INSTRUCTION

for medical use of the medicinal product

 

METRONIDAZOLE

 

Composition:

active substance: metronidazole;

100 ml of solution contain 500 mg of metronidazole;

excipients: sodium chloride, water for injection.

 

Pharmaceutical form. Solution for infusion.

Basic physic-chemical properties: a clear, colourless or slightly yellowish solution.

 

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Imidazole derivatives. ATC code J01X D01.

 

Pharmacological properties.

Pharmacodynamics.

Metronidazole is a stable compound able to penetrate into microorganisms. Under anaerobic conditions metronidazole together with microbial pyruvate-feredoxin-oxidoreductase forms nitroso radicals by oxidation of feredoxin and flavodoxin. Nitroso radicals form adducts with base pairs of the DNA, thus leading to breaking of the DNA chain and consecutively to cell death.

The minimum inhibitory concentration (MIC) has been established by EUCAST (European Committee on Antimicrobial Susceptibility Testing). The breakpoints separating susceptible (S) from resistant organisms (R) 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 organisms

(Source: Central Office for the Evaluation of Resistance Data on Systemic Antibiotics, Germany, January 2011)

Commonly susceptible species

Anaerobes: Bacteroides fragilis, Clostridium difficile¹, Clostridium perfringens^1,2, Fusobacterium spp.¹, Peptoniphilus spp.¹, Peptostreptococcus spp.¹, Porphyromonas spp.¹, Prevotella spp., Veillonella spp.¹.

Other micro-organisms: Entamoeba histolytica¹, Gardnerella vaginalis¹, Giardia lamblia¹, Trichomonas vaginalis¹.

Species for which acquired resistance may be a problem

Gram-negative aerobes: Helicobacter pylori.

Inherently resistant organisms

All obligate aerobes.

Gram-positive micro-organisms: Enterococcus spp., Staphylococcus spp., Streptococcus spp.

Gram-negative micro-organisms: Enterobacteriaceae, Haemophilus spp.

¹ At the time of publication of these tables, no up-to-date data were available. In primary literature, standard reference books and therapy recommendations susceptibility of the respective strains is assumed.

² Only to be used in patients with allergy to penicillin.

Mechanisms of resistance to metronidazole

The mechanisms of metronidazole resistance are still understood only in part.

In H.pylori resistance to metronidazole is caused by mutations of a gene that encodes NADPH nitroreductase. These mutations lead to an exchange of amino acids, rendering the enzyme inactive. Thus the step of activation of metronidazole to the active nitroso radical does not take place.

Strains of Bacteroides being resistant to metronidazole possess genes encoding nitroimidazole reductases converting nitroimidazoles to aminoimidazoles. Therefore the formation of the antibacterially effective nitroso radicals is inhibited.

There is full cross resistance between metronidazole and the other nitroimidazole derivatives (tinidazole, ornidazole, nimorazole).

The prevalence of acquired resistance of individual species may vary, depending on region and time. There-fore especially for the adequate treatment of severe infections specific local information regarding resistance should be available. If there is doubt about the efficacy of metronidazole due to the local resistance situation, expert advice should be sought. Especially in the case of severe infections or failure of treatment, microbiological diagnosis including determination of species of the microorganism and its susceptibility to metronidazole is required.

Pharmacokinetics. 

Absorption

Since Metronidazole is infused intravenously the bioavailability is 100%.

Distribution

Metronidazole is widely distributed in body tissues after injection. Metronidazole appears in most body tissues and fluids including bile, bone, cerebral abscess, cerebrospinal fluid, liver, saliva, seminal fluid, and vaginal secretions, and achieves concentrations similar to those in plasma. It also diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum. Protein binding is less than 20 %, the apparent volume of distribution is 36 litres.

Biotransformation

Metronidazole is metabolised in the liver by side-chain oxidation and glucuronide formation. Its metabolites include an acid oxidation product, a hydroxy derivative and glucuronide. The major metabolite in the serum is the hydroxylated metabolite, the major metabolite in the urine is the acid metabolite.

