{"id":626294,"date":"2024-01-23T14:02:19","date_gmt":"2024-01-23T19:02:19","guid":{"rendered":"https:\/\/www.singlecare.com\/blog\/?p=626294"},"modified":"2024-10-25T10:13:16","modified_gmt":"2024-10-25T14:13:16","slug":"methotrexate-interactions","status":"publish","type":"post","link":"https:\/\/www.singlecare.com\/blog\/methotrexate-interactions\/","title":{"rendered":"Methotrexate interactions to avoid"},"content":{"rendered":"

Methotrexate<\/span><\/a>, known by the brand name <\/span>Trexall<\/span><\/a>, is recognized within a few pharmacologic categories, given its broad use in many medical conditions. It is known as an antineoplastic (chemotherapy) agent, a disease-modifying antirheumatic drug (<\/span>DMARD<\/span>), and an <\/span>immunosuppressant<\/span> agent. <\/span>Methotrexate<\/span> is available in an oral and injectable formulation, is indicated for the <\/span>treatment of <\/span>rheumatoid arthritis<\/span><\/a>, and is a major chemotherapeutic choice for various <\/span>types of cancer<\/span>. Methotrexate is also employed in many <\/span>autoimmune diseases<\/span>, such as <\/span>psoriasis<\/span><\/a>, systemic lupus erythematosus <\/span>(SLE)<\/span><\/a>, inflammatory bowel disease (IBD), and others. <\/span>Methotrexate<\/span> has <\/span>distinct mechanisms of action <\/span><\/a>for its use as chemotherapy versus <\/span>immunosuppression<\/span> in <\/span>autoimmune diseases<\/span>. Certain antibiotics, <\/span>proton pump inhibitors<\/span>, <\/span>non-steroidal anti-inflammatory drugs<\/span> (<\/span>NSAIDs<\/span>), antiepileptics, diuretics, and other medications that can cause kidney problems, like cyclosporine or cisplatin, can result in problems when taken with methotrexate. Given its mechanism of action, <\/span>methotrexate<\/span> should also not be administered with <\/span>folate<\/span> supplementation<\/span>. It’s important to be aware of <\/span>methotrexate<\/span> interactions as other drugs can impact its effectiveness, potentially leading to toxicity and severe side effects.<\/span><\/p>\n

Methotrexate<\/span> drug interactions<\/span><\/h2>\n

Methotrexate<\/span> can interact with any medication, impacting its free drug concentration in the blood or its elimination. Many serious interactions occur with higher <\/span>doses of methotrexate<\/span> employed for its antineoplastic mechanism of action. They can be serious if not identified ahead of time, resulting in permanent <\/span>renal<\/span> damage. Many commonly used drug classes cause interactions with <\/span>methotrexate<\/span>, including certain, (PPIs), and <\/span>non-steroidal anti-inflammatory drugs<\/span> (<\/span>NSAIDs<\/span>). Other less commonly prescribed and used drugs and supplements can potentially interact with methotrexate. Therefore, it’s critical to be aware of these possible drug interactions to avoid the development of unnecessary methotrexate toxicity. <\/span><\/p>\n

Antibiotics<\/span><\/h3>\n

High doses of methotrexate<\/span> administered with certain antibiotics may increase the serum concentrations of <\/span>methotrexate<\/span>. Lower <\/span>doses of methotrexate<\/span>, such as those generally implemented for <\/span>rheumatologic<\/span> conditions, carry less of a risk than higher <\/span>doses of methotrexate<\/span> employed for its antineoplastic effects. <\/span><\/p>\n

The <\/span>penicillin<\/span><\/a> and <\/span>tetracycline<\/span> drug class specifically carries this risk. In addition to <\/span>penicillin<\/span> itself, other interacting <\/span>penicillin<\/span> class antibiotics, including <\/span>amoxicillin<\/span><\/a>, nafcillin, oxacillin, and <\/span>piperacillin<\/span><\/a>, are known to interact with <\/span>methotrexate<\/span>. The mechanism of this interaction is not fully determined, but it is presumed that <\/span>penicillins<\/span> compete with <\/span>methotrexate<\/span> for excretion sites in <\/span>renal<\/span> tubules<\/span><\/a>. This impacts <\/span>methotrexate<\/span> elimination and ultimately increases the risk of <\/span>methotrexate toxicity<\/span>. The extent of this interaction is presumed to be increased with increased doses of either <\/span>penicillin<\/span> antibiotics or <\/span>methotrexate<\/span>. <\/span><\/p>\n

