TAMIFLU

Active material: Oseltamivir
When ATH: J05AH02
CCF: Viricide
ICD-10 codes (testimony): J10
When CSF: 09.01.03
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)

DOSAGE FORM, COMPOSITION AND PACKAGING

Capsules Solid, gelatin, size №2; opaque enclosure, gray, with an inscription “ROCHE” light blue; kryshecka opaque, light yellow colour with the inscription “75 mg”; contents of capsules – powder from white to yellowish.

Excipients: pre-gelatinized starch, povidone K30, Croscarmellose sodium, talc, stearil sodium fumarate.

The composition of the shell capsules: gelatin, dye iron oxide black, Titanium dioxide.
The composition of the capsule caps: gelatin, iron oxide red dye, dye iron oxide yellow, Titanium dioxide.

10 PC. – blisters (1) – packs cardboard.

Powder for oral suspension granulates, from white to light yellow in color, with a fruity odor; komkovanie allowed. After recovering form an opaque suspension from white to light yellow in colour.

Excipients: sorbitol, Titanium dioxide, Sodium benzoate, xanthan gum, Monosodium citrate, sodium saccharin, permasil 11900-31 Tutti-Frutti.

* finished suspension (After breeding in the water) contains oseltamivir 12 mg / ml

30 g – brown glass vials (1) complete with a dosing syringe and thick stakanchikom – packs cardboard.

Pharmacological action

Viricide. Oseltamivir phosphate is prolekarstvom, its active metabolite (oseltamivir carboxylate) effective and selective inhibitor of influenza virus neuraminidase type a and b – enzyme, catalysing the process of release of newly formed virus particles from infected cells, their penetration into the cells of the epithelium of the respiratory tract and the further spread of the virus in the body.

Inhibits the growth of influenza virus in vitro and inhibits the replication of the virus and its pathogenicity in vivo, reduces influenza viruses a and b from the body.

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

In children 1-12 years Tamiflu significantly reduces duration of illness (on 35.8 no), the frequency of acute otitis media. Recovery and return to normal activity occurs almost 2 the day before.

When taken with the aim of preventing, Tamiflu significantly (on 92%) and reliably reduces the incidence of influenza among persons exposed, on 76% – the frequency of clinically established influenza during an outbreak of disease, reduces the frequency of selection of the virus and prevents transmission of the virus from one family member to another.

Children from 1 Year to 12 years of prophylactic administration of Tamiflu reduces the incidence of laboratory-confirmed influenza with 24% to 4%.

Tamiflu does not affect education influenza antibodies, incl. on the production of antibodies in response to the introduction of inactivated influenza vaccine.

Resistance

When taking Tamiflu for prophylaxis (7 days), prophylaxis of exposed in the family (10 days) and seasonal prophylaxis (42 day) cases of resistance to the drug have been noted.

In adults/adolescents, oseltamivir resistance was detected in 0.32% cases (4/1245) using fenotipirovanija and 0.4% cases (5/1245) using fenotipirovanija and genotyping, and the children of 1 Year to 12 years 4.1% (19/464) and in 5.4% (25/464) of cases, respectively. All patients observed a temporary carrier OS-resistant virus. This does not affect virus elimination.

There are several different subtype-specific mutations known viruses. Sensitivity reduction depended on the type of mutation, so when the mutation I222V in N1 sensitivity decreased in 2 times, and when R292K in N2 – in 30 000 time. There was no mutation, reduce the sensitivity of influenza virus neuraminidase type in in vitro.

Patients, receiving treatment with oseltamivir, registered mutations neuraminidase N1 (including H5N1 viruses), leading to resistance/sensitivity reduction OS, were H274Y , N294S (1 event), E119V (1 event), R292K (1 event), and mutations N2 neuraminidase – N294S (1 event) and SASG245-248del (1 event). In one case, the mutation has been identified in influenza virus G402S, expressed in reducing sensitivity 4 times and in one case a mutation D198N with 10 x reduction in the sensitivity of a child with immune deficiency. Viruses with neuraminidase genotype resistant to varying degrees differ in stability from natural strain. Viruses with a mutation R292 K N2 in animals (mice and ferrets) on infectivity, pathogenicity and contagious viruses far below with a mutation E119V in N2 and D198N in and slightly different from natural strain. Viruses with H274Y mutation in the N1 and the N2 N294S occupy an intermediate position.

