Efloran

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Efloran (Efloran®)

Composition:

Active substance: metronidazole;

100 ml of solution (1 vial) contains 500 mg of metronidazole;

Excipients: sodium chloride, sodium edetate, water for injections.

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, almost colorless or slightly yellowish solution, practically free from visible particles.

Pharmacotherapeutic group. Antibacterials for systemic use. Imidazole derivatives. Metronidazole. ATC code J01X D01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole – a synthetic antimicrobial agent, a nitroimidazole derivative, active against anaerobic microorganisms – gram-negative and gram-positive bacteria. It treats certain parasitic infections and has pronounced activity against Giardia and Trichomonas.

Metronidazole acts in several stages: it penetrates into the bacterial cell, where its 5-nitro group is converted into hydroxylamine, leading to suppression of microbial DNA up to a lethal effect; afterward, cytotoxic metabolites of metronidazole break down into non-toxic, inactive metabolites.

Pharmacokinetics.

Absorption

Maximum serum concentration is nearly equivalent following intravenous or oral administration; bioavailability ranges from 90% to 100%. The elimination half-life of the active substance is 8 hours.

Distribution

The active substance penetrates well into all tissues, organs, and body fluids; the volume of distribution reaches 80% of body weight.

Within 4–6 hours, metronidazole concentrations in tissues and cerebrospinal fluid reach 80–90% of serum concentrations. Plasma protein binding is minimal – no more than 20%.

Metabolism

Metronidazole is primarily metabolized in the liver. Mainly oxidative metabolites are formed, which are predominantly excreted in urine as glucuronides.

Presystemic metabolism of the active substance is negligible. Metabolism is slowed in patients with liver disease. In patients with renal insufficiency, metabolites may accumulate.

Elimination

Unmetabolized metronidazole is primarily excreted in urine. From 6% to 15% of the administered dose is excreted in feces.

Metronidazole and its metabolites are rapidly removed by hemodialysis.

Clinical characteristics.

Indications.

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

Treatment should be prescribed in cases of:

• central nervous system infections (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, and 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 administered in addition to metronidazole.

Prophylactic use of metronidazole is always indicated before high-risk surgeries for 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 medicinal product.

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.

Eforan, infusion solution, should never be administered simultaneously with any other substances except amikacin sulfate, sodium ampicillin, sodium carbenicillin, sodium cefazolin, sodium cefotaxime, sodium cefuroxime, sodium cephalothin, sodium chloramphenicol succinate, clindamycin phosphate, gentamicin sulfate, sodium hydrocortisone 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

Cases of QT interval prolongation and development of torsade de pointes have been reported with concomitant use of metronidazole and amiodarone. ECG monitoring of the QT interval 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.

Phenytoin and phenobarbital

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

Busulfan

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

Carbamazepine

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

Cimetidine

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

Contraceptives

Some antibiotics, in individual cases, may reduce the efficacy of oral contraceptives by affecting bacterial hydrolysis of steroid conjugates in the gut, thereby decreasing 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 enhance 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 hepatic metabolism. Monitoring of international normalized ratio (INR) levels 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 considerations regarding INR

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

Cyclosporine

Concomitant treatment with cyclosporine and metronidazole carries a risk of increased serum cyclosporine 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 administered 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 potential renal impairment. Lithium therapy should be restricted or discontinued before initiating metronidazole. Patients receiving lithium require monitoring of serum lithium, creatinine, and electrolyte levels during metronidazole treatment.

Mycophenolate mofetil

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

Tacrolimus

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

Oral anticoagulant therapy: enhanced effects of oral anticoagulants and increased risk of hemorrhagic complications due to slowed hepatic metabolism. Monitoring of INR levels should be performed more frequently. Dose adjustment of the oral anticoagulant is recommended during metronidazole treatment and for 8 days after its discontinuation.

Effect on paraclinical tests

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

Special precautions for use.

Metronidazole should be administered to 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 and administered once daily.

In patients with renal insufficiency, 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 biological monitoring and under the supervision of a specialist.

Metronidazole is not recommended for patients with porphyria.

In patients with a history of haematological disorders during high-dose or long-term metronidazole therapy, regular monitoring of white blood cell count is recommended.

If leucopenia develops, the anticipated benefit of continuing treatment versus potential risk must be carefully evaluated. During prolonged treatment, patients should be monitored for the development of adverse effects such as central and peripheral neuropathies (paresthesia, ataxia, dizziness, or seizures). Peripheral neuropathy and leucopenia are usually reversible. Metronidazole should be used with caution in patients with active CNS disorders, except in cases of brain abscess.

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

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

Post-marketing surveillance 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 splenium of the corpus callosum. In most cases, encephalopathy and MRI changes resolved after discontinuation of the drug. Very rare fatal cases have been reported.

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 often caused by Clostridium difficile). This antibiotic-associated intestinal disorder can be life-threatening and requires immediate appropriate treatment. Antiperistaltic agents 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 appropriate clinical and laboratory monitoring (particularly white blood cell count). Repeated courses of intravenous metronidazole therapy should be considered only in specific clinical situations. These limitations must be strictly observed, as mutagenic activity 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 tests 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 should receive an additional dose of metronidazole immediately after haemodialysis.

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

Metronidazole may cause falsely negative results in serum aspartate aminotransferase (AST) levels.

