Metressa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METRESSA (METRESSA)

Composition:

Active substance: metronidazole;

100 ml of solution contain 500 mg of metronidazole;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or pale yellow solution.

Pharmacotherapeutic group.

Antibacterials for systemic use. Imidazole derivatives. ATC code J01X D01.

Pharmacological properties.

Pharmacodynamics.

The active component of the drug, metronidazole, is a synthetic (a 5-nitroimidazole derivative) agent with antiprotozoal and antibacterial activity. Its mechanism of action involves the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. The reduced 5-nitro group of metronidazole interacts with microbial DNA, inhibiting its synthesis, which leads to the death of microorganisms.

Metronidazole is effective against Trichomonas vaginalis, Giardia intestinalis, Gardnerella vaginalis, Entamoeba histolytica, Balantidium coli, Lamblia spp., as well as obligate anaerobes: Bacteroides spp. (B. fragilis, B. distasonis, B. thetaiotaomicron, B. vulgatus, B. ovatus), Fusobacterium spp., Veillonella spp., Prevotella spp. (P. bivia, P. buccae, P. disins) and certain gram-positive microorganisms: Eubacterium spp., Clostridium spp., Peptostreptococcus spp., Peptococcus spp.

In combination with amoxicillin, metronidazole is active against Helicobacter pylori, since amoxicillin inhibits the development of resistance to metronidazole.

Aerobic microorganisms and facultative anaerobes are insensitive to metronidazole.

Pharmacokinetics.

After intravenous infusion of 500 mg metronidazole (over 20 minutes) to patients with anaerobic infections, the plasma concentration was 35.2 µg/mL after 1 hour, 33.9 µg/mL after 4 hours, and 25.7 µg/mL after 8 hours. The concentration of metronidazole in bile from the gallbladder after intravenous infusion of 500 mg in patients with normal biliary tract function is significantly higher than in blood plasma. Metronidazole reaches bactericidal concentrations in most tissues and body fluids, including brain tissue, cerebrospinal fluid, abscess cavities, saliva, bile, genital secretions, amniotic fluid, and breast milk.

In the human body, 30–60% of metronidazole is metabolized via side-chain oxidation, hydroxylation, and glucuronidation. The main metabolite is 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, which together with its glucuronide accounts for 40–50% of the total excreted substance in urine.

In patients with normal liver function, the elimination half-life of metronidazole after a single dose averages 8 hours (range: 6–12 hours). In cases of alcohol-induced liver dysfunction, the half-life increases to 18 hours (range: 10–29 hours).

Protein binding of metronidazole to plasma proteins is minimal—no more than 10–20%. It readily penetrates tissues, and its volume of distribution is 70–95% of body weight.

Within 24 hours, 35–65% of all nitro-derivatives of the drug are excreted in urine. Renal clearance is 10.2 mL/min. In patients with impaired renal function, repeated administration leads to accumulation of metronidazole in plasma. Therefore, patients with acute renal failure should receive reduced dosing frequency.

Clinical characteristics.

Indications.

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

Treatment is effective in the following cases:

• infections of the central nervous system (CNS) (including brain abscess, meningitis);
• lung and pleural infections (including necrotizing pneumonia, aspiration pneumonia, lung abscess);
• endocarditis;
• gastrointestinal tract and intra-abdominal infections, including peritonitis, liver abscess, postoperative infections following surgery 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 ear, nose, throat, and oral cavity (including Vincent's angina);
• bone and joint infections (including osteomyelitis);
• gas gangrene;
• septicemia with thrombophlebitis.

In mixed aerobic and anaerobic infections, appropriate antibiotics for the treatment of aerobic infections should be used in addition to Metressa.

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

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

Contraindications.

Hypersensitivity to metronidazole, other drugs with a similar chemical structure (nitroimidazoles), or to any component of the drug. Organic CNS disorders (including epilepsy); blood disorders; hepatic insufficiency (if high doses of the drug are required).

The drug should not be used in combination with disulfiram or alcohol.

Pregnancy.

Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Metronidazole should never be administered simultaneously with any substances other than amikacin sulfate, ampicillin sodium, carbenicillin sodium, cefazolin sodium, cefotaxime sodium, cefuroxime sodium, cephalothin sodium, chloramphenicol sodium succinate, clindamycin phosphate, gentamicin sulfate, hydrocortisone sodium succinate, latamoxef disodium, netilmicin sulfate, and tobramycin sulfate.

