Metronidazole

Disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) occurs with concurrent use. Metronidazole is contraindicated during and for at least 3 days after therapy.

Metronidazole increases plasma concentrations of busulfan, resulting in increased risk for serious busulfan toxicity. Should not be administered concomitantly unless benefit outweighs risk.

Psychotic reactions reported in alcoholic patients using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.

Dronabinol oral solution contains alcohol which produces disulfiram-like reactions when co-administered with metronidazole. Discontinue metronidazole at least 14 days before starting dronabinol and do not administer within 7 days of completing treatment.

Concomitant use of mebendazole and metronidazole should be avoided.

Disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) occurs with products containing propylene glycol. Use is contraindicated during and for at least 3 days after therapy.

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole.

Acute encephalopathy has been reported in patients receiving cyclophosphamide and metronidazole. Monitor for neurologic toxicities.

Acute encephalopathy reported; combination associated with increased cyclophosphamide toxicity in animal studies.

Short-term metronidazole therapy associated with elevation of serum lithium and signs of lithium toxicity in patients on high doses. Serum lithium and creatinine levels should be monitored.

May provoke lithium toxicity due to reduced renal clearance; requires close monitoring.

May decrease mycophenolic acid concentrations; concomitant use is not recommended.

Metronidazole potentiates the anticoagulant effect of oral coumarin anticoagulants, resulting in prolongation of prothrombin time. Prothrombin time and INR should be carefully monitored.

7 DRUG INTERACTIONS The following drug interactions were reported for metronidazole, a chemically-related nitroimidazole and may therefore occur with tinidazole: Warfarin and other oral coumarin anticoagulants: Anticoagulant dosage may need adjustment during and up to 8 days after tinidazole therapy ( 7.1 ) Alcohol-containing beverages/preparations: Avoid during and up to 3 days after tinidazole therapy ( 7.1 ) Lithium: Monitor serum lithium concentrations ( 7.1 ) Cyclosporine, tacrolimus: Monitor for toxicities of these immunosuppressive drugs ( 7.1 ) Fluorouracil: Monitor for fluorouracil-associated toxicities ( 7.1 ) Phenytoin, fosphenytoin: Adjustment of anticonvulsant and/or tinidazole dose(s) may be needed ( 7.1 , 7.2 ) CYP3A4 inducers/inhibitors: Monitor for decreased tinidazole effect or increased adverse reactions ( 7.2 ) Although not specifically identified in studies with tinidazole, the following drug interactions were reported for metronidazole, a chemically-related nitroimidazole.

CYP2C9 inhibitor that increases warfarin effect and INR; requires close INR monitoring

CYP2C9 inhibitor that increases warfarin effect and INR; requires closer INR monitoring.

CYP3A4 substrate whose plasma levels may increase with concomitant metronidazole use. Monitor plasma concentrations.

( 5.14 , 7.5 ) Antacids, Multivitamins or Dairy Products: Decreased absorption of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Capsules; do not take concomitantly. ( 7.7 ) CYP inducers and CYP inhibitors: Prolonged or accelerated half-life of metronidazole or concomitant medications; use with caution. ( 7.8 , 7.9 ) 7.1 Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride and disulfiram concurrently.

CYP3A4 substrate whose plasma levels may increase with concomitant metronidazole use. Monitor plasma concentrations.

Cimetidine decreases microsomal liver enzyme activity, prolonging half-life and decreasing plasma clearance of metronidazole.

Cimetidine reduces hepatic metabolism of metronidazole, delaying elimination and increasing blood levels.

CYP3A4 substrate whose plasma levels may increase with concomitant metronidazole use. Monitor plasma concentrations.

CYP inducers may cause accelerated half-life of metronidazole. Monitor for prolonged or accelerated drug effects.

QT prolongation can occur when metronidazole is used with drugs that have QT-prolonging potential.

May increase lithium serum concentrations. Recommend frequent monitoring of serum lithium concentration and dosage adjustment when necessary.

