Calcium Channel Blockers Plus Most Macrolide Antibiotics: A Dangerous Combination

A recent study appearing in the Journal of the American Medical Association (JAMA)[1] provides strong confirmatory evidence that patients who take calcium channel blockers, a widely used class of drugs for treating high blood pressure (hypertension), combined with the macrolide antibiotic clarithromycin have an increased risk of serious side effects, including acute kidney injury, hypotension (low blood pressure) and death.

This finding confirms those of previous studies that showed that the risk of severe hypotension was increased when patients on calcium channel blockers were given the macrolide antibiotic clarithromycin or two other antibiotics from the same class, erythromycin and telithromycin. A fourth macrolide antibiotic, azithromycin, has not been shown to have this dangerous interaction with calcium channel blockers.

Given the potential dangers of these drug combinations and the availability of effective alternatives, patients on calcium channel blockers always should avoid taking clarithromycin, erythromycin or telithromycin.

Overview

Calcium channel blockers are a family of drugs primarily used to treat hypertension. Some of these drugs also are used to treat chest pain caused by coronary artery disease (angina). (See Table for a list of available calcium channel blockers.)

In general, calcium channel blockers are broken down and removed from the body by the liver. A specific enzyme in the liver called cytochrome P450 3A4 (CYP3A4) plays a key role in this process.[2]

Certain drugs, as well as a substance found in grapefruit juice, inhibit the activity of CYP3A4, thus blocking the metabolism of calcium channel blockers and other drugs that are metabolized by this liver enzyme. As a result, patients prescribed CYP3A4 inhibitors together with calcium channel blockers can accumulate dangerously high levels of the calcium channel blockers in their blood, which can cause serious adverse events such as low blood pressure, acute kidney injury and even death.

Oral Calcium Channel Blockers Available in the U.S. for Treating Hypertension and/or Coronary Artery Disease

* Limited Use
** Contains other active drug ingredients (in most cases, other antihypertensive drugs)

Clarithromycin: A known inhibitor of CYP3A4

Clarithromycin (BIAXIN, BIAXIN XL, PREVPAC [a drug combination used to treat peptic ulcer disease that also contains the antibiotic amoxicillin and the stomach acid-suppressing drug lansoprazole]) is one of four members of the macrolide family of antibiotics available in the U.S. It is approved for treatment of several types of infection, including strep throat, sinusitis, acute bronchitis and community-acquired pneumonia. Clarithromycin — like two other macrolide antibiotics available in the U.S., erythromycin (E.E.S., E.E.S. 200, E.E.S. 400, ERYC, ERYPED, ERY-TAB, ERYTHROCIN, PCE, PEDIAMYCIN, PEDIAMYCIN 400) and telithromycin (KETEK, which we have designated as Do Not Use) — is a known potent inhibitor of CYP3A4. A fourth macrolide antibiotic, azithromycin (ZITHROMAX, ZMAX), is not an inhibitor of CYP3A4.[3]

The drug label for clarithromycin specifically warns about serious adverse reactions occurring in patients taking clarithromycin together with other drugs metabolized by CYP3A4, including hypotension in patients using calcium channel blockers.[4]

Prior evidence of risk

There is previous evidence in the scientific literature linking simultaneous use of clarithromycin (and other macrolide antibiotics) and calcium channel blockers to serious adverse events, possibly due to excessive levels of the calcium channel blocker in the blood.

For example, there was a case report published in 2005 of an elderly patient taking the calcium channel blocker nifedipine who developed severe hypotension, shock and multi-organ failure after being prescribed clarithromycin for treatment of a productive cough and difficulty breathing.[5]

In February 2011, researchers in Canada published a well-designed, population-based epidemiology study in the Canadian Medical Association Journal (CMAJ) that analyzed the risk of being hospitalized for hypotension or shock following the simultaneous use of calcium channel blockers and macrolide antibiotics.[6] Using databases of prescription drug and hospital records for all residents aged 66 or older in the province of Ontario, the researchers for the CMAJ study identified 999,234 patients who received a calcium channel blocker between April 1994 and March 2009.[7] From among this group, they then identified a group of 7,100 patients who had been hospitalized for treatment of hypotension and assessed whether treatment with any of three macrolide antibiotics available in Canada at the time (azithromycin, clarithromycin and erythromycin) within seven days prior to the hospitalization was a risk factor associated with these hospitalizations.[8]

