Tamiflu (Oseltamivir) 10 Capsules

4.1. Therapeutic indications

TAMIFLU is indicated for the treatment and treatment of influenza and avian influenza prophylaxis and treatment in older children (1) and adults (see section 4.4 and section 5.3).
4.2. Posology and application form

Posology / application frequency and duration:

Standard dose for influenza treatment

Treatment should be initiated on the first or second day of symptoms of influenza. - Adults and adolescents (13-17 year olds):

Adults and adolescents> 13 years of age may be treated with a 75 mg capsule or a 30 mg capsule and a 45 mg capsule twice daily for 5 days. Adults who can not swallow capsules and adolescents> 13 years of age may receive 75 mg TAMIFLU suspension twice daily for 5 days.

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral ATC code: J05AH02

Oseltamivir phosphate is a prodrug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of the influenza virus neuraminidase enzymes, which are glycoproteins present on the virion surface. Viral neuraminidase enzyme activity is important both for viral entry into uninfected cells, release of newly formed virus particles from infected cells, and increased spread of the contagious virus in the body.

Oseltamivir carboxylate blocks neuraminidase enzymes of influenza A and B viruses in vitro. Oseltamivir phosphate inhibits influenza virus infection and its replication in vitro. Orally given oseltamivir inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of antiviral influenza infection, and this effect is similar to that obtained in humans with 75 mg twice daily.

Oseltamivirin antiviral activity has been supported for influenza A and B in experimental studies in healthy volunteers.

The oseltamivirin neuroaminidase enzyme IC50 values ​​are between 0.1 nM and 1.3 nM for clinically isolated influenza and 2.6 nM for influenza B, respectively. High IC50 values ​​(mean 8.5 nM) for Influenza B were observed in published studies.

Decreased sensitivity of viral neuraminidase

There is no evidence of drug resistance associated with TAMIFLU use in clinical trials conducted to date after exposure to the disease (7 days), after exposure (10 days), and seasonally (42 days) for influenza No resistance was observed in the 12-week prophylaxis trial in immunocompromised patients.

Oseltamivir has been investigated in clinical trials conducted by Roche with the risk of the emergence of influenza viruses with reduced susceptibility or increased resistance. All patients with oseltamivir-resistant viruses have normally cleared the virus and have not experienced any clinical deterioration.

Resistance may be higher in younger patient groups and in immunocompromised individuals. Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza virus include mutations in N1 and N2 neuraminidases. Resistance mutations tend to be specific to the viral subtype (including in H5N1 variants).

Naturally occurring influenza A / H1N1 virus mutations are associated with decreased sensitivity to oseltamivir in vitro and were detected in patients who did not use oseltamivir, based on reported data. The rate of decrease in oseltamivir susceptibility and the prevalence of these viruses varies seasonally and geographically.

Treatment of Influenza infection

Oseltamivir is only effective against diseases caused by influenza virus. For this reason, statistical analysis is presented only for subjects infected with influenza. In the pooled treatment study population (ITT), which included both influenza-positive and influenza-negative subjects, the primary efficacy decreased in proportion to the number of influenza negative persons. In the total treatment population, influenza infection was confirmed in 67% (range, 46% to 74%) of the patients studied. 64% of elderly patients are influenza-positive and 62% of those with chronic cardiac and / or respiratory disease are influenza-positive. In all Phase III treatment trials, patients were taken to work only when the influenza was spread in the local community.

Adults and adolescents aged 13 and over:

Patients were randomly assigned to receive at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, tremor / sweating, exhaustion, fatigue or headache) with fever> 37.8 ° C ) were selected. All influenza positive participating in treatment trials

75 mg oseltamivir, administered twice daily for five days in a collective analysis of adults and adolescents (N = 2413), reduced the mean duration of influenza illness by one day to 4.2 days (95% GA (confidence interval) 4.0-4.4 days; p <0.0001); in the placebo group this figure was 5.2 days (95% GA 4.9 - 5.5 days).

The proportion of subjects with lower respiratory tract complications (especially bronchitis) treated with antibiotics was 12.7% (135/1063) in the placebo group and 8.6% (116/1350) in the oseltamivir-treated population (p = 0.0012).

