Biseptolum

General characteristics. Structure:

Active ingredients: 4 g of sulfamethoxazole, 0,8 g of Trimethoprimum.

Excipients: macrogoal глицерилгидроксистеарат, magnesium aluminosilicate; karmelloza of sodium; citric acid monohydrate; methylparahydroxybenzoate; пропилпарагидроксибензоат; sodium saccharinate; hydrophosphate sodium dodecahydrate; мальтитол; fragrance strawberry; propylene glycol; the water purified.

Pharmacological properties:

Pharmacodynamics. Co-trimoxazole – the combined antimicrobic drug consisting of sulfamethoxazole and Trimethoprimum in the ratio 5:1.
The sulfamethoxazole similar on a structure to para-aminobenzoic acid (PABK), breaks synthesis of dihydrofolic acid in bacterial cells, interfering with inclusion of PABK in its molecule.

Trimethoprimum strengthens effect of sulfamethoxazole, breaking recovery of dihydrofolic acid in tetrahydrofolic – the active form of folic acid responsible for protein metabolism and division of a microbic cell.

Both components, thus, break process of formation of the folic acid necessary for synthesis by microorganisms of purine connections, and then and nucleic acids (RNA and DNA). It breaks formation of proteins and leads to death of bacteria.

In vitro is bactericidal drug of a broad spectrum of activity, however sensitivity can depend on the geographic location.
Usually sensitive activators (the minimum overwhelming concentration (MOC) less than 80 mg/l on sulfamethoxazole): Moraxella (Branhamella) catarrhalis, Haemophilus influenzae (beta lactamazoforming and beta лактамазонеобразующие strains), Haemophilus parainfluenzae, Escherichia coli (including enterotoksogenny strains), Citrobacter spp. (including Citrobacter freundii), Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca), Enterobacter cloaceae, Enterobacter aerogenes, Hafnia alvei, Serratia spp. (including Serratia marcescens, Serratia liquefaciens), Proteus mirabilis, Proteus vulgaris, Morganella morganii, Shigella spp. (including Shigella flexneri, Shigella sonnei), Yersinia spp. (including Yersinia enterocolitica), Vibrio cholerae, Edwardsiella tarda, Alcaligenes faecalis, Burkholderia (Pseudomonas) cepacia, Burkholderia (Pseudomonas) pseudomallei.

Also, Brucella spp can be sensitive., Listeria monocytogenes, Nocardia asteroides, Pneumocystis carinii, Cyclospora cayetanensis.

Partially sensitive activators (MPK of 80-160 mg/l on sulfamethoxazole): koagulazootritsatelny strains of Staphylococcus spp. (including metitsillinochuvstvitelny and metitsillinoustoychivy strains of Staphylococcus aureus), Streptococcus pneumoniae (penitsillinochuvstvitelny and resistant to penicillin strains), Haemophilus ducreyi, Providencia spp. (including Providencia rettgeri), Salmonella typhi, Salmonella enteritidis, Stenotrophomonas maltophilia (which was earlier called by Xanthomonas maltophilia), Acinetobacter lwoffii, Acinetobacter baumanii, Aeromonas hydrophila.

Steady activators (MPK more than 160 mg/l on sulfamethoxazole): Mycoplasma spp., Mycobacterium tuberculosis, Treponema pallidum, Pseudomonas aeruginosa.

If drug is appointed empirically, it is necessary to consider local features of stability to drug of possible causative agents of a specific infectious disease. At infections which can be caused by partially sensitive microorganisms it is recommended to carry out a sensitivity test to exclude resistance of the activator.

Pharmacokinetics. At oral administration absorption bystry and almost full – 90%. After a single dose of 160 mg of Trimethoprimum + 800 mg of sulfamethoxazole the maximum concentration (Cmax) of Trimethoprimum – 1,5-3 mkg/ml, and sulfamethoxazole – 40-80 mkg/ml. Cmax in a blood plasma is reached in 1-4 hours; therapeutic level of concentration remains within 7 hours after a single dose. At multiple dose at an interval of 12 hours the minimum equilibrium concentration (Css) are stabilized within 1,3-2,8 mkg/ml for Trimethoprimum and 32-63 mkg/ml for sulfamethoxazole. Css of drug is reached within 2-3 days.

