METRONIDAZOLE Film-coated tablet Ref.[6986] Active ingredients: Methronidazole

Contains wheat starch. Suitable for people with coeliac disease. Patients with wheat allergy (different from coeliac disease) should not take this medicine.

• Patients should abstain from alcohol for at least 48 hours following discontinuation of therapy with metronidazole. A disulfiram-like reaction with hypotension and flushing has occurred (see section 4.5).
• Caution is advised in patients with porphyria.
• Metronidazole tablets should not be used in patients with blood dyscrasias or with active non-infectious disease of the central nervous system. High doses of metronidazole may mask the presence of syphilis.
• Caution in patients with epilepsy or those who have had seizures as high doses of Metronidazole can induce seizures.
• Use with caution in the second and third trimester when used to treat trichomoniais or bacterial vaginosis (see section 4.6.).
• Regular clinical and laboratory surveillance are advised if treatment continues for more than 10 days.
• Consideration of the therapeutic benefit against the risk of peripheral neuropathy is advised with continuous therapy for chronic conditions.
• 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 readministered immediately after haemodialysis.
• No routine adjustment in the dosage of metronidazole need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IPD) 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 accumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to symptoms of the encephalopathy. Therefore, metronidazole should be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

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.

Combinations to be used with caution

Lithium: 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 concentration of lithium, creatinine, and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

Anticoagulants: 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. No interactions have been reported with anticoagulants of the heparin type. However, anticoagulant activity should be routinely monitored with these products.

Alcohol: Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hours after because of the possibility of a disulfiram-like reaction.

Disulfiram: Psychotic reactions have been reported.

Immunosuppressants: Patients receiving ciclosporin are at risk of elevated ciclosporin serum levels. Serum ciclosporin and serum creatinine should be closely monitored when coadministration is necessary.

Pharmacokinetic interactions

Antiepileptics: Patients receiving phenobarbital metabolise metronidazole at a much greater rate than normally, reducing the half-life to approximately 3 hours. Metronidazole inhibits metabolism of phenytoin (increases plasma-phenytoin concentration). Primidone accelerates the metabolism of Metronidazole causing reduced plasma concentrations.

Cytotoxics: Metronidazole inhibits metabolism of fluorouracil. Therefore, increased toxicity of fluorouracil can result.

Ulcer-healing drugs: Cimetidine inhibits the metabolism of metronidazole (increases plasma-metronidazole concentration).

Oestrogens: broad spectrum antibiotics possibly reduce the contraceptive effect.

Drug-lab modifications: Aspartate amino transferase assays may give spuriously low values in patients taking metronidazole, depending on the method used.

As with all medicines, metronidazole should not be given during pregnancy or during lactation unless it is considered essential, and in these circumstances the short, high-dosage regimens are not recommended.

Pregnancy

Metronidazole is contraindicated in the first trimester (see section 4.3) and should be used with caution in the second and third trimester when used to treat trichomoniais or bacterial vaginosis (see section 4.4).

For all other indications Metronidazole should only be used if the benefits outweigh the risks or no other alternative is available especially in the first trimester.

Breast-feeding

It is advisable to stop breast feeding until 12–24 hours after Metronidazole therapy has been discontinued (see section 4.3).

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.

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 (<10,000); not known (cannot be estimated from the available data.

Serious adverse reactions occur rarely with standard recommended regime. Frequency, type and severity of adverse reactions in children are the same as in adults.

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, bone marrow depression disorders such as aplastic anaemia

Immune system class

Rare: anaphylaxis

Not known: angioedema, urticaria, fever

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, 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: Depression, paraesthesia, 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. Incoordination of movement

Eye disorders

Very rare: diplopia, myopia

Gastrointestinal disorders

Not known: unpleasant taste in the mouth, taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro- intestinal disturbances, diarrhoea, abdominal pain, anorexia

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, pruritus, flushing

Not known: erythema multiforme

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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

None.