Chemical formula: C₆H₉N₃O₃ Molecular mass: 171.154 g/mol PubChem compound: 4173
Methronidazole interacts in the following cases:
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.
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).
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. 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 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.
Broad spectrum antibiotics possibly reduce the contraceptive effect.
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.
Cholestyramine may delay or reduce the absorption of metronidazole.
In co-administration of metronidazole with ciclosporine, there is a risk of elevated serum ciclosporine levels. Where co-administration is considered necessary, serum creatinine and ciclosporine should be closely monitored.
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.
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.
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.
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.
Metronidazole can potentialise the effects of vecuronium.
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.
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.
Patients should be warned that metronidazole may darken urine (due to metronidazole metabolite).
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.
Metronidazole is contraindicated in the first trimester and should be used with caution in the second and third trimester when used to treat trichomoniais or bacterial vaginosis.
Metronidazole cream is contraindicated during the first third of pregnancy. During the middle and the last third of pregnancy metronidazole cream should only be administered if other treatments have been unsuccessful.
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.
Metronidazole is excreted in breast milk. During lactation either breast-feeding or Metronidazole should be discontinued.
It is advisable to stop breast feeding until 12–24 hours after Metronidazole therapy has been discontinued.
After oral administration, up to 100% of the plasma value can be reached. Following topical application of metronidazole cream the plasma levels are lower than after oral administration of metronidazole. Nevertheless, during lactation breast-feeding should either be interrupted or the treatment with metronidazole cream 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.
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.
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.
Therefore it is recommended that patients should not drive or use machines.
Based upon the pharmacodynamic profile and clinical experience performance related to driving and using machines should not to be affected.
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.
Very rare: Agranulocytosis, neutropenia, thrombocytopenia, pancytopenia
Not known: Leucopenia, bone marrow depression disorders such as aplastic anaemia
Rare: Anaphylaxis
Not known: Angioedema, urticaria, fever
Not known: Anorexia
Very rare: Psychotic disorders, including hallucinations
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
Very rare: Diplopia, myopia
Not known: Unpleasant taste in the mouth, taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro- intestinal disturbances, diarrhoea, abdominal pain, anorexia
Very rare: Abnormal liver function tests, cholestatic hepatitis, jaundice and pancreatitis which is reversible on drug withdrawal
Very rare: Skin rashes, pustular eruptions, pruritus, flushing
Not known: Erythema multiforme
Very rare: Myalgia, arthralgia
Very rare: Darkening of urine (due to metronidazole metabolite)
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
The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency, using the following convention: Very common (≥1/10), Common (≥1/100 <1/10), Uncommon (≥1/1,000 <1/100), Rare (≥1/10,000 <1/1,000), Very rare (<1/10,000), including isolated reports.
Rare: Anaphylaxis
Common: Contact dermatitis, dry skin, erythema, pruritus, rash, skin discomfort (burning and stinging), skin irritation, worsening of rosacea
Rare: Angio-edema
Uncommon: Hypothesia, paraesthesia
Common: Pain
Rare: Metallic taste, nausea
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