Alcohol

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

Amiodarone

When metronidazole and amiodarone are used concomitantly, QT interval prolongation and the development of torsade de pointes have been reported. Monitoring of the QT interval on ECG may be advisable when amiodarone is used in combination with metronidazole. Outpatients should be advised to seek medical attention if symptoms suggestive of torsade de pointes occur, such as dizziness, rapid heartbeat, or loss of consciousness.

Antibiotics and sulfonamides

The antimicrobial activity of Metressa is enhanced when used in combination with antibiotics and sulfonamides.

Phenytoin and phenobarbital

These drugs enhance the hepatic metabolism of metronidazole, reducing its plasma half-life to approximately 3 hours. A similar effect is observed with other drugs that induce hepatic microsomal enzymes.

Busulfan

Concomitant use of metronidazole may significantly increase busulfan plasma concentrations. The mechanism of this interaction is not fully described. Due to the potential risk of severe toxicity and fatal outcomes associated with increased busulfan plasma levels, concomitant use with metronidazole should be avoided.

Carbamazepine

Metronidazole may inhibit the metabolism of carbamazepine, thereby increasing its plasma concentrations.

Cimetidine

Concomitant use of cimetidine may, in some cases, reduce the elimination of metronidazole and consequently lead to increased serum concentrations.

Contraceptives

Some antibiotics, in individual cases, may reduce the efficacy of oral contraceptives by affecting bacterial hydrolysis of steroid conjugates in the intestine, thereby reducing the 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 metronidazole.

Coumarin derivatives

Concomitant use of metronidazole may potentiate the anticoagulant effect of coumarin derivatives and increase the risk of bleeding due to reduced hepatic degradation. Dose adjustment of anticoagulants may be necessary.

Oral anticoagulant therapy: enhanced effects of oral anticoagulants and increased risk of hemorrhagic complications due to slowed metabolism in the liver. Monitoring of the international normalized ratio (INR) should be performed more frequently. Dose adjustment of the oral anticoagulant is recommended during metronidazole treatment and for 8 days after its discontinuation. No interaction with heparin has been observed.

Special concerns regarding INR

Numerous cases of increased activity of oral anticoagulants have been observed in patients treated with antibiotics. Risk factors may include infectious and inflammatory conditions and general health status. It is difficult to determine the exact role of infection and its treatment in INR fluctuations. However, certain types of antibacterial agents require particular attention, including fluoroquinolones, macrolides, tetracyclines, clotrimazole, and certain cephalosporins.

Cyclosporine

Concomitant treatment with cyclosporine and metronidazole carries a risk of increased cyclosporine serum concentrations. Frequent monitoring of cyclosporine and creatinine levels is required.

Disulfiram

Concomitant use of disulfiram may cause confusion or even psychotic reactions. The combination of these drugs should be avoided; metronidazole may be administered no earlier than 2 weeks after discontinuation of disulfiram therapy.

Fluorouracil

Metronidazole inhibits the metabolism of fluorouracil when used concomitantly, resulting in increased plasma concentrations of fluorouracil.

Lithium

Caution should be exercised when metronidazole is used concomitantly with lithium salts, as elevated serum lithium concentrations have been observed during metronidazole therapy, sometimes accompanied by signs of possible renal impairment. Lithium treatment should be restricted or discontinued before initiating metronidazole. Patients receiving lithium therapy should undergo monitoring of plasma lithium concentrations, creatinine, and electrolytes during metronidazole treatment.

Mycofenolate mofetil

Agents that alter gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid preparations. Close clinical and laboratory monitoring is recommended during anti-infective therapy to detect a potential reduction in the immunosuppressive effect of mycophenolic acid.

Tacrolimus

Concomitant use of metronidazole may lead to increased blood concentrations of tacrolimus. The likely mechanism involves inhibition of hepatic metabolism of tacrolimus via CYP3A4. Blood levels of tacrolimus and renal function should be monitored frequently, and dosage adjusted accordingly, especially after initiation or discontinuation of metronidazole therapy in patients stabilized on tacrolimus.

Effect on paraclinical tests

It should be remembered that metronidazole may immobilize treponemes, potentially leading to false-positive Nelson tests.

Special precautions for use

Do not remove the inner container from its packaging before use. The outer packaging protects the product from moisture. The inner container ensures sterility of the medicinal product. After removal of the outer packaging, press the container to check for any partial leakage. If leakage occurs, the container must be replaced.

Immediately before administration, the container with the medicinal product should be warmed to room temperature or preferably to 37°C. For single use only. Any unused portion must be discarded.

The solution should be used only if it is clear and if the container or packaging shows no visible signs of damage.

