Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Baxter Healthcare Ltd., Caxton Way, Thetford, Norfolk, IP24 3SE, UK
Hypersensitivity to the active substance, to other imidazole derivatives or to any of the excipients listed in section 6.1.
Caution is needed in patients with severe hepatic impairment. The dose of metronidazole should be reduced as necessary. Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of Metronidazole clearance may occur in the presence of advanced hepatic insufficiency. The risk/benefit ratio of using Metronidazole to treat trichomoniasis in such patients should be carefully considered (for dosage adjustment see section 4.2). Plasma levels of Metronidazole should be closely monitored.
Caution is needed in patients with hepatic encephalopathy. Patients with severe hepatic encephalopathy metabolize metronidazole slowly, with resultant accumulation of metronidazole. This may cause exacerbation of CNS adverse effects. The dose of metronidazole should be reduced as necessary.
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.
Metronidazole should be used with caution in patients with active disease of the Peripheral and Central Nervous System. Severe neurological disturbances (including seizures and peripheral and optic neuropathies) have been reported in patients treated with metronidazole. Stop metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction. The risk of aggravation of the neurological state should be considered in patients with fixed or progressive paraesthesia, epilepsy and active disease of the central nervous system except for brain abscess.
Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, dysarthria, and accompanied by CNS lesions seen on magnetic resonance imaging (MRI). CNS symptoms and CNS lesions, are generally reversible within days to weeks upon discontinuation of metronidazole.
Aseptic meningitis can occur with metronidazole. Symptoms can start within hours of dose administration and generally resolve after metronidazole therapy is discontinued (see section 4.8).
Metronidazole should be used with caution in patients with evidence or history of blood dyscrasia as agranulocytosis, leukopenia and neutropenia have been observed following metronidazole administration.
Metronidazole is removed during haemodialysis and should be administered after the procedure is finished.
Patients with renal impairment, including patients receiving peritoneal dialysis, should be monitored for signs of toxicity due to the potential accumulation of toxic metronidazole metabolites.
This medicinal product contains 13.5 mmol (310 mg) sodium per 100 mL. To be taken into consideration by patients on a controlled sodium diet.
Patients should be advised to discontinue consumption of alcoholic beverages or alcohol-containing products before, during, and up to 72hours after taking metronidazole because of a disulfram-like effect (abdominal cramps, nausea, headaches, flushing, vomiting and tachycardia). See section 4.5.
As a rule, the usual duration of therapy with i.v Metronidazole or other imidazole derivatives is usually less than 10 days. This period may only be exceeded in individual cases after a very strict benefit-risk assessment. Only in the rarest possible case should the treatment be repeated. Limiting the duration of treatment is necessary because damage to human germ cells cannot be excluded.
Intensive or prolonged Metronidazole therapy should be conducted only under conditions of close surveillance for clinical and biological effects and under specialist direction. If prolonged therapy is required, the physician should bear in mind the possibility of peripheral neuropathy or leucopenia. Both effects are usually reversible.
In case of prolonged treatment, occurrence of undesirable effects such as paraesthesia, ataxia, dizziness and convulsive crises should be checked. High dose regimes have been associated with transient epileptiform seizures.
Due to increased risk for adverse reactions, regular clinical and laboratory monitoring (including blood count) are advised in cases of high-dose, prolonged or repeated treatment, in case of antecedents of blood dyscrasia, in case of severe infection and in severe hepatic insufficiency.
Patients should be warned that Metronidazole may darken urine (due to Metronidazole metabolite).
Concurrent use of metronidazole and disulfiram may result in psychotic reactions and confusion. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.
Disulfiram-like effect (warmth, redness, vomiting, tachycardia).
Alcohol beverage and drugs containing alcohol should be avoided. Patients should be advised not to take alcohol during Metronidazole therapy and at least 72 hours afterwards because of a disulfram-like (antabuse effect) reaction (flushing, vomiting, tachycardia).
Metronidazole may increase the anticoagulant effects of warfarin and other oral anticoagulants, resulting in a prolongation of the prothrombin time and increased risk of haemorrhage (decrease in its liver catabolism). Patients taking metronidazole and warfarin or other oral coumarins concomitantly should have their prothrombin time and international normalized ratio (INR) monitored more frequently. Patients should be monitored for signs and symptoms of bleeding.
