Drug Interactions with Vitamins and Minerals

Maria Marzella Sulli, PharmD

Associate Clinical Professor
St. John’s University College of Pharmacy and Allied Health Professions,
Queens, New York

Danielle C. Ezzo, PharmD, BCPS

Assistant Clinical Professor
St. John’s University College of Pharmacy and Allied Health Professions,
Queens, New York
US Pharm. 2007;1:42-55.

Vitamins and minerals serve crucial functions in almost all bodily processes and must
be obtained from foods or supplements, as our bodies are unable to make them. According to
results of the National Health and Nutrition Examination Survey, 52% of adults take dietary
supplements.1Supplement use is typically a safe and effective method of maintaining a
healthy body; however, supplements have the potential to interact with prescribed
medications. In this article, common drug interactions with vitamins and minerals are
discussed, along with suggestions on how the pharmacist should manage these interactions.

It is important for pharmacists to be able to identify patients who are most at risk. Risk
factors for poor outcomes from drug interactions include use of multiple medications and/or
supplements, older age, inadequate kidney or liver function, and the use of medications with
narrow therapeutic indexes. Patients with these risk factors should be targeted for
interventions to prevent drug interactions with vitamins and minerals.

When managing interactions between medications and vitamin/mineral supplements,

the pharmacist has several factors to keep in mind. First, he or she needs to determine the
need for the supplement during the time the medication is to be taken. For a short course of
medication, it is usually possible to discontinue the supplement until the therapy is completed.
Second, the pharmacist should identify alternatives. For example, if the interacting substance
comes from an antacid that the patient needs to treat symptoms of gastroesophageal reflux
disease, an alternative such as an H2-blocker or proton pump inhibitor can be used during the
course of the medication. If the affected medication is to be taken chronically, and the
supplement is deemed necessary, the pharmacist should work with the patient and the
prescriber to suggest alternatives that would limit exposure to potentially dangerous drug
interactions.

Vitamins and Drug Interactions

Vitamin A: Vitamin A is a fat-soluble vitamin found in everyday foods, including

liver, yellow-orange fruits and vegetables such as carrots, margarine, milk, and dark green,
leafy vegetables such as spinach. It is not commonly available as a supplement on its own;
however, it can be found as a component of multivitamins and combination supplements
targeted towards improving skin, hair, and nails. Vitamin A plays an important role in vision,
bone growth, cell differentiation, and the immune system. Vitamin A deficiency often leads
to problems with eyesight, a situation less common in the United States than in
underdeveloped countries where nutrition may be poor. Some conditions such as celiac
disease, Crohn's disease, and pancreatic disorders may lead to malabsorption of vitamin A
from the diet.

Interactions with vitamin A become a concern with the use of products classified as
retinoids--compounds that are chemically similar to vitamin A. Retinoids such as isotretinoin
(Accutane) and acitretin (Soriatane) are indicated for the treatment of acne and psoriasis,
respectively. When retinoid products are prescribed, there is concern of vitamin A
toxicity.2Pharmacists should alert patients who are taking retinoid products to the importance
of avoiding excess vitamin A. They should also educate patients about the signs and
symptoms of vitamin A toxicity, such as nausea, vomiting, dizziness, blurred vision, and poor
musclecoordination.

Vitamin B6 (Pyridoxine): Vitamin B6, or pyridoxine, is a water-soluble vitamin used

to treat deficiencies in vitamin B6and some types of anemia. Foods rich in pyridoxine include
meats, whole grains, and certain fruits and vegetables. Pyridoxine has been shown to decrease
the effects of both phenytoin and levodopa. However, this effect is not seen when levodopa is
prescribed in combination with carbidopa, which prevents the interaction from occurring. In
the rare instance that patients are taking levodopa in absence of carbidopa, pharmacists
should advise their patients to avoid any products containing pyridoxine, because even
smaller doses, such as 10 to 25 mg of pyridoxine, may be enough to inhibit
levodopa.3 Pharmacists should strongly encourage the switch to a levodopa/carbidopa
combination product if a patient is not already taking this combination therapy.

There is limited evidence that high doses of pyridoxine reduce phenytoin serum
concentrations, thereby reducing the efficacy of phenytoin. One study of patients with seizure
disorders found an association between pyridoxine 200 mg/day and reductions in phenytoin
concentration of nearly 50%.4 Effects of pyridoxine doses lower than 200 mg/day on
phenytoin serum concentration have not been established; however, lower doses can be
considered if someone taking a multivitamin presents with low phenytoin serum
concentrations. In these instances, it may be necessary to discontinue or lower the dosage of
the multivitamin or to increase the dosage of phenytoin.