As soon as possible, transition from intravenous infusions of Metress to oral administration of the drug (200–400 mg three times daily) should be initiated.

Alcohol consumption should be avoided during treatment, as a disulfiram-like reaction may occur, including abdominal cramps, nausea, vomiting, headache, and flushing.

Metronidazole should be used in patients with severe liver disease or impaired haematopoiesis (including granulocytopenia) only if the expected benefit outweighs the potential risk.

Since metronidazole is primarily metabolized in the liver, its clearance may be reduced in patients with hepatic impairment. The benefit-risk ratio of metronidazole use for the treatment of trichomoniasis should be carefully evaluated in such patients. Significant accumulation of metronidazole may occur in patients with hepatic encephalopathy. Due to increased plasma concentrations of metronidazole, symptoms of encephalopathy may worsen. If necessary, the daily dose may be reduced to one-third of the usual dose and administered once daily.

In patients with renal impairment, the elimination half-life of metronidazole remains unchanged; therefore, dose adjustment is not required. However, metronidazole metabolites may accumulate in these patients. The clinical significance of this is unknown.

Metronidazole should be used with caution in patients with bone marrow disorders or central nervous system (CNS) diseases, as well as in elderly patients.

Seizures, myoclonus, and peripheral neuropathy characterized primarily by numbness or paresthesia of the extremities have been reported in patients receiving metronidazole. The appearance of abnormal neurological symptoms requires immediate reassessment of the benefit-risk ratio for continuing therapy.

Intensive or prolonged metronidazole therapy should be administered only under close clinical and laboratory monitoring and under the supervision of a specialist.

Metronidazole is not recommended for patients with porphyria.

In patients with a history of haematological disorders, regular monitoring of white blood cell count is recommended during treatment with high doses of metronidazole and/or prolonged administration.

If leucopenia develops, careful consideration of the expected benefit versus potential risk of continuing treatment is essential. During prolonged treatment, patients should be monitored for the development of adverse effects such as central and peripheral neuropathies (paresthesia, ataxia, dizziness, or seizure episodes). Peripheral neuropathy and leucopenia are usually reversible. Metronidazole should be used with caution in patients with active CNS disorders, except for brain abscess.

Treatment with the drug must be discontinued if ataxia, dizziness, or confusion occurs.

Metronidazole should be used cautiously in patients with severe active or chronic disorders of the peripheral and central nervous systems due to the risk of neurological exacerbation.

If aseptic meningitis occurs during metronidazole therapy, re-administration of the drug is not recommended, or the decision to re-administer should be based on benefit-risk assessment in patients with serious infections.

If symptoms characteristic of encephalopathy or cerebellar syndrome occur, treatment must be immediately reassessed and metronidazole discontinued.

Post-marketing surveillance of metronidazole has reported cases of encephalopathy with corresponding MRI changes (see section "Adverse reactions"). Lesions are most commonly located in the cerebellum (particularly in the dentate nucleus) and the corpus callosum. In most cases, encephalopathy and MRI changes resolved after discontinuation of the drug. Fatal outcomes have been reported very rarely.

Patients should be monitored for possible signs of encephalopathy or worsening of symptoms in those with CNS disorders.

Prolonged use of metronidazole may lead to overgrowth of non-susceptible bacteria and protozoa.

Severe persistent diarrhoea occurring during or within weeks after treatment may be due to pseudomembranous colitis (most commonly caused by Clostridium difficile). This antibiotic-associated intestinal disorder can be life-threatening and requires immediate appropriate treatment. Medicinal products that inhibit peristalsis should not be used.

The duration of treatment with metronidazole or other nitroimidazole-containing agents should not exceed 10 days. Only in exceptional cases, when clinically necessary, may the treatment period be extended, with mandatory clinical and laboratory monitoring (particularly white blood cell count). Repeated courses of metronidazole infusion therapy should be considered only in specific clinical situations. These limitations must be strictly observed, as mutagenic potential of metronidazole cannot be excluded, and an increased incidence of certain tumours has been observed in animal studies. Particular attention should be paid to adverse reactions such as peripheral or central neuropathy (manifested by paresthesia, ataxia, dizziness, or seizures).

Blood count and liver function tests should be performed during prolonged treatment (more than 10 days).

After treatment for Trichomonas vaginalis, the possibility of gonococcal infection remains.

Metronidazole and its metabolites are removed by haemodialysis within 8 hours. Therefore, patients undergoing haemodialysis should receive an additional dose of metronidazole immediately after dialysis.

