METRONIDAZOLE TABLETS 400 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Metronidazole Tablets 200mg.

Metronidazole Tablets 400mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Metronidazole Tablets 200mg

Each tablet contains 200mg metronidazole.

Excipients with known effect

Metronidazole Tablets 200 mg contains 120 mg of Lactose.

Metronidazole Tablets 400mg.

Each tablet contains 400mg metronidazole.

Excipients with known effect

Metronidazole Tablets 400mg contains 100 mg of Lactose

Metronidazole Tablets 400mg contains approximately 0.04 mg of Sunset Yellow (E110)

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Metronidazole Tablets 200mg

Metronidazole tablets are presented as white, normal convex tablets, with the company logo engraved one side and B065 engraved on the other.

Metronidazole Tablets 400mg.

Metronidazole 400mg tablets are presented as yellow, normal convex tablets, with the company logo on one side and ‘A’ breakline ‘321’ on the other.

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 microorganisms notably species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci and Gardnerella vaginalis.

It is also active against Trichomonas, Entamoeba histolytica, Giardia lamblia and Balantidium coli.

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

1. The treatment of septicaemia, bacteraemia, peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess and pelvic cellulitis and post-operative wound infections from which pathogenic anaerobes have been isolated. 2. The prevention of post-operative infections due to anaerobic bacteria, particularly species of Bacteroides and anaerobic streptococci.

3. Urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male.

4. Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginosis or gardnerella vaginitis).

5. All forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers).

6. Giardiasis.

7. Acute dental infections (e.g. acute pericoronitis and acute apical infections).

8. Acute ulcerative gingivitis.

9. Anaerobically-infected leg ulcers and pressure sores

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

4. 2 Posology and method of administration

Posology

Metronidazole tablets should be swallowed with water (not chewed). It is recommended that the tablets be taken during or after a meal.

Prophylaxis against anaerobic infection:

Chiefly in the context of abdominal (especially colorectal) and gynaecological surgery.

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: 20–30mg/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.

Anaerobic infections: The duration of a course of Metronidazole tablets treatment is about 7 days but it will depend upon the seriousness of the patient's condition as assessed clinically and bacteriologically.

Treatment of established anaerobic infection:

Adults

800 mg followed by 400 mg 8 hourly.

Children >8 weeks to 12 years of age: The usual daily 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.

Children <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, therefore concentrations of metronidazole in serum should preferably be monitored after a few days therapy.

Protozoal and other infections:

Eradication of Helicobacter pylori in paediatric patients:

As a part of a combination therapy, 20mg/kg/day not to exceed 500 mg twice daily for 7–14 days. Official guidelines should be consulted before initiating therapy.

Method of administration.

Oral use

4. 3 Contraindications

Known hypersensitivity to nitroimidazoles, metronidazole or any of the ingredients listed in section 6.1.

4. 4 Special warnings and precautions for use

Metronidazole has no direct activity against aerobic or faculatative anaerobic bacteria.

Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Metronidazole for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures).

Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.

There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.

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).

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. The daily dosage should be reduced to one third and may be administered once daily.

Patients should be warned that Metronidazole may darken urine.

Due to inadequate evidence on the mutagenicity risk in humans (see section 5.3), the use of Metronidazole for longer treatment than usually required should be carefully considered.

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 benefit-risk 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.

Cases of severe bullous skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEC) or acute generalised exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SJS, TEN or AGEP are present, metronidazole must be immediately discontinued.

Metronidazole Tablets 400mg contains sunset yellow (E110) which may cause allergic reactions.

Metronidazole Tablets 200mg and 400mg contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4. 5 Interaction with other medicinal products and other forms of interaction

Patients should be advised not to take alcohol during Metronidazole therapy and for at least 48 hours afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction. Psychotic reactions have been reported in patients who were using Metronidazole and disulfiram concurrently.

Some potentiation of anticoagulant therapy has been reported when Metronidazole has been used with the warfarin type oral anticoagulants. Dosage of the latter may require reducing. Prothrombin times should be monitored. There is no interaction with heparin.

