Metronidazole 400mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metronidazole 400mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Metronidazole 400 mg
For a full list of excipients see 6.1.
3 PHARMACEUTICAL FORM
Tablet
Flat, white bevelled edge tablets, scored on one side and marked MP36 on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Metronidazole is indicated in the prophylaxis and treatment of infections in which
anaerobic bacteria have been identified or are suspected to be the cause.
Metronidazole is active against a wide range of pathogenic micro-organisms, notably
species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci and
Gardnerella vaginalis.
It is also active against Tricholonas, Entamoeba histolytica, Giardia lamblia, and
Balantidium coli.
Metronidazole is indicated in adults and children for the following indications:
a) The prevention of post-operative infections due to anaerobic bacteria, particularly species of Bacteroides and anaerobic streptococci.
b) The treatment of septicaemia, bacteraemia, peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, and post-operative wound infections from which pathogenic anaerobes have been isolated.
c) Urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male. The male consort of females suffering from urogenital trichomoniasis should be treated concurrently.
d) Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginosis or Gardnerella vaginitis).
e) All forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers).
f) Giardiasis.
g) Acute ulcerative gingivitis.
h) Anaerobically-infected leg ulcers and pressure sores.
i) Acute dental infections (e.g. acute pericoronitis and acute apical infections).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
To be taken orally.
Metronidazole tablets should be swallowed, without chewing, with half a glassful of water during or after meals.
Anaerobic infections: The duration of a course of Metronidazole treatment is about 7 days but it will depend upon the seriousness of the patient's condition as assessed clinically and bacteriologically.
Prophylaxis against postoperative infections caused by anaerobic infection:
Chiefly in the context of abdominal (especially colorectal) and gynaecological surgery
Adults: 400 mg, 8 hourly during 24 hours immediately preceding operation
followed by postoperative intravenous or rectal administration until the patient is able to take tablets.
Children: <12 years: 20-30 mg/kg as a single dose given 1-2 hours before
surgery
Newborns with a gestation age <40 weeks: 10 mg/kg body weight as a single dose before operation
Treatment of established anaerobic infection:
Adults:
Children:
800 mg followed by 400 mg 8 hourly.
>8 weeks to 12 years of age: The usual dose is 20-30 mg/kg/day as a single dose or divided into 7.5 mg/kg every 8 hours. The daily dose may be increased to 40 mg/kg, depending on the severity of the infection. Duration of treatment is usually 7 days.
<8 weeks of age: 15 mg/kg as a single dose daily or divided into 7.5 mg/kg every 12 hours. In newborns with a gestation age <40 weeks, accumulation of metronidazole can occur during the first week of life, thus the concentrations of metronidazole in serum should preferable be monitored after a few days therapy.
Protozoal and other infections:
• Urogenital trichomoniasis: To prevent re-infection the consort should receive a course of treatment concurrently;
Adults and adolescents:
200 mg, 8 hourly, for 7 days;
or 400 mg, 12 hourly, for 5-7 days;
or 800 mg in the morning and 1200 mg in the evening for 2 days; or 2000 mg as a single dose Children:
<10 years: 40 mg/kg orally as a single dose
or 15-30 mg/kg/day divided in 2-3 doses for 7 days; not to exceed 2000 mg/dose
• Bacterial vaginosis:
Adults and adolescents:
400 mg, 12 hourly, for 5-7 days, or 2000 mg as a single dose
• Amoebiasis:
Adults and adolescents:
a) Invasive intestinal disease in susceptible subjects, 800 mg, 8 hourly, for 5 days
b) Intestinal disease in less susceptible subjects and chronic amoebic hepatitis, 400 mg, 8 hourly, for 5-10 days
c) Amoebic liver abscess also forms of extra-intestinal amoebiasis, 400 mg, 8 hourly, for 5 days
d) Symptomless cyst passers. The upper ranges of dosage and duration of treatment seem to be necessary in temperate climate countries 400800 mg, 8 hourly, for 5-10 days.