The researchers found that the use of either clarithromycin or erythromycin by older patients taking calcium channel blockers was associated with an increased short-term risk of being hospitalized for treatment of hypotension, whereas use of azithromycin was not.[9] These findings are consistent with clarithromycin and erythromycin being inhibitors of calcium channel blocker metabolism and azithromycin not being an inhibitor.

The recent JAMA study builds on these prior research results by linking clarithromycin to an increased risk of acute kidney injury, which commonly occurs in the patients who develop hypotension.

JAMA study overview

This large, well-designed population-based epidemiology study was once again performed by researchers in Canada and was published on Dec. 18, 2013.[10]

The researchers used several large linked databases containing detailed information on drug prescriptions, hospitalizations, and demographic and vital statistics for all residents aged 65 or older in the province of Ontario, a population of approximately 1.8 million (though the authors limited their study to those aged 66 and older).[11] The primary goal was to assess the risk of acute kidney injury in older adult patients taking clarithromycin in combination with calcium channel blockers.[12]

From the linked health care databases, the researchers identified 190,309 patients who were continuous users of one of five calcium channel blockers — amlodipine, diltiazem, felodipine, nifedipine and verapamil — and who also received a co-prescription for either clarithromycin (the CYP3A4 inhibitor; 96,226 patients) or, for comparison purposes, azithromycin (not a CYP3A4 inhibitor; 94,083 patients) between June 2003 and March 2012.[13]

Of note, the researchers had previously shown that clarithromycin and azithromycin were prescribed to patients in Ontario who had nearly identical types of infection (for example, respiratory tract infections, sinusitis and pharyngitis) and similar medical problems and similar risk factors for acute kidney injury. The drugs were prescribed by the same type of physicians (three-quarters of whom were primary care physicians).[14] These similarities made it very likely that any significant differences found between the two patient groups in the clinical outcomes being measured would be due to the different antibiotics the patients used, not some other confounding factor.

The researchers excluded patients who had received prescriptions for other antibiotics in addition to clarithromycin or azithromycin, were discharged from the hospital within two days of starting one of these antibiotics, or were on dialysis for end-stage renal disease and thus could not be diagnosed with acute kidney injury.[15]

The primary outcome being studied was hospitalization with acute kidney injury within 30 days of the date on which the prescription for the macrolide antibiotic was filled, and the secondary outcomes were hospitalization with hypotension and death within the same time frame.[16] The investigators calculated both the absolute and relative risks of these outcomes in the clarithromycin-treated patients compared with the azithromycin-treated patients.

JAMA study results

The two patient groups were nearly identical with respect to their demographic characteristics, underlying diseases, baseline medications used, type of prescribing physicians and frequency of hospitalization in the year preceding the prescription for the macrolide antibiotics.[17] For both groups, the average age of patients was 76, and 62 percent were women. Amlodipine was the most frequently used calcium channel blocker in both groups: 53 percent of clarithromycin-treated patients and 54 percent of azithromycin-treated patients. Diltiazem was the second most frequently used calcium channel blocker (22 percent in both groups), and felodipine was the least frequently used (3-4 percent in both groups).

Patients co-prescribed a calcium channel blocker and clarithromycin had a higher risk of being hospitalized with acute kidney injury compared with those patients co-prescribed azithromycin (420 of 96,226 clarithromycin-treated patients [0.44 percent] versus 208 of 94,083 azithromycin-treated patients [0.22 percent]).[18] This represented an absolute increased risk of 0.22 percent for the clarithromycin-treated patients, and a two-fold relative increase in risk.[19] Put another way: The number needed to harm for patients in the clarithromycin-treated group was 464,[20] meaning that for every 464 patients co-prescribed clarithromycin with a calcium channel blocker, one more patient was hospitalized for acute kidney injury in comparison to those patients co-prescribed azithromycin.