Dose adjustment of metronidazole is not required in patients with renal impairment undergoing intermittent peritoneal dialysis (IPD) or continuous ambulatory peritoneal dialysis (CAPD). Metronidazole is ineffective against aerobic and facultative anaerobic microorganisms.

Metronidazole may cause falsely low serum aspartate aminotransferase (AST) levels.

Patients should avoid alcoholic beverages during treatment with metronidazole and for at least 2 days after completion of therapy due to the possibility of disulfiram-like reactions (dizziness, vomiting).

Due to reported carcinogenicity of metronidazole, prolonged use of the drug is not recommended.

Metronidazole and its metabolites have shown mutagenic activity in certain non-mammalian cell tests.

Cases of severe, sometimes fatal, bullous skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported with metronidazole use (see section "Adverse reactions"). Most cases of SJS were reported within the first 7 weeks of starting metronidazole therapy. Patients should be informed of the signs and symptoms and closely monitored for skin reactions. If symptoms suggestive of SJS, TEN, or AGEP occur (e.g., influenza-like symptoms, progressive skin rash, often with blisters or mucosal lesions), treatment must be discontinued immediately (see section "Adverse reactions").

Hepatotoxicity in patients with Cockayne syndrome

Rapid onset of severe hepatotoxicity and acute liver failure, including fatal outcomes, has been observed in patients with Cockayne syndrome receiving systemic metronidazole-containing medicinal products.

Metronidazole should not be used in patients in this group, except when the benefit outweighs the risk and no alternative therapy is available.

Liver function should be monitored immediately before starting treatment, during treatment, and after completion of therapy until liver function tests return to normal or baseline values. If liver function tests show markedly elevated values during treatment, the drug should be discontinued. Patients with Cockayne syndrome should be advised to immediately inform their physician and discontinue metronidazole if any symptoms suggestive of liver dysfunction occur (see section "Adverse reactions").

Special precautions regarding certain excipients

Patients on a sodium-controlled diet should be aware that one dose of the medicinal product contains 790 mg of sodium.

Use during pregnancy or breastfeeding

Use of the medicinal product is contraindicated during pregnancy.

Breastfeeding should be discontinued during treatment with the medicinal product.

Ability to influence reaction speed when driving or operating machinery

Metress may have a slight or moderate influence on reaction speed when driving or operating machinery, especially if alcohol is consumed during treatment. Patients should be warned about possible occurrence of drowsiness, dizziness, confusion, hallucinations, seizures, and transient visual disturbances. The physician should draw the patient's attention to this and advise against driving or operating machinery.

Method of Administration and Dosage

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 guidelines should be observed:

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

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

Patients with renal impairment

Dosage reduction is not required (see section "Pharmacological Properties").

Patients with hepatic impairment

Since the elimination half-life of metronidazole in serum is prolonged and plasma clearance reduced in patients with severe hepatic impairment, lower doses are required for such patients (see section "Pharmacological Properties").

Duration of treatment

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

Pre- and postoperative infection prophylaxis

Adults and children aged 11 years and older

500 mg, administered to be completed approximately 1 hour before surgery. Repeat the dose at 8 and 16 hours.

Children aged 2 to 11 years

15 mg/kg body weight, administered to be completed approximately 1 hour before surgery, followed by 7.5 mg/kg body weight at 8 and 16 hours.

Route of administration

The drug should be administered only intravenously as an infusion at a rate of 5 ml/min. Parenteral administration of Metressa is generally carried out for 7 days; thereafter, if necessary, the patient should be prescribed Metressa tablets orally.

Metressa, infusion solution, may also be diluted prior to administration by adding other drugs or diluting solutions such as 0.9% sodium chloride infusion solution or 5% glucose infusion solution.

Antibiotics administered concomitantly should be given separately.

Children

May be used in children aged 2 years and older, as indicated.

Overdose.

Symptoms: nausea, vomiting, and dizziness; in more severe cases – ataxia, paresthesia, and seizures.

Treatment: symptomatic. There is no specific antidote. Metronidazole and its metabolites are rapidly eliminated by hemodialysis.

Side effects.

Adverse reactions during the use of Metressa infusion are rare. The most commonly observed are nausea and taste disturbances. Physicians considering the possibility of using metronidazole for the treatment of chronic diseases beyond the recommended duration of use should take into account the risk of developing peripheral neuropathy. The following adverse reactions have been reported during prolonged treatment with high doses of the drug (which may be necessary for the treatment of severe infections):

Infections and infestations: Genital superinfections caused by Candida, pseudomembranous colitis, which may occur during or after therapy and manifests as severe persistent diarrhea. A detailed description of emergency treatment is provided in the section "Special precautions".

