Metronidazole-Darnitsa solution for infusions 5 mg/ml bottle 100 ml No. 1

Instructions for use Metronidazole-Darnitsa solution for infusions 5 mg/ml bottle 100 ml No. 1

Composition

active ingredient: metronidazole;

1 ml of solution contains metronidazole - 5 mg;

Excipients: sodium chloride, disodium phosphate dodecahydrate, citric acid monohydrate, water for injections.

Dosage form

Solution for infusion.

Main physicochemical properties: clear colorless or slightly yellowish liquid.

Pharmacotherapeutic group

Antibacterials for systemic use. Imidazole derivatives. Metronidazole.

ATX code J01X D01.

Pharmacological properties

Pharmacodynamics.

The active substance of the drug - metronidazole - belongs to the group of nitroimidazole derivatives. Metronidazole is able to penetrate microorganisms and under anaerobic conditions forms nitrosoradicals with microbial pyruvate-ferredoxin oxidoreductase by oxidizing ferredoxin and flavodoxin. Nitrosoradicals form addition products with DNA base pairs, which leads to DNA strand breakage and bacterial cell death.

The minimum inhibitory concentration (MIC) of metronidazole has been established by the European Committee for Antimicrobial Susceptibility Testing, the breakpoints separating susceptible (S) from resistant (R) organisms are as follows:

Gram-positive anaerobes (S: ≤ 4 mg/ml, R > 4 mg/ml);

Gram-negative anaerobes (S: ≤ 4 mg/ml, R > 4 mg/ml).

List of sensitive and resistant microorganisms:

° The primary literature provides likely standard reference references and therapeutic recommendations for the sensitivity of the relevant species.

Δ Can only be used in patients allergic to penicillin.

Pharmacokinetics.

After intravenous administration, metronidazole is extensively metabolized in body tissues. Plasma protein binding is less than 20%, and the apparent volume of distribution is 36 liters. It is found in most tissues and body fluids, including bile, bone, cerebral abscess, cerebrospinal fluid, liver, saliva, seminal fluid, and vaginal secretions, where concentrations close to those in blood plasma are reached. It also crosses the placenta into breast milk at concentrations equivalent to those in blood plasma.

Metronidazole is metabolized in the liver by side-chain oxidation and glucuronide formation. Its metabolites include an acid oxidation product, a hydroxyl derivative, and a glucuronide. The major metabolite in plasma is 2-hydroxymethylmetronidazole, and the major metabolite in urine is the acid.

Approximately 80% of metronidazole is excreted by the kidneys, of which up to 10% is excreted unchanged. A small amount of metronidazole is excreted by the liver. The half-life is 8 (6–10) hours.

Renal failure delays excretion only to a minor extent.

In severe liver disease, a decrease in plasma clearance and a prolongation of the plasma half-life (up to 30 hours) should be expected.

Indication

Treatment and prevention of infections caused by microorganisms sensitive to metronidazole (mainly anaerobic bacteria):

infections of the central nervous system (including brain abscess, meningitis);

lung and pleural infections (including necrotizing pneumonia, aspiration pneumonia, lung abscess);

endocarditis;

infections of the digestive tract and abdominal cavity (including peritonitis, liver abscess, infections after operations on the colon or rectum, purulent lesions of the abdominal or pelvic cavity);

gynecological infections (including endometritis after hysterectomy or cesarean section, puerperal fever, septic abortion);

infections of the ENT organs and oral cavity (including tonsillitis

Simanovsky – Plaut – Vincent);

bone and joint infections (including osteomyelitis);

gas gangrene;

septicemia with thrombophlebitis.

Prophylactic use is always indicated before surgeries with a high risk of anaerobic infections (before gynecological and intra-abdominal surgeries).

In mixed aerobic and anaerobic infections, appropriate antibiotics should be used in addition to treat aerobic infections.

When using metronidazole, national and international guidelines for the appropriate use of antimicrobials should be taken into account.

Contraindication

Hypersensitivity to metronidazole, other nitroimidazole derivatives or to other components of the drug, organic lesions of the central nervous system, diseases of the blood system, liver failure (if it is necessary to prescribe high doses of the drug). Patients with Cockayne syndrome (see section "Adverse reactions").

