 times a day
> 30 to 60 ml/min
30 mg 2 times a day
> 10 to 30 ml/min
30 mg once daily
≤ 10 ml/min
not recommended (data not available)
patients on hemodialysis
30 mg after each hemodialysis session
patients on peritoneal dialysis*
30 mg once
* Data from studies in patients on continuous ambulatory peritoneal dialysis (CAPD); clearance of oseltamivir carboxylate is expected to be higher when using automated continuous cyclic peritoneal dialysis (CCPD). The treatment regimen may be changed from CCPD to CAPD if deemed necessary by the nephrologist.
Influenza prophylaxis: Dose adjustment is required for adults and adolescents (≥13 - <18 years) with moderate or severe renal impairment (see Table 2).
Table 2
Creatinine clearance
Recommended dose for prevention
> 60 ml/min
75 mg once daily
> 30 to 60 ml/min
30 mg once daily
> 10 to 30 ml/min
30 mg every other day
≤ 10 ml/min
not recommended (data not available)
patients on hemodialysis
30 mg after every second hemodialysis session
patients on peritoneal dialysis*
30 mg once a week
* Data from studies in patients on PAPD; oseltamivir carboxylate clearance is expected to be higher with automated PCPD. Treatment regimen may be changed from PCPD to PAPD if deemed necessary by the nephrologist.
There are insufficient data to make dosage recommendations for children with renal impairment under 12 years of age.
Elderly patients
No dose adjustment is necessary, except in the presence of moderate or severe renal impairment.
Immunocompromised patients
Treatment: The recommended oral dose is 75 mg of oseltamivir twice daily for 10 days for adults. Treatment should be started as soon as possible within the first two days after the onset of flu symptoms.
Seasonal prophylaxis. Seasonal prophylaxis of influenza for 12 weeks is recommended in immunocompromised patients (see sections “Special warnings and precautions for use”, “Adverse reactions”).
Children.
Use in children over 1 year of age with a body weight of more than 10 kg who are able to swallow the capsule.
Overdose
Reports of overdose have been received during clinical trials and during post-marketing use of the drug. In the majority of cases of overdose, no adverse reactions were reported.
Adverse reactions reported in overdose were similar in nature and type to those observed with therapeutic doses of the drug (see section "Adverse reactions").
There is no specific antidote.
Children
Overdose has been reported more frequently in children than in adults and adolescents. Caution should be exercised when administering the drug to children.
Adverse reactions
The overall safety profile of the drug is based on influenza treatment data in 6049 adults/adolescents and 1473 children treated with the drug or placebo, and influenza prevention data in 3990 adults/adolescents and 253 children treated with the drug or placebo in clinical trials. In addition, 475 immunocompromised patients (including 18 children, 10 in the drug group, 8 in the placebo group) received Seltavir or placebo for influenza prevention.
In adults/adolescents, the most common adverse events when taking the drug for the treatment of influenza were nausea and vomiting, and for the prevention of influenza - nausea. They were transient and usually occurred on the first or second day of treatment and disappeared after 1-2 days. In children, the most common adverse event was vomiting. In most cases, adverse reactions did not lead to discontinuation of the drug.
The following serious adverse reactions have been reported rarely during post-marketing use of oseltamivir: anaphylactic and anaphylactoid reactions, liver disorders (hepatitis fulminant, liver function abnormalities and jaundice), angioedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders (for neuropsychiatric disorders, see section 4.4).
The following categories were used to describe the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency unknown. Adverse reactions are assigned to a specific category based on the analysis of pooled clinical trial data.
Treatment and prevention of influenza in adults and adolescents
The most common adverse reactions that have been reported in studies of the use of the drug for the treatment and prevention of influenza in adults and adolescents and in the post-marketing period when using the recommended dose (75 mg 2 times a day for 5 days for treatment and 75 mg 1 time a day for up to 6 weeks for prevention) are listed below.
The safety profile observed in patients receiving prophylaxis (75 mg once daily for up to 6 weeks) was similar to that observed in treatment studies, despite the longer duration of the prophylaxis studies:
infections and invasions: common – bronchitis, herpes simplex, upper respiratory tract infections, nasopharyngitis, sinusitis;
Blood and lymphatic system disorders: rarely – thrombocytopenia;
Immune system disorders: uncommon – hypersensitivity reaction; rare – anaphylactic and anaphylactoid reactions;
General disorders and administration site conditions: common: dizziness (including vertigo), weakness, pain, hyperthermia, pain in extremities.
