Methosulfabol - instructions for use, doses, side effects, contraindications

Excipients: propylene glycol -2.0 g, benzyl alcohol - 75 mg, ethanol (ethyl alcohol 95%) - 500 mg, sodium disulfite (sodium metabisulphite) - 5 mg,2M sodium hydroxide solution to pH 9.5-11.0, water for injection - up to 5 ml.

Description:Transparent colorless or slightly colored liquid.

Pharmacotherapeutic group:Antimicrobial combination

ATX: & nbsp

J.01.E.E.01 Co-trimoxazole [sulfamethoxazole in combination with trimethoprim]

Pharmacodynamics:Combined antimicrobial drug consisting of sulfamethoxazole and trimethoprim. Sulfamethoxazole, similar in structure to paraaminobenzoic acid (PABA), disrupts the synthesis of dihydrofolic acid in bacterial cells, preventing the incorporation of PABA into its molecule. Trimethoprim enhances the action of sulfamethoxazole, disrupting the reduction of dihydrofolic acid into tetrahydrofolic - active, form of foliawhich is responsible for the protein metabolism and division of the microbial cell. Metosulfabol^® is a broad-spectrum bactericide.

Usually, sensitive pathogens (MIC of less than 80 mg / l for sulfamethoxazole): Moraxella (Branhamella) catarrhalis, Haemophilus influenzae (beta-lactamase-forming and beta-lactamase-forming strains), Haemophilus parainjluenzae, Escherichia coli (including enterotoxogenic strains), Citrobacter spp. (incl. Citrobacter freundii), Klebsiella spp. (incl. Klebsiella pneumoniae, Klebsiella oxytoca), Enterobacter cloaceae, Enterobacter aerogenes, Hafnia alvei, Serratia spp. (incl. Serratia marcescens, Serratia liquefaciens), Proteus mirabilis, Proteus vulgaris, Morganella morganii, Shigella spp. (incl. Shigella flexneri, Shigella sonnei), Yersinia spp. (incl. Yersinia enterocolitica), Vibrio cholerae, Edwardsiella tarda, Alcaligenes faecalis, Burkholderia (Pseudomonas) cepacia, Burkholderia (Pseudomonas) pseudomallei.

Clinical experience shows that sensitive can be and Brucella spp., Listeria monocytogenes, Nocardia asteroides, Pneumocystis carinii, Cyclospora cayetanensis.

Partially sensitive pathogens (IPC 80-160 mg / l for sulfamethoxazole): Staphylococcus spp. (coagulase-negative), including Staphylococcus aureus (methicillin-sensitive and methicillin-resistant strains), Streptococcus pneumoniae (penicillin-sensitive and penicillin-resistant strains), Haemophilus ducreyi, Providencia spp. (incl. Providencia rettgeri), Salmonella typhi, Salmonella enteritidis, Stenotrophomonas maltophilia (former name Xanthomonas maltophilia), Acinetobacter Iwoffii, Acinetobacter baumanii, Aeromonas hydrophila.

If the drug is prescribed empirically, it is necessary to take into account the local characteristics of drug resistance of possible pathogens specificallyth infectious disease.

In infections that can be caused by partially sensitive microorganisms, it is recommended that the sample be tested for sensitivity in order to exclude the resistance of the pathogen.

The drug is stable Acinetobacter spp., Pseudomonas aeruginosa, Treponema spp., Mycoplasma spp., Mycobacterium tuberculosis, Leptospira spp., most spore-forming and non-spore forming anaerobes, as well as viruses and fungi.

Pharmacokinetics:

After intravenous (iv) infusion of 160 mg of trimethoprim and 800 mg of sulfamethoxazole, the maximum serum concentrations of the drug components are, on average,9 μg / ml and 106 μg / ml, respectively. Trimethoprim and sulfamethoxazole are well distributed in the body. The volume of distribution of trimethoprim is about 130 liters, sulfamethoxazole is about 20 liters. Penetrates through the blood-brain barrier, placental barrier and into breast milk. In the lungs and urine creates concentrations exceeding the content in the plasma. Trimethoprim is somewhat better than sulfamethoxazole penetrates into the non-inflamed prostate tissue, seminal fluid, vaginal secretions, saliva, healthy and inflamed lung tissue, bile, while in the cerebrospinal fluid and watery eyes, both components of the drug penetrate equally. Large amounts of trimethoprim and slightly lower amounts of sulfamethoxazole come from the bloodstream into the interstitial and other extravasal body fluids, with concentrations of trimethoprim and sulfamethoxazole exceeding the minimum inhibitory concentrations (MICs) for most pathogenic microorganisms.