Pharmacokinetics

Absorption

After taking oseltamivir phosphate drug inside completely absorbed from the digestive tract and under the influence of hepatic and intestinal esterases largely biotransformiroetsa to active metabolite. The concentration of the active metabolite in plasma is defined within 30 minutes after taking Tamiflu inside, C_max achieved through 2-3 h and significantly (more than 20 time) higher than the concentration prodrug. No less 75% an oral dose reaches the systemic circulation as the active metabolite, less 5% -in the form of the original drug. Concentration as a prodrug, and the active metabolite in plasma is proportional to dose and does not depend on the meals.

Distribution

In humans the average V_d the active metabolite is about 23 l.

After oral administration of oseltamivir phosphate its active metabolite detected in the lungs, bronchial lavage, the mucosa of the nasal cavity, the middle ear and the trachea in concentrations, providing antiviral effect.

Active metabolite binding to plasma proteins is negligible (about 3%). Linking plasma protein is prodrug 42% (that is not enough, to serve the cause of existing drug interaction).

Metabolism

Oseltamivir phosphate highly biotransformiroetsa in the active metabolite by the action of esterases, located mainly in the liver and intestines. Neither oseltamivir phosphate, nor the active metabolite are not substrates or inhibitors, izofermentov zitohroma r450.

Deduction

Vsosavshijsja oseltamivir is mainly (> 90%) in the form of the active metabolite of kidneys. The active metabolite is not subjected to further transformation and excreted in the urine (>99%) by clubockova filtering and kanalzeva secreta. T_1/2 the active metabolite of 6-10 no. Renal clearance (18.8 l /) exceeds the speed clubockova filtering (7.5 l /), which indicates, that the drug appears again and by kanalzeva secreta. Faeces thrown less than 20% product.

Pharmacokinetics in special clinical situations

Impaired renal function. When prescribing Tamiflu to patients with varying degrees of kidney failure AUC values are inversely proportional to the decrease in kidney function.

Abnormal liver function. In vitro in patients with diseases of the liver not been a significant increase in AUC of oseltamivir phosphate, nor reduce its active metabolite AUC.

Patients senile age. In patients aged patients (65-78 years) the exposition of the active metabolita in equilibrium was 25-35% higher, than in younger patients when assigning similar doses of Tamiflu. T_1/2 the elderly are not significantly differed from such younger patients. Patients senile age does not require dose adjustment in the treatment and prevention of influenza.

Children. In young children the excretion of prodrug and the active metabolite faster, than in adults, that leads to lower the AUC relative to a particular dose. The drug at a dose of 2 mg/kg delivers the same AUC oseltamivir karboksilata, What is achieved in adults after a single dose capsules 75 mg (equivalent to approximately 1 mg / kg). Pharmacokinetics of oseltamivir for children older than 12 years of the same, in adults.

Testimony

-treatment of influenza in adults and children over the age of 1 year;

-Prevention of influenza in adults and adolescents over the age of 12 years, located in virus infection among high-risk groups (in military units and large industrial groups, the weakened patients);

-Prevention of influenza in children aged 1 year.

Dosage regimen

The drug is taken orally, at the time of delivery or regardless of mealtimes. Tolerance of the drug can be improved, If you take it while eating.

The standard dosing regimen

Treatment

Admission drug should start no later than 2 days from the onset of symptoms of influenza.

Adults and adolescents aged 12 and older the drug is prescribed for 75 mg (capsules or suspension) 2 times / day for 5 days. Increasing the dose more 150 mg / day did not lead to increased effect.

For children 8 years and older or weighing more than 40 kg, who can swallow capsules, You can also assign Tamiflu in capsules for 75 mg 2 times / day, as an alternative to the recommended dose of Tamiflu suspension.

For children 1 year and older Tamiflu should be taken in the form of suspension.

The recommended dosage of Tamiflu in the form of suspensions is presented in table.

For dispensing the suspension should use the supplied syringe with labels 30 mg, 45 mg 60 mg. The required number of suspensions are selected from the bottle the dosing syringe, transfer to a measuring cup and inwards.

Prevention

Adults and adolescents aged 12 and older After contact with an infected person Tamiflu is prescribed for 75 mg 1 times/day inwards for a period of not less than 10 days. Admission drug should start no later than, than in the first 2 the day after contact. During seasonal influenza epidemics – by 75 mg 1 times / day for 6 weeks. Preventive action continues so much, How long does a drug.