Treatment of influenza in high-risk populations:

The mean duration of influenza disease in elderly patients (> 65 years) receiving 75 mg oseltamivir twice daily for five days and in patients with chronic cardiac and / or respiratory disease did not significantly decrease. The total duration of fever decreased by one day in the oseltamivir group. In influenza-positive age, the incidence of lower respiratory tract complications (especially bronchitis) was 19% (52/268) in the placebo group treated with antibiotics, but decreased to 12% (29/250) in the oseltamivir-treated population (p = 0.0156).

In influenza-positive patients with chronic cardiac and / or respiratory disease, the combined incidence of lower respiratory tract complications (especially bronchitis) treated with antibiotics was 17% (22/133) in the placebo group versus 14% (16/118) in the oseltamivir-treated population (p = 0.5976).

Treatment of influenza in children:

In a study of healthy children (65% influenza-positive) aged between 1 and 12 years (mean age 5.3) with fever (> 37.8 ° C) and coughing or fever, 67% of influenza-positive patients were influenza and 33% were influenza B I was infected with. Oseltamivir treatment started within 48 hours after the onset of symptoms and decreased by approximately 1.5 days compared to placebo (95% GA 0.6 - 2.2 days; p <0.0001), with a significant improvement in recovery from disease (return to normal health and activity, fever, cough and remission of fever) . Oseltamivir reduced the incidence of acute otitis media from 26.5% (53/200) in the placebo group to 16% (29/183) in children treated with oseltamivir (p = 0.013).

The second study was completed in 334 asthmatic children aged 6 to 12 years, with 53.6% being influenza-positive. The mean duration of illness in the group treated with oseltamivir did not significantly decrease. From day 6 (the last day of treatment), ZEV1 (forced expiratory volume) increased from 4.7% in the placebo arm to 10.8% in the oseltamivir-treated group (p = 0.0148).

Treatment of Influenza B infection:

In total, 15% of the influenza-positive population was infected with influenza B; the ratios in the studies are between 1 and 33%. The mean duration of disease in patients infected with influenza B did not vary significantly between treatment groups. Data were collected for 504 infected infected individuals with Influenza B from all studies for analysis. Oseltamivir has been shown to reduce the duration of all symptoms by 0.7 days (95% GA 0.1 - 1.6 days; p = 0.022), cough, fever (> 37.8 ° C)

xcipient (s):

• Croscarmellose sodium 3.40 mg

• Sodium stearyl fumarate 1.70 mg For the

auxiliary substances, see 6.1.

3. PHARMACEUTICAL FORM

Hard gelatin capsule

Capsule contains a blue colored "ROCHE" print on opaque gray body and a "75 mg" blue print on light yellow colored lid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

TAMIFLU is indicated for the treatment and prevention of influenza and avian influenza prophylaxis in children (1) and adults (see section 4.4 and section 5.3).

COMPLETE is indicated for temporary influenza prophylaxis and treatment of children younger than 1 year (see section 5.2), provided that they are used during an epidemic, by a physician's recommendation, or under the supervision of a physician.

4.2 Posology and method of administration

Posology / application frequency and duration:

Standard dose for influenza treatment Treatment

should be initiated on the first or second day of symptoms of influenza.

Adults and adolescents (13-17 year olds):

Adults and adolescents aged ≥13 years may be treated with a recommended dose of 75 mg capsules or 30 mg capsules and 45 mg capsules twice daily for 5 days. Adults who are unable to swallow capsules and adolescents aged ≥13 may receive 75 mg of TAMIFLU suspension twice daily for 5 days.

