A Review of Ranolazine (RANEXA) For Chronic Chest Pain

Editor’s note: The following article is meant to help introduce Worst Pills readers to a new drug that will probably receive a substantial amount of public attention. This article compiles the most important information, alternative treatments for the drug’s indication and our recommendation for use of this drug in an easy-to-read format. This guide will help answer questions about ranolazine, allowing you to make better choices when faced with new drug decisions in the future.  

What is Ranolazine?
Ranolazine was approved by the Food and Drug Administration (FDA) in January 2006 for the treatment of chronic chest pain (angina). This drug has not been shown to be safe and effective for any other purposes. Ranolazine should be used in combination with other drugs for angina such as amlodipine (NORVASC); beta-blocker drugs [atenolol (TENORMIN) and metoprolol (LOPRESSOR, TOPROL XL) are examples]; and the nitroglycerine-like drugs called nitrates.

The effect of ranolazine on prevention of heart attacks is unknown.

Ranolazine is marketed by CV Therapeutics Inc, a drug company based in Palo Alto, Calif.

What is Chronic Angina?
Angina is chest pain or discomfort that occurs when the heart muscle does not receive enough blood. Angina may feel like pressure or a squeezing pain in the chest. It might feel like indigestion. The pain may also occur in the shoulders, arms, neck, jaw or back.

Angina is a symptom of coronary artery disease (CAD), which occurs when plaque builds up in the coronary arteries. It is the most common type of heart disease.

In the research submitted prior to ranolazine’s approval, the patients studied had all been diagnosed with coronary artery disease and were still having angina attacks despite taking maximum doses of other antianginal drugs, such as nitrates.

What is Known About the Safety of Ranolazine?
The long-term safety of ranolazine is unknown.

The FDA medical officer in charge of reviewing ranolazine had some major questions about its safety. Specifically, she was concerned about the drug’s effect on electrical conduction in the heart, which can lead to life-threatening heart rhythm disturbances.

The medical officer recommended that ranolazine’s professional product labeling (also known as a package insert) display a black box warning about potential disruption in the heart’s electrical cycle. (A black box warning is the strongest type of alert that the FDA can request from a manufacturer and is usually reserved for drugs which cause serious injury or death.)

Unfortunately, ranolazine does not have a black box warning.

Scientists are not sure exactly how ranolazine works. When CV Therapeutics first applied for approval, they proposed that ranolazine had an effect on the breakdown of fatty acids that would benefit the heart. In a later submission, though, the company said the drug works by blocking sodium currents in heart muscle cells. 

Because ranolazine is the first in a new of drugs that works in a new way, it is possible that unknown and unpredictable adverse effects may occur after the drug is used in large numbers of patients.

When Should Ranolazine Not Be Used?
Ranolazine should never be used by the following types of patients:

• Patients with a preexisting disruption in the heart’s electrical cycle (called QT prolongation). This is determined by a physician using an electrocardiograph (ECG or EKG) machine.
• Patients with liver problems.
• Patients who are taking other drugs that cause QT prolongation. A list of these drugs appears below.

• Patients who are taking any of a long list of other drugs with which ranolazine can dangerously interact. (A list of some of the possible interacting drugs appears below. See ranolazine label for complete list.)

• Patients who are taking diltiazem or verapamil. Ranolazine interacts with diltiazem (CARDIZEM, DILACOR XR) and verapamil (CALAN, ISOPTIN), both of which are also FDA-approved to treat angina.

What Are the Most Common Adverse Drug Reactions Seen with Ranolazine in the Clinical Trails Submitted to the FDA?
The three most common adverse drug reactions seen in the clinical trials submitted to the FDA before ranolazine was approved are constipation, dizziness and nausea. The table below lists the adverse drug reactions that occurred in more than one percent of the patients taking ranolazine.

What Evidence Did the FDA Use to Approve Ranolazine?
The FDA relied on three clinical trials, called pivotal trials, submitted by CV Therapeutics Inc. to approve ranolazine. The average ages of the patients in these three trials ranged from 61.4 to 64.3 years. More than 70 percent of the patients were male. All had histories of heart problems and were taking drugs to manage angina.

In the three trials, 747 patients received one or more different doses of ranolazine for periods that ranged from four to seven weeks.

How Was the Effectiveness of Ranolazine Measured?
In two of the three clinical trials submitted to the FDA, exercise treadmill testing, which measures the amount of time a patient could tolerate walking on a treadmill, was used to measure the effectiveness of ranolazine. In the third clinical trial, the average number of weekly angina attacks was used as the measure of effectiveness.

How Effective was Ranolazine in the Three Clinical Trails?
In one clinical trial that measured exercise treadmill testing, the patients given 750 milligrams of ranolazine twice daily were able to walk an average of 23.7 seconds longer than they could before treatment compared to those receiving a placebo. In the group of patients receiving 1,000 milligrams of ranolazine twice daily, the average improvement over the placebo was 24 seconds.

The FDA medical officer responsible for evaluating ranolazine noted that this result was statistically significant “although not compelling.” Results that are statistically significant are not necessarily important to patients. In this case, study participants were able to walk on a treadmill only a short time longer than they could without treatment. This small of an improvement does not justify the high cost and added medical risk of ranolazine.

The results of the second clinical trial using exercise treadmill testing were similar to the trial described above. In patients receiving 500 milligrams of the drug twice daily, the difference compared to placebo was an average of 23.8 seconds. In the group who received 1,000 milligrams of ranolazine twice daily, the difference on average was 33.7 seconds compared to placebo. In the final group receiving the highest dose of ranolazine – 1,500 milligrams twice daily, the average difference compared to placebo was 45.9 seconds.

In the clinical trial that used the average number of angina attacks per week to measure the effectiveness, 277 patients received ranolazine. At the start of the study the median number of angina attacks was 4.5. At the end of six weeks the median number of attacks had decreased to 2.18 attacks per week. This is a median statistically significant difference of 2.32 attacks per week.

The modest effect of ranolazine seems to be more pronounced in women. The reason for this is unknown; however, most of the patients in the clinical trials submitted to the FDA were men. Studying more women may shed more light on the value of the drug in females. The FDA medical officer responsible for evaluating ranolazine recommended that CV Therapeutics Inc. evaluate the effectiveness of the drug in women. At this time we do not know if this recommendation has been followed.

Are There Other Treatments Available to Treat Chronic Angina?
Yes. There are a number of drugs approved by the FDA to treat chronic angina. These drugs belong to the beta-blocker, calcium channel blocker and nitrate drug families. Some of these drugs are listed below by their respective families.

What is the Cost of a One-Month Supply of Ranolazine?
Ranolazine is expensive. A one-month supply, 60 tablets, at a dose of 500 milligrams twice daily, is $195.94 at a popular Internet pharmacy.

What You Can Do
Do not use ranolazine until 2014 – seven years after the date of FDA approval.  

In general, people should wait at least seven years from the date of FDA approval to take any new drug unless it is one of those rare “breakthrough” drugs that offers a documented therapeutic advantage over older, proven drugs. This is because 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 the first seven years of 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.

We call this our Seven Year Rule, and it is based on a study we co-authored in the May 1, 2002 Journal of the American Medical Association. This study found that one-half of all new drug safety withdrawals occurred within two years of their FDA approval. One-half of all black box warnings, the strongest type of safety warning the FDA can request, and drug safety withdrawals combined occurred within seven years of new drug approvals – thus the Seven Year Rule.

The information in this article is based on publicly available documents prepared by FDA scientific and medical staff that is available here. These FDA documents are the most complete and objective information available at the time a new drug is approved.