Connection with plasma proteins - 66% at sulfamethoxazole, in trimethoprim - 45%. Metabolised in the liver. Some metabolites possess antimicrobial activity.Sulfamethoxazole is metabolized predominantly by N4-acetor, to a lesser extent, conjugation with glucuronic acid.

It is excreted by the kidneys inide of metabolites (80% within 72 hours) and unchanged (20% sulfamethoxazole, 50% trimethoprim); a small amount - through the intestine.

Both substances, as well as their metabolites, are excreted through the kidneys, both by glomerular filtration and tubular secretion, so that the concentrations of both active substances in the urine are significantly higher than in the blood.

Half-life (T_1/2) sulfamethoxazole - 9-11 h, trimethoprim-10-12 h; in children the half-life period is much less and depends on the age: up to 1 year - 7-8 hours, 1-10 years - 5-6 hours. In elderly and patients with impaired renal function (creatinine clearance 15-20 ml / min ) T_1/2increases, which requires dose adjustment. Both components are removed during hemodialysis.

Indications:

Infectious diseases caused by susceptible to Methosulfafolu^® microorganisms:

- respiratory tract infections: chronic bronchitis (exacerbation); treatment of pneumocystis pneumonia in adults and children; infection of the ENT organs: otitis media (in children); urinary tract infections;

- gastrointestinal tract infections: typhoid fever, paratyphoid, shigellosis (caused by susceptible strains Shigella flexneri and Shigella sonnei); travelers diarrhea caused by enterotoxic strains Escherichia coli, Cholera (in addition to replenishment of fluid and electrolytes);

other bacterial infections (possibly with other antimicrobial drugs): nocardiosis, brucellosis (acute), actinomycosis, osteomyelitis (acute and chronic), South American blastomycosis, toxoplasmosis (as part of complex therapy).

Contraindications:

Hypersensitivity to the components of the drug (including other sulfonamides); severe hepatic and / or severe renal insufficiency (creatinine clearance <15 ml / min), if it is not possible to regularly determine plasma concentrations of the drug; aplastic anemia, B 12-deficiency anemia, agranulocytosis, leukopenia; deficiency of glucose-6-phosphate dehydrogenase, lactation period, children's age (for parenteral administration - up to 2 months or up to 6 weeks at birth from mothers with HIV infection), simultaneous reception with dofetilide.

Carefully:Porphyria, deficiency of folic acid, bronchial asthma, thyroid gland diseases, severe allergic reactions in the anamnesis.

Pregnancy and lactation:

Since both trimethoprim and sulfamethoxazole penetrate the placental barrier and, thus, can affect the metabolism of folic acid, during pregnancy the drug should be administered only if the expected benefit from its use exceeds the possible risk to the fetus. Pregnant women who receive the drug, it is recommended to appoint 5 mg of folic acid per day. In late pregnancy, the use of the drug should be avoided because of the possible risk of nuclear jaundice in newborns.

Both trimethoprim and sulfamethoxazole penetrate into breast milk. If it is necessary to use lactation, breastfeeding should be discarded.

Dosing and Administration:

Methosulfobol^® injected intravenously drip; duration of infusion - 60-90 min.

In adults and children over 12 years of age apply in doses of 960-1440 mg every 6, 8 or 12 hours, depending on the location and severity of the infection.

Children 6-12 years old The average therapeutic dose is 480 mg, which is administered 2 times a day; in children aged 6 months to 5 years - 240 mg twice a day; Children aged 6 weeks to 5 months Enter 120 mg every 12 hours.

Also for calculating the dose, table 1 can be used (based on the volume of concentrate for the preparation of a solution for infusions):

Table 1.

