SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Flagyl 1g Suppositories.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each suppository contains 1.0g metronidazole.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Suppository

A cream coloured, smooth, torpedo-shaped suppository.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

1. Treatment of infections in which anaerobic bacteria have been identified or are suspected as pathogens, particularly Bacteroides fragilis and other species of Bacteroides and including other species for which metronidazole is bactericidal, such as Fusobacteria, Eubacteria, Clostridia and anaerobic cocci.

Flagyl has been used successfully in: septicaemia, bacteraemia, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, peritonitis and post-operative wound infection from which one or more of these anaerobes have been isolated.

2. Prevention of post-operative infections due to anaerobic bacteria, particularly species of Bacteroides and anaerobic Streptococci.

4.2 Posology and method of administration

Route of administration: Rectal 1. Treatment of Anaerobic Infections:

Adults and children over 10 years: 1 gram suppository inserted into the rectum eight hourly for three days. Oral medication with 400 mg three times daily should be substituted as soon as this becomes feasible. If rectal medication must be continued for more than three days, the suppositories should be inserted at 12 hourly intervals.

Children (5-10 years): As for adults but with 500 mg suppositories and oral medication with 7.5 mg/kg bodyweight three times daily.

Infants and children under 5 years: As for children of 5-10 years but with appropriate reduction in dosage of suppositories (one half of a 500 mg suppository for 1 to 5 years and one quarter of a 500 mg suppository for under 1 year).

2. Prevention of Anaerobic Infections:

In appendectomy and post-operative medication for elective colonic surgery

Adults and children over 10 years'., 1 gram suppository inserted into the rectum two hours before surgery and repeated at eight hourly intervals until oral medication (200 to 400 mg three times daily) can be given to complete a seven day course.

If rectal medication is necessary after the third post-operative day, the frequency of administration should be reduced to 12 hourly.

Children (5-10 years): 500 mg suppositories administered as for adults until oral medication (3.7 to 7.5 mg/kg bodyweight three times daily) becomes possible.

4.3 Contraindications

Known hypersensitivity to nitroimidazoles, metronidazole or any of the excipients.

4.4 Special warnings and precautions for use

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

Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Flagyl 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 paresthesia, 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 Flagyl 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. Flagyl 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 flagyl for longer treatment than usually required should be carefully considered.

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 Pregnancy and lactation

There is inadequate evidence of the safety of metronidazole in pregnancy. Flagyl should not be given during pregnancy or during lactation unless the physician considers it essential; in these circumstances the short, high-dosage 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 (eg. confusion, fever, headache, hallucinations, paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (eg. 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.

•    aseptic meningitis

Eye disorders:

Very rare: vision disorders such as diplopia and 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, 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.

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 readily absorbed from the rectal mucosa and widely distributed in body tissues. Maximum concentrations occur in the serum after about 1 hour and traces are detected after 24 hours.

At least half the dose is excreted in the urine as metronidazole and its metabolites, including an acid oxidation product, a hydroxy derivative and glucoronide. Metronidazole diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum.

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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Flagyl suppository also contain the following excipients: Suppository base E75 and suppository base W35

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for    storage

Store below 20°C.