Metronidazole-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METRONIDAZOLE-DARNITSA (METRONIDAZOLE-DARNITSA)

Composition:

active substance: metronidazole;

1 ml of solution contains metronidazole – 5 mg;

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

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, colorless or slightly yellowish liquid.

Pharmacotherapeutic group.

Antibacterials for systemic use. Imidazole derivatives. Metronidazole.

ATC code J01X D01.

Pharmacological properties.

Pharmacodynamics.

The active substance of the medicinal product, metronidazole, belongs to the group of nitroimidazole derivatives. Metronidazole is capable of penetrating into microorganisms and, under anaerobic conditions, forms nitro radicals via oxidation of ferredoxin and flavodoxin by microbial pyruvate-ferredoxin oxidoreductase. The nitro radicals form adducts with DNA base pairs, leading to DNA strand breaks and subsequent death of bacterial cells.

The minimum inhibitory concentration (MIC) of metronidazole has been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The breakpoints distinguishing susceptible (S) organisms from resistant (R) ones 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 susceptible and resistant microorganisms:

° In primary literature, probable standard reference citations and therapeutic recommendations on susceptibility of the respective species are provided.

Δ Can be used only in patients with penicillin allergy.

Pharmacokinetics.

After intravenous administration, metronidazole is extensively distributed and metabolized in body tissues. Plasma protein binding is less than 20%, and the apparent volume of distribution is 36 liters. It is detected in most tissues and body fluids, including bile, bones, cerebral abscesses, cerebrospinal fluid, liver, saliva, seminal fluid, and vaginal secretions, where concentrations approach those in plasma. Metronidazole also crosses the placenta and is excreted into breast milk at concentrations equivalent to those in plasma.

Metronidazole is metabolized in the liver by side-chain oxidation and glucuronide formation. Its metabolites include the acid oxidation product, hydroxylated derivative, and glucuronide. The main metabolite in plasma is 2-hydroxymethylmetronidazole, while the primary metabolite in urine is the acid form.

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

Renal insufficiency only slightly delays elimination.

In severe liver disease, a reduction in plasma clearance and prolonged elimination half-life from plasma (up to 30 hours) should be expected.

Clinical characteristics.

Indications.

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

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

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

• endocarditis;

• gastrointestinal and intra-abdominal infections (including peritonitis, liver abscess, postoperative infections following surgery on the colon or rectum, purulent abdominal or pelvic infections);

• gynecological infections (including post-hysterectomy or post-cesarean endometritis, puerperal fever, septic abortion);

• infections of the ear, nose, throat, and oral cavity (including Vincent’s angina*);

• bone and joint infections (including osteomyelitis);

• gas gangrene;

• sepsis associated with thrombophlebitis.

Prophylactic use is always indicated prior to surgeries with a high risk of anaerobic infections (e.g., gynecological and intra-abdominal surgeries).

In mixed aerobic and anaerobic infections, appropriate additional antibiotics should be administered to treat the aerobic component.

When using metronidazole, national and international guidelines on appropriate antimicrobial use should be followed.

Contraindications.

Hypersensitivity to metronidazole, other nitroimidazole derivatives, or any component of the medicinal product; organic central nervous system disorders; blood system disorders; hepatic insufficiency (if high-dose therapy is required). Patients with Cockayne syndrome (see section "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

The following interactions may occur when metronidazole is used concomitantly with other medicinal products:

with amiodarone – QT interval prolongation and torsades de pointes have been reported; ECG monitoring of the QT interval is recommended during concomitant use, and patients should seek medical attention if symptoms suggestive of torsades de pointes occur, such as dizziness, rapid heartbeat, or loss of consciousness;

with barbiturates – enhanced hepatic metabolism of metronidazole and reduced plasma half-life down to 3 hours;

with busulfan, carbamazepine, lithium, fluorouracil – increased plasma concentrations of the latter; caution is advised when metronidazole is used concomitantly with lithium salts, as elevated serum lithium concentrations have been observed during metronidazole therapy. Combination of metronidazole with busulfan should be avoided due to the potential risk of severe toxicity and fatal outcomes;

with disulfiram – confusion or even psychotic reactions; this combination should be avoided. Metronidazole should not be administered to patients who have taken disulfiram within the previous two weeks;

with tacrolimus – concomitant use with metronidazole may lead to increased blood concentrations of tacrolimus. The likely mechanism is inhibition of hepatic metabolism of tacrolimus via CYP3A4. Frequent monitoring of tacrolimus blood levels and renal function is recommended, with appropriate dose adjustments, especially after initiation or discontinuation of metronidazole therapy in patients stabilized on tacrolimus;

with cyclosporine – concomitant use with metronidazole may increase the risk of elevated cyclosporine serum concentrations. Frequent monitoring of cyclosporine and creatinine levels is required;

