Protubipira® (Protubpira®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIsoniazid + PyrazinamideIsoniazid + Pyrazinamide
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  • Protubipira®
    pills inwards 
    FARMASINTEZ, JSC (Irkutsk)     Russia
  • Phthisopyram®
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    AKRIKHIN HFK, JSC     Russia
    • Dosage form: & nbspTabletki.
    Composition:For one tablet:

    Active substances:

    Isoniazid

    150 mg

    300 mg

    Pyrazinamide

    500 mg

    750 mg

    Inactive Ingredients: potato starch, carboxymethyl starch sodium (sodium starch glycolate), microcrystalline cellulose, gelatin, magnesium stearate, silicon dioxide colloid (aerosil grade A-300), talc.

    Description:

    For tablets containing 150 mg of isoniazid and 500 mg of pyrazinamide: round tablets of flat-cylindrical shape, white or white with a yellowish tint of color, with a facet and a risk on one side.

    For tablets containing 300 mg of isoniazid and 750 mg of pyrazinamide: oval tablets of biconvex form, white or white with a yellowish tint of color, with a risk on one side.

    Pharmacotherapeutic group:antituberculous agent combined
    ATX: & nbsp

    J.04.A.C.51   Isoniazid in combination with other drugs

    Pharmacodynamics:

    Isoniazid has a bactericidal effect on actively dividing cells Mycobacterium tuberculosis. The mechanism of its action is the inhibition of the synthesis of mycolic acids, which are a component of the cell wall of mycobacteria.For mycobacteria tuberculosis, the minimum inhibitory concentration of the drug is 0.025-0.05 mg / l. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.

    Pyrazinamide. Pyrazinamide has a bactericidal action at acidic pH values. Well penetrates into the tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. It is subjected to enzymatic conversion into the active form - pyrazinic acid. At acidic pH values, the minimum inhibitory concentration of pyrazinamide in vitro is 20 mg / l. On non-tuberculosis pathogens does not work.
    Pharmacokinetics:

    Isoniazid

    Taking isoniazid in together with the preparations that make up Protebpira® does not affect the rate of its absorption from the gastrointestinal tract. Isoniazid quickly and completely absorbed when ingested, food reduces absorption and bioavailability. The effect of "first passage" through the liver has a great influence on the bioavailability index. Time to reach the maximum concentration of the drug in the blood (TCmax) - 1-2 hours, the maximum concentration of the drug in the blood (Cmax) after ingestion of a single dose of 300 mg - 3-7 μg / ml. The connection with proteins is insignificant - up to 10%. The volume of distribution is 0.57-0.76 l / kg. Well distributed throughout the body, penetrating all tissues and fluids, including cerebrospinal, pleural, ascites; high concentrations are created in the lung tissue, kidneys, liver, muscles, saliva and sputum. Penetrates through the placental barrier and into breast milk.

    It is metabolized in the liver by acetylation with the formation of inactive products. The liver is acetylated with N-acetyltransferase to form N-acetylisoiniazide, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a mixed oxidase system of cytochrome P450 upon N-hydroxylation of the active intermediate metabolite. The rate of acetylation is genetically determined; in people with "slow" acetylation, there is little N-acetyltransferase. It is an inhibitor of CYP2C9 and CYP2E1 isoenzymes in the liver. The half-life of blood (T1/2) for "fast acetylators" - 0.5-1.6 hours; for "slow" - 2-5 hours With renal failure T1/2 can increase to 6.7 hours. T1/2 for children aged 1.5 to 15 years - 2.3-4.9 hours, and in newborns - 7.8-19.8 hours (which is due to the imperfection of the processes of acetylation in newborns). Despite the fact that the indicator T1/2 significantly varies depending on the individual intensity of the acetylation processes, the average value of T1/2 is 3 hours (intake of 600 mg) and 5.1 hours (900 mg). With repeated appointments T1/2 shortened to 2-3 hours.

    Excreted mainly by the kidneys: within 24 hours 75-95% of the drug is excreted, mainly in the form of inactive metabolites - N-acetylisoiniazide and isonicotinic acid. At the same time, "fast acetylators" contain N-acetyl isosine is up to 93%, while in "slow" - not more than 63%. Small amounts are excreted with feces. The drug is removed from the blood during hemodialysis; 5 h hemodialysis allows you to remove from the blood to 73% of the drug.

    Pyrazinamide

    Quickly and completely absorbed in the gastrointestinal tract. The connection with plasma proteins is 10-20%. Time to reach the maximum concentration of the drug in the blood TSmOh - 1-2 hours. It penetrates well into tissues and organs.

    Metabolised in the liver, where an active metabolite, pyrazinic acid, is first formed, which is then converted into an inactive metabolite, 5-hydroxypyrazinic acid. Half-life of blood T1/2 - 8-9 hours.

    It is excreted by the kidneys: unchanged, 3%, pyrazinic acid 33%, other metabolites 36%. Removed during hemodialysis.

    Indications:

    Tuberculosis (any localization, in adults and children, treatment and prevention as part of combination therapy).

    Contraindications:

    Hypersensitivity, epilepsy, epileptic syndrome, bronchial asthma, psoriasis, chronic renal failure, hepatitis, cirrhosis, hyperuricemia, acute gout; Stomach ulcer and duodenal ulcer; myxedema, pregnancy, lactation, children under 3 years old.