Elimination

Approximately 80% of the substance is excreted in urine with less than 10% in the form of the unchanged drug substance . Small quantities are excreted via the liver. Elimination half-life is 8 (6-10) hours.

Paediatric population

See section «Method of administration and dosage».

Characteristics in special patient groups

Renal insufficiency delays excretion only to an unimportant degree.

Delayed plasma clearance and prolonged serum half-life (up to 30 h) is to be expected in severe liver disease.

 

Clinical particulars.

Indications.

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

Metronidazole is indicated in adults and children for the following indications:

– infections of the central nervous system (e. g. brain abscess, meningitis);

– infections of lung and pleura (e. g. necrotising pneumonia, aspiration pneumonia, lung abscess);

– endocarditis;

– infections in the gastrointestinal tract and the abdominal area (e.g. peritonitis, liver abscess, postoperative infections after colonic and rectal surgery, purulent diseases in the abdominal and pelvic cavities);

– gynaecologic infections (e. g. endometritis, after hysterectomy or caesarean section, childbed fever, septic abortion);

– infections in the ear-nose-throat and tooth-mouth-jaw regions (e.g. Simanovsky-Plaut-Vincent-angina)

– bone and joint infections (e. g. osteomyelitis);

– gas gangrene;

– septicaemia with thrombophlebitis.

In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole.

A prophylactic use is always indicated prior to operations with a high risk of anaerobic infections (gynaecologic and intra-abdominal operations).

Consideration should be given to national and international guidance on the appropriate use of antibacterial agents.

 

Contraindications.

Hypersensitivity to metronidazole, other drugs with a similar chemical structure (nitroimidazoles) or to any other component of the drug.

 

Interactions with other medicinal products and other forms of interaction.

Amiodarone

QT interval prolongation and torsade de pointes have been reported with the co-administration of metronidazole and amiodarone. It may be appropriate to monitor QT interval on the ECG if amiodarone is used in combination with metronidazole. Patients treated on an outpatient basis should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope..

Barbiturates

Phenobarbital may increase the hepatic metabolism of metronidazole, reducing its plasma half-life to 3 hours.

Busulfan

Co-administration with metronidazole may significantly increase the plasma concentrations of busulfan. The mechanism of interaction has not been described. Due to the potential for severe toxicity and mortality associated with elevated busulfan plasma levels, concomitant use with metronidazole should be avoided.

Carbamazepine

Metronidazole may inhibit the metabolism of carbamazepine and raise the plasma concentrations as a consequence.

Cimetidine

Concurrently administered cimetidine may reduce the elimination of metronidazole in isolated cases and subsequently lead to increased metronidazole concentrations in serum.

Contraceptive drugs

Some antibiotics can, in some exceptional cases, decrease the effect of contraceptive pills by interfering with the bacterial hydrolysis of steroid conjugates in the intestine and hereby reduce the re-absorption of unconjugated steroid. Therefore the plasma levels of the active steroid decrease. This unusual interaction can occur in women with a high excretion of steroid conjugates through the bile. There are case reports of oral contraceptive failure in association with different antibiotics, e.g. ampicillin, amoxicillin, tetracyclines and also metronidazole.

Coumarin derivatives

Concomitant treatment with metronidazole may potentiate the anticoagulant effect of these and increase the risk for bleeding as a consequence of decreased hepatic degradation. Dose adjustment of the anticoagulant can be necessary.

Cyclosporine

During simultaneous therapy with cyclosporine and metronidazole there is a risk for increased serum concentrations of cyclosporine. Frequent monitoring of cyclosporine and creatinine is required.

Disulfiram

Simultaneous administration of disulfiram may cause states of confusion or even psychotic reactions. Combination of both agents must be avoided.