Children:
7-10 years: 200-400 mg 3 times daily for 5-10 days
3-7 years: 100-200 mg 4 times daily for 5-10 days
1-3 years: 100-200 mg 3 times daily for 5-10 days
Alternatively, dose may be expressed by body weight: 35-50 mg/kg daily in 3 divided doses for 5-10 days, not to exceed 2400 mg/day
• Giardiasis:
Adults and adolescents:
2000 mg once daily for 3 days or 400 mg three times daily for 5 days or 500 mg twice daily for 7-10 days Children:
7-10 years: 1000 mg once daily for 3 days
3-7 years: 600-800 mg once daily for 3 days
1-3 years: 500 mg once daily for 3 days
Alternatively, as expressed in mg per kg of body weight: 15-40 mg/kg/day divided in 2-3 doses
• Acute ulcerative gingivitis:
Adults and adolescents: 200 mg, 8 hourly, for 3 days.
• Acute dental infections:
Adults and adolescents: 200 mg, 8 hourly, for 3-7 days.
• Leg ulcers and pressure sores:
Adults and adolescents: 400 mg, 8 hourly, for 7 days.
Eradication of Helicobacter pylori in paediatric patients:
As a part of a combination therapy, 20 mg/kg/day not to exceed 500 mg twice daily for 7-14 days. Official guidelines should be consulted before initiating therapy.
Elderly: Metronidazole is well tolerated by the elderly but a pharmacokinetic study suggests cautious use of high dosage regimens in this age group.
4.3 Contraindications
Known hypersensitivity to Metronidazole, or any of the excipients
4.4 Special warnings and precautions for use
Regular clinical and laboratory monitoring are advised if administration of Metronidazole for more than 10 days is considered to be necessary. The possibility that an accompanying gonococcal infection might persist in a symptomless state after trichomonas vaginalis has been eliminated should be borne in mind.
Metronidazole should be prescribed with caution in patients with active disease of the central nervous system or porphyria.
Metronidazole is mainly metabolized by hepatic oxidation. Substantial impairment of Metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant accumulation 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. The daily dosage should be reduced to one third and may be administered once daily.
The elimination half-life of Metronidazole remains unchanged in the presence of renal failure. The dosage of Metronidazole therefore needs no reduction. Such patients however retain the metabolites of Metronidazole. The clinical significance of this is not known at present.
In patients undergoing haemodialysis Metronidazole and metabolites are efficiently removed during an eight hour period of dialysis. Metronidazole should therefore be re-administered immediately after haemodialysis.
No routine adjustment in the dosage of Metronidazole need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).
4.5 Interaction with other medicinal products and other forms of interaction
Patients should be advised not to take alcohol during therapy and for at least 48 hours afterwards because of possibility of a disulfiram-like (antabuse effect) reaction.
Phenobarbitone causes increased metabolisation of Metronidazole reducing the halflife to about 3 hours. Metabolism of Metronidazole is also accelerated by Primidone.
Cimetidine inhibits the metabolism of Metronidazole.
Some potentiation of anticoagulant therapy has been reported when Metronidazole has been used with the warfarin type oral anticoagulants. Dosage of Warfarin may require reducing. Prothrombin times should be monitored. There is no interaction with heparin.
Metronidazole inhibits the metabolism of phenytoin.
Lithium retention accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and Metronidazole. 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.
Metronidazole reduces the clearance of 5-fluorouracil and can therefore result in increased toxicity of 5-fluorouracil.
Patients receiving ciclosporin are at risk of elevated ciclosporin serum levels. Serum ciclosporin and serum creatinine should be closely monitored when co-administration is necessary.
Plasma levels of busulfan may be increased by Metronidazole which may lead to severe busulfan toxicity
4.6. Pregnancy and Lactation
As there is insufficient evidence of the safety of Metronidazole in pregnancy. Metronidazole should not be given during pregnancy or during lactation unless considered essential by a physician; in such circumstances short-term high-dosage therapy is not recommended.
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 advised not to drive or operate machinery if these symptoms occur.
