Aminosalicylic acid + Isoniazid (Acidum aminosalicylicum + Isoniazidum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
Read on
Clinical and pharmacological group: & nbsp

Other synthetic antibacterial agents

Included in the formulation
  • Isopascus
    pills inwards 
    FARMASINTEZ, JSC (Irkutsk)     Russia
  • IAC-PAS Plus
    granules inwards 
    McLeodz Pharmaceuticals Co., Ltd.     India
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    7 nosologies

    ONLS

    АТХ:

    J.04.A.C.01   Isoniazid

    J.04.A.A.01   Aminosalicylic acid

    Pharmacodynamics:

    Aminosalicylic acid

    It acts bacteriostatically. Competitively suppresses the synthesis of folate in a bacterial cell. Slightly affects the pathogen, located intracellularly. Under the influence of gastric juice aminosalicylic acid quickly turns into an inactive metabolite. Acid-resistant shell protects the granules from the destructive effects of gastric juice. In a neutral environment, for example, in the small intestine, the granule membrane dissolves and the drug releases.

    Isoniazid

    It acts bactericidal on the process of cell division of M. tuberculosis. The primary mechanism is to inhibit the synthesis of long chain mikolievyh acids which are part of the cell wall of mycobacteria. For inhibiting Gram-positive and Gram-negative bacteria requires isoniazid concentration not less than 600 mg / ml and the minimum concentration to inhibit M. tuberculosis is 0.05-0.025 mg / ml.

    Pharmacokinetics:

    Aminosalicylic acid

    Characterized by high absorption; moderately penetrates into the cerebrospinal fluid (only with inflammation of the meninges). Easily passes other histohematological barriers and is distributed in tissues. Binding to proteins - 50-60%. The average time to achieve Cmax in plasma is 6 hours (varies from 1.5 to 24 hours). The concentration of the drug 2 mg / ml in the plasma is maintained for 7.9 hours (variability from 5 to 9 hours), and 1 mg / ml - on average, for 8.8 hours (variability from 6 to 11.5 hours). Metabolised, half the dose is determined in the urine in the form of an acetylated derivative. T1 / 2 is 30 minutes. The total clearance depends on both the metabolic rate and the excretion of the kidneys. 80% of aminosalicylic acid is excreted by the kidneys, while 50% or more is excreted in the acetylated form.

    Isoniazid quickly and completely absorbed when ingested, food reduces absorption and bioavailability. The effect of the first passage through the liver has a great influence on the bioavailability index. Time to reach Cmax in blood plasma - 1-2 h. Cmax in the blood after ingestion of a single dose of 300 mg - 3-7 μg / ml. Binding to proteins is insignificant - up to 10%. Vd-0.57-0.76 l / kg. It is well distributed throughout the body, penetrating into all tissues and fluids, including spinal, pleural,ascitic; 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.

    T1 / 2 for fast acetylators is 0.5-1.6 h; for slow - 2-5 hours. In case of renal insufficiency, T1 / 2 may 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 explained by imperfection processes of acetylation in newborns). Despite the fact that the T1 / 2 index varies considerably depending on the individual intensity of the acetylation processes, the average T1 / 2 value is 3 hours (ingestion 600 mg) and 5.1 h (900 mg).With repeated appointments, T1 / 2 is shortened to 2-3 hours. It is excreted mainly by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites, N-acetylisiniazide and isonicotinic acid. In fast acetylators, the content of N-acetylisiniazide is 93%, while in slow acetylsinides it is not more than 63%. Small amounts are excreted with feces. The drug is removed from the blood during hemodialysis; hemodialysis, conducted for 5 hours, allows you to remove from the blood to 73% of the drug.

    Indications:

    Multidrug-resistant tuberculosis.

    ICD-10

    I.A15-A19.A15.8   Tuberculosis of other respiratory organs, confirmed bacteriologically and histologically

    Contraindications:

    Medicinal Hepatitis; liver failure; liver disease in the acute stage; kidney failure; children and adolescents under 18; increased sensitivity to any of the components of the drug. With caution - convulsive seizures, concomitant diseases of the gastrointestinal tract, amyloidosis, decompensated diseases of the cardiovascular system, hypothyroidism, age over 60 years and body weight less than 50 kg, alcoholism.

    Carefully:

    Convulsive seizures, concomitant diseases of the gastrointestinal tract, amyloidosis, decompensated diseases of the cardiovascular system, hypothyroidism, age over 60 years and body weight less than 50 kg, alcoholism.

    Pregnancy and lactation:

    The use of the drug in pregnancy is possible if the expected benefit for the mother exceeds the potential risk for the fetus. If it is necessary to use the drug during lactation, breastfeeding should be stopped.

