Folate (Folic Acid) : Interactions, Part 2

by MedlinePlus

(Page 4 of 4)

Metformin (Glucophage®): Reduced vitamin B12 and, to a lesser extent, folate levels occur in some people with diabetes and can contribute to hyperhomocysteinemia, which adds to their already increased risk of cardiovascular disease. The reduced folate levels seen in diabetics have been linked to metformin use in some cases, possibly as a result of reduced folic acid absorption. Symptomatic folate deficiency is unlikely to occur with metformin, but people with diabetes may need folic acid supplements to reduce hyperhomocysteinemia. Diabetes should be treated by a qualified healthcare provider.

Methotrexate: Methotrexate is a folate antagonist which prevents conversion of folic acid to its active form, and lowers plasma and red blood cell folate levels. Folic acid supplements (1 to 5mg per day) reduce side effects without reducing the efficacy of methotrexate in treating rheumatoid arthritis or psoriasis. Patients taking methotrexate for these conditions may be advised to take a folic acid supplement (1mg per day is probably sufficient), especially if their dietary folate intake is low and they are experiencing the side effects. People who have experienced side effects may need to continue taking folic acid for the duration of methotrexate therapy. Patients being treated with methotrexate for cancer should avoid folic acid supplements, unless recommended by their oncologist. Folic acid could interfere with the anticancer effects of methotrexate. There is some evidence that folic acid supplements reduce the effectiveness of methotrexate in the treatment of acute lymphoblastic leukemia, and theoretically they could reduce methotrexate effectiveness in the treatment of other cancers.

Methylprednisolone: Reduced serum folate levels have been noted in people with multiple sclerosis (MS) after treatment with methylprednisolone sodium succinate (Solu-Medrol®) 1 gram daily for 10 days. Clinical significance is unknown.

Nonsteroidal anti-inflammatory drugs (NSAIDs): Folate-dependent enzymes have been inhibited in laboratory experiments by certain NSAIDs (ibuprofen (Advil®, Motrin®, Nuprin®), naproxen (Anaprox®, Aleve®), indomethacin (Indocin®), and sulindac (Clinoril®). Clinical significance is unknown.

Pancreatic enzymes, pancrelipase, pancreatin: Reduced folate levels can occur in some people taking pancreatic extracts (such as Pancrease®, Cotazym®, Viokase®, Creon®, Ultrase®) possibly due to reduced absorption. Folate levels should be checked in patients taking pancreatic enzymes for prolonged periods.

Pentamidine: Pentamidine is a prescription drug used to treat PCP pneumonia. Decreased serum folate levels and megaloblastic bone marrow changes can occur rarely with prolonged intravenous pentamidine (Pentacarinat®, Pentam 300®) therapy. Most patients are unlikely to need folic acid supplements.

Phenobarbital (Luminal®), Primidone (Mysoline®): These drugs can reduce serum folate levels, occasionally leading to megaloblastic anemia (usually in people with low dietary folate intake), and possibly contributing to neurological side effects, mental changes, and cerebral atrophy. Pregnant women taking phenobarbital or primidone may be especially at risk from reduced folate levels. Folic acid can have direct convulsant activity in some people, reversing the effects of phenobarbital or primadone and worsening seizure control. Folic acid may increase metabolism of phenobarbital. Seizure activity should be monitored closely.

Phenytoin (Dilantin®): Folic acid, in doses of 1mg per day or more, can reduce serum levels of phenytoin in some patients. Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, serum phenytoin levels should be monitored closely. If phenytoin and folic acid are started at the same time and continued together, adverse changes in phenytoin levels can be avoided. Phenytoin can also reduce serum folate levels, occasionally leading to megaloblastic anemia, and possibly contributing to neurological side effects and mental status changes. Folic acid supplements may reduce phenytoin side effects. Pregnant women taking phenytoin may be especially at risk from reduced folate levels.

Proton pump inhibitors (PPIs): PPIs are prescription drugs used for reflux disease and ulcers. They include esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®), pantoprazole (Protonix®), and rabeprazole (Aciphex®). Folic acid absorption in the small intestine is optimal at pH 5.5 to 6. The increased pH associated with use of PPIs could theoretically reduce folic acid absorption. However, preliminary data suggests use of PPIs for several years does not cause folate deficiency. Maintenance of the recommended dietary intake of folic acid is recommended.

Pyrimethamine (Daraprim®): Pyrimethamine is a folate antagonist that prevents conversion of folic acid to its active form. At high doses used to treat toxoplasmosis (50 to 75mg per day), megaloblastic anemia may occur due to deficiency of active folate, and it is recommended that all patients receive folinic acid to prevent this adverse effect. Folinic acid does not antagonize the therapeutic effect of pyrimethamine. Patients taking pyrimethamine should avoid folic acid supplements since they can antagonize the therapeutic effects against Toxoplasmosis and Pneumocystis carinii pneumonia. Patients taking lower doses of pyrimethamine for prolonged periods should maintain the recommended dietary folate intake and monitored for folate deficiency. Folic acid does not antagonize the effects of pyrimethamine in the treatment of malaria. Folinic acid may be used as an alternative to folic acid when indicated. Pyrimethamine also reduces serum folate levels.

