Instructions Flucap capsules 75 mg blister No. 10
Composition
active ingredient: oseltamivir;
1 capsule contains oseltamivir phosphate equivalent to oseltamivir 75 mg.
Excipients: pregelatinized starch, croscarmellose sodium, povidone, talc, sodium stearyl fumarate, hard gelatin capsules.
capsule shell: red iron oxide, yellow iron oxide, black iron oxide, titanium dioxide, gelatin, blue ink.
Dosage form
Capsules.
Main physicochemical properties: hard gelatin capsules size "2" with an opaque light yellow cap and an opaque gray body with blue ink inscription "H" on the cap and "5" on the body, filled with white or almost white granular powder.
Pharmacotherapeutic group
Antivirals for systemic use. Direct-acting antivirals. Neuraminidase inhibitors. Oseltamivir. ATC code J05A H02.
Pharmacological properties
Pharmacodynamics
Oseltamivir phosphate is a prodrug of the active metabolite (oseltamivir carboxylate), which is a selective inhibitor of the influenza virus neuraminidase enzyme, a glycoprotein found on the surface of the virion. The activity of the influenza virus neuraminidase enzyme is essential for the entry of the virus into uninfected respiratory epithelial cells and the release of newly formed viral particles from infected cells and subsequent spread of the virus in the body.
Oseltamivir carboxylate inhibits influenza A and B neuraminidase in vitro. Oseltamivir phosphate inhibits influenza virus and influenza virus replication in vitro. When administered orally, oseltamivir inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of influenza infection at antiviral concentrations similar to those 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 involving healthy volunteers.
The IC50 values of oseltamivir for the neuraminidase enzyme of clinical isolates of influenza A viruses ranged from 0.1 nmol to 1.3 nmol, and for influenza B viruses it was 2.6 nmol. In published studies, higher IC50 values were noted for influenza B viruses, with a median of 8.5 nmol.
Pharmacokinetics
Absorption
After oral administration, oseltamivir phosphate (prodrug) is readily absorbed from the gastrointestinal tract and is extensively converted to the active metabolite (oseltamivir carboxylate), primarily by hepatic esterases. At least 75% of an oral dose reaches the systemic circulation as the active metabolite, and less than 5% as the prodrug. Plasma concentrations of both the prodrug and the active metabolite are dose-proportional and therefore independent of food intake.
Distribution
In humans, the mean steady-state volume of distribution of oseltamivir carboxylate is approximately 23 L, which is equivalent to the volume of extracellular body fluid. Because neuraminidase activity is extracellular, oseltamivir carboxylate reaches all major sites of influenza infection.
The binding of oseltamivir carboxylate to human plasma proteins is low (approximately 3%).
Metabolism
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, which are predominantly found in the liver. Neither oseltamivir 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 oseltamivir carboxylate declines with a half-life of 6–10 hours. The active metabolite is excreted entirely (> 99%) 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.
Other special groups.
Children aged 1 year and over
The pharmacokinetics of oseltamivir have been studied in children aged 1 to 16 years in a single-dose pharmacokinetic study and a small number of multiple-dose clinical efficacy studies in children. In younger children, the elimination of prodrugs and the active metabolite occurred more rapidly than in adults, resulting in lower exposures expressed 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 75 mg dose (equivalent to approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to those in adults.
Steady-state exposure to the active metabolite was 25-35% higher in elderly subjects (aged 65 to 78 years) than in adults younger than 65 years receiving comparable doses of oseltamivir. The elimination half-life in elderly subjects was similar to that in younger subjects. Based on drug exposure and tolerability, no dose adjustment is required in the elderly unless there is moderate or severe renal impairment (creatinine clearance less than 60 mL/min) (see Dosage and Administration).
Kidney dysfunction
Administration of 100 mg oseltamivir phosphate twice daily for 5 days to 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.