Body weight, kg	Volume of concentrate for solution for infusion, ml
	Mode of administration and single dose
	Every 12 hours	Every 8 hours	Every 6 hours
5	0,8-1,6	0,5-1,1	0,4 - 0,8
10	1,6-3,2	1,0-2,1	0,8-1,6
20	3,1-6,3	2,1-4,2	1,6-3,2
40	6,2-12,6	4,1-8,4	3,1-6,3
60	9,3 -18,9	6,2 - 12,6	4,7-9,5

The duration of administration of Methosulfabol^® are established individually, proceeding from localization, severity of infection and isolated pathogens.

In acute infections, the minimum course of treatment, on average, is 5 days; After the disappearance of symptoms, therapy is continued for another 2 days. The course of treatment for urinary tract infection - 10 days, shigellosis - 5 days, cholera - 7 days, nocardiosis - 12 weeks, brucellosis - from 2 weeks to 2 months.

With pneumonia caused by Pneumocystis carinii, children and adults injected at a dose of 120 mg / kg / day, which is divided into 4 injections with an interval of 6 hours. The upper limit of a single dose is determined depending on the body weight: 8 kg - 240 'mg, 16 kg - 480 mg, 24 kg - 720 mg, 32 kg - 960 mg, 40 kg - 1200 mg, 48 kg - 1440 mg, 64 kg - 1920 mg, 80 kg-2,400 mg; To calculate the dose, also use Table 2:

Table 2.

Body weight, kg	Single dose concentrate for the preparation of r-ra for infusions, ml
5	1,6
10	3,1
20	6,3
40	12,5
60	18,8
80	25

The duration of treatment is 14-21 days. For maximum efficacy, a constant concentration of trimethoprim in plasma or serum should be maintained within 5 μg / ml or higher.

In patients with impaired renal function, dosage adjustment of Methosulfabol® is required depending on the creatinine clearance (CC): with QC above 25 ml / min - the standard dose; at 15-25 ml / min - the standard dose for 3 days, then half the standard dose. With QC less than 15 ml / min and the impossibility of hemodialysis - reception is not recommended. Patients on hemodialysis after the administration of the usual loading dose, subsequent doses should be 1/2 or 1/3 of the standard dose every 24-48 hours.

Preparation of a solution for intravenous infusion

Before the introduction a drug bred in following proportions immediately before administration: 480 mg (5 ml concentrate for solution for infusion) per 125 ml compatible infusion solution, 960 mg (10 ml) - 250 ml, 1440 mg (15 ml) - 500 ml. If there is clouding or crystallization of the solution before or during infusion, the mixture can not be used. The duration of administration is 1-1.5 hours.

It is desirable to prepare the infusion solution immediately before administration. Concentrate can be diluted in the following infusion solutions: 5 and 10% solutions of dextrose; 0.9% solution of sodium chloride; an aqueous solution containing 0.18% sodium chloride and 4% dextrose; 6% dextran solution [cf. Mol. weight 64000-76000] for in 5% a solution of dextrose or in a 0.9% solution of sodium chloride; 10% dextran [cf. Mol. weight 35000-45000] in a 5% solution of dextrose or in a 0.9% solution of sodium chloride; Ringer's solution.

If necessary, the restriction in the volume of the injected fluid is administered at higher concentrations - 5 ml is dissolved in 50-75 ml of a 5% solution of dextrose.

Side effects:

From the nervous system: headache, dizziness; aseptic meningitis, peripheral neuritis, convulsions, ataxia, ringing in the ears, depression, hallucinations, apathy, nervousness.

From the respiratory system: pulmonary infiltrates: eosinophilic infiltrate, allergic alveolitis (cough, dyspnea).

From the digestive system: nausea, vomiting, decreased appetite, diarrhea, gastritis, abdominal pain, glossitis, stomatitis, cholestasis, increased activity of "liver" transaminases, hepatitis incl.cholestatic, gepatonekroz "disappearing bile duct" syndrome, hyperbilirubinemia, pseudomembranous colitis, acute pancreatitis.

Co sides of hemopoiesis: leukopenia, neutropenia, anemia, hypoprothrombinemia, agranulocytosis, anemia (megaloblastic, hemolytic / or autoimmune aplastic), methemoglobinemia, eosinophilia.