Tetracycline<\/span><\/a> antibiotics, including <\/span>doxycycline<\/span><\/a>, minocycline, and <\/span>tetracycline<\/span><\/a> itself, may increase the serum concentrations of <\/span>methotrexate<\/span>, but this is likely not a clinical issue when using antirheumatic <\/span>doses of methotrexate<\/span>. If used concomitantly, individuals should be monitored for the toxic <\/span>effects of methotrexate<\/span>, especially when either a <\/span>penicillin<\/span> or <\/span>tetracycline<\/span> antibiotic is initiated or the dose increased. In the setting of <\/span>high-dose methotrexate<\/span> with antibiotics in either of these drug classes, alternative agents should be used for treatment to avoid any possibility of <\/span>toxicity<\/span>. <\/span><\/p>\n

In addition to these 2 classes of antibiotics, significant drug-<\/span>drug interactions<\/span> exist between <\/span>methotrexate<\/span> and <\/span>trimethoprim<\/span>–<\/span>sulfamethoxazole<\/span>. Unlike the interaction between <\/span>methotrexate<\/span> and <\/span>penicillin<\/span> antibiotics, which is likely to only be clinically significant with higher <\/span>doses of methotrexate<\/span>, many case reports describe the development of <\/span>methotrexate toxicity<\/span> (including severe <\/span>bone marrow<\/span> suppression, at times <\/span>fatal<\/span><\/a>) in patients taking even low doses of weekly <\/span>methotrexate<\/span> for autoimmune conditions with <\/span>trimethoprim<\/span>–<\/span>sulfamethoxazole<\/span><\/a>. Given the significance of this interaction, any individual to be started on <\/span>methotrexate<\/span> should avoid concomitantly receiving <\/span>trimethoprim<\/span>–<\/span>sulfamethoxazole<\/span>. If taken together, contact a <\/span>healthcare provider<\/span> immediately to increase monitoring of <\/span>methotrexate<\/span> serum levels and signs or symptoms of <\/span>toxicity<\/span>. An alternative antibiotic should replace <\/span>trimethoprim<\/span>–<\/span>sulfamethoxazole<\/span>. <\/span><\/p>\n

Non-steroidal anti-inflammatory drugs<\/span> (<\/span>NSAIDs<\/span>)<\/span><\/h3>\n

Coadministration of <\/span>methotrexate<\/span> with <\/span>NSAIDs<\/span><\/a>, which include <\/span>diclofenac<\/span>, <\/span>ibuprofen<\/span>, ketorolac, meloxicam, and <\/span>naproxen<\/span>, may increase the blood levels of <\/span>methotrexate<\/span>. <\/span>NSAIDs<\/span> may decrease <\/span>renal<\/span> elimination of <\/span>methotrexate<\/span> by <\/span>inhibiting <\/span>renal<\/span> transport proteins <\/span><\/a>or by decreasing blood perfusion of the kidneys. The severity of this interaction is likely greater with higher <\/span>doses of methotrexate<\/span>, such that the coadministration of <\/span>NSAIDs<\/span> and higher <\/span>doses of methotrexate<\/span> should be avoided. <\/span>Ibuprofen<\/span><\/a> may decrease <\/span>methotrexate<\/span> clearance by up to 40%. While the same level of evidence doesn’t exist across the board for <\/span>NSAIDs<\/span>, given their similar properties, they are presumed to respond similarly. <\/span>Caution should still be exercised <\/span><\/a>during the coadministration of <\/span>NSAIDs<\/span> and lower <\/span>doses of methotrexate<\/span>, even in people who have received <\/span>methotrexate<\/span> long-term. Some studies have demonstrated increased <\/span>methotrexate<\/span> levels within one day of coadministration, so avoidance is the safest bet. <\/span><\/p>\n