CYP inhibitors may cause prolonged half-life of metronidazole or concomitant medications. Monitor for effects.

Phenobarbital induces microsomal liver enzymes, accelerating elimination of metronidazole and reducing plasma levels.

Phenytoin induces microsomal liver enzymes, accelerating elimination of metronidazole and reducing plasma levels. Impaired clearance of phenytoin has also been reported.

CYP3A4 substrate whose plasma levels may increase with concomitant metronidazole use. Monitor plasma concentrations.

CYP3A4 substrate whose plasma levels may increase with concomitant metronidazole use. Monitor plasma concentrations.

7.3 Drugs which Cause Peripheral Neuropathy The use of drugs which cause peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) can cause an additive effect and should be used with caution.

Serum concentrations of ciprofloxacin and metronidazole were not altered when given concomitantly.

albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide The Effect of Other Drugs on Theophylline Serum Concentration Measurements: Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline.

7 DRUG INTERACTIONS 7.1 Disulfiram Psychotic reactions have been reported in patients who are concurrently taking disulfiram and nitroimidazole agents (structurally related to benznidazole, but not with benznidazole).

Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of CD including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.

Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of CD including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.

Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of CD including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.

Disulfiram/metronidazole Lopinavir and ritonavir oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Concurrent administration of any of the following drugs with lorazepam had no effect on the pharmacokinetics of lorazepam: metoprolol, cimetidine, ranitidine, disulfiram, propranolol, metronidazole, and propoxyphene.

Drug interactions Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. The effect of topical metronidazole on prothrombin time is not known.

7 DRUG INTERACTIONS The intravaginal administration of a single dose of metronidazole vaginal gel results in lower systemic exposure to metronidazole that is approximately 2% to 4% of that achieved following oral administration of 500 mg metronidazole tablets [see Clinical Pharmacology ( 12.3 )]. The following drug interactions were reported for oral metronidazole. • Warfarin and other coumarin anticoagulants: Prolonged anticoagulant effects of warfarin and other coumarin anticoagulants have been reported with co-administration of oral metronidazole.

Drug Interactions Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Norfloxacin and Metronidazole Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC 0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p< 0.05). Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole.

There was no effect on neostigmine action on rocuronium reversal by cefuroxime, metronidazole, cefuroxime or metronidazole.

All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH).

Antialcoholics: disulfiram/ metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Antialcoholics: disulfiram/ metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.* albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without methylprednisolone sulbactam metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and sulfamethoxazole) norfloxacin ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride Sorbitol (purgative doses do not inhibit hydrocortisone theophylline absorption) isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin * Refer to PRECAUTIONS, Drug Interactions for information regarding table.

albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without sulbactam methylprednisolone atenolol metronidazole azithromycin metoprolol caffeine, dietary ingestion nadolol cefaclor nifedipine co-trimoxazole (trimethoprim and sulfamethoxazole) nizatidine diltiazem norfloxacin dirithromycin ofloxacin enflurane omeprazole famotidine prednisone, prednisolone felodipine ranitidine finasteride rifabutin hydrocortisone roxithromycin isoflurane Sorbitol (purgative doses do not inhibit theophylline absorption) isoniazid sucralfate isradipine terbutaline, systemic influenza vaccine terfenadine ketoconazole tetracycline lomefloxacin tocainide

Diltiazem Felodipine Nicardipine Nisoldipine Verapamil ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil Disulfiram/Metronidazole Combination with TPV/ritonavir not studied APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).

7 DRUG INTERACTIONS The intravaginal administration of a single 5 gram dose of VANDAZOLE results in relatively lower mean systemic exposure to metronidazole that is approximately 2% to 5% of that achieved following a 500 mg oral dose of metronidazole [see Clinical Pharmacology ( 12.3 )] . VANDAZOLE should not be used by patients who have taken disulfiram within the last two weeks [see Contraindications ( 4.2 )] . Alcoholic beverages and preparations containing ethanol or propylene glycol should not be consumed during and for at least three days after VANDAZOLE therapy [see Contraindications ( 4.3 )] .