Interaction with other medicinal products and other types of interactions

When using the drug simultaneously with other medicines, the following interactions are possible:

with amiodarone - QT prolongation and torsades de pointes have been reported; with concomitant use of the drugs, monitoring of the QT interval on the electrocardiogram is recommended, and in case of symptoms that may indicate torsades de pointes, such as dizziness, palpitations or loss of consciousness, consult a doctor;

with barbiturates – increased hepatic metabolism of metronidazole and a decrease in its half-life from blood plasma to 3 hours;

with busulfan, carbamazepine, lithium, fluorouracil - increased plasma concentrations of the latter; caution should be exercised when using metronidazole with lithium salts, since increased serum lithium concentrations have been observed during metronidazole therapy. The combination of metronidazole with busulfan should be avoided due to the potential risk of severe toxicity and death;

with disulfiram – a state of confusion or even psychotic reactions; this combination of drugs should be avoided; metronidazole should not be prescribed to patients who have taken disulfiram within the last two weeks;

with tacrolimus - simultaneous use with metronidazole may lead to an increase in tacrolimus blood concentrations. The probable mechanism of inhibition of hepatic metabolism of tacrolimus is through CYP3A4. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, especially after the start of metronidazole therapy withdrawal in patients stabilized on tacrolimus;

with cyclosporine - with simultaneous treatment with metronidazole there is a risk of increased serum concentrations of cyclosporine. Frequent monitoring of cyclosporine and creatinine levels is necessary;

with contraceptives - some antibiotics may in some cases reduce the effectiveness of oral contraceptives by affecting the bacterial hydrolysis of steroid conjugates in the intestine and thus reducing the reabsorption of unconjugated steroids, resulting in reduced plasma levels of active steroids. This unusual interaction may be noted in women with high levels of biliary excretion of steroid conjugates. Known cases of ineffectiveness of oral contraceptives have been associated with the use of various antibiotics, including ampicillin, amoxicillin, tetracyclines, and metronidazole;

with mycophenolate mofetil - reduced oral bioavailability; with concomitant use of drugs, careful clinical and laboratory monitoring is recommended to detect a decrease in the immunosuppressive effect of mycophenolic acid;

with coumarin derivatives - increased anticoagulant effect of coumarin derivatives and increased risk of bleeding due to reduced degradation in the liver. If possible, their combined use should be avoided. It is recommended to adjust the dose of oral anticoagulant during metronidazole administration and for 8 days after its withdrawal. No interactions have been reported with heparin-type anticoagulants. However, anticoagulant activity should be constantly monitored;

with phenytoin – inhibition of hepatic metabolism of phenytoin and reduction of its plasma concentration, as well as reduction of the effectiveness of metronidazole;

with primidone – accelerates the metabolism of metronidazole, leading to a decrease in its concentration in blood plasma;

with cimetidine – increased plasma concentration of metronidazole due to decreased excretion;

impact on paraclinical tests: metronidazole can immobilize treponemas, which leads to a false-positive Nelson test.

Metronidazole inhibits alcohol dehydrogenase and other enzymes that oxidize ethanol.

Alcoholic beverages should be avoided during metronidazole therapy and for at least 48 hours after the end of treatment, due to the possibility of developing adverse reactions such as dizziness and nausea (disulfiram-like effect).

Application features

The drug should be used in patients with severe liver damage, impaired hematopoiesis (including granulocytopenia), and active or chronic severe disorders of the peripheral or central nervous system only if the expected benefit outweighs the potential risk.

During the use of the drug, the development of convulsive seizures and peripheral neuropathy, characterized by numbness or paresthesia of the extremities, is possible.

In the event of neurological signs, an urgent benefit/risk assessment should be performed to continue metronidazole therapy.

Severe persistent diarrhoea, which may develop during treatment or in the following weeks, may be due to pseudomembranous colitis (in many cases caused by Clostridium difficile) (see section "Adverse reactions"). This intestinal disease caused by antibiotics can be life-threatening and requires immediate treatment. During treatment with metronidazole, drugs that inhibit intestinal peristalsis should not be used.