A large number of patients have been reported showing an increase in oral anticoagulant activity whilst receiving concomitant antibiotic therapy. The infectious and inflammatory status of the patient, together with their age and general well-being are all risk factors in this context. However, in these circumstances it is not clear as to the part played by the disease itself or its treatment in the occurrence of prothrombin time disorders. Some classes of antibiotics are more likely to result in this interaction, notably fluoroquinolones, macrolides, cyclines, cotrimoxazole and some cephalosporins.
Metronidazole can potentialise the effects of vecuronium.
Increase in the toxicity of 5 fluoro-uracile due to a decrease of its clearance.
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.
Cholestyramine may delay or reduce the absorption of Metronidazole.
Concomitant administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy.
Concomitant administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may cause decreased metabolism and reduced plasma clearance of metronidazole which may result in metronidazole toxicity.
Concomitant use of metronidazole and CYP3A4 substrates (e.g. amiodarone, tacrolimus, cyclosporine, carbamazepine, and quinidine) may increase respective CYP3A4-substrate plasma levels. Monitoring of plasma concentrations of CYP3A4 substrates may be necessary.
Plasma concentrations of busulfan may increase during concomitant treatment with metronidazole, which can result in serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease.
Metronidazole may immobilise Treponema and thus may lead to falsely positive Nelson’s test.
Metronidazole may interfere with serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase determinations. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.
Metronidazole crosses the placental barrier.
Clinical data on a large number of exposed pregnancies and animal data did not show a teratogenic or foetotoxic effect. However unrestricted administration of nitroimidazolene to the mother may be associated with a carcinogenic or mutagenic risk for the unborn or newborn child.
Therefore Metronidazole should not be given during pregnancy unless clearly necessary.
Metronidazole is excreted in breast milk. During lactation either breast-feeding or Metronidazole should be discontinued.
There are no clinical data relating to the effect of metronidazole on fertility.
Animal studies demonstrated adverse effects on the male reproductive system that are wholly or partially reversible after treatment withdrawal (see section 5.3).
No studies have been performed following intravenous treatment with Metronidazole on the ability to drive and use machines. Some adverse reactions to metronidazole such as seizure, dizziness, optic neuropathy, may impair the ability to drive or operate machines (see section 4.8).
Therefore it is recommended that patients should not drive or use machines.
There are no data available on adverse reactions from Baxter-sponsored clinical trials conducted with Metronidazole. The following adverse reactions have been reported with Metronidazole, listed by MedDRA System Organ Class (SOC), Preferred Term and frequency. The following frequency groupings are used: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).
Frequency, type and severity of adverse reactions in children are the same as in adults.
Uncommon: Leukopenia
Rare: Agranulocytosis, Pancytopenia, Neutropenia, Thrombocytopenia
Not known: Eosinophilia
Rare: Anaphylactic shock, Jarisch-Herxheimer reaction
Not known: Hypersensitivity
Not known: Decreased appetite
Rare: Hallucinations
Not known: Depression, Confusional state, Insomnia
Common: Dysgeusia
Uncommon: Headache
Rare: Encephalopathy, Meningitis aseptic, Seizure, Somnolence, Neuropathy peripheral, Ataxia, Dizziness, Dysarthria
Not known: Hypoaesthesia, Paraesthesia
Rare: Optic neuropathy, Diplopia, Myopia
Not known: Tachycardia, Palpitations
Not known: Dyspnoea
Common: Glossitis, Stomatitis, Dry mouth
Rare: Pancreatitis, Abdominal pain upper, Diarrhoea, Nausea, Vomiting
Not known: Constipation, Tongue discoloration
Rare: Jaundice cholestatic
Rare: Stevens-Johnson syndrome, Toxic epidermal necrolysis, Angioedema, Erythema multiforme
Not known: Pruritus, Swelling face, Urticaria, Hyperhidrosis, Rash
Common: Myalgia
Not known: Muscle spasms, Arthralgia
Rare: Chromaturia
Not known: Dysuria
Uncommon: Asthenia
Rare: Mucosal inflammation, Pyrexia
Not known: Injection site reaction, Malaise, Face oedema, Oedema peripheral, Chest pain, Chills
Not known: Hepatic enzyme increased
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.
Do not use equipment containing aluminum (e.g. needles, cannulae) that would come in contact with the drug solution as precipitates may form.
Metronidazole is incompatible with (includes but is not limited to):
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal product except for those mentioned in 6.6.
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