Nancy A. Melville

November 13, 2013

ATLANTA — The antibiotic clarithromycin prescribed for patients already taking antihypertensive calcium-channel blockers is associated with increases in hospitalization for acute kidney injury, hypotension, and death, according to new research.

Coprescribing the 2 drugs is a common practice, despite warnings of serious interactions.

"Although the absolute risk increases were small, these outcomes have important clinical implications," said senior author Amit Garg, MD, from the London Health Sciences Centre and the University of Western Ontario.

"Our results suggest that potentially hundreds of hospitalizations and deaths in our region may have been associated with this largely preventable drug–drug interaction," he told Medscape Medical News. "This burden on the healthcare system, given the high cost of managing acute kidney injury, might have been avoided."

The results, presented here at Kidney Week 2013, were also published online November 9 in JAMA to coincide with their presentation.

Clarithromycin is an inhibitor of the cytochrome P453A4, the enzyme that metabolizes calcium-channel blockers. Previous research has shown that the antibiotic can send blood concentrations of calcium-channel blockers soaring by as much as 500%.

Soaring Serum Calcium-Channel Blocker Levels

A warning from the US Food and Drug Administration states that "serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates, which includes hypotension with calcium-channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, diltiazem)."

The reasons for the continued coprescribing of the drugs, despite the warnings, remain unclear, said Dr. Garg.

"We do know that some physicians and pharmacists are either unaware, or have remained unconvinced, about the potential dangers of using these 2 types of drugs together," he said.

In an effort to gauge the extent of serious adverse clinical events resulting from coprescribing, Dr. Garg and his team conducted a population-based retrospective study of older adults in Ontario who were prescribed the 2 drugs together.

They identified 96,226 adults older than 76 years who were newly prescribed clarithromycin and 94,083 patients who were prescribed the alternative, azithromycin, while taking a calcium-channel blocker such as amlodipine, felodipine, nifedipine, diltiazem, or verapamil.

Because azithromycin is only a weak inhibitor of CYP34A, the type of intensification of the calcium-channel blocker that occurs with clarithromycin is not expected.

The most common calcium-channel blocker — amlodipine — was prescribed to more than 50% of patients.

For patients taking a calcium-channel blocker, the absolute risk of hospitalization for acute kidney injury was higher in patients also taking clarithromycin than in those also taking azithromycin (0.44% vs 0.22%; odds ratio [OR], 1.98).

More Hospitalizations

Patients coprescribed clarithromycin also had a higher risk of hospitalization for hypotension (OR, 1.60) and all-cause mortality (OR, 1.74).

"Although the absolute risk increases may have been underestimated due to the limited sensitivity of the diagnostic codes, we captured the more severe forms of the conditions, making these findings of particular interest to clinicians and policy decision makers," the researchers report.

A subgroup analysis showed dihydropyridines, particularly nifedipine, to be the calcium-channel blockers associated with the highest risk (OR, 5.33), with an absolute risk increase of 0.63%. The risk with nifedipine was followed by felodipine and amlodipine.

The researchers previously confirmed that there are no significant differences between clarithromycin and azithromycin in terms of rates of 30-day risk of hospitalization for acute kidney injury, in the absence of other interacting medications. The use of calcium-channel blockers alone in the 90 days prior to the antibiotic coprescription did not affect 30-day outcomes.

"This information reinforces the primary results of our study," the researchers note.

Because of the role of the kidneys in eliminating clarithromycin, guidelines call for reduced dosing of the antibiotic in patients with chronic kidney disease, but the researchers found that this rarely occurs in routine practice.

 
Newer electronic prescription programs with built-in interaction recognition software will decrease the risk significantly.
 

They observed no greater relative risk of hospitalization, but noted that "the absolute number needed to harm from the coprescription was far lower in patients with chronic kidney disease than in those without."

Although clarithromycin can be a powerful antibiotic for challenging infections, clinicians have easy options for preventing interactions, said nephrologist Jorge Cerda, MD, from the Albany Medical College and Capital District Renal Physicians in New York.

"Clarithromycin may be the top choice for an antibiotic in some cases, particularly in patients who are severely immunosuppressed, such as HIV/AIDS patients, or in the treatment of extremely drug-resistant bugs," he told Medscape Medical News. "But in such cases, it is perfectly feasible to take the patient off the calcium-channel blocker. You just need to change the blood pressure medication, which is easy to do."

He added that the growing ease in quickly accessing safety information on drugs, through mobile applications and other technologies, should help improve awareness of which combinations to avoid.

"Drug–drug interactions are usually under-recognized by doctors, but newer electronic prescription programs with built-in interaction recognition software will decrease the risk significantly," he said.

"Patients should then have 2 safety mechanisms — at the time of the e-prescription, and at the time of dispensing the drug by the pharmacist."

Dr. Garg received an investigator-initiated grant from Astellas and Roche to support a Canadian Institutes of Health Research study of living kidney donors, and his institution received unrestricted research funding for the study from Pfizer. Dr. Cerda has disclosed no relevant financial relationships.

Kidney Week 2013: The American Society of Nephrology 46th Annual Meeting. Abstract SA-PO031. Presented November 9, 2013.

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