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Calcium Channel Blocker Drug Interactions

Worst Pills, Best Pills Newsletter article May, 2008

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...

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.

 

Table 1. Calcium channel blockers

 amlodipine (NORVASC)

diltiazem (CARDIZEM, DILACOR XR TIAZAC)

felodipine (PLENDIL)

isradipine (DYNACIRC)

nicardipine (CARDENE)

nifedipine short acting (PROCARDIA, ADALAT)

nifedipine long acting (PROCARDIA XL, ADALAT CC)

nisoldipine (SULAR)

verapamil (COVERA-HS, CALAN, ISOPTIN, VERELAN)

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. 

 

Table 2. Substances That Inhibit CYP3A4 Activity, Increase Calcium Channel Blocker Blood Levels 

 Generic Name

 Brand Name

 Amprenavir  AGENERASE
 Aprepitant  EMEND
 Atazanavir  REYATAZ
 Clarithromycin**  BIAXIN
 Conivaptan  VAPRISOL
 Cyclosporine  NEORAL
 Darunavir  PREZISTA
 Dasatinib  SPRYCEL
 Delavirdine  RESCRIPTOR
 Erythromycin  EES, ERYTHROCIN
 Fluconazole  DIFLUCAN
 Fluvoxamine**  LUVOX
 Fosamprenavir  LEXIVA
 Grapefruit  
 Imatinib  GLEEVEC
 Indinavir  CRIXIVAN
 Itraconazole  SPORANOX
 Ketoconazole  NIZORAL
 Lapatinib  TYKERB
 Mifepristone  MIFEPREX
 Nefazodone*  SERZONE
 Nelfinavir  VIRACEPT
 Posaconazole  NOXAFIL
 Quinupristin  SYNERCID
 Ritonavir  NORVIR, KALETRA
 Saquinavir  INVIRASE, FORTOVASE
 Telithromycin*  KETEK
 Voriconazole  VFEND
 Zafirlukast*  ACCOLATE

* Do not use in Worst Pills, Best Pills
** Limited use in Worst Pills, Best Pills

 

Table 3. Substances That Increase CYP3A4 Activity, Decrease Calcium Channel Blocker Blood Levels

 Generic Name

  Brand Name

 Carbamazepine  TEGRETOL, CARBATROL
 Efavirenz  SUSTIVA
 Nafcillin  UNIPEN, NALLPEN
 Nevirapine  VIRAMUNE
 Phenobarbital**  LUMINAL, SOLFOTON
 Primidone  MYSOLINE
 Phenytoin  DILANTIN
 Rifabutin  MYCOBUTIN
 Rifampin  RIFADIN, RIMACTANE
 Rifapentine  PRIFTIN
 St. John’s wort  

* Do not use in Worst Pills, Best Pills
** Limited use in Worst Pills, Best Pills

 

Table 4. Drugs That May Reach Toxic Levels in Blood When Combined with Diltiazem and Verapamil  

 Drugs  

Potential Effect of Interaction

 Alprazolam*   XANAX Increased sedation; reduced motor skills
 Atorvastatin  LIPITOR Muscle damage (symptoms: muscle pain, weakness,darkened urine)
 Buspirone**  BUSPAR  Increased sedation; reduced motor skills
 Carbamazepine  TEGRETOL, CARBATROL  Common Carbamazepine toxicity (headache, nausea,dizziness, confusion); AVOID IF POSSIBLE
 Clonazepam  KLONOPIN  Increased sedation; reduced motor skills
 Colchicine    Colchicine toxicity (diarrhea, fever, muscle pain, numbness & tingling); may be serious; DO NOT USE COMBINATION
 Cyclosporine  NEORAL, SANDIMMUNE  Cyclosporine toxicity; combination can be used with good results if monitored
 Diazepam*  VALIUM  Increased sedation; reduced motor skills
 Digoxin  DIGITEK, LANOXICAPS,LANOXIN  Digoxin toxicity (nausea, vomiting, visual disturbances, confusion, agitation, lethargy); combination can be used with good results if monitored
 Ergotamine  ERGOMAR, ERGOSTAT  Ergotamine toxicity (hands, feet or tongue may become cold, painful, blue); DO NOT USE COMBINATION
 Flurazepam*  DALMANE  Increased sedation; reduced motor skills
 Lovastatin  MEVACOR  Muscle damage (symptoms: muscle pain, weakness,darkened urine)
 Midazolam  VERSED  Increased sedation; reduced motor skills
 Nateglinide*  STARLIX  Increased nateglinide effect; low blood sugar
 Pimozide  ORAP  Possible heart arrhythmias; DO NOT USE COMBINATION
 Pioglitazone*  ACTOS  Increased pioglitazone effect; low blood sugar
 Repaglinide*  PRANDIN  Increased repaglinide effect; low blood sugar
 Sildenafil**  VIAGRA  Sildenafil toxicity (fainting, low blood pressure,visual disturbances)
 Simvastatin  ZOCOR  Muscle damage (symptoms: muscle pain, weakness, darkened urine)
 Sirolimus  RAPAMUNE  Sirolimus toxicity; combination can be used with good results if monitored
 Tacrolimus  PROGRAF, PROTOPIC  Tacrolimus toxicity; combination can be used with good results if monitored
 Tadalafil***  CIALIS  Tadalafil toxicity (fainting, low blood pressure, visual disturbances)
 Triazolam*  HALCION  Increased sedation; reduced motor skills
Vardenafil*** LEVITRA Vardenafil toxicity (fainting, low blood pressure, visual disturbances)
Vinblastine VELBAN Vinblastine toxicity (nerve toxicity: numbness, tingling, pain, severe constipation); DO NOT USE WITH CALCIUM CHANNEL BLOCKER UNLESS ADVISED BY PHYSICIAN
 Vincristine  ONCOVIN  Vincristine toxicity (mainly suppression of bone marrow); DO NOT USE WITH CALCIUM CHANNEL BLOCKER UNLESS ADVISED BY PHYSICIAN

* Do not use in Worst Pills, Best Pills
** Limited use in Worst Pills, Best Pills
*** Do not use for 7 years after FDA approval (2011) in Worst Pills, Best Pills