Proton pump inhibitors<\/span><\/h3>\n

Methotrexate<\/span> consumed with <\/span>proton pump inhibitors<\/span><\/a> (PPIs) may also increase the blood concentration of <\/span>methotrexate<\/span>. Medications within the class of PPIs include <\/span>omeprazole<\/span> and pantoprazole, among others. The mechanism of this interaction isn’t entirely determined but is likely due to inhibition of <\/span>methotrexate<\/span> elimination due to PPI inhibition of certain activities within kidneys. In a study including 79 patients, PPI consumption was associated with <\/span>delayed <\/span>methotrexate<\/span> elimination<\/span><\/a>. Pantoprazole <\/span>prescribing information<\/span><\/a> recommends temporarily holding the PPI therapy for patients receiving <\/span>high-dose methotrexate<\/span> due to the interaction, which may result in <\/span>methotrexate toxicity<\/span>. The clinical significance of this interaction is highest with antineoplastic <\/span>doses of methotrexate<\/span>, but if a patient on antirheumatic <\/span>doses of methotrexate<\/span> can receive an alternative class to PPIs, it is the safest option to avoid any risk of <\/span>methotrexate toxicity<\/span> and delayed <\/span>methotrexate<\/span> elimination. <\/span><\/p>\n

Anticonvulsants<\/span><\/h3>\n

Anticonvulsants<\/span><\/a> are less commonly prescribed medications than the antibiotics, <\/span>NSAIDs<\/span>, and PPIs already described to interact with <\/span>methotrexate<\/span>, but may also interact with <\/span>methotrexate<\/span> and cause devastating effects. <\/span><\/p>\n

Levetiracetam<\/span><\/a> may increase the serum concentrations of <\/span>methotrexate<\/span> and cause <\/span>delayed <\/span>methotrexate<\/span> elimination<\/span><\/a>, presumably through competing with <\/span>methotrexate<\/span> for active tubular excretion in the kidney. Individuals receiving concomitant therapy should be evaluated for increased <\/span>methotrexate<\/span> blood concentrations and associated <\/span>toxicities<\/span>.<\/span><\/p>\n

Unlike the result of all the interactions discussed so far, coadministration of <\/span>methotrexate<\/span> and <\/span>phenytoin<\/span><\/a> may increase the serum concentrations of <\/span>methotrexate<\/span> but may also decrease the serum concentrations of <\/span>phenytoin, a<\/span> dual interaction. The mechanism for these interactions is not fully established and is likely the result of multiple scenarios. Individuals receiving this combination of medications must be closely monitored through therapeutic drug monitoring of both <\/span>phenytoin<\/span> and <\/span>methotrexate<\/span> serum concentrations. <\/span>Methotrexate<\/span> serum concentrations should be monitored more closely while receiving <\/span>phenytoin<\/span> and the onset of symptoms associated with <\/span>methotrexate toxicity<\/span>. <\/span><\/p>\n

The interaction between <\/span>valproic acid<\/span><\/a> and <\/span>methotrexate<\/span> is also unique in that the interaction is a possible <\/span>decrease in the serum concentration<\/span><\/a> of valproic acid, such that doses may need to be increased to avoid the increased frequency of seizures or other symptoms managed by the valproic acid. <\/span>Methotrexate<\/span> and valproic acid likely compete for protein binding, leading to valproic acid displacement and increased metabolism.<\/span><\/p>\n

Probenecid<\/span><\/h3>\n

Probenecid<\/span><\/a> is a <\/span>uricosuric agent<\/span><\/a>, a drug used to control elevated uric acid levels in patients with <\/span>gout<\/span><\/a>. <\/span>Newer drug classes and agents have largely replaced probenecid<\/span> for this indication. However, given its unique mechanism of action, <\/span>probenecid<\/span> is still occasionally used for its ability to serve as a <\/span>pharmacokinetic<\/span> enhancer of <\/span>penicillin<\/span> in the management of sexually transmitted infections by blocking their route of elimination. <\/span>Probenecid<\/span> can also serve as a <\/span>renal<\/span> protective agent in patients requiring treatment with an antiviral known as cidofovir. While few people receive <\/span>probenecid<\/span>, it can significantly interact with <\/span>methotrexate,<\/span> either in <\/span>high<\/span><\/a> or <\/span>low<\/span><\/a> doses, by <\/span>probenecid<\/span> inhibition of <\/span>renal<\/span> tubular secretion of <\/span>methotrexate<\/span>, allowing <\/span>methotrexate<\/span> to accumulate. Prescribing information for both <\/span>probenecid<\/span> and <\/span>methotrexate<\/span> mentions the risk of developing severe adverse reactions when these medications are taken concomitantly. If the <\/span>use of methotrexate<\/span> is required, then patients should be monitored closely for adverse reactions related to increased <\/span>methotrexate<\/span> blood concentrations with a possible <\/span>methotrexate<\/span> dose reduction. <\/span><\/p>\n