Vitamin E: Vitamin E is a fat-soluble vitamin that is used in an array of ailments,

including vitamin E deficiency, atherosclerosis, Alzheimer's disease, and various cancers. It
is also a common supplement taken by patients with cardiovascular disease. Case reports
have documented an increased risk of bleeding in patients taking vitamin E and warfarin
concomitantly. This adverse effect is more likely to occur with larger doses of vitamin E
(>800 IU) rather than smaller doses found in multivitamins.5,6 Therefore, pharmacists should
advise patients taking warfarin to take a multivitamin for their daily source of vitamin E
rather than a supplement containing only vitamin E.

There is controversy over vitamin E and other antioxidants with respect to

chemotherapy. A theoretical interaction has been proposed whereby antioxidants interfere
with the oxidative mechanism of the chemotherapeutic agent, thereby reducing its
effectiveness. The clinical implications of this interaction is still unknown; but it might be
worthwhile, until more is known, to counsel patients about avoiding antioxidant supplements
while undergoing chemotherapy treatments that rely on this mechanism. However, it is
important to note that antioxidants are sometimes used to prevent or lessen the toxic effects
of specific agents. Patients on chemotherapy should be counseled not to supplement on their
own and to inform their oncologist of all dietary supplements and alternative therapies.7
 Vitamin K: Vitamin K is indicated to reverse supratherapeutic international
normalized ratio (INR) caused by warfarin. When warfarin and vitamin K–containing
products are taken together, the activity of warfarin is decreased and results in a decreased
prothrombin time and INR.8 This puts the patient at risk for suboptimal anticoagulation,
possibly leading to thromboembolic events such as deep venous thrombosis, pulmonary
embolism, myocardial infarction, or stroke. Vitamin K is obtained from the diet through
green, leafy vegetables such as spinach and broccoli. Pharmacists should advise all patients
taking warfarin to eat consistent diets of green, leafy vegetables and avoid inconsistent use of
supplements that contain vitamin K (i.e., patients should not routinely change their intake of
vitamin K–containing supplements).

Niacin: Niacin is a B-complex vitamin used for the treatment of hyperlipidemia and
pellagra. Patients may try to self-treat high cholesterol with a niacin supplement. The
combination of niacin and HMG-CoA reductase inhibitors (statins) may increase the risk of
myopathies or rhabdomyolysis.9,10 Pharmacists are likely to encounter this interaction, since
statins are among the most commonly prescribed medications. The use of niacin with statins
should be recommended only if the benefits of lipid-lowering outweigh the risks of
myopathies and rhabdomyolysis. Typically, the interaction occurs at doses of 1 g/day or
greater of niacin. Generally, over-the-counter niacin supplements are not supplied in doses
this high. Pharmacists should encourage patients to take niacin supplements only under the
supervision of a physician.

Folic Acid: Folic acid is a B-complex vitamin used to treat and prevent folic acid
deficiency. Folic acid supplementation is commonly recommended during methotrexate
therapy as prophylaxis against toxicities in patients with rheumatoid arthritis and psoriasis.
Folic acid deficiency is common in these patients, since methotrexate inhibits dihydrofolate
reductase (an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid).11 Once
metabolized to tetrahydrofolate, folic acid aids in multiple biochemical processes to
synthesize DNA, RNA, and various proteins. Studies have shown that folic acid
supplementation reduces toxicities of methotrexate without affecting efficacy in long-term,
low-dose methotrexate therapy for rheumatoid arthritis or psoriasis. Pharmacists should
recommend folic acid supplementation in patients prescribed methotrexate for rheumatoid
arthritis or psoriasis, especially if adverse effects or toxicities, such as abnormalities in blood
cell counts and varying degrees of mucositis and diarrhea, are present. However, it is
important to note that some evidence suggests that folic acid reduces the efficacy of
methotrexate in cancer therapy.12

Folic acid has also been reported to decrease the efficacy of phenytoin, but only at
doses 5 mg/day or greater, which would be an unlikely dose for supplementation with over-
the-counter products.13

Minerals and Drug Interactions

Calcium: Calcium is a mineral supplement taken primarily to prevent or treat

osteoporosis. It is found in dairy products and is available as a supplement or as a component
of some antacids, such as Tums. One study determined that 67% of women and 25% of men
take a calcium supplement regularly; because calcium is associated with significant drug
interactions, pharmacists should question their patients about calcium intake.14
 Calcium interacts with prescription medications by limiting their absorption through
chelation. Significant interactions have been observed between calcium and certain
antibiotics--namely tetracyclines and fluoroquinolones. Calcium carbonate can reduce the
bioavailability of ciprofloxacin by 40%, which could result in inadequate infection treatment
and increased complications.15Patients taking tetracyclines or fluoroquinolones should avoid
the supplement altogether during the course of therapy, which is usually a short period of
time.16,17

Typically, pharmacists will instruct patients to space the doses of medications and/or
supplements whose absorption is affected by binding. Controversy, however, exists on how
much time is long enough to wait between doses. A minimum of two hours is usually
mandated, with some sources citing four to six hours as a minimum recommendation. For
example, it is recommended that doses of calcium and levothyroxine be separated by at least
four hours, because the former decreases the bioavailability of the latter.18