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- Children (1 year and older infants and 2-12 year olds) As

an alternative to the recommended TAMIFLU suspension doses, children weighing> 40 kg who do not have difficulty in swallowing capsules, 75 mg capsules twice a day or 30 mg capsules and 45 mg capsules & lt; / RTI & gt;

Recommended oral medication doses for children aged ≥ 1 years:Recommended treatment for

Body weight5 days Dose ≤ 15 kg> 15 - 23 kg> 23 - 40 kg> 40 kg

twice daily 30 mg twice daily 45 mg twice daily once daily 60 mg twice daily 75 mgthan

Oral TAMIFLU doses recommended for babies younger12 months of age: Recommended treatment for

babies younger than 12 months during an influenza outbreak is between 2 mg / kg-3 mg / kg twice daily. This dose recommendation is based on a limited pharmacokinetic basis. According to this, plasma drug exposures similar to those of clinically shown efficacy in older children and adults in the majority of infant infants less than 12 months of age receiving the recommended dose have been provided (see section 5.2).

The following dosing regimens are given according to the weight recommended for the treatment of infants under 1 year of age.

Age Recommended treatment for 5 days Dose 3babies

mg / kg twice a day for

older than 3 months old,babies older than 3 months old, 3

2.5 mg / kg twice a day formg / kg for

babies less than 1 month old 2 mg / kg

* There is no data on TAMIFLU use in infants under 1 month of age.

The use of TAMIFLU for infants under the age of 1 years should be decided after the careful evaluation of the potential benefit of the drug treatment against the possible risks of infant birth.

Age-related dose recommendations are not premature (for example, those with a postmenstrual age less than 37 weeks) for infants. Insufficient data are available for these patients, who may need different doses depending on their complete physiological function.

The standard dose for influenza prophylaxis

- Adults and adolescents (13-17 year

olds):After close contact with the infected person, the recommended oral dose of Tamiflu for prophylaxis of influenza for 10 days, once daily, 75 mg capsule, or one 30-mg

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capsuleand 45 mg they can be treated with capsules. Treatment should begin within two days after close contact with infected persons. The recommended dose for prophylaxis during influenza outbreaks in the community is 75 mg daily. Within six weeks TAMIFLU's safety and effectiveness have been proven. Protection continues as long as you continue to use the medication.

- Children (1 year and older infants and 2-12 year olds) As

an alternative to the recommended TAMEFLU suspension doses, children weighing> 40 kg who do not have difficulty in swallowing capsules may be prescribed prophylactically for 10 days, once daily 75 mg capsules or 30 mg capsules and 45 mg capsules.

Recommended prophylactic oral doses for children aged ≥ 1 years:

Body weight Recommended body weight for 10 days Prophylaxis dozu ≤ 15 kg once daily 30 mg> 15 - 23 kg once daily 45 mg> 23 - 40 kg once daily 60 mg> 40 kg once daily 75 mgthan

oral TAMIFLU doses for post-exposure prophylaxis recommended for babies younger12 months:

During the influenza outbreak, the recommended (daily) oral prophylaxis daily dose for infants 12 months of age is half of the daily dose. This is based on clinical evidence in adults and adults over 1 year of age showing the clinical efficacy of the prophylactic dose equivalent to half of the treatment dose to prevent influenza. The following dosing regimens are given according to the weight recommended for prophylaxis of infants under 1 year of age.

Age Recommended prophylaxis for 10 days Dose 3

mg / kg

infants less than 3 months old,infants less than 3 months old,

once daily for2.5 mg / kg once daily for2 mg / kg

once daily for infants less than 1 month old / kg

* There is no data for TAMIFLU use in infants under 1 month of age.

The use of TAMIFLU for infants under the age of 1 years should be decided after the careful evaluation of the potential benefit of the drug treatment against the possible risks of infant birth.

Dosage recommendations based on this age are not for premature (postmenstrual age less than 37 weeks) infants. Insufficient data are available for these patients, who may need different doses depending on their complete physiological function.

Application form: Oral is used by swallowing with some water.

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COMPLETE can be taken alone or in combination with food (see section 5.2). Tamiflu taken with food can increase tolerance in some patients.

EXAMPLES (FOR USE) _ FORMULATIONS WITHOUT TOMATO oral suspension Adults, adolescents or children who can not swallow capsules may take TAMIFLU doses by draining the capsule in a small amount of sweetened food to mask bitter taste, if there is no TAMIFLU oral suspension. section 6.6).