Methotrexate<\/span> food interactions<\/span><\/h2>\n

The use of <\/span>high-dose methotrexate<\/span> interacts with <\/span>cola-containing drinks<\/span><\/a>, with an observed increase in serum concentrations of <\/span>methotrexate<\/span>. Cola beverages contain high amounts of inorganic acids, which lower the urinary pH and possibly delay <\/span>methotrexate<\/span> elimination. Patients requiring antineoplastic <\/span>doses of methotrexate<\/span> should avoid cola-containing drinks during and for several days following <\/span>methotrexate<\/span> infusions, ideally until adequate <\/span>methotrexate<\/span> elimination is confirmed with routine therapeutic drug monitoring. <\/span>Licorice<\/span><\/a> may also increase <\/span>methotrexate<\/span> blood levels due to delayed <\/span>methotrexate<\/span> elimination by inhibiting specific transporters responsible for eliminating <\/span>methotrexate<\/span>. Finally, <\/span>methotrexate<\/span> may suppress the <\/span>immune system<\/span>, so avoiding unwashed fruits and vegetables or unpasteurized milk and soft cheeses is best.<\/span><\/p>\n

Other <\/span>methotrexate<\/span> interactions<\/span><\/h2>\n

Other types of <\/span>methotrexate<\/span> interactions to be aware of include those that may enhance the <\/span>toxicities<\/span> associated with <\/span>methotrexate<\/span>. <\/span><\/p>\n

Methotrexate<\/span> and alcohol <\/span><\/h3>\n

Alcohol may enhance the hepatotoxic <\/span>effects of methotrexate<\/span>, so alcohol consumption should be limited throughout the course of <\/span>methotrexate<\/span>. In patients with autoimmune conditions being evaluated for treatment with <\/span>methotrexate<\/span>, it is considered contraindicated in those individuals with <\/span>alcoholism or alcoholic <\/span>liver disease<\/span><\/a>. <\/span><\/p>\n

How to minimize <\/span>methotrexate<\/span> interactions<\/span><\/h2>\n

Always carry a complete list of medications, including <\/span>supplements<\/span>, on your person. Any time you receive <\/span>medical advice<\/span> with new therapy recommendations, provide this list so that a thorough review and <\/span>drug information<\/span> assessment can be performed. This can minimize the risk of <\/span>drug interactions<\/span>. <\/span><\/p>\n

When to talk to a <\/span>healthcare provider<\/span> about <\/span>methotrexate<\/span> interactions<\/span><\/h2>\n

This article is not a complete list of <\/span>methotrexate<\/span> interactions. Discuss any new signs or symptoms, no matter how mild, with your healthcare professional when starting a new medication. Be mindful of the risk of additive <\/span>side effects<\/span> and direct <\/span>drug interactions,<\/span> which may occur when <\/span>methotrexate<\/span> is used in combination with prescription and <\/span>over-the-counter<\/span> medications or <\/span>supplements<\/span>. Communicate directly with a <\/span>healthcare professional<\/span> anytime you require <\/span>methotrexate<\/span> so that a comprehensive review of interactions with medications, diet, and conditions can occur to ensure a proper monitoring plan is put in place. <\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

Methotrexate, known by the brand name Trexall, is recognized within a few pharmacologic categories, given its broad use in many medical conditions. It is known as an antineoplastic (chemotherapy) agent, a disease-modifying antirheumatic drug (DMARD), and an immunosuppressant agent. Methotrexate is available in an oral and injectable formulation, is indicated for the treatment of rheumatoid […]<\/p>\n","protected":false},"author":133,"featured_media":626295,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[4589],"tags":[12164,794,814],"coauthors":[10869],"class_list":["post-626294","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-drug-info","tag-arthritis","tag-cancer","tag-drug-interactions","wpautop"],"acf":[],"yoast_head":"\nMethotrexate interactions to avoid | SingleCare<\/title>\n<meta name=\"description\" content=\"Methotrexate (Trexall) interacts with antibiotics, PPIs, NSAIDs, cola, and licorice. 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