    Dosing and Administration:

    It is taken orally, after eating 1-3 tablets once a day (at the rate of 5-15 mg / kg / day isoniazid - (maximum dose of 900 mg / day).

    The duration of the course of treatment during intensive care is 3-4 months daily, then 2 months - every other day.

    It is possible to use the drug in combination with other anti-tuberculosis drugs, such as streptomycin, etc.

    Appointment of the drug children over three years old is performed proceeding from the maximum daily dosages of isoniazid (5-10 mg / kg / day).

    Side effects:

    Side effects in the treatment with the drug Protubipira® are determined by the active ingredients that are included in its composition.

    Isoniazid

    From the central nervous system (CNS): headache, dizziness, rarely excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of limbs, peripheral neuropathy, optic neuritis, polyneuritis, psychosis, mood change, depression. Seizures can occur in patients with epilepsy.

    From the side of the cardiovascular system: palpitation, angina, increased blood pressure.

    From the digestive system: nausea, vomiting, gastralgia, toxic hepatitis.

    Allergic reactions: skin rash, itching, hyperthermia, arthralgia.

    Other: very rarely - gynecomastia, menorrhagia, a tendency to bleeding and hemorrhage.

    Pyrazinamide

    From the digestive systemNausea, vomiting, diarrhea, "metallic" aftertaste in the mouth, liver dysfunction (loss of appetite, liver pain, hepatomegaly, jaundice, yellow atrophy of the liver); exacerbation of peptic ulcer.

    From the central nervous system: headache, sleep disturbance, increased excitability, depression; in some cases - hallucinations, convulsions, confusion.

    On the part of the organs of hematopoiesis and the system of hemostasis: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

    From the side of the musculoskeletal system: arthralgia, myalgia.

    From the urinary system: dysuria, interstitial nephritis.

    Allergic reactions: skin rash, hives.

    Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.
    Overdose:

    Isoniazid

    Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, hepatic dysfunction, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, seizures (1-3 hours after drug administration), coma.

    Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic acid, nicotinamide; massage, physiotherapy procedures); seizures (in / m pyridoxine hydrochloride - 200-250 mg, in / m 25% solution of magnesium sulfate - 10 ml, diazepam); abnormal liver function (methionine, thioctic acid, cyanocobalamin).

    Pyrazinamide

    Symptoms: impaired liver function, increased severity of side effects from the central nervous system.

    Treatment: symptomatic.

    Interaction:

    Isoniazid

    When combined with paracetamol, hepato- and nephrotoxicity increases; isoniazid induces a system of cytochrome P450, which increases the metabolism of paracetamol to toxic products.

    Ethanol increases the hepatotoxicity of isoniazid and speeds up its metabolism.

    Reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.

    Reduces metabolic transformations and increases the concentration in the blood of alfentanil.

    Cycloserine and disulfiram enhance the adverse central effects of isoniazid.

    Combination with pyridoxine reduces the risk of peripheral neuritis.

    Caution should be combined with potentially neuro-, hepato- and nephrotoxic drugs because of the risk of side effects.

    Strengthens the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, as it reduces their metabolism by activating the cytochrome P450 system.

    Glucocorticosteroids accelerate metabolism in the liver and reduce active concentrations in the blood.

    It suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and an increase in the toxic effect (correction of the dosing regimen of phenytoin may be necessary, especially in patients with slow acetylation of isoniazid).

    Pyrazinamide

    Compatible with other antituberculous drugs: in chronic destructive forms pyrazinamide it is recommended to combine with rifampicin or ethambutol (better tolerability than when combined with rifampicin, but weaker effect).

    When used simultaneously with drugs that block tubular secretion, it is possible to reduce their excretion and enhance toxic reactions.

    Strengthens the anti-tuberculosis effect of ofloxacin and lomefloxacin.

    Special instructions:

    During the treatment it is necessary to refrain from taking ethanol.

    With prolonged therapy and in patients with impaired liver function, it is necessary to regularly monitor the general blood test and liver function parameters.

    For the prevention and treatment of peripheral polyneuropathy, which can develop against the background of therapy, additionally designate pyridoxine (vitamin B6).

    Patients with episodes of gout in the anamnesis periodically monitor the concentration of uric acid in the serum.

    When appointing patients with hypoplastic anemia, the effect of the drug on the time of blood coagulation is taken into account.

    Form release / dosage:

    Tablets, 150 mg + 500 mg and 300 mg + 750 mg.

    Packaging:

    For 100, 500 or 1000 tablets (for hospitals) in a jar of polypropylene or low-density polyethylene with a lid of polypropylene or high-pressure polyethylene, or a can of polyethylene terephthalate with a screw cap or with a control of the first opening.

    Banks along with an equal number of instructions for use in group packaging.

    Storage conditions:

    In a dry, the dark place at a temperature of no higher than 25 ° C.

    Keep away from children.

    Shelf life:

    2 years.

    Do not use after the time specified on the package.

    Terms of leave from pharmacies:For hospitals
    Registration number:LSR-004226/09
    Date of registration:28.05.2009
    Expiration Date:Unlimited
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Representation: & nbspPharmasynthesis, JSCPharmasynthesis, JSC
    Information update date: & nbsp16.12.2016
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