From the urinary system: interstitial nephritis, renal failure, hematuria, elevated levels of blood urea nitrogen hypercreatininemia, toxic nephropathy with oliguria and anuria, crystalluria.

From the side of the musculoskeletal system: arthralgia, myalgia, rhabdomyolysis (mainly in patients with AIDS).

Allergic reactions: fever, angioneurotic edema, pruritus, photosensitivity, skin rash, urticaria, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, allergic myocarditis, hyperemia of conjunctiva, sclera; anaphylactic / anaphylactoid reaction, serum sickness, hemorrhagic vasculitis (Henoch-Schonlein purpura), periarteritis nodosa, lupus-like syndrome.

Local Reactions: thrombophlebitis (in the place of venipuncture), tenderness at the injection site.

Other: hyperkalaemia (mainly in patients with AIDS in the treatment of pneumocystis pneumonia), hyponatremia, hypoglycemia, weakness, fatigue, insomnia, candidiasis.

Overdose:

Symptoms: acute poisoning - nausea, vomiting, intestinal colic, dizziness, headache, drowsiness, depression, fainting, confusion, visual impairment, fever, hematuria, crystalluria; with chronic overdose: thrombocytopenia, leukopenia, megaloblastic anemia, jaundice.

Treatment: drug cancellation; abundant drink, (if not possible - infusion therapy), forced diuresis; Acidification / urine (increased excretion of trimethoprim); in / m - 5-15 mg / day calcium folinata (eliminates the effect of trimethoprim on the bone marrow); when oppression of hematopoietic functions of the bone marrow caused by trimethoprim, folic acid preparations intramuscularly (3.0-6.0 mg / day with a course of 5-7 days) are used to stimulate erythropoiesis, if necessary - hemodialysis (peritoneal dialysis is ineffective).

Interaction:

Pharmaceutically compatible with the following drugs: 5 and 10% solutions of dextrose, 0.9% solution of sodium chloride, an aqueous solution,containing 0.18% sodium chloride and 4% dextrose, 6% dextran solution [cf. Mol. weight 64000-76000] in a 5% solution of dextrose or in a 0.9% solution of sodium chloride, 10% solution of dextran [cf. Mol. weight 35000-45000] in a 5% solution of dextrose or in a 0.9% solution of sodium chloride, Ringer's solution.

Methosulfobol^®can enhance the anticoagulant effect of warfarin. The possibility of such interaction should be remembered in the appointment of Methosulfabol^® patients who are already receiving anticoagulants. In such cases, the blood clotting time must be re-determined. Sulfamethoxazole, like other sulfonamides, can potentiate the effect of oral hypoglycemic drugs.

In patients receiving indomethacin, the concentration of sulfamethoxazole in the blood can increase.

Methosulfobol^® can increase serum concentrations of digoxin, especially in elderly patients, therefore, monitoring serum digoxin concentrations is necessary.

Reduces the effectiveness of tricyclic antidepressants.

Sulfonamides, including sulfamethoxazole, can compete for protein binding and renal transport of methotrexate, thereby increasing the concentration of free methotrexate and its systemic effect.Trimethoprim has a low affinity for human dehydrofolate reductase, but it can increase the toxicity of methotrexate, especially in the presence of other risk factors such as senile age, hypoalbuminemia, impaired renal function, bone marrow depression. Such side reactions are more likely if methotrexate appoint in large doses. For the prevention of myelosuppression, it is recommended that folic acid or folinate calcium should be administered to such patients.

Drugs that inhibit bone marrow hematopoies increase the risk of myelosuppression.

One case of toxic delirium has been described after simultaneous administration of cotrimoxazole and amantadine.

When used simultaneously with ACE inhibitors (angiotensin converting enzyme), especially in elderly pts, hyperkalemia may develop.

Methosulfobol^® can inhibit the hepatic metabolism of phenytoin (prolongs its half-life by 39%). With the simultaneous administration of both drugs, it is important to monitor the toxic effects of phenytoin.

With the simultaneous administration of Methosulfabol^® patients who receive pyrimethamine for the prevention of malaria in doses of more than 25 mg per week, may develop megaloblastic anemia.