Children weighing more 40 kg, who can swallow capsules, the preparation may be nominated prophylaxis by 1 capsule (75 mg) 1 time / day, as an alternative to the recommended dose of Tamiflu in the form of suspensions.

For children 1 and older preparation in the form of suspension is prescribed prophylaxis the following doses.

For dispensing the suspension should use the supplied syringe with labels 30 mg, 45 mg 60 mg. The required number of suspensions are selected from the bottle the dosing syringe, transfer to a measuring cup and inwards.

The dosage regimen in special cases

Treatment

Patients with impaired kidney function if more QC 30 ml / min dose adjustment is not required. When values KK from 10 to 30 ml / min dose should be reduced to 75 mg 1 times / day for 5 days. Recommendations for dosing at patients, located on the permanent hemodialysis or peritoneal dialysis chronic about the terminal stages of chronic renal insufficiency, and for patients with CC ≤ 10 ml / min no.

Prevention

Patients with KK more 30 ml / min dose adjustment is not required. When values KK from 10 ml / min to 30 ml / min to reduce the dose of Tamiflu to 75 mg a day, or 30 mg of suspension every day.

Recommendations for dosing at patients, located on the permanent hemodialysis or peritoneal dialysis chronic about the terminal stages of chronic renal insufficiency, and for patients with CC ≤ 10 ml / min no.

Patients with liver mild in the treatment and prevention of influenza dose adjustment is not required. Safety and pharmacokinetics of Tamiflu in patients with severe violations of the liver was not studied.

Patients senile in the treatment and prevention of influenza for dose adjustment is not required.

The safety and efficacy of Tamiflu at children aged 1 year not set.

Rules suspension

1. Gently knock on the closed bottle so, to powder evenly on the bottom of the bottle.

2. Measure 52 ml of water, using the measuring cup, filling it up to specified level.

3. Add 52 ml of water in a bottle, close the CAP and shake well for 15 sec.

4. Remove the CAP and insert it into the neck of the vial adapter.

5. Tightly screw the bottle cap to ensure correct positioning of the adapter.

The bottle on the label should indicate the end date of expiry prepared. Before applying the skin with suspension to stir. For batching of suspension dosing syringe is attached with labels, indicate the dose levels 30 mg, 45 mg 60 mg.

The use of capsules

In cases, When Adult, adolescents aged 12 years and older and children weighing more than 40 kg or aged 8 and older There is a problem with swallowing capsules, or if there are signs of “Aging” capsules, You must open the capsule and pour its contents into a small amount of (maximally 1 tea spoon) suitable food sweetened with (chocolate syrup with normal sugar or sugar-free), honey, light brown sugar or table sugar, dissolved in water, Sweet dessert, evaporated milk with sugar, applesauce or yogurt) for, to hide the bitter taste. Mixture should be mixed thoroughly and give the patient a whole. Swallow the mixture immediately after cooking.

Side effect

Adult

From the digestive system: common – nausea and vomiting (there, usually, after the first dose, are transient in nature and in most cases do not require the preparation); ≥1% – diarrhea, pain abdomen, dyspepsia.

CNS: ≥1% – dizziness, headache, sleep disorders, weakness.

The respiratory system: ≥1% – bronchitis, cough, There may be rhinorrhea, infections of the upper respiratory tract.

Other: ≥1% – pain of various localization.

Children

Frequently: vomiting.

Maybe: abdominal pain, nose bleed, violations by the hearing, conjunctivitis (There were suddenly, stopped, Despite continued treatment, and in the vast majority of cases do not cause discontinuation of treatment), nausea, diarrhea, asthma (including the exacerbation of), pneumonia, sinusitis, bronchitis, acute otitis media, dermatitis, lymphadenopathy.

Postmarketingovoe monitoring

Dermatological reactions: rarely – dermatitis, skin rash, eczema.

Allergic reactions: rarely – hives; rarely – erythema multiforme, Stevens-Johnson syndrome and toksičeskij épidermalʹnyj necrolysis, anaphylactic and anaphylactoid reactions, angioedema.

