The Health Research Group’s Seven Year Rule
You should wait at least seven years from the date of release to take any new drug unless it is one of those rare “breakthrough” drugs that offers you a documented therapeutic advantage over older proven drugs. New drugs are tested in a relatively small number of people before being released, and serious adverse effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of...
The Health Research Group’s Seven Year Rule
You should wait at least seven years from the date of release to take any new drug unless it is one of those rare “breakthrough” drugs that offers you a documented therapeutic advantage over older proven drugs. New drugs are tested in a relatively small number of people before being released, and serious adverse effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people. A number of new drugs have been withdrawn within their first seven years after release. Also, warnings about serious new adverse reactions have been added to the labeling of a number of drugs, or new drug interactions have been detected, usually within the first seven years after a drug’s release.
Eplerenone (INSPRA) was initially approved by the Food and Drug Administration (FDA) in September 2002 to treat high blood pressure but the drug’s manufacturer, Pfizer Inc. of New York, chose not to enter the market at that time.
Rather, the company opted to wait to market eplerenone until it had gained approval for the drug to improve the survival of stable patients with a damaged left ventricle (large chamber of the heart) and evidence of congestive heart failure after a heart attack. This approval was granted in October 2003.
This additional approved use for the drug allows Pfizer to legally advertise eplerenone as more than just another high blood pressure lowering drug. This is important for Pfizer because the marketplace for high blood pressure lowering drugs is crowded, with dozens of competing agents, and eplerenone is not much of a high blood pressure lowering drug.
Eplerenone belongs to the family of water pills, or diuretics, known as potassium-sparing diuretics and is most similar to the older drug spironolactone (ALDACTONE).
Spironolactone was first cleared for sale in the U.S. in January 1960. One of the major concerns of potassium-sparing diuretics such as spironolactone and eplerenone is that they can lead to dangerously high levels of potassium (hyperkalemia) that can potentially cause death in the elderly and in persons with poor kidney function.
This statement appears in the professional product labeling, or package insert, for eplerenone: “The principal risk of INSPRA is hyperkalemia. Hyperkalemia can cause serious, sometimes fatal, arrhythmias (heart rhythm disturbances).”
Through mergers and acquisitions over the years, both eplerenone and brand name spironolactone are now owned by Pfizer Inc.
This article is based on the publically available FDA reviews of data submitted by the manufacturer to support the approval of eplerenone for high blood pressure and on the published medical literature supporting its use to improve survival in heart failure patients after a heart attack. We prefer relying on the FDA’s reviews of new drugs because drug manufacturers may have significant control of what is and what is not published in medical journals.
Eplerenone for High Blood Pressure
As mentioned above eplerenone is not much of a high blood pressure lowering drug. A senior FDA scientist wrote in a September 27, 2002 memo about the drug’s effectiveness and the risk of increasing potassium blood levels:
...we have no reason to think eplerenone is anything but a garden-variety antihypertensive [blood pressure lowering drug] of ordinary effectiveness; i.e., there is no reason to accept increased risk [elevated potassium levels] compared to alternative agents.
The FDA reviewed a number of clinical trials in which eplerenone was compared directly to other high blood pressure lowering drugs. Eplerenone was found comparable to spironolactone, the thiazide diuretic hydrochlorothiazide (HYDRODIURIL), and the angiotensin converting enzyme (ACE) inhibitor enalapril (VASOTEC). Nothing special was found with eplerenone.
The Medical Letter on Drugs and Therapeutics, a publication we frequently cite because of its reputation as an independent source of drug information, concluded its May 12, 2003 review of eplerenone by saying the drug is “...modestly effective for treatment of hypertension....”
Eplerenone to Improve Survival
A large clinical trial funded by eplerenone’s manufacturer was published in the April 3, 2003 New England Journal of Medicine that found the addition of the drug to the best standard therapy improved the survival of patients who had a heart attack complicated by a damaged left ventricle and heart failure.
This study found that death from all causes was lower in those taking eplerenone compared to patients receiving a placebo. In the placebo group, 16.7 percent of patients died. This was decreased to 14.4 percent in the eplerenone group. Longtime readers of Worst Pills, Best Pills News know that subtracting the percentage of patients who died taking eplerenone from those who died in the placebo group gives the absolute difference in risk of dying between the two groups — 2.3 percent. Knowing the absolute risk allows calculation of the number of patients that need to be treated with eplerenone to prevent one death. This number is 44 patients for a period of 16 months.
The down side of eplerenone, as alluded to above, is the risk of developing a serious elevation in blood potassium level, or hyperkalemia. In those taking eplerenone, 5.5 percent of the patients experienced a serious elevation in their potassium blood level. Whereas in those given the placebo, only 3.9 percent had a serious episode of hyperkalemia. This is an absolute difference of 1.6 percent in risk of developing hyperkalemia with eplerenone. With this percentage, the number of patients taking eplerenone that must be treated before there is one case of hyperkalemia develops can be calculated. This is referred to as the number needed to harm and is 63 patients on eplerenone treated for over 16 months.
