SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Metronidazole 500mg/100ml Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 5 mg of metronidazole 100 ml of solution contain 500 mg of metronidazole Excipients:

1 ml solution contains Sodium chloride    7.4 mg

Disodium phosphate dodecahydrate 1.5 mg Electrolyte content (per 100 ml):

Sodium 14 mmol

Chloride    13 mmol

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Solution for infusion;

Clear, colourless or slightly yellowish aqueous solution

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metronidazole 500 mg/100 ml Solution for Infusion is indicated in adults and children for the prophylaxis and treatment of infections in which susceptible anaerobic micro-organisms have been identified or are suspected to be the cause (see sections 4.4 and 5.1).

1.    The prevention of post-operative infections where anaerobic bacteria are expected to be causative pathogens

2.    The treatment of peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, and post-operative wound infections from which pathogenic anaerobes have been isolated.

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

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

500 mg (100 ml) every 8 hours. Alternatively 1000 mg - 1500 mg may be given daily as a single dose.

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 although a duration of 10 days should not normally be exceeded. (See also section 4.4.)

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.

The Elderly:

Caution is advised in the elderly, particularly at high doses, although there is limited information available on modification of dosage.

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.

•    Neonates and infants < 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 gestational 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

Limited data are available in this population. These data do not indicate the need for dose reduction (see section 5.2.)

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

No routine dose adjustment is necessary in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

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 5.2).

In patients with hepatic encephalopathy, the daily dosage should be reduced to one third and may be administered once daily (see section 4.4).

Method of administration Intravenous use.

The contents of one bottle are to be infused slowly i.v., i.e. 100 ml max. over not less than 20 minutes, but normally over one hour.

Metronidazole 500mg/100ml Solution for Infusion 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.

4.3 Contraindications

Hypersensitivity to metronidazole or other nitroimidazole derivatives or to any of the excipients.

4.4 Special warnings and precautions for use

Patients with hepatic impairment

In patients with severe liver damage metronidazole should only be used if its expected benefits clearly outweigh potential hazards.

Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Metronidazole should therefore be administered with caution to patients with hepatic encephalopathy. (see section 4.2).

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 clearly outweigh potential hazards.

Convulsive seizures, myoclonus and peripheral neuropathy, the latter mainly characterized by numbness or paresthesia 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.

Patients should be advised not to take alcohol during Metronidazole therapy and at least 48 hours afterwards because of a disulfram-like effect (flushing, vomiting, tachycardia).

In the case of severe hypersensitivity reactions (e.g. anaphylactic shock), treatment with Metronidazole 500mg/100ml Solution for Infusion 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 pseudomembranous colitis (in most cases caused by clostridium difficile), see section 4.8. 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. Manifestations see section 4.8. Blood cell counts should be carefully monitored during prolonged therapy.

This medicinal product contains 14 mmol (or 322 mg) sodium per 100 ml. 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.

Patients should be warned that Metronidazole may darken urine.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions with other medicinal products Amiodarone

QT interval prolongation and torsade de pointes have been reported with the coadministration 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

Coadministration 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.

Ciclosporine

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.

Disufiram

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. Lithium treatment should be tapered or withdrawn before administering metronidazole. Plasma concentrations of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

Mycophenolat 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

Coadministration 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.

Other forms of interaction

Alcohol

Disulfiram-like effect. Alcoholic beverages and drugs containing alcohol should be avoided.

4.6 Fertility, pregnancy and lactation

Fertility

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

Contraception in males and females

- See section 4.5 ‘contraceptive drugs’

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 malformations. In animal studies with metronidazole no teratogenicity was observed (see section 5.3).

During the first trimester, Metronidazole 500 mg/100 ml Solution for Infusion should only be used to treat severe life-threatening infections, if there is no safer alternative. During the second and third trimester, Metronidazole 500 mg/100 ml Solution for Infusion may also be used to treat other infections if its expected benefits clearly outweigh any possible risk.

Breast-feeding

Since metronidazole is secreted into breast milk, nursing should be stopped 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.

4.7 Effects on ability to drive and use machines

Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and are advised not to drive or operate machinery if these symptoms occur.

4.8 Undesirable effects

Undesirable effects 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.

In the following listing, for the description of the frequencies of undesirable effects the following terms are used:

Very common:> 1/10 Common :> 1/100 to < 1/10

>    1/1,000 to < 1/100

>    1/10,000 to < 1/1,000 < 1/10,000

(Frequency cannot be estimated from the available data)

Infections and infestations

Common:    Superinfections with candida (e.g. genital infections)

Rare:    Pseudomembranous colitis,

Blood and lymphatic system disorders

Very rare:    granulocytopenia, agranulocytosis, pancytopenia and

thrombocytopenia

Not known:    Leucopenia, aplastic anaemia

Immune system disorders

Rare:    • Severe acute systemic hypersensitivity reactions: anaphylaxis, up

to anaphy lactic shock.

Not known:    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 move    ment, vertigo, ataxia, dysarthria,

convulsions.

Not known:    • Somnolence or insomnia, myoclonuis, seizures, peripheral

neuropathy

manifesting as paraesthesia, pain, furry sensation, and tingling in the

extremities.

