New Data Show Dangerous Interaction Between Blood Pressure Drugs

June 18, 1998

Case Studies Show One Person Died And Three Went Into Shock

CHICAGO—Patients taking mibefradil, a drug withdrawn from the market on June 8 because of harmful drug interactions, went into shock within 12 hours after their physicians switched their blood pressure medication from mibefradil to other calcium channel blocker (CCB) drugs to control their high blood pressure, according to four case reports that will be published in July 8, 1998 issue of The Journal of the American Medical Association (JAMA).

Michael E. Mullins, M.D., of the Oregon Poison Center at Oregon Health Sciences University in Portland and colleagues report that one of the patients, who ranged in age from 55 to 79, died as a result; the other three survived after intensive treatment in hospital emergency departments and critical care units.

Mibefradil is a new type of calcium channel blocker drug released in the United States in mid-1997 for the management of high blood pressure and chronic stable angina (chest pain). It was withdrawn by the manufacturer because of adverse drug-to-drug interactions.

In all four case studies, patients were taking 50 to 100 mg of mibefradil daily to control their high blood pressure, and in most cases, also taking other drugs to treat other health conditions. Their doctors discontinued the mibefradil because they believed the drug was not controlling the patients' high blood pressure effectively and prescribed other CCBs, such as nifedipine, felodipine or nisoldipine. Within one to 12 hours after taking the first dose of the new drugs, the patients went into shock or suffered other serious side effects and were rushed to hospital emergency departments.

The four case studies demonstrate the potential hazard of beginning treatment with one of the older CCBs on patients who are already taking mibefradil and a ß-blocker, according to the researchers. They write: "These patients had other medical conditions and other medications -- which may have contributed to the hypotension [dangerously low blood pressure] they experienced. However, the timing of hypotension soon after ingesting the CCB within a day of taking mibefradil suggests that this combination should be avoided." The researchers continue that the long half-life of mibefradil (17 to 25 hours) may require a prolonged 'washout' period before starting therapy with antihypertensive drugs, as well as the at least 26 other medications metabolized by the liver enzymes inhibited by mibefradil.

Roche Laboratories, the manufacturers of mibefradil under the brand name PosicorR, issued a warning letter to physicians in December 1997 cautioning them about the use of mibefradil with other types of blood pressure medication, such as ß-blockers, digoxin, diltiazem and verapamil. Roche then issued a voluntary withdrawal and recall of the drug last week (June 8, 1998), after numerous indications that the drug blocked the liver's ability to metabolize other drugs and caused many other drugs to accumulate to dangerous levels.

The authors write: "In response to [the four case reports] and similar cases, Roche Laboratories issued a supplemental letter on June 12, 1998, to advise a delay of seven days after discontinuation of mibefradil before beginning therapy with most other CCBs and ß-blockers. Felodipine and timolol require a 14-day washout period after discontinuation of mibefradil. A.C.E. inhibitors, angiotensin-II antagonists and diuretics do not require special precautions."

Almost 200,000 Americans were believed to be taking mibefradil before the recall.
(JAMA. 1998;280:157-158)
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Editor's Note: The full text of this article will be available on the AMA's Web site (www.ama-assn.org/jama) at 3 p.m. CT Friday, June 19, 1998.
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The JAMA Network Journals

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