Long-term therapy with metronidazole may lead to impaired hematopoiesis due to bone marrow suppression. Its manifestations are listed in the section "Adverse reactions". During long-term use of the drug, the blood count should be carefully monitored.

If leukopenia develops, treatment should be continued only if the expected benefit significantly outweighs the potential risk.

The duration of treatment with metronidazole or drugs containing other nitroimidazoles should not exceed 10 days.

Only in exceptional cases of urgent need may the treatment period be extended, accompanied by appropriate clinical and laboratory monitoring. Repeated therapy should be limited to isolated cases as much as possible. These restrictions should be strictly observed, since a possible mutagenic activity of metronidazole cannot be excluded due to an increase in the incidence of certain tumors, which has been observed in animal studies.

Metronidazole may affect the results of enzymatic-spectrophotometric determination of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, triglycerides and glucose hexokinase, reducing their values (possibly to zero).

Metronidazole may interfere with liver enzyme assays using the continuous flow NADH assay, which is based on the end point determination of reduced NADH. Abnormally low liver enzyme concentrations, including zero values, may be observed.

The medicinal product is for single use only. Any unused portion should be discarded.

Important information about excipients.

This medicinal product contains sodium compounds. Caution should be exercised when administered to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

The safety of metronidazole during pregnancy has not been well studied. In particular, reports of its use are contradictory. Some studies have shown an increased incidence of malformations. Animal studies have not shown teratogenic effects of metronidazole.

During the first trimester, metronidazole should only be used to treat severe, life-threatening infections if there is no safer alternative.

In the II and III trimesters, metronidazole can also be used to treat other infections (e.g., trichomoniasis) if the expected benefit to the mother clearly outweighs the possible risk to the fetus, but short, high-dose regimens should not be used in these situations.

Since metronidazole passes into breast milk, breastfeeding should be discontinued during treatment. Breastfeeding should not be resumed earlier than 2-3 days after the end of therapy, since metronidazole has a prolonged half-life.

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients should be warned about the possibility of drowsiness, dizziness, confusion, hallucinations, seizures or temporary visual disturbances, which may impair the ability to drive and use machines. These effects are most common at the beginning of treatment.

Method of administration and doses

The drug should be administered as a slow intravenous infusion (i.e. a maximum of 100 ml over at least 20 minutes, usually over 1 hour).

The drug can be diluted before administration by adding other drugs or diluents, such as 0.9% sodium chloride solution for infusion or 5% glucose solution for infusion.

Antibiotics that are prescribed simultaneously should be administered separately.

The dose should be adjusted according to the patient's individual response to treatment, their age and body weight, as well as the type and severity of the disease.

The following dosage instructions should be followed.

Treatment.

Adults and children aged 12 and over.

The usual dose is 500 mg every 8 hours. If medically indicated, a loading dose of 15 mg/kg body weight may be administered at the beginning of treatment.

Children aged 2 to 12 years.

The usual dose of the drug is 7-10 mg/kg of body weight every 8 hours, which corresponds to a daily dose of 20-30 mg/kg of body weight.

Patients with renal failure.

There is no need to adjust the dose of the drug (see section "Pharmacological properties").

Patients with liver failure.

Patients with severe hepatic impairment may require dose adjustment due to prolonged half-life and reduced plasma clearance (see section 5.2).

The duration of treatment depends on its effectiveness. In most cases, a 7-day course will be sufficient. If there are clinical indications, treatment may be extended (see section "Special instructions").

Pre- and postoperative prophylaxis.

The usual dose of the drug is 500 mg. Metronidazole administration should be completed approximately 1 hour before surgery. The drug should be re-administered at the same dose after 8 and 16 hours.

Children aged 2 to 11 years.

The usual dose is 15 mg/kg body weight. Metronidazole should be administered approximately 1 hour before surgery. The drug should be re-administered at a dose of 7.5 mg/kg body weight after 8 and 16 hours.

Method of application

Do not insert the needle(s) into any areas of the polymer vial that are not intended for this purpose, but only into sterile ports!

To carry out infusion treatment, you must follow the following algorithm:

Remove the protective plastic cover with first-time opening control (if present).

Tear off the safety valve(s) No. 1 as shown in Fig. 1 and Fig. 2 (the manufacturer may use different types and materials for the safety valves).