4.8 Undesirable effects
Serious adverse reactions occur rarely with standard recommended regimens. Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.
Frequency, type and severity of adverse reactions in children are the same as in adults.
The frequency of adverse events listed below is defined using the following convention:
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 (cannot be estimated from the available data)
Blood and lymphatic system disorders:
Very rare: agranulocytosis, neutropenia, thrombocytopenia, and pancytopenia
Not known: leucopenia.
Immune system disorders:
Rare: anaphylaxis
Not known: angiodema, urticaria.
Metabolism and nutrition disorders:
Not known: anorexia.
Psychiatric disorders:
Very rare: psychotic disorders, including hallucinations.
Nervous system disorders:
Very rare: encephalopathy (e.g. Confusion, fever, headache, hallucinations,
paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (e.g. ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve on discontinuation of the drug.
drowsiness, dizziness, convulsions, headaches
Not known: during intensive and/or prolonged Metronidazole therapy, peripheral
sensory neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.
Eye disorders:
Very rare: diplopia, myopia.
Gastrointestinal disorders:
Not known: taste disorders, oral mucositis, furred tongue, nausea, vomiting,
gastro-intestinal disturbances.
Hepatobiliary disorders:
Very rare: abnormal liver function tests, cholestatic hepatitis, jaundice and
pancreatitis which is reversible on drug withdrawal.
Skin and subcutaneous tissue disorders:
Very rare: skin rashes, pustular eruptions, pruritis
Not known: erythema multiforme.
Musculoskeletal, connective tissue and bone disorders:
Very rare: myalgia, arthralgia.
Very rare: darkening of urine (due to Metronidazole metabolite).
4.9. Overdose
There is no specific treatment for gross over-dosage of Metronidazole.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Metronidazole is an anti-microbial drug primarily active against obligate anaerobic micro-organisms, both bacteria and protozoa. The 5-nitro group undergoes reductive transformation to an active intermediate which exerts an inhibitory or lethal effect against DNA and subsequent DNA strand breakage. Other reduction-oxidation processes within anaerobic organisms may also be inhibited (an example is the phosphoroclastic reaction in clostridia).
Metronidazole is very active against trichomonas vaginalis, giardia lamblia and E-histolytica, with minimal inhibition concentrations. Metronidazole is also especially active against strains of bacteroides fragilis and related species. It is moderately active against the facultative anaerobes gardnerella vaginates and campylobacter foetus.
5.2. Pharmacokinetic Properties
The bio-availability of oral Metronidazole produces 90-100%. Peak plasma levels of Metronidazole after a single 500 mg oral dose ranges between 9 and 13 mg/l and occurs 0.33-3 hours after the dose. With multiple oral doses, there is some drug accumulation on day 3 after a dose of 500 mg 6-hourly, with no evidence of further accumulation by day 7. Serum levels are directly proportional to the dose over a broad therapeutic range.
Pre-systemic metabolism is negligible. The plasma half-life range is 7.9-9.8 hours. Plasma protein binding 0%-20%. Volume of distribution of 0.76-1.02 1/kg reflects the wide distribution throughout the body.
5.3. Preclinical Safety Data
No relevant information additional to that contained elsewhere in the SPC.
6.1 List of excipients
Dicalcium phosphate
Povidone K25 Maize starch Crospovidone Magnesium stearate
6.2. Incompatibilities
Not applicable
6.3. Shelf Life
24 months
6 4. Special Precautions for Storage
Do not store above 25°C. Store in the original container and keep the container tightly closed.
6.5 Nature and contents of container
High density polystyrene containers with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane/polythene wads
Pack sizes: 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 140, 150, 168, 180, 500, 1000, 5000 and 50000
6.6. Instruction for Use/Handling Not applicable.
7 MARKETING AUTHORISATION HOLDER
Metwest Pharmaceuticals Limited
15 Runnelfield
Harrow on the Hill
Middlesex
HA1 3NY
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 17521/0036
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/02/2009
10 DATE OF REVISION OF THE TEXT
02/03/2012