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.

Patients receiving phenobarbital or phenytoin metabolise metronidazole at a much greater rate than normally, reducing the half-life to approximately 3 hours.

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 coadministration is necessary.

Plasma levels of busulfan may be increased by Metronidazole which may lead to severe busulfan toxicity.

4. 6 Fertility, pregnancy and lactation

There is inadequate evidence of the safety of metronidazole in pregnancy but it has been in wide use for many years without apparent ill consequence. Nevertheless metronidazole, like other medicines should not be given during pregnancy or lactation unless the physician considers it essential. Metronidazole diffuses across the placenta and is found in breast milk. In these circumstances, the short, high-dose regimens are 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

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).

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.

Blood and lymphatic system disorders:

Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia Not known: leucopenia.

Immune system disorders:

Rare: anaphylaxis.

Not known: angiodema, urticaria, fever.

Metabolism and nutrition disorders:

Not known: anorexia.

Psychiatric disorders:

Very rare: psychotic disorders, including confusion and hallucinations.

Not known: depressed mood.

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, dysarthria, 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.

aseptic meningitis.

Eye disorders:

Very rare: vision disorders such as diplopia, myopia which, in most cases, is transient

Not known: optic neuropathy/ne­uritis.

Ear and labyrinth disorders:

Not known: hearing impaired/hearing loss (including sensorineural), tinnitus.

Gastrointestinal disorders:

Not known: taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbances such as epigastric pain and diarrhoea.

Hepatobiliary disorders:

Very rare: increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, jaundice and pancreatitis which is reversible on drug withdrawal.

Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.

Skin and subcutaneous tissue disorders:

Very rare: skin rashes, pustular eruptions, acute generalised exanthematous pustulosis, pruritis, flushing.

Not known: erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis, fixed drug eruption.

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia.

Renal and urinary disorders:

Very rare: darkening of urine (due to Metronidazole metabolite)..

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 or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

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.

There is no specific antidote for Metronidazole overdosage. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, ATC code: J01X D01.

Metronidazole has antiprotozoal and antibacterial actions and is effective against Trichomonas vaginalis and other protozoa including Entamoeba histolytica and Giardia lamblia and against anaerobic bacteria.

5.2 Pharmacokinetic properties

Metronidazole is rapidly and almost completely absorbed on administration of Metronidazole tablets; peak plasma concentrations occur after 20 mins to 3 hours.

The half-life of Metronidazole is 8.5±2.9 hours. Metronidazole can be used in chronic renal failure; it is rapidly removed from the plasma by dialysis.

Metronidazole is excreted in milk but the intake of a suckling infant of a mother receiving normal dosage would be considerably less than the therapeutic dosage for infants.

5.3 Preclinical safety data

Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans.

Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while other studies were negative

6.1 List of excipients

Lactose

Microcrystalline cellulose

Pregelatinised starch

Magnesium stearate

Metronidazole Tablets 200mg also contains:

Maize Starch

Metronidazole Tablets 400mg also contains:

Quinoline Yellow Aluminium Lake E104

Sunset Yellow Aluminium Lake E110

6.2 Incompatibilities

None

6.3 Shelf life

36 months in tablet containers

48 months in blister packs

6.4 Special precautions for storage

Store in the original package. Do not store above 25°C.

6.5 Nature and contents of container

1. Opaque plastic containers composed of polypropylene tubes and polyethylene made tamper evident closures in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500 and 1000 tablets.

2. Opaque plastic container composed of either high density polypropylene or high density polyethylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene with a packing inclusion of standard polyether foam or polyethylene or polypropylene made filler in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 50, 56, 84, 100, 250, 500 and 1000 tablets.

3. Blister packs of aluminium/white opaque PVC with PVDC coating in pack sizes of 9, 10, 14, 15, 20, 21, 28, 30, 56 and 84 tablets.

6.6 Special precautions for disposal

None stated

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited

Units 3 & 4, Quidhampton Business Units

Polhampton Lane

Overton

Hants

RG25 3ED

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0105

PL 20416/0106

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

12/01/2004