Summary of medicine characteristics - METRONIDAZOLE 5 MG / ML SOLUTION FOR INFUSION
1 NAME OF THE MEDICINAL PRODUCT
Metronidazole 5 mg/ml solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each bag of 100 ml of solution for infusion contains 500 mg metronidazole.
Each ml of solution for infusion contains 5 mg metronidazole.
Excipient(s) with known effect:
Each ml of solution for infusion contains 3.22 mg of sodium chloride (equivalent to 0.14 mmol sodium)
Each 100 ml of solution for infusion contains 322 mg of sodium chloride (equivalent to 14 mmol sodium)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for infusion
Clear, colourless or slightly yellowish aqueous solution.
pH: 4.5 – 7.0
Osmolality: 275 – 335 mOsmol/Kg
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Metronidazole 5 mg/ml Solution for Infusion is indicated in adults and children for the prophylaxis and treatment of infections in which susceptible anaerobic microorganisms have been identified or are suspected to be the cause (see sections 4.4 and 5.1).
1. The prophylaxis of post-operative infections where anaerobic bacteria are expected to be causative pathogens (gynaecologic and intra-abdominal operations)
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 any of the infections listed above.
In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole 5 mg/ml.
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 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.
Concurrently prescribed antibiotics are to be administered separately.
4.3 Contraindications
Hypersensitivity to the active substance metronidazole or other nitroimidazole derivatives or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Regular clinical and laboratory monitoring (including full blood count) are advised in cases of high-dose or prolonged treatment, in case of antecedents of blood dyscrasia, in case of severe infection and in severe hepatic insufficiency.
In patients with severe liver damage or impaired haematopoiesis (e.g. granulocytopenia) 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 (see section 4.8).
In the case of severe hypersensitivity reactions (e.g. anaphylactic shock; see also section 4.8), treatment with Metronidazole 5 mg/ml 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 nicotinamideadenine 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.
Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefitrisk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued.
Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking metronidazole.
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.
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. 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.
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
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
Intake of alcoholic beverages must be avoided during metronidazole therapy since adverse reactions such as dizziness and vomiting may occur (disulfiram-like effect)
4.6 Fertility, pregnancy and lactation
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 5 mg/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 5 mg/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.
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.
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
4.8 Undesirable effectsUndesirable 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)
– uncommon (> 1/1,000 to < 1/100)
– rare (> 1/10,000 to < 1/1,000)
– very rare (< 1/10,000)
– Not known (Frequency cannot be estimated from the available data)
System Organ Class (MedDRA) | Common | Rare | Very Rare | Not Known |
Infections and infestations | Superinfections with candida (e.g. genital infections) | Pseudomembranous colitis, which may occur during or after therapy, manifesting as severe persistent diarrhea. For details regarding emergency treatment (see section 4.4) | ||
Blood and lymphatic system disorders | Granul ocytopenia, Agranulocytosis, thrombocytopeni a, pancytopenia. See section 4.4 | Leucopenia, aplastic anaemia | ||
Immune system disorders | Severe acute systemic hypersensitivity reactions: anaphylaxis, up to anaphylactic shock (see section 4.4). | Mild to moderate hypersensitivity reactions, e. g. skin reactions (see “Skin and subcutaneous disorders” below) Angiodema | ||
Metabolism and nutrition disorders | Anorexia | |||
Psychiatric disorders | Psychotic disorders, including states confusion, hallucination | Depression | ||
Nervous system | Encephalopathy, | Somnolenc |
disorders | fever, headache, disturbances in sight and movement, ataxia, dysathria, vertigo drowsiness, dizziness, convulsions | e 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 4.4 | ||
Eye disorders | Disturbance of vision, e.g.diplopia, myopia | Oculogyric crisis, Optic neuropathy/ neuritis (isolated cases) | ||
Cardiac disorders | ECG changes like flattening of the T-wave | |||
Gastrointestinal disorders | Vomiting, nausea, diarrhoea, glossitis and stomatitis, eructation with taste, epigastric pressure, metallic taste,furred tongue Dysphagia (caused by central nervous effects of metronidazole) | |||
Hepatobiliary disorders | Abnormal values of hepatic enzymes and |
bilirubin Hepatitis, jaundice, pancreatitis | ||||
Skin and subcutaneous tissue disorders | Allergic skin reactions, e. g. pruritus, urticaria Stevens-Johnson syndrome | Toxic epidermal necrolysis Erythema multiforme | ||
Musculoskeletal and connective tissue disorders | Myalgia, arthralgia | |||
Renal and urinary disorders | Dark coloured urine (due to metronidazole metabolite) | |||
General disorders and administration site conditions | Vein irritations (up to thrombophlebitis) after IV infusion 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, Website: 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
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.
Metronidazole acts in a concentration dependent manner. The efficacy of metronidazole mainly depends on the quotient of the maximum serum concentration (cmax) and the minimum inhibitory concentration (MIC) relevant for the microorganism concerned.
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 7.1, March 2017) breakpoints separating susceptible (S) from resistant organisms ® are as follows:
Organism | Susceptible | Resistant |
Clostridium difficile1 | < 2 mg/l | > 2 mg/l |
Other Gram-positive anaerobes | < 4 mg | > 4 mg/l |
Gram-negative anaerobes | < 4 mg | > 4 mg/l |
1 The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility.
List of susceptible and resistant organisms.
Commonly susceptible species
Anaerobes
Clostridium difficile °
Clostridium perfringens °A
Fusobacterium spp.°
Peptoniphilus spp.°
Peptostreptococcus spp.°
Porphyromonas spp.°
Prevotella spp.
Veillonella spp.°
Bacteroides fragilis
Other micro-organisms
Entamoeba histolytica °
Gardnerella vaginalis °
Giardia lamblia°
Trichomonas vaginalis °
Species for which acquired resistance may be a problem
Gram-negative aerobes
Helicobacter pylori
Anaerobes
Inherently resistant organisms
All obligate aerobes
Gram-positive micro-organisms
Enterococcus spp.
Staphylococcus spp.
Streptococcus spp.
Gram-negative micro-organisms
Enterobacteriaceae
Haemophilus spp.
° 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.
o Only to be used in patients with allergy to penicillin
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.
Since Metronidazole 5 mg/ml solution for infusion is infused intravenously the bioavailability is 100%.
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.
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.
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 tumorigenic potential
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, anhydrous
Citric acid, anhydrous
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
Polypropylene bag: 2 years
Use immediately after first opening.
6.4 Special precautions for storage
Do not store above 25 °C.
Do not refrigerate. Keep the bag in the original packaging (aluminum overwrap) in order to protect from light.
6.5 Nature and contents of container
Polypropylene bags with a polypropylene twist off port inside an aluminum overwrap, containing 100 ml of solution, packed in cartons of 1 and 10 bags.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
6.6 Special precautions for disposalThis product is for single use only. Any unused solution should be discarded.
Do not use if there are any visible particulate matter or if the solution is cloudy.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Hikma Farmaceutica (Portugal), S.A.
Estrada do Rio da Mó, 8, 8A e 8B – Fervenca
2705–906 Terrugem SNT
Portugal
Tel.:+ 351 219 608 410
Email: portugalgeral@hikma.com
8 MARKETING AUTHORISATION NUMBER(S)
PL 15413/0053
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
11/05/2017