Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics, PO Box 62027, Sylvia Park Auckland 1644, Freecall: 0800 283 684, Email: medinfo.australia@sanofi.com
Alcoholic beverages and drugs containing alcohol, should not be consumed by patients being treated with metronidazole and for at least a day after treatment as nausea, vomiting, abdominal cramps, headaches, tachycardia and flushing may occur. There is the possibility of a disulfiramlike (Antabuse) effect reaction.
If, for compelling reasons, metronidazole must be administered for longer than the usually recommended duration it is recommended that haematological tests, especially leucocyte count, should be carried out regularly, and that patients should be monitored for adverse reactions such as peripheral or central neuropathy (paraesthesia, ataxia, dizziness, vertigo, convulsive seizures). If leucopenia or abnormal neurological signs occur, the drug should be discontinued immediately.
Use of metronidazole does not obviate the need for aspiration of pus whenever indicated.
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 removed during an eight hour period of dialysis. Metronidazole should therefore be administered immediately after haemodialysis. No routine adjustment in the dosage of Flagyl need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IPD) or continuous ambulatory peritoneal dialysis (CAPD).
Patients should be warned that metronidazole may darken urine (due to metronidazole metabolite).
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 impaired liver function or hepatic encephalopathy. The daily dosage should be reduced to one-third and may be administered once a day. Metronidazole may interfere with certain chemical analyses of serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose to give abnormally low values.
Caution is advised in patients with active disease of the central nervous system other than brain abscess. Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system diseases due to the risk of neurological aggravation. Treatment should be immediately discontinued if signs of neuropathy or encephalopathy are noticed.
Cases of suicidal ideation with or without depression have been reported during treatment with metronidazole. Patients should be advised to discontinue treatment and contact their healthcare provider immediately if they experience psychiatric symptoms during treatment.
The simultaneous use of Flagyl suppositories with condoms or diaphragms may increase the risk of rupture of the latex.
There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.
Candida overgrowth in the gastrointestinal or genital tract may occur during metronidazole therapy and require treatment with a candidacidal drug.
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 (TEN) or acute generalised exanthematous pustulosis (AGEP) have been reported with metronidazole (see section 4.8). If symptoms or signs of SJS, TEN or AGEP are present, metronidazole treatment must be immediately discontinued.
Metronidazole may interfere with certain types of blood test determinations in blood (aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], triglycerides, glucose), which may lead to false negative or an abnormally low result. These analytical determinations are based on a decrease in ultraviolet absorbance, a fact that occurs when nicotinamide adenine dinucleotide hydrogen (NADH) is oxidized to nicotinamide adenine dinucleotide (NAD). The interference is due to the similarity in the absorption peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
Some potentiation of anticoagulant effect (and increased haemorrhagic risk caused by decreased hepatic catabolism) 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 more frequently monitored. No interactions have been reported with anticoagulants of the heparin type. However, anticoagulant activity should be routinely monitored with these products.
Plasma levels of lithium may be increased by metronidazole. 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 phenobarbitone or phenytoin metabolise metronidazole at a much greater rate than normally, reducing the half life to approximately 3 hours.
Patients should be advised not to take alcohol during metronidazole therapy and for at least one day afterwards, because of the possibility of a disulfiram-like (antabuse) reaction.
Psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.
Metronidazole should be used with caution in patients receiving carmustine and/or cyclophosphamide. Concomitant use of cyclosporin and metronidazole could result in increased serum levels of cyclosporin. When it is necessary to co-administer the two together close monitoring of serum cyclosporin and creatinine is advisable.
The clearance of 5-fluorouracil is reduced resulting in increased toxicity of 5-fluorouracil.
Aspartate amino transferase assays may give spuriously low values in patients taking metronidazole, depending on the method used.
Plasma levels of busulfan may be increased by metronidazole, which may lead to severe busulfan toxicity.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.
QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.
Category B2
There is inadequate evidence of the safety of metronidazole in pregnancy. However, as Flagyl crosses the placental barrier it, like other medicines, should not be given during pregnancy or during lactation unless the physician considers it essential; in these circumstances the short highdosage regimes are not recommended.
As metronidazole is excreted in human milk, unnecessary exposure to the drug should be avoided.
No data available.
Patients should be warned about the potential for confusion, dizziness, vertigo, hallucinations, convulsions or transient visual disorders and advised not to drive or operate machinery if these symptoms occur.
Serious adverse reactions occur very rarely with standard recommended regimens.
When given orally, metronidazole is well tolerated. The most common adverse reactions refer to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia and occasionally vomiting, diarrhoea, epigastric pain or distress and abdominal cramping; constipation, taste disorders and oral mucositis have also been reported. A metallic, sharp, unpleasant taste is not unusual. Cases of pancreatitis which abated on withdrawal of the drug, have been reported. Crohn’s disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. If patients receiving metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing or headache. A modification of the taste of alcoholic beverages has also been reported.
Furry tongue, tongue discolouration, glossitis and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during effective therapy.
Hypersensitivity reactions include urticaria, fever, rash, pruritus, flushing, angioedema and anaphylactic shock. Nasal congestion and dryness of the mouth have been reported. Mild erythematous eruptions have been experienced, as have fleeting joint pains sometimes resembling serum sickness. Pustular eruptions and acute generalised exanthematous pustulosis have been reported. Fixed drug eruption has been reported. Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported.
Drowsiness, dizziness, headache and uncoordinated movements have been reported. During intensive and/or prolonged metronidazole therapy, a few instances of peripheral neuropathy (characterised mainly by numbness or paraesthesia of an extremity) or convulsions have been reported. There have been reports of encephalopathy (e.g. confusion, vertigo) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus and tremor). In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, such subjects should be specifically warned about these reports and should be told to stop the drug and report immediately if any neurological symptoms occur. Aseptic meningitis has been reported.
Psychotic disorders, such as confusion and hallucinations have been reported. Depression, depressed mood, insomnia, irritability and weakness have also been reported.
Frequency not known: vertigo
Optic neuropathy/neuritis and transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity and changes in colour vision have been reported.
Impaired hearing/hearing loss (including sensorineural) and tinnitus have been reported.
Cases of agranulocytosis, neutropenia and thrombocytopenia have been reported. A moderate leucopenia has been reported in some patients. If this occurs, the total leucocyte count may be expected to return to normal after the course of medication is completed. One case of bone marrow depression has been reported. If profound bone marrow suppression occurs, use of metronidazole should be ceased and appropriate supportive therapy instituted.
Increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice, have been reported.
Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.
Proliferation of Candida also may occur in the vagina. Dryness of the vagina or vulva, pruritus, dysuria, cystitis and a sense of pelvic pressure have been reported. Very rarely dyspareunia, fever, polyuria, incontinence, decrease of libido, proctitis and pyuria have occurred in patients receiving the drug.
Instances of darkened urine have been reported and this manifestation has been the subject of special investigation. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole. It seems certain that it is of no clinical significance and may be encountered only when metronidazole is administered in higher than recommended doses.
Flattening of the T wave may be seen in ECG tracings.
Frequency not known: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.
Reporting suspected adverse reactions after registration 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 at https://nzphvc.otago.ac.nz/reporting/.
Not applicable.
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