Folic acid, or vitamin B9, is an essential nutrient that is needed for cell growth and division, DNA formation, and red blood cell production. Certain medications can interfere with folate absorption and metabolism, which can lead to folate deficiency. Knowing which medications are the biggest culprits of folate deficiency can help prevent complications like anemia, fatigue, or neurological symptoms. We will discuss some of the most common medications that cause folate deficiency, as well as supplementation and monitoring suggestions.
Methotrexate
Methotrexate is the most well-known medication that causes folate deficiency. When used as a cancer agent, it inhibits the enzyme dihydrofolate reductase that converts dihydrofolate into tetrahydrofolate, which is the active form. It has a completely different mechanism of action when used in rheumatoid arthritis, however it can still cause hepatotoxicity and other significant GI side effects. These unwanted effects can be prevented and/or treated with folate supplementation. It is more common to see folic acid 1mg daily during treatment with weekly methotrexate. Alternatively, 5-10mg once weekly, 48 hours before the methotrexate dose may be utilized (as seen in European guidelines). There is conflicting data on whether taking folic acid the same day as methotrexate will decrease its efficacy, so in some cases, clinicians will have patients skip folic acid just to be cautious. There is no recommendation in the guidelines on checking a folate level during treatment, although the provider may check at baseline, annually, and if there is clinical suspicion of a folate deficiency.
Sulfasalazine
Sulfasalazine is another medication that is used in rheumatoid arthritis and ulcerative colitis. It is a competitive inhibitor of different intestinal folate transport enzymes and inhibits hepatic metabolism, which may lead to folate deficiency. However, the data is still mixed on whether or not daily supplementation is necessary for patients. Some data suggests folate supplementation can help decrease the risk of developing colon cancer in patients with ulcerative colitis. Doses between 400-800mcg daily or increasing dietary intake can be used to help with folate deficiency. In women who are planning to become pregnant or are pregnant, it is recommended to take 5mg daily to help prevent or treat folate deficiency. Currently, there is no recommended routine monitoring of folate levels during treatment, but similar to methotrexate, a clinician may check at baseline, annually, and if there is suspicion of a folate deficiency.
Trimethoprim
Trimethoprim is an antibiotic that inhibits the enzyme dihydrofolate reductase in bacteria, which causes DNA synthesis disruption and bacterial cell death. It is used mostly in combination with sulfamethoxazole to treat bacterial infections. It can also inhibit dihydrofolate reductase in human cells, which can lead to folate deficiency, most notably when used for prophylactic treatment (common board exam nugget). It may be beneficial to supplement with 400-800mcg daily or increase dietary intake if using prophylactic sulfamethoxazole/trimethoprim, although the data is limited on supporting additional supplementation. In patients being treated with short-term trimethoprim, deficiency is unlikely.
Carbamazepine
Carbamazepine is an antiseizure medication that reduces folate levels through increased hepatic metabolism of folic acid and, to a lesser extent, through decreased intestinal absorption. It may be beneficial to patients who are taking carbamazepine long-term to take 400-800mcg daily or increase dietary intake. In general, folic acid is considered safe with few interactions, so there is little harm in taking it as a precaution. There are also no guideline recommendations on routinely checking a folate level; it may be checked if deemed necessary by the provider.
This article was written by Kaylee Poppen, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP
0 Comments