Liver dysfunction
In vitro studies have shown that neither a significant increase in oseltamivir exposure nor a significant decrease in exposure to the active metabolite is expected in patients with hepatic impairment (see section 4.2).
Pregnant women
A pooled population pharmacokinetic analysis suggests that the oseltamivir phosphate dosing regimen described in the Dosage and Administration section results in lower exposure (on average 30% across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. The lower predicted exposure, however, remains above the inhibitory concentrations (IC95) and therapeutic levels for a range of influenza virus strains. In addition, there is evidence from observational studies that suggests a benefit of this dosing regimen in this patient population. Therefore, no dose adjustment is necessary for pregnant women for the treatment or prevention of influenza (see Use during pregnancy and lactation).
Indication
Flu treatment
Flucap is indicated for adults and children aged 1 year and over who have symptoms consistent with influenza during the influenza virus's circulation. Efficacy has been demonstrated when treatment is initiated within two days of symptom onset.
Flu prevention
Prevention of influenza in adults and children aged 1 year and older after contact with a person with clinically diagnosed influenza during the circulation of the influenza virus. The appropriate use of Flucap for the prevention of influenza should be determined on a case-by-case basis, taking into account the circumstances and the patient group 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 children aged 1 year and older.
The use of Flucap 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. Co-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.
Renal excretion
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
In phase III clinical trials of oseltamivir for the treatment and prevention of influenza, oseltamivir phosphate 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 Flucap was used together with the listed drugs, changes in the safety profile and the frequency of adverse reactions were not 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 Flucap does not replace influenza vaccination. The use of Flucap should not affect the screening of individuals for annual influenza vaccination. Protection against influenza continues only while taking Flucap. Flucap should be used for the treatment and prevention of influenza only when there is reliable epidemiological data indicating that the virus is circulating. It has been demonstrated that the susceptibility of circulating influenza virus strains to Flucap is highly variable, therefore the physician should consider the most recent information on the susceptibility to oseltamivir of currently circulating viruses before making a decision to use Flucap.
Severe skin reactions and hypersensitivity reactions
Cases of anaphylaxis and severe skin reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, have been reported during post-marketing use of oseltamivir. Flucap 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 Flucap for treatment and prophylaxis is recommended for adults and adolescents (≥13 - <18 years) with severe renal impairment. There are insufficient clinical data on use in children aged 1 year and older with renal impairment to make dosage recommendations (see sections “Method of administration and dosage”, “Pharmacokinetics”).
Neuropsychiatric disorders
Neuropsychiatric disorders have been reported in patients with influenza (predominantly children and adolescents) treated with oseltamivir. Such disorders have also been reported in patients with influenza who did not receive this drug. Patients should be closely monitored for behavioral changes, and the benefits and risks of continued treatment should be carefully weighed for each patient (see section 4.8).
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, use a so-called waste collection system, if available.
Ability to influence reaction speed when driving vehicles or other mechanisms
Flucap has no effect on the reaction speed when driving or using other mechanisms.
Use during pregnancy or breastfeeding
Pregnancy
Controlled clinical studies on the use of oseltamivir in pregnant women have not been conducted, data on use during pregnancy were obtained from post-marketing and observational studies (see sections "Pharmacodynamics" and "Pharmacokinetics"). The data obtained and the results of studies in animals indicate the absence of direct or indirect harmful effects on pregnancy, embryonal/fetal development and postnatal development. Flucap can be prescribed to pregnant women taking into account the available information on safety, pathogenicity of the circulating influenza virus strain and the condition of the pregnant woman.
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 oseltamivir on male or female fertility.
Method of administration and doses
Method of application
For oral use.
Dosage
Doses of 75 mg can be taken as:
1 capsule of 75 mg, or 1 capsule of 30 mg plus 1 capsule of 45 mg.
Adults and adolescents aged 13 and over
Treatment. The recommended dosage regimen of Flucap 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 of Flucap for post-exposure prophylaxis is 75 mg orally once daily for 10 days in 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 daily for 6 weeks.