On its face it appears that the benefits of eplerenone outweigh the risk of hyperkalemia and not all cases of hyperkalemia result in death. Although the patients in this study were carefully watched by the researchers, this is not always the case in the everyday practice of medicine. In addition, patients were excluded from entering the study if they were taking a potassium-sparing diuretic or had decreased kidney function. Both of which increase the risk of hyperkalemia. If, for example, once eplerenone is widely prescribed and say that the percentage of patients who develop hyperkalemia increases by a modest 1.0 percent, from 5.5 percent to 6.5 percent, the number needed to harm drops to 38 patients on eplerenone for 16 months.
Eplerenone vs Spironolactone
Eplerenone and spironolactone are very similar but the two drugs have not been compared directly in patients after a heart attack with damaged left ventricles and heart failure. However, a study was published in the New England Journal of Medicine on September 2, 1999 testing spironolactone in patients similar to those in the eplerenone study discussed above. This study was funded by the company that owned spironolactone which is now controlled by Pfizer Inc., the maker of eplerenone. The lead author and several co-authors are the same on this study and the eplerenone study published in the April 3, 2003 New England Journal of Medicine.
The spironolactone clinical trial was discontinued early, after an average follow-up of 24 months, because it was determined that the drug was reducing death from all causes compared to placebo. There were 386 deaths in those taking the placebo (46 percent) and 284 in the group taking spironolactone (35 percent). This is an absolute difference in the risk of death of 11 percent. This translates to nine patients being treated for 24 months to prevent one death.
Two percent of the patients in the spironolactone group developed a serious elevation in their potassium blood levels, whereas this adverse event occurred in one percent of the group given the placebo. This is a one percent absolute difference in the risk of developing a serious elevation in blood potassium levels. This means that for every 100 patients taking spironolactone for 24 months, one patient will experience a serious potassium elevation.
There are pitfalls in trying to draw conclusions about drugs from two separate clinical trials. The major problem is trying to decide if the patients in the spironolactone and eplerenone studies were comparable. Not enough detail was given to call these two patient groups comparable.
Even though the effect of spironolactone on survival was substantial it is not possible to say that spironolactone is superior to eplerenone.
When Eplerenone Should Not Be Used (Contraindications)
Eplerenone should not be used if the following circumstances exist:
• elevated potassium level (greater than 5.5 milliequivalents per liter when starting the drug)
• decreased kidney function (creatinine clearance of 30 milliliters per minute or less; this is a measure of kidney function)
• use in combination with the following drugs; ketoconazole (NIZORAL), itraconazole (SPORANOX), nefazodone (SERZONE), troleandomycin (TAO), clarithromycin (BIAXIN), ritonavir (RITONAVIR),and nelfinavir (VIRACEPT)
Eplerenone also should not be used for the treatment of high blood pressure in patients with the following conditions:
• type 2 diabetes with protein in the urine (microalbuminuria)
• serum creatinine greater than 2.0 milligrams per deciliter in males or 1.8 milligrams per deciliter in females (this a measure of kidney function)
• creatinine clearance less than 50 milliliters per minute (this is also a measure of kidney function)
• use of potassium supplements or potassium-sparing diuretics amiloride (MIDAMOR), spironolactone (ALDACTONE), or triamterene (DYAZIDE, DYRENIUM)
Several other drugs can interact with eplerenone that can increase the chance of elevated potassium levels. These include erythromycin (ERYTHROCIN, EES), saquinavir (INVIRASE), verapamil (CALAN SR, COVERA-HS, ISOPTIN SR, VERELAN) and fluconazole (DIFLUCAN).
Two families of high blood pressure lowering drugs that may be used in combination with eplerenone also increase potassium blood levels. These are the angiotensin converting enzyme (ACE) inhibitors that include benazepril (LOTENSIN), captopril (CAPOTEN), enalapril (VASOTEC), fosinopril (MONOPRIL), lisinopril (PRINIVIL, ZESTRIL), moexipril (UNIVASC), and trandolapril (MAVIK).
The other family of high blood pressure lowering drugs that can raise potassium levels are the angiotensin receptor blockers (ARBs); these include candesartan (ATACAND), eprosartan (TEVETEN), irbesartan (AVAPRO), losartan (COZAAR), olmesartan (BENICAR), telmisartan (MICARDIS), and valsartan (DIOVAN).
If any members of these families of drugs are being used in conjunction with eplerenone, the prescribing physician must carefully monitor blood potassium levels.
It is our practice to list new drugs as a Do Not Use Drug Until Seven Years After Release. Though eplerenone is similar to spironolactone in chemical structure, the difference may result in unexpected toxicity that will not be detected until the drug has been on the market for years and taken by millions of people.
A final word, the manufacturer of spironolactone could have pursued approval from the FDA for use of the drug for heart failure after a heart attack but did not. Rather, the company made the decision to develop a new drug, eplerenone, as spironolactone is no longer protected by a patent. You can bet that eplerenone will be more expensive than spironolactone. This appears to be another example of the pharmaceutical industry placing economics ahead of public health.
What You Can Do
You should wait at least seven years, until January 2011, before taking eplerenone.