Likewise, the clarithromycin-treated patients had higher risks of both being hospitalized with hypotension (absolute risk difference 0.04 percent; 1.6-fold relative increase in risk; number needed to harm 2,321) and dying (absolute risk difference 0.43 percent; 1.7-fold relative increase in risk; number needed to harm 231).[21]

When analyzing the risk of acute injury for each of the five calcium channel blockers, the highest risk was seen among patients co-prescribed clarithromycin with nifedipine (0.63 percent absolute risk increase and a five-fold relative risk increase), followed in order of decreasing risk by co-prescription of clarithromycin with felodipine and amlodipine.[22] Statistically significant increases in the risk were not seen in patients treated with clarithromycin in combination with diltiazem or verapamil.[23]

Conclusions

Although the absolute increase in risk of serious adverse events from co-prescription of calcium channel blockers and clarithromycin is very low, the fact that so many people take these drugs means that a significant number of patients are at risk.

Given the pharmacologic interactions between clarithromycin and calcium channel blockers and the results of both the CMAJ and JAMA studies discussed in this article, there is little doubt that large numbers of preventable serious events — including hypotension, acute kidney injury and death — are occurring each year due to co-prescribing of calcium channel blockers and clarithromycin. The mechanism of the acute kidney injury documented in the JAMA study is almost certainly due to drops in blood pressure caused by excess blood levels of calcium channel blockers, causing decreased blood supply to the kidneys.

The researchers who conducted the JAMA study estimated that possibly hundreds of hospitalizations and deaths may have been caused in the Ontario region alone due to patients being exposed to this dangerous “preventable drug-drug interaction.”[24] Even larger numbers of these preventable adverse drug reactions are likely occurring throughout the U.S.

What You Can Do

You should take antibiotics only when you have or are likely to have a bacterial infection. Too often, patients take antibiotics for sore throats, cold symptoms and coughs caused by viruses. Antibiotics are not useful for treating such infections.

If you are taking a calcium channel blocker and have a bacterial infection that requires treatment with an antibiotic, you should follow these guidelines:

• Always try to avoid taking clarithromycin, erythromycin and telithromycin. For many infections, antibiotics other than a macrolide will suffice.
• If a macrolide antibiotic is the best treatment option for your infection, take azithromycin.
• If for some reason the only treatment choice is clarithromycin, erythromycin or telithromycin, which should rarely be the case, discuss with your doctor whether your dose of calcium channel blocker should be temporarily reduced while taking the antibiotic.
• Regardless of whether your dose of calcium channel blocker is reduced, be alert for symptoms of toxic levels of the calcium channel blocker, such as dizziness, swelling, flushing and heart palpitations (a fluttering sensation in your chest). You should contact your health care provider promptly if any of these symptoms develop while taking a calcium channel blocker with clarithromycin, erythromycin or telithromycin.

By following these guidelines, you can avoid suffering a serious adverse reaction caused by the dangerous interaction between calcium channel blockers and clarithromycin, erthromycin or telithromycin.

References

[1] Gandhi S, Fleet JL, Bailey DG, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA. 2013;310(23):2544-2553.

[2] Ibid.

[3] AbbVie, Inc. Drug label for BIAXIN. October 2013.

[4] Ibid.

[5] Gerónimo-Pardo M, Cuartero-del-Pozo AB, Jimenez-Vizuete JM, et al. Clarithromycin-nifedipine interaction as possible cause of vasodilatory shock. Ann Pharmacother. 2005;39(3):538-542.

[6] Wright AJ, Gomes T, Mamdani MM, et al. The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. CMAJ. 2011;183(3):303-307.

[7] Ibid.

[8] Ibid.

[9] Ibid.

[10] Gandhi S, Fleet JL, Bailey DG, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA. 2013;310(23):2544-2553.

[11] Ibid.

[12] Ibid.

[13] Ibid.

[14] Gandhi S, Fleet JL, Bailey DG, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA. 2013;310(23):2544-2553.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] Ibid.

[21] Ibid.

[22] Ibid.

[23] Ibid.

[24] Ibid.