CNS: patients (mainly in children and adolescents), taking Tamiflu for treatment of influenza, were registered by convulsions and delirium (including such symptoms, as consciousness, disorientation in time and space, abnormal behavior, delirium, hallucinations, excitation, alarm, nightmares). These cases have rarely been accompanied by life-threatening actions. The role of Tamiflu in the development of these phenomena is unknown. Such neuropsychiatric disturbances also were noted in patients with the flu, not receiving Tamiflu.

From the digestive system: rarely – cases of gastrointestinal bleeding during treatment Tamiflu (in particular, You cannot delete the relationship between the phenomena of hemorrhagic colitis and taking Tamiflu, Since these phenomena disappear as the patient recovers from the flu or after drug withdrawal); rarely – hepatitis, increase in liver enzymes.

Contraindications

- Chronic renal failure (permanent hemodialysis, chronic peritoneal dialysis, CC ≤ 10 mL/min);

- Hypersensitivity to the drug.

FROM caution should appoint drug in pregnancy and lactation (breast-feeding).

Pregnancy and lactation

Category (B). IN experimental studies shows, that oseltamivir and the active metabolite stand out with breast milk from lactating rats. Whether allocated oseltamivir or its active metabolite in breast milk in humans, unknown, but their quantity in breast milk may be 0.01 mg / day 0.3 mg/day respectively.

Since data on the use of the drug in pregnant women is not enough, Tamiflu should be appointed during pregnancy or lactation only if, If the intended benefits from their use outweighs the potential risk to the fetus or baby.

Cautions

Patients (mainly in children and adolescents), taking Tamiflu for treatment of influenza, were registered by convulsions and delirium-like neuropsychiatric violations. These cases have rarely been accompanied by life-threatening actions. The role of Tamiflu in the development of these phenomena is unknown. Such neuropsychiatric disturbances also were noted in patients with the flu, not receiving Tamiflu.

When applying the Tamiflu, we recommend that you closely monitor the behavior of patients, especially for children and adolescents, with a view to detecting signs of abnormal behavior.

Data on the efficacy of Tamiflu in all diseases, caused by other pathogens, In addition to the influenza viruses a and b, no.

In vial 30 grams of Tamiflu powder for suspension contains 25.713 g sorbitol. When taking Tamiflu dose 45 mg 2 times/day in the organism enters 2.6 g sorbitol. In patients with congenital lactose fruktozy this number exceeds the daily norm of sorbitol.

Overdose

Currently, the cases of drug overdose not described.

Alleged symptoms of acute overdose: nausea, vomiting.

One-off doses of Tamiflu to 1000 mg was deferred for good, except for the nausea and vomiting.

Drug Interactions

Clinically significant drug interaction unlikely.

Drug Interactions, due to competition and linking with the active centers esterases, make oseltamivir phosphate active ingredient, not submitted. Low degree of binding of oseltamivir and its active metabolita with proteins do not give grounds to presume the presence of interaction, associated with the displacement of drugs from the blood.

In vitro of oseltamivir phosphate and the active metabolite are not the preferred substrate for Polyfunctional oxidase cytochrome P450 system or for gljukuroniltransferaz.

Reason to interact with oral contraceptives no.

Cimetidine, nonspecific inhibitor, izofermentov zitohroma r450, amoksiцillin, paracetamol does not affect the plasma concentrations of oseltamivir and its active metabolite.

The simultaneous appointment probenecida leads to an increase in AUC of the active metabolite of oseltamivir at approximately 2 times. However, dose adjustment while applying with Probenecid is not required.

When assigning Tamiflu, along with ACE inhibitors (Enalapril, captopril), thiazide diuretics (bendrofljuazid), antibiotics (penicillin, cephalosporins, azithromycin, Erythromycin, doxycycline), blokatorami gistaminovykh n₂-receptors (ranitidine, cimetidine), beta-blockers (propranolol), ksantinami (theophylline), simpatomimetikami (Pseudoephedrine), opioid receptor agonists (codeine), kortikosteroidami, inhalants bronholitikami, analgesics-antipyretics and NSAIDS (acetylsalicylic acid, ibuprofen and paracetamol) changes in the nature or frequency of adverse events was observed.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

Capsules should be stored at a temperature of no higher than 25° c. Shelf life - 7 years.

Powder for suspension should be stored at a temperature of no higher than 25° c. Shelf life – 2 year.

After cooking the suspension can be stored at a temperature between 2° and 8° c for 17 days or at a temperature of no higher than 25° c 10 days and not use the retention period expires.

The drug should be stored out of reach of children.