Montelukast has relatively few strict drug interactions compared to many other medications. The FDA prescribing information confirms that no dose adjustment is needed when taking it alongside most common drug classes, including blood thinners, anti-inflammatory drugs, oral contraceptives, thyroid hormones, and benzodiazepines. That said, a few specific medications, substances, and health considerations are worth knowing about.
Gemfibrozil and Other CYP2C8 Inhibitors
The most significant drug interaction involves gemfibrozil, a cholesterol-lowering medication. Your body breaks down montelukast primarily through a liver enzyme called CYP2C8, which handles about 72% of its metabolism. Gemfibrozil strongly blocks this enzyme, and in clinical studies, taking the two together increased montelukast blood levels by 4.5 times the normal amount. That kind of spike raises the likelihood of side effects, particularly the neuropsychiatric symptoms montelukast is already known for.
Other medications that inhibit the same liver enzyme can have a similar, though usually less dramatic, effect. The antibiotic trimethoprim is one example. If you take any medication that affects CYP2C8, your prescriber should be aware you’re also on montelukast.
Alcohol and Substances Affecting Mood
Montelukast carries a boxed warning from the FDA for serious mental health side effects. These include agitation, depression, anxiety, hallucinations, trouble sleeping, confusion, memory problems, and suicidal thoughts. These effects can appear in both adults and children, sometimes within days of starting the medication.
While the FDA warning does not name specific substances that worsen these risks, it notes that many documented cases of severe psychiatric events involved people already using other medications or having conditions linked to behavioral disturbances. Alcohol, recreational drugs, and other substances that affect mood or sleep could plausibly compound the risk. If you notice any behavioral or mood changes while on montelukast, stop taking it and talk to your prescriber right away.
Phenobarbital and CYP Enzyme Inducers
On the opposite end of the spectrum, certain drugs can make montelukast less effective rather than more toxic. Phenobarbital and other medications that rev up your liver enzymes (known as enzyme inducers) speed up the breakdown of montelukast in your body. The FDA label acknowledges this interaction but states that no dose adjustment is formally recommended. Still, if you’re taking a strong enzyme inducer and your asthma or allergy symptoms aren’t well controlled, this interaction could be a factor worth discussing.
What About NSAIDs and Aspirin?
This is a common concern, and the answer is reassuring: montelukast does not have a harmful interaction with NSAIDs like ibuprofen or with aspirin. The FDA prescribing information explicitly states that no dose adjustment is needed when the two are taken together.
In fact, for people with aspirin-sensitive asthma, montelukast actually provides partial protection against aspirin-triggered reactions. A study in the European Respiratory Journal found that a standard 10-mg dose partially blocked the airway and nasal symptoms triggered by aspirin challenge in these patients, though it didn’t eliminate the reaction entirely. So montelukast is not a replacement for avoiding aspirin if you’re sensitive to it, but it works alongside that caution rather than against it.
Food and Timing Considerations
The standard 10-mg tablet for adults and teens can be taken with or without food. Its absorption isn’t meaningfully affected by meals. The chewable tablet for younger children is slightly different: bioavailability drops from 73% on an empty stomach to 63% with a morning meal, a modest difference that doesn’t typically require any special planning.
For the oral granules used in toddlers and young children, a high-fat meal doesn’t change the total amount of drug absorbed, but it does slow down how quickly levels peak, pushing peak absorption from about 2.3 hours to over 6 hours. This matters less for a medication taken daily for ongoing control, but it’s worth noting if timing feels inconsistent. The granules can be mixed into applesauce without any effect on absorption.
Medications Confirmed Safe to Combine
The FDA label specifically tested and cleared montelukast for use alongside a long list of common medications:
- Theophylline (for asthma)
- Prednisone and prednisolone (oral steroids)
- Warfarin (blood thinner)
- Digoxin (heart medication)
- Oral contraceptives
- Thyroid hormones
- Benzodiazepines (anxiety medications)
- NSAIDs (ibuprofen, naproxen, etc.)
None of these require a dose change when taken with montelukast. This is part of why montelukast is considered a relatively easy medication to fit into a regimen that already includes other drugs.
Liver Disease and Montelukast
Because montelukast is processed almost entirely by the liver, people with significant liver disease may clear the drug more slowly. The FDA label includes pharmacokinetic data for patients with mild to moderate liver impairment, and while formal dose adjustments aren’t required for that group, severe liver disease is a different situation. If your liver function is compromised, your prescriber needs to weigh whether the drug’s slower clearance could lead to higher-than-intended blood levels and increased side effect risk.