In patients taking co-trimoxazole and ciclosporin after a kidney transplant, there may be a reversible impairment of kidney function, manifested by hypercreatininaemia.

Trimethoprim, by inhibiting the kidney transport system, increases the area under the concentration-time curve (AUC) by 103% and the maximum concentration by 93% of dofetilide. With an increase in concentration, dofetilide can cause severe ventricular arrhythmias with lengthening of the interval QT, including arrhythmia torsades de pointes. The simultaneous administration of dofetilide and trimethoprim is contraindicated.

In elderly and senile patients who simultaneously took certain diuretics (mainly thiazides), an increased incidence of thrombocytopenia was observed.

Special instructions:

Because the sensitivity of bacteria to antibacterial drugs in vitro changes in different geographic areas and in time, when selecting a drug, local peculiarities of bacterial sensitivity should be taken into account.

Duration of treatment by Methosulfabol^® should be as short as possible, especially in elderly and senile patients.It is desirable to determine the concentration of sulfamethoxazole in the plasma every 2-3 days just before the next infusion. If the concentration of sulfamethoxazole exceeds 150 μg / ml, treatment should be interrupted until it decreases, below 120 μg / ml. It is also inappropriate to use food products containing large quantities of PABC, green parts of plants (cauliflower, spinach, beans), carrots, tomatoes.

With long courses of treatment, regular blood tests are necessary, since there is a possibility of hematological changes (most often asymptomatic). These changes can be reversible in the appointment of folic acid (3-6 mg / day), which does not violate the antimicrobial activity of the drug. Particular caution should be shown in the treatment of elderly patients or patients with suspected initial folate deficiency. The purpose of folic acid is also suitable for long-term treatment with co-trimoxazole in high doses. With a significant reduction in the number of any blood cells, the drug should be discarded.

Patients receiving long-term treatment with Methosulfabol^® (especially with kidney failure), you need to regularly make a general urine test, and monitor kidney function. During treatment, you need to ensure a sufficient supply of fluid in the body and adequate diuresis to prevent crystalluria.

The likelihood of toxic and allergic complications of sulfonamides significantly increases with a decrease in the filtration function of the kidneys.

When the first appearance of skin rash or any other serious adverse reaction, the drug should be discarded.

Trimethoprim disrupts the exchange of phenylalanine, but this does not affect patients with phenylketonuria, provided that the appropriate diet is observed. Patients whose metabolism is characterized by "slow acetylation" are more likely to develop idiosyncrasy to sulfonamides.

As with the administration of any sulfonamides, caution should be exercised in patients with porphyria or thyroid dysfunction.

Avoid excessive sunlight and UV irradiation during treatment with Methosulfabol®. The risk of side effects is much higher in patients with AIDS.

Laboratory research: trimethoprim and sulfamethoxazole may also affect the results of the Jaffe reaction (determination of creatinine by reaction with picric acid in alkaline medium), while in the range of normal values the results are overestimated by approximately 10%. Co-trimoxazole and, in particular, the trimethoprim included in its composition may affect the results of determination of serum mono-methotrexate concentration by competitive binding with proteins using bacterial dihydrofolate reductase as a ligand. However, in the definition of methotrexate by radioimmunity, interference does not occur.

Effect on the ability to drive transp. cf. and fur:

No data indicating a negative effect of Methosulfabol^® on the ability to drive vehicles and to engage in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Given the likely development of side effects of the drug from the nervous system, during the treatment period, care must be taken when driving vehicles and practicing potentially dangerous activities that require,increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 96 mg / ml.

Packaging:

5 ml of the preparation into ampoules from a colorless or light-shielding neutral glass.

5 ampoules are placed in a contour cell pack.

For 1 or 2 contour mesh packages along with the instruction for use are placed in a pack of cardboard.

Storage conditions:

Store in a dry, dark place at a temperature of 2 ° C to 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:3 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000012

Date of registration:22.10.2010

Expiration Date:22.10.2015

The owner of the registration certificate:ABOLMED, LLC ABOLMED, LLC Russia

Manufacturer: & nbsp

ABOLMED, LLC Russia

Information update date: & nbsp10.05.2018

Illustrated instructions

Instructions

Methosulfobol (Metosulfabol)