    Dosing and Administration:

    Assign inside as granules, which should be taken after meals, washed down with water, 2-3 times / day. for 9-12 g / day. or at the rate of 10 mg / kg body weight / day. on aminosalicylic acid (at lunch and dinner). A measuring spoon is attached to the packing of 100.0 g for the convenience of dosing. Each measuring spoon (full 4.3 g of granules) contains sodium aminosalicylate dihydrate - 3.44 g; isoniazid - 100 mg. It is also recommended to take isoniazid 300 mg once after breakfast.

    Side effects:

    Possible as a result of the action of individual components included in the drug.

    Aminosalicylic acid

    On the part of the digestive system: decreased appetite, nausea, vomiting, flatulence, abdominal pain,diarrhea or constipation, hepatomegaly, increased hepatic transaminase activity, hyperbilirubinemia, partially expressed malabsorption syndrome; rarely - drug-induced hepatitis. From the urinary system: proteinuria, hematuria, crystalluria. From the hemopoietic system: rarely - thrombocytopenia, leukopenia, B12-deficient megaloblastic anemia. Allergic reactions: fever, dermatitis (urticaria, purpura, enanthema), eosinophilia, arthralgia, bronchospasm. With prolonged use in high doses or when exceeding the dose - hypothyroidism, goiter, myxedema.

    Isoniazid

    From the side of the nervous system: 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 cardiovascular system: palpitation, angina pectoris, increased blood pressure. On the part of the digestive system: nausea, vomiting, gastralgia, toxic hepatitis. Allergic reactions: skin rash, itching, hyperthermia, arthralgia.Other: very rarely - gynecomastia, menorrhagia, tendency to bleeding and hemorrhage.

    Overdose:

    Treatment is symptomatic.

    Interaction:

    Aminosalicylic acid

    Compatible with other antituberculous drugs.

    It is not recommended to have a joint reception with rifampicin. aminosalicylic acid reduces its concentration. If you need co-therapy with rifampicin, taking medications should be divided: rifampicin before breakfast, sodium aminosalicylate after dinner and overnight.

    Violates the absorption of erythromycin and lincomycin.

    Disrupts the assimilation of cyanocobalamin (vitamin B12) (risk of developing anemia). Absorption of Vitamin B12 when 5 g of aminosalicylic acid is taken up, it breaks by 55%, which leads to significant changes in erythrocytes. Thus, when treating patients with aminosalicylic acid for more than 1 month, vitamin B therapy12.

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

    Cycloserine and disulfiram increase the adverse effects of the central nervous system.

    Increases hepatotoxicity of rifampicin.

    The combination with pyridoxine reduces the risk of peripheral neuritis and side reactions from the CNS.

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

    Enhances the effect of derivatives of coumarin and indandione, benzodiazepines, carbamazepine, theophylline, as reduces their metabolism by activating the cytochrome P450 system.

    SCS accelerates metabolism in the liver and reduces the active concentration of isoniazid 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).

    Antacids (especially aluminum-containing ones) slow down absorption and reduce the concentration of isoniazid in the blood (antacids shouldtake no earlier than 1 hour after taking isoniazid).

    When used simultaneously with enflurane isoniazid can increase the formation of inorganic fluoride metabolite, which has a nephrotoxic effect.

    Reduces the concentration of ketoconazole in the blood.

    Isoniazid - an antagonist of hypoglycemic action of insulin, it increases the level of glucose in the blood. This is explained by the significant absorption of isoniazid by the walls of the intestine.

    Special instructions:

    Possible damage to the liver and kidneys due to the drug.

    Careful observation of patients throughout the course of treatment is necessary.

    Laboratory indicators - ALT, AST, bilirubin concentration in blood serum - can transiently increase without clinical manifestations.

    When there are signs of toxic hepatitis caused by the drug, the drug is canceled.

    Decreased kidney function against tuberculous intoxication or specific damage is not a contraindication to the appointment. The development of proteinuria and hematuria require a temporary discontinuation of the drug.

    In connection with the different metabolic rate before the use of isoniazid, it is expedient to determine the rate of its inactivation (according to the dynamics of the contentin the blood and urine). With rapid inactivation isoniazid used in higher doses.

    At a risk of peripheral neuritis (patients over 65, patients with diabetes, pregnant women, patients with chronic renal failure in remission, alcoholics, eating disorders, concomitant anticonvulsant therapy), 10-25 mg / day of pyridoxine is recommended.

    During treatment, cheese, fish (especially tuna, sardine) should be avoided, since the simultaneous use of them with isoniazid may cause reactions (skin hyperemia, itching, sensation of heat or cold, palpitations, increased sweating, chills, headache, dizziness); associated with the suppression of monoamine oxidase and diaminoxidase activity and leading to a disruption of the metabolism of tyramine and histamine contained in fish and cheese.

    It should be borne in mind that isoniazid can cause hyperglycemia with secondary glucosuria; tests with the reduction of copper ions can be false positive, and the enzyme tests for glucose drug does not affect.

    Instructions
    Up