In addition, it is important to note that several medications, when used chronically,

can affect the body's utilization of calcium. Corticosteroids decrease the absorption of
calcium, which, over time, can lead to osteoporosis. Loop diuretics increase the excretion of
calcium, while drugs that affect vitamin D (which promotes of calcium absorption), such as
phenytoin, phenobarbital, and orlistat, may decrease the amount of calcium absorbed from
the diet.19 Patients taking these medications could benefit from a calcium supplement,
especially one containing vitamin D. Pharmacists are in a key position to speak with patients
taking these medications and to recommend adequate calcium intake and supplementation,
particularly for patients with other risk factors for osteoporosis.

Aluminum and Magnesium: Aluminum and magnesium are unlikely to be used solely
as supplements; however, they are found in common over-the-counter antacid products. Like
calcium, they can bind to vulnerable medications, decreasing their bioavailability and
lessening their efficacy. Fluoroquinolone and tetracycline antibiotics, bisphosphonates, and
levothyroxine may be affected by aluminum and magnesium; therefore, doses of these drugs
should not be taken within two hours of aluminum or magnesium consumption. If the patient
is not responding to therapy as expected, the pharmacist should recommend that the
aluminum or magnesium product be discontinued and an alternative identified.

Iron: Iron supplements are needed if the body cannot produce a sufficient amount of
red blood cells. Lack of iron may lead to tiredness, shortness of breath, decreases in physical
performance, learning problems, and an increased risk of infection.

Patients taking iron supplements or multivitamins that contain iron should be

instructed to avoid taking their supplement within two hours of a dose of tetracycline or
fluoroquinolone antibiotics, digoxin, or levothyroxine.20,21 In addition, patients taking both
calcium and iron supplements should be informed that because these supplements compete
for absorption, they should be dosed at different times of the day.

Iron salts can also interfere with the absorption of levodopa, decreasing peak levels by
55% and area under the curve by 51%.20 If the patient is experiencing breakthrough
parkinsonian symptoms, iron should be avoided. If this is not possible, the dose of the
levodopa should be increased. Iron can also cause worsening of hypertension in patients
taking methyldopa, and concomitant administration is not recommended.22
 The absorption of iron can be affected by gastric acidity, and a fair amount of
evidence exists to support limited iron absorption in patients taking proton pump inhibitors
and medications that decrease gastric acidity.23-26 In iron-deficient patients who require
proton pump inhibitors, intravenous administration of iron is recommended. Interactions
between iron and omeprazole, which was recently switched to over-the-counter status, may
not be easily identifiable; therefore, pharmacists should question patients about their
consumption of omeprazole and iron supplements.

Potassium: Although most patients taking potassium supplementation receive this

mineral in the form of a prescription product, some over-the-counter products contain
potassium. Any medication that increases potassium levels in the body has the potential to
interact with supplemental potassium. Patients should use caution when taking extra
potassium if they take any of the following prescription medications: angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers, digoxin, indomethacin, prescription
potassium supplements, and the potassium-sparing diuretics triamterene or spironolactone.

While the amount of potassium found in over-the-counter vitamin and mineral

supplements is unlikely to cause major interactions, the pharmacist should warn patients of
the potential for interaction, particularly if the patient is at risk for renal insufficiency. When
counseling patients about the importance of avoiding excess potassium, pharmacists should
mention that most common salt substitutes available in supermarkets contain potassium;
therefore, these products should be avoided in patients at risk for hyperkalemia. Salt
substitutes contain significantly higher amounts of potassium than do combination
vitamin/mineral supplements sold over-the-counter. For example, a 1/4-teaspoon serving of
NoSalt provides 650 mg of potassium. Considering that a 20-mEq prescription tablet contains
780 mg of potassium, a patient can easily accumulate potassium if using a salt substitute and
thus should be warned against consuming these products if taking medications that retain
potassium.
 Conclusion
There are many different types of drug interactions with vitamins and minerals,
ranging in severity and significance. Patients may not think to share information with their
pharmacist about the vitamins and minerals they take, or they may feel the substances are
harmless and irrelevant to their medication regimen. Because of the likelihood of an
interaction, pharmacists should question patients not only about the drug allergies they have
but also about the vitamins and minerals they ingest daily. Although this article did not
discuss herbal products and other nutraceuticals, use of these products is important to
document as well. Without this information, pharmacists cannot provide the necessary
screening for interactions. Information about the use of vitamins, minerals, herbal products,
and other nutraceuticals should be documented in patients' records for future reference. In
addition, pharmacists should encourage software vendors and employers to provide fields in
their profile systems for over-the-counter medications and supplements, since these products
can impact care and cause easily avoidable drug interactions that could put the patient at risk
for poor outcomes or adverse effects.
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