Patients should avoid alcohol consumption during metronidazole therapy and for at least 2 days after its completion due to the possible occurrence of disulfiram-like reactions (dizziness, vomiting).

Due to reported carcinogenicity of metronidazole, long-term use of the drug is not recommended.

Metronidazole and its metabolites have demonstrated mutagenicity in certain non-mammalian cell tests.

Rapid development of severe hepatotoxicity/acute liver failure, including fatal outcomes, has been observed in patients with Cockayne syndrome receiving systemic metronidazole-containing medications. Metronidazole should be administered to patients in this group only after careful benefit-risk assessment and solely when no alternative treatment is available.

Liver function should be monitored immediately before starting the drug, during treatment, and after completion 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.

Cases of severe bullous skin reactions, sometimes fatal, including 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 of SJS, TEN, or AGEP occur (e.g., flu-like symptoms, progressive skin rash, often with blisters or mucosal lesions), treatment must be immediately discontinued (see section "Adverse reactions").

Special warnings regarding certain components of Efloran.

Patients on a sodium-restricted diet should be aware that one dose of the drug contains 276.61 mg of sodium.

Use during pregnancy or breastfeeding.

The use of this drug is contraindicated during pregnancy.

Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Efloran may have a minor or moderate effect on reaction speed when driving or operating machinery, particularly if alcohol is consumed during treatment. Patients should be warned about the possible occurrence of somnolence, dizziness, confusion, hallucinations, seizures, and transient visual disturbances. The physician should inform patients accordingly and advise against driving or operating machinery.

Method of Administration and Dosage

The metronidazole 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 recommendations should be observed for dosing.

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 in severe hepatic impairment the plasma half-life of metronidazole is prolonged and plasma clearance reduced, 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, 7 days of treatment is sufficient for most patients. Treatment may be extended if clinically indicated (see section "Special Warnings and Precautions for Use").

Pre- and postoperative infection prophylaxis

Adults and children aged 11 years and older

Administer a 500 mg dose, completing infusion 1 hour before surgery. Repeat the dose at 8 and 16 hours after the initial dose.

Children aged 2 to 11 years

15 mg/kg body weight, completing infusion approximately 1 hour before surgery, followed by 7.5 mg/kg body weight at 8 and 16 hours after the initial dose.

Method of administration

Administer as an intravenous infusion.

The contents of one vial should be administered intravenously slowly, i.e., at a maximum rate of 100 ml over at least 20 minutes, but usually over 1 hour.

Efloran infusion solution should not be diluted with any diluents, and no other medicinal products should be added.

Antibiotics prescribed by the physician for concomitant therapy should be administered separately.

Children

May be administered to children aged 2 years and older, according to indications.

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.

Adverse Reactions.

Unwanted effects are mainly associated with prolonged use of high doses. The most commonly observed are nausea and taste disturbances. Serious adverse reactions occur rarely when the drug is used according to the recommended dosage regimens.

Physicians considering the use of metronidazole for the treatment of chronic conditions beyond the recommended duration of use should take into account the risk of peripheral neuropathy.

Blood and lymphatic system disorders: neutropenia, pancytopenia, thrombocytopenia, leukopenia, agranulocytosis.

Immune system disorders: anaphylaxis, angioneurotic edema, prolonged hyperemia, febrile reactions, rare cases of anaphylactic shock, hypersensitivity reactions, Jarisch-Herxheimer reaction.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: psychotic disorders, including confusion, hallucinations.

Nervous system disorders: depressed mood, reversible encephalopathy (confusion, fever, headache, hallucinations, paralysis, photophobia, visual and motor disturbances, nuchal rigidity) and subacute cerebellar syndrome (ataxia, dysarthria, gait disturbances, nystagmus, tremor), which resolve after discontinuation of the drug; dizziness, somnolence or insomnia, seizures, headache.

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

Eye disorders: transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, color vision disturbances, optic neuropathy/neuritis.

Ear and labyrinth disorders: vertigo, hearing disturbances/hearing loss (including sensorineural), tinnitus.

Gastrointestinal disorders: taste disturbances, mucositis of the oral mucosa, coated tongue, stomatitis, discoloration of the tongue, "hairy tongue" (e.g., due to excessive fungal flora growth), dry mouth sensation, nausea, vomiting, diarrhea, gastrointestinal discomfort, epigastric pain.

Hepatobiliary and biliary tract disorders: reversible pancreatitis, disturbances in liver function tests, cholestatic hepatitis, jaundice, mixed hepatitis and hepatocellular injury, cases of liver failure requiring liver transplantation in patients treated with metronidazole in combination with other antibiotics.

Skin and subcutaneous tissue disorders: rash, pustular rash, pruritus, flushing, AGEP, erythema multiforme, urticaria, fixed drug eruption, SJS, TEN.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Renal and urinary system disorders: dark or reddish-brown urine (due to metronidazole metabolites).

Cardiac disorders: ECG changes.

Vascular disorders: thrombophlebitis.

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

General disorders: increased body temperature.

Infections and infestations: oral candidiasis and vaginal candidiasis, aseptic meningitis.

In the event of severe adverse effects, treatment should be discontinued.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging.

100 ml in a bottle; 1 bottle per cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia /
KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of business operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia /
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.