Blood and lymphatic system disorders: Leukopenia, granulocytopenia, thrombocytopenia, neutropenia, pancytopenia, agranulocytosis, aplastic anemia.

Regular monitoring of blood counts is mandatory during prolonged treatment.

Immune system disorders: Hypersensitivity reactions ranging from mild to moderate, including skin reactions (see “Skin and subcutaneous tissue disorders”), angioedema, and drug fever; severe systemic hypersensitivity reactions: anaphylaxis up to anaphylactic shock, severe skin reactions (see “Skin and subcutaneous tissue disorders”), prolonged hyperemia, febrile manifestations, and the Jarisch-Herxheimer reaction.

Severe reactions require immediate therapeutic intervention.

Metabolism and nutrition disorders: Anorexia.

Psychiatric disorders: Irritability, depression, increased excitability, weakness, depressed mood, psychotic disorders including confusion and hallucinations.

Nervous system disorders: Headache, dizziness, sleep disturbances, seizures, peripheral neuropathy (myalgia, paresthesia), sensations of heaviness and tingling in the extremities, encephalopathy, and subacute cerebellar syndrome (ataxia, dysarthria, impaired coordination, nystagmus, tremor), which resolve after discontinuation of the drug; diplopia, myopia, febrile manifestations, optic neuropathy/neuritis.

During intensive and/or maintenance therapy with metronidazole, peripheral sensory neuropathy or transient epileptic seizures may occur. In most cases, neuropathy resolves after discontinuation or dose reduction of the drug. Fatal outcomes have been very rarely reported (see section "Special precautions").

In case of seizures or signs of peripheral neuropathy, a physician should be informed immediately.

Eye disorders: Transient visual disturbances such as blurred vision, decreased visual acuity, color vision changes, diplopia, myopia, ocular hypertensive crisis (isolated cases).

Ear and labyrinth disorders: Vertigo, hearing impairment/hearing loss (including sensorineural), tinnitus.

Cardiac disorders: Changes in ECG (flattening of the T-wave).

Gastrointestinal disorders: Disturbances in taste sensation, mucositis of the oral mucosa, vomiting, nausea, diarrhea, glossitis and stomatitis, bitter eructation, epigastric fullness, epigastric pain, loss of appetite, dryness or metallic taste in the mouth, coated tongue, discoloration of the tongue, hairy tongue (e.g., due to excessive fungal flora growth).

Endocrine disorders: Decreased libido, dysmenorrhea.

Hepatobiliary disorders: Abnormal liver enzyme and bilirubin levels, hepatitis, jaundice, hepatocellular injury, cases of liver failure requiring liver transplantation in patients treated with metronidazole in combination with other antibiotics.

In patients with Cockayne syndrome, cases of severe irreversible hepatotoxicity/acute liver failure, including fatal cases with rapid progression after initiation of systemic metronidazole therapy, have been reported (see section "Special precautions").

Skin and subcutaneous tissue disorders: Allergic skin reactions including pruritus, urticaria, erythema multiforme, rash, pustular rash; hives, skin hyperemia, flushing, AGEP, fixed drug eruption, SJS (isolated reports), TEN (isolated reports).

Severe reactions require immediate therapeutic intervention.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Renal and urinary disorders: Discoloration of urine to reddish-brown (due to water-soluble pigments, metabolites of metronidazole), dysuria, cystitis, enuresis, burning sensation in the urethra, increased risk of vaginal fungal flora (candidiasis).

Reproductive system and breast disorders: Gynecomastia, burning sensation in the urethra or vagina.

General disorders and administration site conditions: Pain, prolonged hyperemia, hyperemia or swelling at the injection site, thrombophlebitis (local), pustular rash, elevated body temperature.

Other: Sinusitis, pharyngitis, aseptic meningitis.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Any unused medicinal product remaining should be disposed of properly.

Incompatibilities.

Metressa for intravenous infusion should not be mixed with other medicinal products except those specified in the section "Dosage and administration". Concomitant administration with a mixture of 10% dextrose, penicillin G, potassium, lactose, and Ringer's solution is contraindicated, as these substances are chemically incompatible.

Packaging. 100 ml of the drug in containers. One container in polyvinyl chloride film, together with the instructions for medical use, in a carton.

Prescription status. Prescription only.

Manufacturer. Euro Life Healthcare Pvt. Ltd.

Manufacturer's address and place of business.

Plot No. 520, Bhagwanpur, Roorkee, Haridwar, Uttarakhand, India.

Marketing Authorization Holder. Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.