Metronidazole interactions to avoid

Key takeaways | Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Metronidazole, known under its brand name as Flagyl and Flagyl XR, is a nitroimidazole antimicrobial that treats a variety of anaerobic bacterial infections, including bacterial vaginosis, a severe form of diarrhea due to Clostridioides difficile infection, giardiasis, management of Helicobacter pylori, protozoal infections including amebiasis and giardiasis, sexually transmitted infections like pelvic inflammatory disease (PID) and trichomoniasis, and in gastrointestinal conditions like Crohn’s disease. Some of these medical conditions require a single dose, but others require much more involved frequencies and duration, which can result in the development of side effects independently of drug interactions. 

Common side effects of metronidazole include a metallic taste while on therapy, loss of appetite, constipation, and nervous system changes like the development of peripheral neuropathy. In the setting of elimination and metabolic impairments like kidney disease or liver disease, metabolites of metronidazole may accumulate and increase the risk of development of more serious side central nervous system (CNS) effects like encephalopathy. 

Metronidazole interacts with alcohol and any medication formulations that contain it or propylene glycol, as the combination may result in central nervous system reactions. Do not take metronidazole with disulfiram, busulfan, anticoagulants, lithium, mycophenolate, and cimetidine. It’s important to be aware of metronidazole interactions as other drugs and foods can affect metronidazole’s effectiveness or worsen side effects. 

Key takeaways:

• Metronidazole taken with alcoholic beverages, propylene glycol, or any prescription drug containing either component, can result in a dangerous drug interaction. 
• Serious adverse effects include the development of psychoses and encephalopathy, which occurs when metronidazole is taken with disulfiram and is also the reason for the contraindication to be consumed in combination with alcohol or propylene glycol. 
• Many drug interactions between metronidazole and other medications occur because of increased side effects of one of the medications, either metronidazole or the other drug
• In the event of a metronidazole interaction, promptly seek medical advice. Metronidazole is an antibiotic, so often prescribed for an acute condition that cannot go untreated. An alternative antibiotic may need to be considered, or increased monitoring while on the interacting medications concurrently. 

Metronidazole drug interactions

Metronidazole-drug interactions generally result in increased serum concentrations of either metronidazole or the other drug. Depending on the combination, the interaction may increase the risk of an inconvenient side effect or be serious and need to be avoided entirely. 

Disulfiram

Disulfiram is a medication used in moderate to severe alcohol use disorder in patients who want to abstain from alcohol. It inhibits the usual metabolism of alcohol, so if taken concomitantly with alcohol, it results in what is known as a disulfiram reaction; which is the build-up of serum acetaldehyde levels. Disulfiram may enhance the adverse effects of metronidazole, specifically the central nervous system (CNS) toxicities such as psychosis. In one study, use of both disulfiram and metronidazole together resulted in a 21% incidence of CNS toxicities in 29 hospitalized patients, including acute psychoses, confusion, hallucinations, and/or delusions. No CNS toxicity was noted in the patients who received disulfiram alone. Concomitant use of metronidazole and disulfiram is contraindicated in metronidazole prescribing information, and metronidazole use should be avoided in patients who have taken disulfiram within the previous two weeks.

Alcohol and propylene glycol-containing products

Similar to concurrent use of alcohol, concurrent use of propylene glycol with metronidazole or within three days after completing metronidazole is considered a contraindication in FDA metronidazole prescribing information. The concern is that a disulfiram-like reaction could result, although current treatment guidelines state that avoidance is unnecessary as the evidence stands against the development of the reaction. Propylene glycol is primarily limited to injectable and rectal dosage forms of some medications, including diazepam, digoxin, lorazepam, phenobarbital, phenytoin, and sulfamethoxazole. Alcohol may be contained in many pharmaceutical products, like elixirs. 

It is important to be aware of the case reports that describe signs and symptoms of a disulfiram-like reaction during coadministration of metronidazole with these products, but that more robust studies have failed to demonstrate these reactions and if it were to occur, suggest that the reaction would be relatively mild. If possible, avoid combinations whenever possible. 

Busulfan

Busulfan is an alkylating, antineoplastic agent that is used as part of conditioning regimens in hematopoietic cell transplant recipients for hematologic malignancies, and other serious conditions. Metronidazole may increase the serum concentration of busulfan when taken concurrently, which could result in busulfan toxicity. Serum concentrations of busulfan increased from 79% to 87% in 14 patients when busulfan was administered with metronidazole, and busulfan toxicity was increased in those patients. 

Busulfan toxicity signs and symptoms include veno-occlusive disease, hemorrhagic cystitis, elevated liver function tests, and gastrointestinal mucositis and ulcers. Metronidazole prescribing information states that metronidazole should be administered with busulfan unless the benefit outweighs the risk of increased risk of busulfan toxicity, and that if coadministration cannot be avoided busulfan serum concentrations should be monitored more frequently with the busulfan dose adjusted accordingly. 

Lithium

Lithium is a medication employed in the management of unipolar major depressive disorder as well as bipolar disorder. Lithium has a narrow therapeutic index, meaning that toxic levels in the blood are very close in proximity to its therapeutic range. Therapeutic drug monitoring is employed to ensure blood levels remain within a therapeutic range, and drug interactions that can increase lithium concentrations can be very problematic. 