Children aged ≥ 1 – <13 years.
The recommended dose for prevention during a seasonal flu epidemic is 75 mg once a day for 6 weeks.
Treatment: The recommended doses of oseltamivir based on body weight are given in the table:
| Body weight | Recommended dose for 5 days |
| 10 kg to 15 kg | 30 mg 2 times a day |
| > 15 kg to 23 kg | 45 mg twice daily |
| > 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.
Post-exposure prophylaxis. The recommended dose of oseltamivir for post-exposure prophylaxis based on body weight is given in the table:
| Body weight | Recommended dose for 10 days |
| 10 kg to 15 kg | 30 mg once daily |
| > 15 kg to 23 kg | 45 mg once daily |
| > 23 kg to 40 kg | 60 mg once daily |
| > 40 kg | 75 mg once daily |
Prophylaxis during seasonal influenza epidemics. Prophylaxis during seasonal influenza epidemics in children under 12 years of age has not been studied.
Dosage in special cases
Patients with hepatic impairment
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. The dose adjustments for oseltamivir required for adults and adolescents (≥ 13 - < 18 years) with moderate or severe renal impairment are given in the table below:
| Creatinine clearance | Recommended dose for prevention |
| > 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 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 |
* 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 prevention. The dose adjustment of oseltamivir required for adults and adolescents (≥13 - <18 years) with moderate or severe renal impairment is shown in the table:
| 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 |
There are insufficient data to make dosage recommendations for children under 12 years of age with renal impairment.
Elderly patients
No dose adjustment is necessary, except in the presence of moderate or severe renal impairment.
Immunocompromised patients
Seasonal influenza prophylaxis 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 with Flucap have been received during clinical trials and during post-marketing use of the drug. In most 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 Flucap (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 using Flucap in children.
Adverse reactions
In adults/adolescents taking oseltamivir for the treatment of influenza, the most common adverse events 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). 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 oseltamivir 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 reported in patients receiving oseltamivir for 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;
mental disorders: rarely common - agitation, abnormal behavior, anxiety, confusion, delusions, delirium, hallucinations, nightmares, self-harm;
Nervous system disorders: very common – headache; common – insomnia; uncommon – impaired consciousness, convulsions;
On the part of the organs of vision: rarely - visual impairment;
Cardiac disorders: uncommon – cardiac arrhythmias;
Respiratory, thoracic and mediastinal disorders: common – cough, rhinorrhea, sore throat;
Gastrointestinal: very common - nausea; common - vomiting, abdominal pain (including upper), dyspepsia; rare - gastrointestinal bleeding, hemorrhagic colitis;
Hepatobiliary system: uncommon – increased liver enzymes; rare – fulminant hepatitis, hepatic failure, hepatitis;
Skin and subcutaneous tissue disorders: uncommon – dermatitis, rash, eczema, urticaria; rare – angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown – allergy, facial swelling;
General disorders and administration site conditions: common: dizziness (including vertigo), weakness, pain, hyperthermia, pain in extremities.
Treatment and prevention of influenza in children
The most common adverse reactions that have been reported in studies of oseltamivir for the treatment and prevention of influenza in children (when using age-based dosing - from 30 mg to 75 mg 1 time per day):
Infections and infestations: common – otitis media; frequency unknown – bronchitis, pneumonia, sinusitis;
Nervous system: common – headache;
Blood and lymphatic system disorders: frequency unknown – lymphadenopathy;
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 receiving oseltamivir. These events have occurred primarily 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 oseltamivir, as neuropsychiatric disorders have also been reported in patients with influenza who did not receive this 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, e.g. 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.
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
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ºС, out of the reach of children.
Packaging
10 capsules in a blister. 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
Hetero Labs Limited.
Location of the manufacturer and its business address
Unit III, Formulation Plot No. 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.