Remove the cap from the needle and insert it into any of the special ports No. 2 of the infusion drug vial (see Fig. 1 and Fig. 2).

Another sterile port can be used to introduce other drugs into the infusion bottle (No. 4, see Fig. 3), or, in case of insufficient flow rate, for the air needle (No. 4, see Fig. 3).

Hang the solution bottle using the special ring No. 3 located at the bottom of the bottle (see Fig. 3).

Children.

The medicine should be used in children over 2 years of age.

Overdose

Symptoms: development of adverse reactions described below.

Treatment: If necessary, metronidazole can be effectively removed by hemodialysis. There is no specific treatment or antidote. In case of suspected overdose, symptomatic and supportive treatment should be administered.

Side effects

Adverse effects are mainly associated with prolonged use of high doses. The most common are nausea, altered taste, and a risk of neuropathy with long-term use.

On the part of the organs of vision: visual disturbances, double vision, myopia, oculogyric crisis (in isolated cases).

From the respiratory system: sinusitis, pharyngitis, bronchitis.

Gastrointestinal: nausea, vomiting, diarrhea, glossitis and stomatitis, belching with a bitter taste, pain and feeling of heaviness in the epigastric region, loss of appetite, metallic taste in the mouth, coated tongue, pancreatitis (in isolated cases), oral mucositis, abdominal spasm, constipation.

Hepatobiliary disorders: hepatobiliary disorders, abnormal liver enzymes and bilirubin, abnormal liver function tests, hepatitis, jaundice. These events are reversible and usually resolve after completion of treatment or discontinuation of the drug. Frequency unknown: Cases of severe irreversible hepatotoxicity or acute hepatic failure, including fatal cases with a very rapid course, have been reported in patients with Cockayne syndrome following systemic metronidazole administration (see section "Contraindications").

On the part of the kidneys and urinary system: dark urine (due to the excretion of a metabolite of metronidazole), dysuria, cystitis and urinary incontinence.

Nervous system: irritability, headache, dizziness, drowsiness or insomnia, convulsions, peripheral neuropathy (symptoms of which are paresthesias, pain, feeling of heaviness and tingling in the extremities), encephalopathy, development of subacute cerebellar syndrome (symptoms of which are ataxia, dysarthria, gait disturbance, nystagmus, tremor).

If you experience seizures or signs of peripheral neuropathy, you should immediately notify your doctor.

On the part of the psyche: a state of confusion, irritability, depression, psychotic disorders, including hallucinations, depressed mood, decreased libido.

Cardiovascular system: electrocardiogram changes similar to T wave flattening, hypotension.

From the blood and lymphatic system: leukopenia, granulocytopenia, thrombocytopenia, agranulocytosis, aplastic anemia.

During long-term use of the drug, regular monitoring of blood counts is mandatory.

Immune system, skin and subcutaneous tissue disorders: mild to moderate hypersensitivity reactions, including skin reactions (pruritus, urticaria, erythema multiforme), angioedema, drug fever, severe systemic hypersensitivity reactions (anaphylaxis up to anaphylactic shock); Stevens-Johnson syndrome (isolated reports), Lyell's syndrome (isolated reports).

Severe reactions, such as Stevens–Johnson syndrome and Lyell syndrome, require immediate therapeutic intervention.

Musculoskeletal system: arthralgia, myalgia.

From the reproductive system: dysmenorrhea.

General disorders and administration site reactions: hyperemia, vein irritation (up to thrombophlebitis) after intravenous administration, itching, pain, pustular rash; weakness.

Infections and infestations: genital superinfections (caused by Candida), pseudomembranous colitis, which may occur during or after therapy and manifests itself in the form of severe persistent diarrhea.

A description of emergency treatment is provided in the section "Special instructions for use".

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 ° C. Do not freeze.

Keep out of reach of children.

Packaging

100 ml in a bottle; 1 bottle in a pack; 100 ml in bottles.

Vacation category

According to the recipe.

Producer

PrJSC "Pharmaceutical Company "Darnitsa".

Location of the manufacturer and address of its place of business.

Ukraine, 02093, Kyiv, Boryspilska St., 13.