Lithium toxicity can result in cardiac arrhythmias and can cause a variety of CNS effects, including lethargy, confusion, slurred speech, and hallucinations. Metronidazole is one such medication that may enhance the adverse effects of lithium, resulting in lithium toxicity or other adverse effects of lithium, such as reduced renal function, in patients receiving both medications concomitantly. Increased monitoring of serum lithium concentrations as well as renal function is recommended if a course of metronidazole is necessary while on long-term lithium therapy. 

Mycophenolate

Mycophenolate is an immunosuppressive agent with many indications, including graft-versus-host disease in allogeneic hematopoietic cell transplantation, lupus, and as maintenance immunosuppression to prevent rejection in solid organ transplant recipients. The medication requires close monitoring to ensure blood levels remain within a range for both efficacy but also to avoid toxicities, of which there are many with this specific medication. 

Metronidazole may decrease the blood levels of mycophenolate, which could result in decreased effectiveness. The mechanism behind this interaction is suspected to have to do with the elimination of metronidazole of specific bacteria in the intestinal tract that ultimately interferes with the bacteria-mediated elimination of mycophenolate and active metabolites. Therefore, use of multiple antibiotics with activity against bacteria in the gastrointestinal tract may potentiate this effect and result in life-threatening conditions. Increased monitoring of mycophenolate blood levels may be requested if receiving this combination of therapy. Prolonged durations of metronidazole in individuals requiring immunosuppressive therapy with mycophenolate should be avoided. 

Vitamin K antagonists

Warfarin, which is a vitamin K Antagonist, is a blood thinning medication used in cardiac conditions like atrial fibrillation (afib) and in the management of acute venous thromboembolism (VTE)—or blood clots. Inherently, the use of warfarin comes with a risk of bleeding, which is why monitoring is regularly performed of international normalized ratio (INR) with goal ranges established based upon indication. 

Many medications and changes in diet can interact with warfarin, causing changes to a person’s INR, which is a measure of how long it takes blood to clot (e.g., the higher the INR, the longer it will take for clotting to occur, meaning the more at risk of a significant bleed). When a person is on a combination of warfarin and metronidazole, close monitoring of the effect on the INR is recommended, with a dose adjustment of warfarin to be made accordingly (most commonly, a dose decrease). Many cases have been reviewed to come to this conclusion, including one evaluating a strategy of preemptive warfarin dose reduction versus usual care (INR monitoring, but with increased frequency) in warfarin-treated patients initiated on metronidazole. It was found that a 35% preemptive reduction in warfarin dose resulted in no change in INR, while INR increased by 1.47 in those receiving usual care. The mechanism behind this interaction is believed to be due to metronidazole-mediated inhibition of the liver enzyme CYP2C9, which is responsible for warfarin metabolism. 

Cimetidine

Cimetidine is a histamine blocker that is often used in the management of heartburn or stress ulcer prophylaxis in critically ill patients. Cimetidine use concurrently with metronidazole may increase the blood concentration of metronidazole, warranting monitoring for metronidazole toxicity. The mechanism behind this interaction is likely, in part, due to cimetidine-mediated inhibition of the liver enzyme CYP3A4—a minor pathway in metronidazole metabolism. 

Metronidazole food interactions

Generally, metronidazole can be taken with or without food, but any food containing alcohol or propylene glycol should be avoided while taking metronidazole, and for three days after the course of metronidazole has been completed. Propylene glycol may be used as a solvent or preservative in some foods, including baked goods, certain marinades, salad dressings, as well as some beverages. Check food labels for inclusion of propylene glycol while on a course of metronidazole. 

Other metronidazole interactions

Use of alcohol should be avoided while taking metronidazole to avoid the development of serious side effects. In addition, certain medical conditions require avoidance of metronidazole. 

Metronidazole and alcohol

Drinking any beverages or products containing alcohol is not recommended during a treatment course of metronidazole, as it can lead to serious adverse effects. Metronidazole is thought to interfere with and block the enzyme in the body responsible for the metabolism of alcohol. By blocking this enzyme, the accumulation of an alcohol byproduct known as acetaldehyde will cause side effects like headache, flushing, nausea, and vomiting. Rarely, the combination can result in the development of encephalopathy, peripheral neuropathy, or seizures. Avoidance is the best prevention. 

Metronidazole and Cockayne syndrome

Cockayne syndrome is an uncommon genetic disorder characterized by certain physical and intellectual disabilities. One case series reports eight cases of acute liver failure after metronidazole administration, three of which were fatal within a range of six to 11 days after initial metronidazole administration. Awareness of this interaction in this rare medical condition is warranted, and metronidazole should be avoided in these individuals. 

How to minimize metronidazole interactions

Always carry a complete list of medications, including supplements, on your person. Any time you’re receiving medical advice with new therapy recommendations, provide this list so that a thorough review and drug information assessment can be performed to minimize the risk of drug interactions. Anytime you start a new medication, and new signs or symptoms arise—however mild they might be—it’s best to review them with your healthcare professional. 

When to talk to a healthcare provider about metronidazole interactions

This article is not a complete list of metronidazole interactions. Be mindful of the risk of additive side effects and direct drug interactions, which may occur when metronidazole is used in combination with prescription and over-the-counter medications or supplements. Communicate directly with a healthcare professional anytime you require metronidazole so that a comprehensive review of interactions—of both medications, diet, and conditions—can occur to ensure a proper monitoring plan is put in place.