with contraceptives – some antibiotics may, in individual cases, reduce the efficacy of oral contraceptives by affecting bacterial hydrolysis of steroid conjugates in the gut, thereby reducing reabsorption of unconjugated steroids and lowering plasma levels of active steroids. This unusual interaction may occur in women with high biliary excretion of steroid conjugates. Cases of oral contraceptive failure have been reported with various antibiotics, including ampicillin, amoxicillin, tetracyclines, and also metronidazole;

with mycophenolate mofetil – reduced oral bioavailability; careful clinical and laboratory monitoring is recommended during concomitant use to detect reduced immunosuppressive effect of mycophenolic acid;

with coumarin derivatives – enhanced anticoagulant effect of coumarin derivatives and increased risk of bleeding due to reduced hepatic degradation. Whenever possible, concomitant use should be avoided. Dose adjustment of the oral anticoagulant is recommended during metronidazole therapy and for 8 days after its discontinuation. No interaction has been reported with heparin-type anticoagulants. However, anticoagulant activity should be continuously monitored;

with phenytoin – inhibition of hepatic metabolism of phenytoin and reduced plasma concentration, as well as reduced efficacy of metronidazole;

with primidone – accelerates metronidazole metabolism, leading to reduced plasma concentration;

with cimetidine – increased plasma concentration of metronidazole due to reduced elimination;

effects on paraclinical tests: metronidazole may immobilize treponemes, leading to false-positive Nelson test results.

Metronidazole inhibits alcohol dehydrogenase and other enzymes involved in ethanol oxidation.

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

Special precautions for use.

Metronidazole should be administered to patients with severe liver impairment, impaired haematopoiesis (including granulocytopenia), or active or chronic severe disorders of the peripheral or central nervous system only when the expected benefit outweighs the potential risk.

Convulsive seizures and peripheral neuropathy characterized by numbness or paresthesia of the extremities may occur during treatment with this medicinal product.

If neurological symptoms develop, an urgent benefit-risk assessment should be performed to determine whether metronidazole therapy should continue.

Treatment with this medicinal product may be associated with severe hypersensitivity reactions (including anaphylactic shock). If such reactions occur, the drug should be discontinued immediately and appropriate emergency therapy initiated.

Severe persistent diarrhoea, which may develop during or within several weeks after treatment, may be a sign of pseudomembranous colitis (often caused by Clostridium difficile) (see section "Adverse reactions"). This antibiotic-associated intestinal disorder can be life-threatening and requires immediate treatment. Drugs that inhibit intestinal motility should not be used during metronidazole therapy.

Prolonged metronidazole therapy may lead to impaired haematopoiesis due to bone marrow suppression. Manifestations are described in the section "Adverse reactions". Complete blood counts should be closely monitored during prolonged treatment.

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

The duration of treatment with metronidazole or other nitroimidazole-containing agents should not exceed 10 days.

Only in exceptional cases and under urgent clinical need may the treatment period be extended, with appropriate clinical and laboratory monitoring. Repeated courses of therapy should be strictly limited to individual cases. These limitations must be strictly observed, as mutagenic activity of metronidazole cannot be excluded due to increased incidence of certain tumours observed in animal studies.

Metronidazole may interfere with enzymatic spectrophotometric assays for aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, triglycerides, and glucose hexokinase, leading to reduced values (possibly down to zero).

Metronidazole may interfere with the measurement of hepatic enzymes using the continuous-flow method based on monitoring the decrease in reduced NADH at the endpoint. Unusually low concentrations of hepatic enzymes, including zero values, may be observed.

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

Important information on excipients.

This medicinal product contains sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

The safety of metronidazole use during pregnancy has not been fully established. Reports on its use in pregnancy are conflicting. Some studies have indicated an increased risk of congenital malformations. Animal studies have not shown teratogenic effects of metronidazole.

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

In the second and third trimesters, metronidazole may also be used for the treatment of other infections (e.g., trichomoniasis), provided that the expected benefit to the mother clearly outweighs the potential risk to the fetus. However, in these cases, short-course high-dose regimens should be avoided.

Since metronidazole is excreted in breast milk, breastfeeding should be discontinued during treatment. Breastfeeding may be resumed no earlier than 2–3 days after completion of therapy, due to the prolonged elimination half-life of metronidazole.

Ability to influence the ability to drive and use machines.

Patients should be warned about the possible occurrence of somnolence, dizziness, confusion, hallucinations, seizures, or transient visual disturbances, which may impair the ability to drive or operate machinery. These effects typically occur at the beginning of treatment.

Method of Administration and Dosage.

The medicinal product 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 medicinal product may be diluted prior to administration by adding other medicinal products or diluent solutions such as 0.9% sodium chloride infusion solution or 5% glucose infusion solution.