Seizure medications:Folic acid, in doses of 1mg per day or more, can reduce serum levels of the anti-seizure medication phenytoin in some patients. Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, serum phenytoin levels should be monitored closely. If phenytoin and folic acid are started at the same time and continued together, adverse changes in phenytoin levels can be avoided. Phenytoin can also reduce serum folate levels, occasionally leading to megaloblastic anemia, and possibly contributing to neurological side effects and mental status changes. Folic acid supplements may reduce phenytoin side effects. Pregnant women taking phenytoin may be especially at risk from reduced folate levels. Valproic acid, sodium valproate, and divalproex sodium (Depakene®, Depakote®)may reduce folate levels in some people, but symptomatic deficiency has not been reported. Pregnant women taking valproate may be especially at risk from reduced folate levels. However, folic acid supplements have worsened seizure control in some people with epilepsy. The drug gabapentin may alter the folic acid levels in the body. Fosphenytoin andprimidone may decrease serum folate concentrations and cause deficiency.

Sulfasalazine (Azulfidine®): Sulfasalazine inhibits absorption and metabolism of folic acid. Long-term sulfasalazine therapy can cause reduce serum and red blood cell folate levels and cause hyperhomocysteinemia, which is a risk factor for cardiovascular disease. Occasionally, megaloblastic anemia develops, usually with higher doses of sulfasalazine (greater than 2 grams per day), and when there are other factors contributing to folate deficiency. Reduced folate levels are often found in people with severe chronic ulcerative colitis, due both to the disease and sulfasalazine therapy. Reduced folate levels might contribute to the increased risk of colon cancer and its precursor, colonic mucosal dysplasia, seen in people with ulcerative colitis. Preliminary evidence suggests that folate supplements can reduce this risk. Patients on chronic sulfasalazine therapy may be advised to increase their dietary folate intake, and to take a supplement if they have any other condition which could also contribute to deficiency.

Triamterene (Dyrenium®): Triamterene is a folate antagonist that prevents conversion of folic acid to its active form, and also reduces folate absorption. Reduced serum and red blood cell folate levels have occurred, and occasional cases of megaloblastic anemia, usually in people with other conditions contributing to folate deficiency. Patients on chronic triamterene therapy should to maintain the recommended dietary folate intake, or take a supplement if advised by their physician.

Trimethoprim (Trimpex®): Trimethoprim, including trimethoprim contained in the combination antibiotic trimethoprim/sulfamethoxazole (TMP/SMX, co-trimoxazole, Bactrim®, Septra®), inhibits the enzyme involved in conversion of folic acid to its active form. If megaloblastic anemia occurs, trimethoprim should be stopped and treatment with folinic acid (an active form of folic acid) should be given. This can be followed by treatment with folic acid if necessary, once the activating enzymes have had time to recover from the effects of trimethoprim. Whether folic acid or folinic acid can be given concurrently with trimethoprim to prevent megaloblastic anemia is controversial. The practice may not be effective, especially in people with AIDS in whom immunologic reactions, as well as folate deficiency is of concern. There is a general belief that folic/folinic acid supplements do not interfere with the therapeutic effects of trimethoprim. However, this view has been challenged, and failure of trimethoprim therapy has occurred rarely when folinic acid is given concurrently. Patients taking low doses of trimethoprim (100 to 200mg per day) for treatment or prevention of urinary tract infections are unlikely to need folate supplements. Patients taking high doses of trimethoprim (20mg/kg per day) should maintain good dietary folate intake, and to avoid folate supplements unless prescribed by their physician.

Interactions with Herbs and Dietary Supplements

Estrogenic agents: Reduced serum and red blood cell folate levels can occur in some women taking conjugated estrogens (Premarin®) or oral contraceptives, but this is unlikely in women with adequate dietary folate intake. Theoretically this interaction may occur with estrogenic herbs and supplements as well. Possible examples include alfalfa, black cohosh, bloodroot, burdock, hops, kudzu, licorice, pomegranate, red clover, soy, thyme, white horehound, and yucca.

Vitamin B12: Taking folic acid along with vitamin B12 may increase the risk of vitamin B12 deficiency. Caution is advised when taking both of these vitamins together.

Zinc: Normal supplemental doses of folic acid are unlikely to have an adverse effect on zinc balance in people with adequate dietary zinc intake. The data on the effects of supplemental folic acid on dietary zinc absorption are conflicting.

Interactions with Food

The absorption of supplemental folic acid is reduced slightly when taken with food.

Interactions with Labs

Liver function tests:Abnormal liver function tests have been reported.

Homocysteine level:Decreased homocysteine levels have been reported.

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