It is well distributed in an organism. The volume of distribution (Vd) of Trimethoprimum makes about 130 l, sulfamethoxazole – about 20 l. Gets through a blood-brain barrier, a placental barrier and into breast milk. In lungs and urine creates the concentration exceeding the content in plasma. Trimethoprimum is slightly better, than sulfamethoxazole gets into uninflammed tissue of a prostate gland, semen, a vagina secret, the saliva healthy and the inflamed tissue of lungs, bile while both components of drug get into cerebrospinal fluid and watery moisture of an eye equally. Large numbers of Trimethoprimum and a little smaller amounts of sulfamethoxazole arrive from a blood-groove in intersticial and other ekstravazalny liquids of an organism, at the same time concentration of Trimethoprimum and sulfamethoxazole exceed MPK for the majority of pathogenic microorganisms.

Communication with proteins of plasma – 66% at sulfamethoxazole, at Trimethoprimum – 45%. It is metabolized in a liver. Some metabolites have antimicrobic activity. Sulfamethoxazole is metabolized preferential by N4 acetylation and, to a lesser extent, by conjugation with glucuronic acid.

It is removed by kidneys in the form of metabolites (80% during 72 h) and in not changed look (20% of sulfamethoxazole, 50% of Trimethoprimum); insignificant quantity – through intestines.

Both substances, and also their metabolites, are removed by kidneys, as by glomerular filtering, and canalicular secretion owing to what concentration of both active agents in urine are much higher, than in blood.

The elimination half-life (T1/2) of sulfamethoxazole – 9-11 h, Trimethoprimum – 10-12 h, at children – significantly less also depends on age: till 1 year – 7-8 h, 1-10 years – 5-6 h. At elderly patients and/or patients with a renal failure (the clearance of creatinine (CC) of 15-20 ml/min.) T1/2 increases that demands dose adjustment.

Indications to use:

The infectious and inflammatory diseases caused by microorganisms, sensitive to drug:

• respiratory infections: chronic bronchitis (aggravation), pneumocystic pneumonia (treatment and prevention) at adults and children;
• infections of ENT organs: average otitis (at children);
• infections of urinogenital bodies: infections of urinary tract, venereal ulcer;
• digestive tract infections: the typhoid, a paratyphoid, a shigellosis (caused by sensitive strains of Shigella flexneri and Shigella sonnei); the diarrhea of travelers caused by enterotoksichny strains of Escherichia coli, cholera (in addition to completion of liquid and electrolytes);
• other bacterial infections (the combination to antibiotics is possible): a nocardiosis, a brucellosis (acute), an actinomycosis, osteomyelitis (acute and chronic), the South American zymonematosis, a toxoplasmosis (as a part of complex therapy).

Route of administration and doses:

Inside, after meal with enough liquid. Adults and children are more senior than 12 years: on 960 mg each 12 hours; at the heavy course of infections – on 1440 mg each 12 hours; at an infection of uric ways – 10-14 days, at an exacerbation of chronic bronchitis – 14 days, at diarrhea of travelers and shigelloses – 5 days. The minimum dose and a dose for prolonged treatment (more than 14 days) – on 480 mg each 12 hours.

Children: of 2 months (or 6 weeks at the birth from mothers with HIV infection) to 5 months – on 120 mg, from 6 months to 5 years – on 240 mg, from 6 to 12 years – on 480 mg each 12 hours that approximately corresponds to a dose of 36 mg/kg a day.

Course of treatment at infections of uric ways and acute otitis – 10 days, shigelloses – 5 days. At heavy infections of a dose for children it is possible to increase by 50%.

At acute infections the minimum duration of treatment – 5 days; after disappearance of symptoms therapy is continued within 2 days. If in 7 days of therapy of clinical improvement does not come, it is necessary to estimate repeatedly the patient's condition for possible correction of treatment.

Venereal ulcer – on 960 mg each 12 hours; if in 7 days of healing of a skin element does not occur, it is possible to prolong therapy for 7 days. However lack of effect can testify to resistance of the activator.

One-time reception of 1920-2880 mg, whenever possible after food or before going to bed is recommended in the evening to women with acute uncomplicated infections of uric ways.

At the pneumonia caused by Pneumocystis carinii – 30 mg/kg 4 times a day at an interval of 6 hours within 14-21 days.

For prevention of the pneumonia caused by Pneumocystis carinii, to adults and children 12 years – 960 mg a day are more senior. For children 12 years – 450 mg / кв.м each 12 hours, for 3 days in a row every week are younger. The total daily dose should not exceed 1920 mg. At the same time it is possible to use the following instructions: on 0,26 sq.m of a body surface – 120 mg, respectively on 0,53 sq.m – 240 mg, on 1,06 sq.m – 480 mg.

At other bacterial infections the dose is selected individually depending on age, body weight, function of kidneys and disease severity, for example, at a nocardiosis, adult – 2880-3840 mg/days within not less than 3 months (sometimes up to 18 months).