Antibiotics administered concurrently should be given separately.

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

The following dosage recommendations should be observed.

Treatment.

Adults and children aged 12 years and older.

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

Children aged 2 to 12 years.

The usual dose is 7–10 mg/kg body weight every 8 hours, corresponding to a daily dose of 20–30 mg/kg body weight.

Patients with renal impairment.

There is no need to adjust the dosage of the medicinal product (see section "Pharmacological Properties").

Patients with hepatic impairment.

Dose adjustment may be required for patients with severe hepatic impairment due to prolonged elimination half-life and reduced plasma clearance (see section "Pharmacological Properties").

The duration of treatment depends on its effectiveness. In most cases, a 7-day course is sufficient. Treatment may be extended if clinically indicated (see section "Special Warnings and Precautions for Use").

Pre- and postoperative prophylaxis.

Adults and children aged 11 years and older.

The usual dose is 500 mg. Metronidazole administration should be completed approximately 1 hour before surgery. The medicinal product should be repeated 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 administration should be completed approximately 1 hour before surgery. The medicinal product should be repeated at a dose of 7.5 mg/kg body weight after 8 and 16 hours.

Method of administration

Do not insert needle(s) into non-designated areas of the polymer bottle, only into sterile ports!

For infusion administration, follow this procedure:

1. Remove the tamper-evident plastic cap (if present).
2. Remove protective closure(s) No. 1 as shown in Fig. 1 and Fig. 2 (the manufacturer may use different types and materials for protective closures).
3. Remove the needle cap and insert the needle into either of the designated sterile ports No. 2 of the infusion bottle (see Fig. 1 and Fig. 2).
4. The other sterile port may be used for adding other medicinal products into the infusion bottle (No. 4, see Fig. 3), or, if necessary, for a venting needle (No. 4, see Fig. 3) in case of insufficient flow rate.
5. Hang the solution bottle using the special ring No. 3 located at the bottom of the bottle (see Fig. 3).

Children.

The medicinal product is indicated for use in children aged 2 years and older.

Overdose.

Symptoms: development of adverse reactions described below.

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

Adverse reactions

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

Eye disorders: visual disturbances, double vision, myopia, ocular hypertension crisis (isolated cases).

Respiratory system disorders: sinusitis, pharyngitis, whooping cough.

Gastrointestinal disorders: nausea, vomiting, diarrhea, glossitis and stomatitis, bitter regurgitation, epigastric pain and discomfort, loss of appetite, metallic taste in the mouth, coated tongue, pancreatitis (isolated cases), oral mucositis, abdominal cramps, constipation.

Hepatobiliary and biliary disorders: hepatobiliary disorders, abnormal liver enzyme and bilirubin levels, liver function test abnormalities, hepatitis, jaundice. These manifestations are reversible and usually resolve after completion of treatment or discontinuation of the drug. Frequency not known: severe irreversible hepatotoxicity or acute liver failure, including fatal cases with rapid progression, have been observed in patients with Cockayne syndrome following systemic administration of metronidazole (see section "Contraindications").

Renal and urinary disorders: dark urine (due to excretion of metronidazole metabolite), dysuria, cystitis, urinary incontinence.

Nervous system disorders: irritability, headache, dizziness, drowsiness or insomnia, seizures, peripheral neuropathy (symptoms include paresthesia, pain, heaviness and tingling in the extremities), encephalopathy, development of subacute cerebellar syndrome (symptoms include ataxia, dysarthria, gait disturbances, nystagmus, tremor).

If seizures or signs of peripheral neuropathy occur, a physician should be notified immediately.

Psychiatric disorders: confusion, irritability, depression, psychotic disorders including hallucinations, depressed mood, decreased libido.

Cardiovascular disorders: ECG changes resembling T-wave flattening, hypotension.

Blood and lymphatic system disorders: leukopenia, granulocytopenia, thrombocytopenia, agranulocytosis, aplastic anemia.

During prolonged use of the drug, regular monitoring of blood counts is mandatory.

Immune system, skin and subcutaneous tissue disorders: hypersensitivity reactions ranging from mild to moderate, 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's syndrome require immediate therapeutic intervention.

Musculoskeletal system disorders: arthralgia, myalgia.

Reproductive system disorders: dysmenorrhea.

General disorders and administration site conditions: hyperemia, venous irritation (up to thrombophlebitis) following intravenous administration, pruritus, pain, pustular rash; weakness.

Infections and infestations: genital superinfections (caused by Candida), pseudomembranous colitis, which may occur during or after therapy and manifest as severe persistent diarrhea.

Emergency treatment instructions are provided in the section "Special precautions for use".

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 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 vial; 1 vial per carton; 100 ml in vials.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13 Borispilska Street, Kyiv, 02093, Ukraine.