Fluorouracil

Metronidazole inhibits the metabolism of concurrently administered fluorouracil, i.e. the plasma concentration of fluorouracil is increased.

Lithium

Caution is to be exercised when metronidazole is administered simultaneously with lithium salts, because under metronidazole therapy raised serum concentrations of lithium have been observed.

Mycophenolate mofetil

Substances that alter the gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid products. Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effect of mycophenolic acid is recommended during concomitant therapy with anti-infective agents.

Phenytoin

Metronidazole inhibits the metabolism of concurrently administered phenytoin, i.e. the plasma concentration of phenytoin is increased. On the other hand, the efficacy of metronidazole is reduced when phenytoin is administered concurrently.

Tacrolimus

Co-administration with metronidazole may increase the blood concentrations of tacrolimus. The proposed mechanism is inhibition of hepatic tacrolimus metabolism via CYP 3A4. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of metronidazole therapy in patients who are stabilized on their tacrolimus regimen.

Alcohol

Intake of alcoholic beverages must be avoided during metronidazole therapy since adverse reactions such as dizziness and vomiting may occur (disulfiram-like effect).

 

Precautions for use.

In patients with severe liver damage or impaired haematopoiesis (e. g. granulocytopenia), metronidazole should only be used if its expected benefits outweigh potential risks.

Due to the risk of aggravation, metronidazole should also be used in patients with active or chronic severe peripheral and central nervous system diseases only if its expected benefits outweigh potential risks.

Convulsive seizures, myoclonus and peripheral neuropathy, the latter mainly characterized by numbness or paraesthesia of an extremity, have been reported in patients treated with metronidazole. The appearance of abnormal neurological signs demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see section «Adverse reactions»).

In the case of severe hypersensitivity reactions (e.g. anaphylactic shock (see section «Adverse reactions») 4.8), treatment with metronidazole must be discontinued immediately and established emergency treatment must be initiated by qualified healthcare professionals.

Severe persistent diarrhoea occurring during treatment or during the subsequent weeks may be due to pseu-domembranous colitis (in most cases caused by Clostridium difficile) (see section «Adverse reactions»). This intestinal disease, precipitated by the antibiotic treatment, may be life-threatening and requires immediate appropriate treatment. Anti-peristaltic medicinal products must not be given.

The duration of therapy with metronidazole or drugs containing other nitroimidazoles should not exceed 10 days. Only in specific elective cases and if definitely needed, the treatment period may be extended, accompanied by appropriate clinical and laboratory monitoring. Repeat therapy should be restricted as much as possible and to specific elective cases only. These restrictions must be observed strictly because the possibility of metronidazole developing mutagenic activity cannot be safely excluded and because in animal experiments an increase of the incidence of certain tumours has been noted.

Prolonged therapy with metronidazole may be associated with bone marrow depression, leading to an impairment of haematopoiesis (see section «Adverse reactions»). Blood cell counts should be carefully monitored during prolonged therapy.

Special warnings about some components of the medicinal product

This medicinal product contains 790 mg/dose of sodium. This is to be taken into consideration for patients on a controlled sodium diet.

Interference with laboratory tests

Metronidazole interferes with the enzymatic-spectrophotometric determination of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase resulting in decreased values (possibly down to zero).

Metronidazole has a high absorbance at the wavelength at which nicotinamide-adenine dinucleotide (NADH) is determined. Therefore elevated liver enzyme concentrations may be masked by metronidazole when measured by continuous-flow methods based on endpoint decrease in reduced NADH. Unusually low liver enzyme concentrations, including zero values, have been reported.

 

Pregnancy and lactation.

Contraception in males and females

See section «Interaction with other medicinal products and other forms of interaction».

Pregnancy

The safety of the use of metronidazole during pregnancy has not sufficiently been demonstrated. In particular, reports on the use during early pregnancy are contradictory. Some studies indicated an increased rate of mal-formations. In animal experiments metronidazole did not show teratogenic effects.