Course of treatment at an acute brucellosis – 3-4 weeks, at a typhoid and a paratyphoid – 1-3 months.

Features of use:

It is only necessary to appoint co-trimoxazole when advantage of such combination therapy before other antibacterial monodrugs exceeds possible risk. As sensitivity of bacteria to the antibacterial drugs in vitro changes in different geographical areas and in time, at the choice of drug it is necessary to consider local features of bacterial sensitivity.

At long courses of treatment regular blood tests as there is a probability of emergence of hematologic changes are necessary (most often symptomless). These changes can be reversible at purpose of folic acid (3-6 mg/days) that significantly does not break antimicrobic activity of drug. Extra care has to be shown at treatment of elderly patients or patients with suspicion on initial shortage of folates. Purpose of folic acid is reasonable also at prolonged treatment in high doses. At considerable decrease in number of any blood cells drug should be cancelled.

It is inexpedient to use also against the background of treatment the foodstuff containing in large numbers of PABK – green parts of plants (a cauliflower, spinach, bean), carrots, tomatoes.

At long courses (especially at a renal failure), it is regularly necessary to carry out the general analysis of urine and to control function of kidneys.

For prevention of a crystalluria it is recommended to support the sufficient volume of the emitted urine. The probability of toxic and allergic complications of streptocides considerably increases at decrease in filtrational function of kidneys.

At the first emergence of skin rash or any other heavy side reaction drug should be cancelled.

At sudden emergence or increase of cough or asthma it is necessary to inspect repeatedly the patient and to consider a question of the treatment termination by drug.

It is necessary to avoid excessive solar and ultraviolet radiation.

The risk of side effects is much higher at patients with AIDS.

It is not recommended to apply at the diseases caused by a beta and hemolitic streptococcus of group A because of eurysynusic resistance of strains.

At the patients accepting co-trimoxazole pancytopenia cases were described. Trimethoprimum has low affinity to a degidrofolatreduktaza of the person, however can increase toxicity of a methotrexate, especially in the presence of other risk factors, such as senile age, a hypoalbuminemia, a renal failure, oppression of marrow. Similar side reactions are more probable if the methotrexate is appointed in high doses. For prevention of a miyelosupressiya such patients are recommended to appoint folic acid or calcium фолинат.

Trimethoprimum breaks phenylalanine exchange, however it does not influence patients with a fenilketonuriya on condition of observance of the corresponding diet.

Patients of whose metabolism "slow acetylation" is characteristic are more inclined to development of an idiosyncrasy to sulfonamides. Duration of treatment has to be shorter, especially at patients of advanced and senile age.

Co-trimoxazole and, in particular, Trimethoprimum which is its part can affect results of definition of concentration of the methotrexate in serum which is carried out by method of competitive linkng with proteins using a bacterial digidrofolatreduktaza as a ligand. However when determining a methotrexate by a radio immune method of an interference does not arise.

Trimethoprimum and sulfamethoxazole can influence results of reaction of Jaffe (definition of creatinine on reaction with picric acid in the alkaline environment), at the same time in the range of normal values results are overestimated approximately by 10%.

Driving of vehicles and service of the working mechanical devices. Considering a possibility of development of significant side effects, during treatment it is necessary to be careful during the driving of motor transport and occupation potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Use at pregnancy and in the period of a lactation. At pregnancy it is necessary to appoint drug only if the expected advantage of its use surpasses possible risk for a fruit as, both Trimethoprimum, and sulfamethoxazole get through a placental barrier and, thus, can influence exchange of folic acid.

On late durations of gestation it is necessary to avoid use of drug because of possible risk of development of a kernicterus in newborns.

Because Trimethoprimum and sulfamethoxazole get into breast milk, use to-trimaksozola in the period of a lactation contraindicated.

To the pregnant women receiving drug about 5 mg of folic acid a day are recommended to appoint.

Side effects:

From a nervous system: a headache, dizziness, aseptic meningitis, peripheral neuritis, spasms, an ataxy, a ring in ears, a depression, hallucinations, apathy, nervousness.

From respiratory system: pulmonary infiltrates: eosinophilic infiltrate, allergic alveolitis (cough, short wind).

From the alimentary system: nausea, vomiting, loss of appetite, diarrhea, gastritis, abdominal pain, glossitis, stomatitis, cholestasia, increase in activity of "hepatic" transaminases, hepatitis (including cholestatic), гепатонекроз, syndrome of "a disappearing bilious channel" (duktopeniye), hyperbilirubinemia, pseudomembranous colitis, acute pancreatitis.