Additional information on special populations:

Renal insufficiency: Used for influenza therapy: Dose adjustment is not necessary for patients with creatinine clearance> 30 mL / min; you can continue to use 75 mg twice a day. In patients with creatinine clearance 10-30 mL / min, it is recommended that the dose be reduced to 75 mg once daily or 30 mg twice daily for 5 days, or to 30 mg capsules twice daily for TAMIFLU. In patients with end-stage renal disease entering routine hemodialysis or continuous peritoneal dialysis, and in patients with creatinine clearance ≤10 mL / min, there is no recommended dose (see section 5.2 and section 4.4).

For influenza prophylaxis: Dose adjustment is not necessary for patients with creatinine clearance> 30 mL / min; 75 mg once a day can be continued to use. Patients receiving TAMIFLU with creatinine clearance 10-30 mL / min are advised to reduce the dose to 75 mg twice daily or alternatively once daily, to 30 mg capsules or 30 mg suspensions. In patients with end-stage renal disease entering routine hemodialysis or continuous peritoneal dialysis, and in patients with creatinine clearance ≤10 mL / min, there is no recommended dose (see section 5.2 and section 4.4).

Clinical data are insufficient to recommend any dose in children with renal insufficiency.

Hepatic insufficiency: For influenza treatment or prophylaxis, dosage adjustment is not necessary for patients with mild to moderate hepatic dysfunction (see section 5.2). Safety and pharmacokinetic properties of patients with severe hepatic insufficiency have not been studied. Pediatric patients with hepatic insufficiency have not been studied.

Pediatric population: In children under 1 year, the safety and efficacy of TAMIFLU has not been established (see section 5.2). COMPLETE can only be used for the treatment of influenza in children under 1 year, provided that it is temporarily used during an epidemic, by a doctor's recommendation or under the supervision of a physician. In all other cases, TOMMY should not be used in children under 1 year of age (see section 5.3).

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Geriatric population: For influenza treatment or prophylaxis, elderly patients do not require dose adjustment (see section 5.2).

Immune system deprived patients: Up to 12 weeks, longer seasonal prophylaxis has been evaluated in patients with impaired immunosuppression (see sections 4.4, 4.8 and 5.1).

4.3 Contraindications

Oseltamivir is contraindicated in persons who are known to be hypersensitive to any of the ingredients of the phosphate or drug.

4.4 Special warnings and precautions for use

Neuropsychiatric events such as convulsions and delirium have been reported in patients receiving influenza treatment with COMPLETE, especially in children and adolescents. In rare cases, these incidents have caused injury by accident. The contribution of TAMIFLU to these events is unknown. Neuropsychiatric events have also been reported in influenza patients who do not use COMPLETE (see section 4.8).

Patients, especially children and adolescents, should be carefully monitored for abnormal behavior.

There is no evidence that tamiflu is effective in the diseases caused by other agents other than influenza A and B viruses.

The safety and efficacy of oseltamivir therapy or prophylaxis in immunosuppressed patients has not been proven precisely (see section 5.1).

The efficacy of oseltamivirin has not been demonstrated in the treatment of patients with chronic heart failure and / or respiratory disease. There was no difference in the incidence of complications between the treatment and placebo groups in this population (see section 5.1).

Data providing a dose recommendation for premature infants (postmenstrual age * <37 weeks) is not currently available. * Time between the first day of the last normal menstrual cycle and the evaluation day, gestational age plus postnatal age.

It is not used in place of IMPACTED influenza vaccine. Tamiflu is not expected to affect the evaluation of individuals for annual influenza vaccination. Protection against Influenza lasts until TAMIFLU is given. Reliable epidemiologic data can be used in the treatment and prevention of TOTAL influenza if the population shows influenza virus circulation.

Dosage adjustment during influenza treatment and prophylaxis is recommended for patients with creatinine clearance of 10-30 mL / min. There are no recommended doses for patients with end-stage renal disease and patients with creatinine clearance ≤10 mL / min who are on routine hemodialysis and continuous peritoneal dialysis treatment.renal insufficiency

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Clinical data are insufficient to recommend any dose in children with(see sections 4.2 and 5.2).