During the first trimester, metronidazole should only be used to treat severe life-threatening infections, if there is no safer alternative. During the second and third trimester, metronidazole may also be used to treat other infections if the expected benefit to the mother clearly outweighs the potential risk to the foetus.

Breast-feeding

Since metronidazole is secreted into breast milk, nursing is to be interrupted during therapy. Also after the end of the therapy with metronidazole, nursing should not be resumed before another 2 – 3 days because of the prolonged half-life period of metronidazole.

Fertility

Preclinical studies only indicate a potential negative influence of metronidazole on the male reproductive system if high doses exceeding the maximum recommended dose for humans were administered.

Effects on ability to drive and use machines.

Even when used as directed, metronidazole may alter reactivity so far that the ability to drive or to use ma-chinery is impaired. This holds true to still a higher degree at the beginning of treatment or in combination with alcohol intake.

 

Method of administration and dosage.

The dosage is adjusted according to the patient’s individual response to therapy, her/his age and body weight and according to nature and severity of the disease.

The following dosage guidelines should be followed:

Adults and adolescents

Treatment of anaerobic infections

Usually a single dose of 1500 mg (300 ml) is given on the first day of treatment followed by 1000 mg (200 ml) given as single doses on the subsequent days.

Alternatively, 500 mg (100 ml) may be given every 8 hours. If medically indicated a loading dose of 15 mg/kg body weight (BW) may be given at the beginning of treatment. The duration of therapy is dependent on the effect of the treatment. In most cases a treatment course of 7 days will be sufficient. If clinically indicated, treatment may be continued beyond this time.

Prophylaxis against post-operative infection caused by anaerobic bacteria

500 mg, with administration completed approximately one hour before surgery. The dose is repeated after 8 and 16 hours.

Paediatric population

Treatment of anaerobic infections

– Children > 8 weeks to 12 years of age: the usual daily dose is 20 – 30 mg per kg BW per day as a single dose or divided into 7.5 mg per kg BW every 8 hours. The daily dose may be increased to 40 mg per kg BW, depending on the severity of the infection.

– Children < 8 weeks of age: 15 mg per kg BW as a single dose daily or divided into 7.5 mg per kg BW every 12 hours..

In newborns with a gestation age < 40 weeks, accumulation of metronidazole can occur during the first week of life; therefore the concentrations of metronidazole in serum should preferably be monitored after a few days therapy.

Duration of treatment is usually 7 days.

Prophylaxis against postoperative infections caused by anaerobic bacteria

– Children < 12 years: 20 – 30 mg/kg BW as a single dose given 1 – 2 hours before surgery.

– Newborns with a gestation age <40 weeks: 10 mg/kg BW as a single dose before surgery.

Patients with renal insufficiency

No dose reduction is required (see section «Pharmacological properties»).

In patients undergoing haemodialysis the conventional dose of metronidazole should be scheduled after haemodialysis on dialysis days to compensate the escape of metronidazole during the procedure.

Patients with hepatic insufficiency

As serum half-life is prolonged and plasma clearance is delayed in severe hepatic insufficiency, patients with severe liver disease will require lower doses (see section «Pharmacological properties»).

Method of administration

Intravenous use. The contents of one bottle should be infused slowly i.v., i.e. 100 ml max. over not less than 20 minutes, but normally over one hour. Metronidazole B can also be diluted before administration, adding the medicinal product to an i.v. vehicle solution such as 0.9 % sodium chloride or 5 % glucose infusion solution.

Concurrently prescribed antibiotics are to be administered separately.

 

Children.

Use for children from the first days of life.

 

Overdose.

Symptoms: overdose may cause the adverse reactions described in section «Adverse reactions».

Treatment: there is no specific treatment or antidote that can be applied in the case of gross overdose of metronidazole. If required, metronidazole can be effectively eliminated by haemodialysis.

 

Adverse reactions.