Treatment and prevention of influenza in children
A total of 1473 children (including healthy children aged 1–12 years and children with asthma aged 6–12 years) participated in clinical trials of oseltamivir for the treatment of influenza. Of these, 851 children were treated with oseltamivir suspension. A total of 158 children received the recommended dose once daily in the home-based post-exposure prophylaxis studies (n=99), the 6-week seasonal prophylaxis studies (n=49), and the 12-week seasonal prophylaxis studies in immunocompromised children (n=10).
The most common adverse reactions that have been reported in studies of the use of the drug for the treatment and prevention of influenza in children (when using age-based dosages - from 30 to 75 mg once a day):
Infections and infestations: common – otitis media; frequency unknown – bronchitis, pneumonia, sinusitis;
Nervous system: common – headache;
Blood and lymphatic system disorders: frequency unknown – lymphadenopathy;
Visual disturbances: common – conjunctivitis (including eye redness, eye discharge and pain);
From the side of the organs of hearing and vestibular apparatus: common - earache; uncommon - disorders of the eardrum;
Respiratory, thoracic and mediastinal disorders: very common – cough, nasal congestion; common – rhinorrhea; frequency unknown – asthma (including exacerbation), epistaxis;
Gastrointestinal: very common – vomiting; common – nausea, abdominal pain (including upper), dyspepsia; frequency unknown – diarrhea;
Skin and subcutaneous tissue disorders: uncommon – dermatitis (including allergic and atopic dermatitis).
Description of selected adverse reactions
Mental and neurological disorders
Influenza can be associated with neuropsychiatric disorders, manifested by hallucinations, delirium, and inappropriate behavior, in some cases with fatal outcomes. These phenomena may be observed as a manifestation of encephalitis or encephalopathy, but may occur without obvious severe illness.
Convulsions and delirium (including altered level of consciousness, confusion, inappropriate behavior, delusions, hallucinations, agitation, anxiety, nightmares), which in isolated cases resulted in accidental self-harm or death, have also been reported in patients with influenza while taking the drug. These events have been reported mainly in children and adolescents and often have had a sudden onset and rapid resolution. It is not known whether neuropsychiatric disorders are associated with the use of the drug, as neuropsychiatric disorders have also been reported in patients with influenza who did not take the drug.
Hepatobiliary disorders
Hepatobiliary disorders, including cases of hepatitis and elevated liver enzymes, have been observed in patients with influenza-like illness. These cases included fatal fulminant hepatitis/hepatic failure.
Additional information about specific patient groups
Elderly patients and patients with chronic heart and respiratory diseases
The study population for the treatment of influenza included healthy adults/adolescents and patients with risk factors (patients at increased risk of developing complications associated with influenza, such as elderly patients and patients with chronic heart or respiratory diseases). Overall, the safety profile in adolescents and adults with chronic heart and/or respiratory diseases was qualitatively comparable to that in healthy volunteers.
Immunocompromised patients
In a 12-week prophylaxis study in 475 immunocompromised individuals, including 18 children aged 1-12 years, the safety profile in 238 patients treated with oseltamivir was comparable to that observed in clinical trials of the drug for prophylaxis.
Children with bronchial asthma
Overall, the adverse reaction profile in children with bronchial asthma was qualitatively comparable to that in children healthy with respect to other diseases.
Expiration date
5 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging
10 capsules in a blister. 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
McLeods Pharmaceuticals Limited.
Location of the manufacturer and address of its place of business
Village Theda, PO Lodhimaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.
Specifications
Characteristics
Active ingredient
Oseltamivir
Adults
Can
ATC code
J ANTIMIBRICANTS FOR SYSTEMIC USE; J05 ANTIVIRALS FOR SYSTEMIC USE; J05A DIRECT-ACTING ANTIVIRALS; J05A H Neuraminidase inhibitors; J05A H02 Oseltamivir
Country of manufacture
India
Diabetics
Can
Dosage
75 мг
Drivers
Can
For allergies
With caution
For children
From the 1st year
Form
Capsules
Method of application
Inside, solid
Nursing
Considering the benefit/risk ratio
Pregnant
Considering the benefit/risk ratio
Producer
McLeods Pharmaceuticals
Quantity per package
10 pcs
Series/Line
For children
Trade name
Seltavir
Vacation conditions
By prescription
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