Croscarmellose sodium and sodium stearyl fumarate: This medicinal product contains less than 1 mmol (23 mg) of sodium per dose. No adverse effects due to sodium are expected.

COMPLETE can only be used for the treatment of influenza in children under 1 year (see section 5.3), provided that it is temporarily used during an epidemic, with a doctor's recommendation or under the supervision of a physician.

4.5 Interactions with other medicinal products and other forms of interaction

According to information obtained from pharmacological and pharmacokinetic studies, clinically significant drug interactions with oseltamivir phosphate are unlikely to occur.

Oseltamivir phosphate is largely converted into its active metabolite, mostly by esterases found in the liver. Drug interactions, including competition for esterases, have not been widely reported in the literature. Low binding of oseltamivir and its active metabolite to plasma proteins demonstrates that there is no problem in terms of drug interactions.

In vitro studies have shown that oseltamivir phosphate or active metabolite is not a good substrate for microsomal P450 cytochrome enzymes and glucuronyl transferases (see section 5.2). There is no evidence that it interacts with oral contraceptives.

There is no effect on the plasma levels of cetethidine, oseltamivir, or active metabolite, which is a non-specific inhibitor of cytochrome P450 isoforms and competing for renal tubular secretion of basic or cationic drugs.

Clinically significant drug interactions involving competition for renal tubular secretion are unlikely, depending on the known safety limits of these drugs, the active metabolite elimination characteristics (glomerular filtration and anionic tubular secretion), and the breakthrough capacities of these pathways. Due to the decrease in active tubular secretion in the kidney, the concentration of active metabolite is about 2-fold increased as a result of use with probenecid. However, depending on the wide safety margin of the active metabolite, dose adjustment is not necessary when the renal function is normal during use with probenecid.

Co-administration with amoxicillin does not alter the plasma levels of both compounds due to the weakness of the competitor for anionic secretion pathways.

Use with paracetamol does not affect plasma levels of oseltamivirin, active metabolite, or paracetamol.

When used in combination with paracetamol, acetic salicylic acid, cimetidine or antacids (Magnesium and aluminum hydroxides and calcium carbonates), no pharmacokinetic interaction between oseltamivir or major metabolite is observed.

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Phase III treatment and prophylaxis clinical trials have shown that tamiflu, ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporin, azithromycin, erythromycin, doxycycline), H

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-receptor blockers (ranitidine, have been applied with commonly used medications such as blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine), corticosteroids, induction bronchodilators and analgesics (aspirin, ibuprofen and paracetamol). There was no change in the profile or frequency of ending adverse events of administration of tamiflu with these compounds.

Caution should be exercised when administering oseltamivir to patients with the same route of administration and with narrow therapeutic interventions (eg chlorpropamide, methotrexate, phenylbutazone).

Additional information on

special populations No interaction studies have been done on specific populations.

Pediatric population: No interaction studies of the pediatric population have been conducted.

4.6 Pregnancy and lactation

General advice Pregnancy category: C

Women with childbearing potential / Birth control (Contraception) There is no recommendation for the use of medication in women with childbearing potential and contraception.

Pregnancy period Although pregnant women using oseltamivir have not undergone controlled studies, there are limited data from post-marketing and retrospective observational follow-up reports. These data, together with studies conducted on animals, do not indicate that they are directly or indirectly harmful in relation to pregnancy / embryonal / fetal development / birth or postnatal development (see section 5.3). Given current safety data, the pathogenicity of circulating influenza virus strain and the underlying condition of the pregnant woman, TAMIFLU can be used in pregnant women. TAMIFLU should not be used in pregnant women unless the potential benefit to the patient is greater than the potential risk to the fetus.

Lactation The studies on animals show that oseltamivir is poured into the milk. There is very limited data as to whether oseltamivir is excreted in human milk. This limited data shows that oseltamivir and its active metabolite are detected in the mother's milk. However, the levels set in the milk are very low and therefore the baby will receive an amount under the therapeutic dose. When deciding whether or not to stop breastfeeding or stopping TAMIFLU treatment, it is important to consider the pathogenicity of circulating influenza virus strains, the benefit of breastfeeding for the child