• Aseptic meningitis.

Eye disorders

Very rare:    Disturbance of vision,    e.g. diplopia, myopia.

Not known:    Oculogyric crisis, optic neuropathy/neuritis (isolated cases)

Cardiac 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 , toxic epidermal necrolysis Not known:    erythema multiforme

Musculoskeletal and connective tissue 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 Paediatric population

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

As signs and symptoms of overdose the undesirable effects described under section 4.8 may appear. Single oral doses of metronidazole, up to 12g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Anti-infectives for systemic use - imidazole derivatives

ATC Code:    J01X D01

Mechanism of action

Metronidazole itself is ineffective. It is a stable compound able to penetrate into microorganisms.

Under anaerobic conditions nitroso radicals acting on DNA are formed from metronidazole by the microbial pyruvate-ferredoxin-oxidoreductase, with oxidation of ferredoxin 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.

PK/PD relationship

Metronidazole acts in a concentration dependent manner. The efficacy of metronidazole mainly depends on the quotient of the maximum serum concentration (c_max) and the minimum inhibitory concentration (MIC) relevant for the microorganism concerned.

Breakpoints

For the testing of metronidazole usual dilution series are applied. The following minimum inhibitory

concentration have been established to distinguish susceptible from resistant microorganisms:

EUCAST (European Committee on Antimicrobial Susceptibility Testing, Version 1.3, January 5, 2011) breakpoints separating susceptible (S) from resistant organisms (R) are as follows:

Gram-positive anaerobes (S: < 4 mg/l R > 4 mg/l)

Gram-negative anaerobes (S: < 4 mg/l R > 4 mg/l)

List of susceptible and resistant organisms._

Commonly susceptible species_

Anaerobes_

_Bacteroides ^ fragilis_

_Clostridium difficile°_

_Clostridium perfringens^oX_

_Eubacterium_

_Fusobacterium spp.°_

_Peptoniphilus spp.°_

_Peptostreptococcus spp.°_

_Porphyromonas spp.°_

_Prevotella spp._

_Veillonella spp.°_

Other micro-organisms

_Entamoeba histolytica⁰_

_Gardnerella vaginalis⁰_

_Giardia lamblia°_

_Trichomonas vaginalis⁰_

° 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.

^A 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. 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. Therefore 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.

5.2 Pharmacokinetic properties

Absorption:

Metronidazole is readily absorbed from the gastrointestinal tract and the oral bioavailability is > 90%. Consequently, the same mg dose will result in similar exposure (AUC) when switching between intravenous and oral dosing.

Distribution:

Metronidazole is widely distributed in body tissues after injection. 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.

Characteristics in special patient groups:

Renal insufficiency delays excretion only to an unimportant degree. The elimination half-life of metronidazole remains unchanged in the presence of renal failure, however such patients retain the

metabolites of metronidazole. The clinical significance of this is not known at present.

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

5.3 Preclinical safety data

Repeated dose toxicity

Following repeated administration ataxia and tremor were observed in the dog and a dose-dependent increase in hepatocellular degeneration was observed in the monkey during a 12 month study.

Mutagenic and tumorigenicpotential

Metronidazole was mutagenic in bacteria after nitroreduction, however it was not mutagenic in mammalian cells in vitro and in vivo. In addition, DNA damage was not observed in the lymphocytes of patients treated with metronidazole.

There is evidence to suggest that metronidazole is tumorigenic in the mouse and rat. There was an increase in the incidence of lung tumours in mice (after the oral administration of 3.1-fold the maximum recommended human dose of metronidazole of 1,500 mg/d), however, this does not seem to be due to a genotoxic mechanism as no changes in the mutation rates were observed in various organs of transgenic mice following high doses of metronidazole.

Reproduction toxicity

No teratogenicity or embryotoxicity was observed in the rat or rabbit.

Following repeated administration for 26-80 weeks to rats, testicular and prostatic dystrophy were observed at high doses (14.2 to 28.5-fold the maximum recommended human dose of metronidazole of 1,500 mg/d).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride,

Disodium phosphate dodecahydrate, Citric acid monohydrate,

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Unopened

3 years.

After first opening the container

Unused contents must be discarded and not be stored for later use.

6.4 Special precautions for storage

Do not store above 25 °C.

Keep the container in the outer carton in order to protect from light.

6.5 Nature and contents of container

The product is supplied in:

- bottles of low-density polyethylene, contents: 100 ml available in packs of 10 x 100 ml, 20 x 100 ml Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements Other handling instructions:

For single use only. Discard container and any unused contents after use.

Only to be used if solution is clear and colourless or slightly yellowish and the container and its closure do not show visible signs of damage.

7 MARKETING AUTHORISATION HOLDER

B. Braun Melsungen AG Carl-Braun-StraBe 1 34212 Melsungen, Germany

Postal address: 34209 Melsungen, Germany

Phone: +49/5661/71-0 Fax: +49/5661/71-4567

8    MARKETING AUTHORISATION NUMBER(S)

PL 03551/0033

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/03/2004

10    DATE OF REVISION OF THE TEXT

07/10/2014