UNIGYL Oral suspension Ref.[115710] Active ingredients: Methronidazole

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

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

The elimination of 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 (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 cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of encephalopathy.

Metronidazole should be administered with caution to patients with hepatic encephalopathy. The daily dosage may be reduced to one third and may be administered once daily.

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.

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.

Hepatotoxicity in patients with Cockayne Syndrome

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 not be used unless the benefit is considered to outweigh the risk and 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 (see section 4.8).

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

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 anti-coagulants. Dosage of the anticoagulant may require reduced. Prothrombin time should be monitored. No interactions have been reported of the heparin type. 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.

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

Increased serum carbamazepine levels and toxicity have been seen in patients given concomitant metronidazole.

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

Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods no longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

Metronidazole reduces the clearance of 5-fluorouracil and can therefore result in increased toxicity of 5-fluorouracil.

Patients receiving ciclosporin or tacrolimus with metronidazole are at risk of elevated ciclosporin/tacrolimus serum levels. Serum ciclosporin/tacrolimus 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.

There is inadequate evidence of the safety of metronidazole in pregnancy. Metronidazole should not therefore be given during pregnancy or during lactation unless the physician considers it essential, in these circumstances short, high dosage regimes are not recommended. A significant amount of metronidazole is found in breast milk and breast feeding should be avoided after a large dose. This could give a bitter taste to the milk.

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.

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).

Frequency, type and severity of adverse reactions in children are the same as in adults. Serious adverse reactions occur very rarely with standard recommended regimens. However, 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 and pancytopenia, often reversible on drug withdrawal, although fatalities have occurred.

Not known: A moderate leucopenia has been reported in some patients, but the white cell count has always returned to normal before or after treatment has been completed.

Immune system disorders

Rare: Anaphylaxis

Not known: urticaria, angioedema and 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) have been reported very rarely which may resolve on discontinuation of the drug

• Drowsiness, dizziness, convulsions, headache, ataxia, inco-ordination of movement

Not known:

• During intensive and/or prolonged metronidazole therapy a few instances of peripheral neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.
• Aseptic meningitis has been reported

Eye disorders

Very rare: transient visual disorders such as diplopia and myopia have been reported

Not known: Optic neuropathy/neuritis has been reported

Ear and labyrinth disorders

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

Gastrointestinal disorders

Not known: Unpleasant taste in the mouth, oral mucositis, furred tongue, nausea, vomiting, gastrointestinal disturbances such as epigastric pain and diarrhoea.

Hepatobiliary disorders

Very rare:

• Abnormal liver function tests, increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, and hepatocellular liver injury, jaundice and pancreatitis, reversible on drug withdrawal have been reported.
• Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.
• Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (see section 4.4).

Skin and subcutaneous tissue disorders

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

Not known: Erythema multiforme may occur, which may be reversed on drug withdrawal. StevensJohnson 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 the urine (due to metronidazole metabolite)

Metronidazole Oral Suspension contains glycerol, which can cause headache, gastro-intestinal disturbance and diarrhoea.

The parahydroxybenzoates used in Metronidazole Oral Suspension may cause immediate or delayed hypersensitivity reactions.

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.

None known.