Calcium Channel Blocker Drug Interactions

A new study has found a substantially increased risk of side effects when calcium channel blockers (see table) — used in the treatment of high blood pressure, chest pain, migraine headaches and heart rhythm disturbances — are used with certain other drugs.

The study, published in the January 2008 issue of the journal Pharmacoepidemiology and Drug Safety, involved 17,430 patients receiving calcium channel blockers. Some of the patients also were taking other drugs that impeded the metabolism of calcium channel blocker drugs. Those patients had 53 percent more adverse drug reactions than those not on metabolism-blocking drugs.

Calcium channel blockers have been available for many years. Although these drugs have been associated with an increased risk of heart attacks and death, they are still widely used. In 1995, Public Citizen’s Health Research Group filed a petition with the Food and Drug Administration (FDA) to add warnings to the labeling of all calcium channel blockers about the increased risk of heart attack and death. The strongest evidence concerning the dangers of these drugs was for short-acting calcium channel blockers such as nifedipine (ADALAT, PROCARDIA) and we continue to advise against the use of short-acting calcium channel blockers for any purpose.

Our petition helped to bring about important labeling changes in February 1996 for the shortacting form of nifedipine. The labeling for this form of nifedipine now warns doctors that this product should not be used for the treatment of high blood pressure.

How do calcium channel blockers interact with other drugs?

There are a few ways calcium channel blockers can interact with other drugs to cause side effects. Calcium channel blockers are metabolized by the enzyme CYP3A4, which is found in the intestine as well as the liver. When a calcium channel blocker is taken by the usual oral route, it is extensively metabolized in the intestine and liver before it gets distributed throughout the body in the blood stream.

Many other drugs inhibit CYP3A4, so there is a high potential for drug interactions, resulting in elevated blood levels of calcium channel blockers. Common side effects of increased calcium channel blocker blood levels include flushing, headache, heart palpitations and dizziness. (Examples of drugs that have the potential to increase calcium channel blocker toxicity are included in Table 2.)

Calcium channel blockers also interact when they are combined with other drugs that increase CYP3A4 activity. Such drugs are called “enzyme inducers,” and they can dramatically reduce the blood levels of calcium channel blockers. In some cases these interactions are so large that the calcium channel blocker is rendered completely ineffective. (Examples of “enzyme inducers” are included in Table 3.)

Finally, two of the calcium channel blockers — verapamil (COVERA-HS, CALAN, ISOPTIN, VERELAN) and diltiazem (CARDIZEM, DILACOR XR, TIAZAC) — inhibit CYP3A4 themselves. This can result in increased blood levels of other drugs when they are combined with verapamil or diltiazem. Because it has been estimated that around 50 percent of prescribed drugs are metabolized by CYP3A4, it is clear that verapamil and diltiazem interact with many other medications. (Examples of these interactions are included in Table 4. If the other medication happens to have significant toxicity, the interaction can be serious, and these have been noted in the table.)

Do the calcium channel blockers differ in their interactions?

Yes. As noted above, diltiazem and verapamil are inhibitors of CYP3A4, and thus have many more drug interactions than other calcium channel blockers. Among the other calcium channel blockers, felodipine (PLENDIL) appears to be the most susceptible to the interacting drugs listed in Tables 2 and 3, and amlodipine (NORVASC) appears to be the least susceptible. The other calcium channel blockers fall somewhere in between, but these are only differences in magnitude. All calcium channel blockers should be expected to interact with the drugs listed in Tables 2 and 3.

Note that new drug interactions are being regularly discovered, so always check with a physician or pharmacist for additional information. Not every single possible interaction appears on these tables. Something new could be discovered next month, or a new drug could be marketed that would not appear on the tables. Moreover, judgment calls are made to not include some interactions in the tables that are very poorly documented or appear to have minimal clinical importance. But one can never rule out that an isolated case might have problems with such interactions. 

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