Adverse reactions are mainly associated with prolonged use or high doses. The most commonly observed effects include nausea, abnormal taste sensations and the risk of neuropathy in case of long term treatment.

The frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100–<1/10), uncommon (≥1/1000–<1/100), rare (≥1/10000–<1/1000), very rare (<1/10000), not known (frequency cannot be estimated from the available data).

Infections and infestations. Common: superinfections with Candida (e.g. genital infections). Rare: pseudomembranous colitis, which may occur during or after therapy, manifesting as severe persistent diarrhoea. For details regarding emergency treatment see section «Precautions for use».

Blood and lymphatic system disorders. Very rare: during therapy with metronidazole, decreases of leukocyte and platelet counts (granulocytopenia, agranulocytosis, pancytopenia and thrombocytopenia) (see section «Precautions for use»). Not known: leucopenia, aplastic anaemia.

Immune system disorders. Rare: severe acute systemic hypersensitivity reactions: anaphylaxis, up to anaphylactic shock; severe skin reactions (see «Skin and subcutaneous disorders» below). These severe reactions demand immediate therapeutic intervention. Not known: mild to moderate hypersensitivity reactions, e.g. skin reactions (see «Skin and subcutaneous disorders» below), angioedema.

Metabolism and nutrition disorders. Not known: anorexia.

Psychiatric disorders. Very rare: psychotic disorders, including states of confusion, hallucination. Not known: depression.

Nervous system disorders. Very rare: encephalopathy, headache, fever, drowsiness, dizziness, disturbances in sight and movement, vertigo, ataxia, dysarthria, convulsions. Not known: somnolence or insomnia, myoclonus, seizures, peripheral neuropathy manifesting as paraesthesia, pain, furry sensation, and tingling in the extremities, aseptic meningitis. If seizures or signs of peripheral neuropathy or encephalopathy appear, the attending doctor should be informed immediately (see section «Precautions for use»).

Eye disorders. Very rare: disturbance of vision, e.g. diplopia, myopia. Not known: oculogyric crisis, optic neuropathy/neuritis.

Cardiovascular system disorders. Rare: ECG changes like flattening of T-wave.

Gastro-intestinal disorders. Not known: Vomiting, nausea, diarrhoea, glossitis and stomatitis, eructation with bitter taste, epigastric pressure, metallic taste, furred tongue. Dysphagia (caused by central nervous effects of metronidazole)

Hepatobiliary disorders. Very rare: Abnormal values of hepatic enzymes and bilirubin, hepatitis, jaundice, pancreatitis.

Skin and subcutaneous tissue disorders. Very rare: allergic skin reactions, e.g. pruritus, urticaria Stevens-Johnson syndrome. Not known: toxic epidermal necrolysis. The two latter reactions demand immediate therapeutic intervention. Not known: erythema multiforme.

Musculoskeletal, connective tissue and bone disorders. Very rare: Arthralgia, myalgia.

Renal and urinary disorders. Uncommon: dark coloured urine (due to a metabolite of metronidazole).

General disorders and administration site conditions. Not known: vein irritations (up to thrombophlebitis) after intravenous administration states of weakness, fever.

Frequency, type and severity of adverse reactions in children are the same as in adults.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national pharmacovigilance system.

 

Shelf life. 3 years.

 

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °С.

Keep out of reach of children.

Discard any unused portions of the medicinal product.

Incompatibility.

Metronidazole for intravenous infusions must not be mixed with other medicinal products except those mentioned in «Method of administration and dosage».

 

Packaging. 100 ml of the medicinal product in containers. 1 film-coated container in in a box.

 

Terms of dispensing. On prescription.

 

Manufacturer. Eurolife Healthcare Pvt. Ltd.

 

Manufacturer’s address.

Khasra No. 520, Bhagwanpur, Roorkee, Haridwar, India

 

Applicant.

Ananta Medicare Ltd.

 

Applicant and/or applicant's representative registered address.

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