From bodies of a hemopoiesis: leukopenia, neutropenia, thrombocytopenia, prothrombinopenia, agranulocytosis, anemia (megaloblastny, hemolitic/autoimmune or aplastic), methemoglobinemia, eosinophilia.

From an urinary system: intersticial nephrite, a renal failure, a hamaturia, increase in content of urea of blood, a giperkreatininemiya, a toxic nephropathy with an oliguria and an anury, a crystalluria.

From a musculoskeletal system: an arthralgia, a mialgiya, рабдомиолиз (mainly at patients with AIDS).

Allergic reactions: fervescence, Quincke's disease, itch, photosensitization, skin rash, small tortoiseshell, multiformny exudative erythema (including Stephens-Johnson's syndrome), toxic epidermal necrolysis (Lyell's disease), exfoliative dermatitis, allergic myocarditis, hyperemia of a conjunctiva, scleras, anaphylactic/anaphylactoid reactions, serum disease, hemorrhagic vasculitis (Shenleyn-Genokh's purpura), nodular periarteritis, volchanochnopodobny syndrome.

Others: a hyperpotassemia (mainly at patients with AIDS at therapy of pneumocystic pneumonia), a hyponatremia, a hypoglycemia, weakness, fatigue, sleeplessness, candidiasis.

Interaction with other medicines:

Increases anticoagulating activity of indirect anticoagulants (anticoagulant dose adjustment), and also effect of hypoglycemic medicines and a methotrexate (competes for linkng with proteins and renal transport of a methotrexate, increasing concentration of a free methotrexate).

Reduces intensity of hepatic metabolism of Phenytoinum (extends it with T1/2 for 39%), strengthening its effect and toxic action.

At simultaneous use of co-trimoxazole with Pyrimethaminum in the doses exceeding 25 mg/week the risk of development of megaloblastny anemia increases.
Diuretics (tiazida and at elderly patients are more often) increase risk of development of thrombocytopenia.

Can increase serumal concentration of digoxin, especially at elderly patients, monitoring of concentration of digoxin in serum is necessary.

Efficiency of tricyclic antidepressants at the combined reception with co-trimoxazole can be reduced.

At the patients receiving co-trimoxazole and cyclosporine after renal transplantation the reversible deterioration in function of kidneys which is shown increase in level of creatinine can be observed.

The medicines oppressing a marrowy hemopoiesis increase risk of a miyelosupressiya.

At combined use of co-trimoxazole with indometacin increase in concentration of sulfamethoxazole in blood is possible.

One case of a toxic delirium after a concomitant use of co-trimoxazole and an amantadin is described.

At simultaneous use with inhibitors of the angiotensin-converting enzyme (ACE), especially at elderly patients, development of a hyperpotassemia is possible.

Trimethoprimum, inhibiting transport system of kidneys, increases the area under a curve "concentration of medicinal substance – time" (AUC) by 103% and Cmax for 93% of a dofetilid. At increase in concentration дофетилид can cause ventricular arrhythmias with lengthening of an interval of Q-T, including arrhythmia like "pirouette". Co-administration of a dofetilid and Trimethoprimum is contraindicated.

Contraindications:

• Hypersensitivity to streptocides, Trimethoprimum and/or to other components of drug;
• liver and/or renal failure (clearance of creatinine less than 15 ml/min.);
• aplastic anemia, B12 - scarce anemia, an agranulocytosis, a leukopenia;
• deficit glyukozo-6-fosfatdegidrogenazy;
• concomitant use with dofetilidy;
• lactation period;
• children's age up to 2 months or up to 6 weeks at the birth from mother with HIV infection.

With care: dysfunction of a thyroid gland, heavy allergic reactions in the anamnesis, bronchial asthma, deficit of folic acid, a porphyria, pregnancy.

Overdose:

Symptoms: nausea, vomiting, intestinal colic, dizziness, headache, drowsiness, depression, unconscious states, confusion of consciousness, fever, hamaturia, crystalluria; at long overdose – thrombocytopenia, a leukopenia, megaloblastny anemia, jaundice.

Treatment: the gastric lavage, an artificial diuresis, acidulation of urine increases removal of Trimethoprimum, in oil – 5-15 mg/days of calcium of a folinat (eliminates action of Trimethoprimum on marrow), if necessary – a hemodialysis.

Storage conditions:

To store at a temperature not above 25 °C. To protect from light. To store in places unavailable to children. Not to apply after expiry date. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

Suspension for intake of 240 mg / 5 ml. On 80 ml of drug in bottles of dark glass with the screwed covers from polyethylene. 1 bottle together with the application instruction and a polypropylene measure with a scale in a cardboard pack.