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The Health Research Group's 7-Year Rule You should wait at least seven years from the date of release to take any new drug, unless it is a rare breakthrough drug that offers a documented therapeutic advantage over older, proven drugs. Before being marketed, new drugs are tested on a relatively small number of people, and serious adverse effects or life-threatening drug interactions may not be detected until the new drug has been... |
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The Health Research Group's 7-Year Rule You should wait at least seven years from the date of release to take any new drug, unless it is a rare breakthrough drug that offers a documented therapeutic advantage over older, proven drugs. Before being marketed, new drugs are tested on a relatively small number of people, 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A number of new drugs have been withdrawn within their first seven years (e.g., rofecoxib [VIOXX], cerivastatin [BAYCOL] and dexfenfluramine [REDUX]). There have also been cases where, within the first seven years after a drug’s release, warnings about serious new adverse reactions were added to the drug’s label or new drug interactions were detected. |
The Food and Drug Administration’s (FDA’s) approvals of the antiarrhythmic dronedarone (MULTAQ) and three anticoagulants — prasugrel (EFFIENT), dabigatran (PRADAXA) and rivaroxaban (XARELTO) — underscore the vital importance of Public Citizen’s Health Research Group’s Seven-Year Rule. The risks associated with these drugs make it clear that the Seven-Year Rule should be applied even for drugs that we have not yet reviewed in Worst Pills, Best Pills News, unless they are breakthrough drugs (which none of the aforementioned four are).
The Seven-Year Rule is based on a study Public Citizen co-authored in the May 1, 2002, Journal of the American Medical Association (“Timing of New Black Box Warnings and Withdrawals for Prescription Medications”). This study found that half of the combined number of drug safety withdrawals and black box warnings, the strongest type of safety warning the FDA can request, that occurred in the first 25 years of marketing occurred within seven years of new drug approvals: hence the Seven-Year Rule. In addition, half of all new drug safety withdrawals occurred within the first two years after FDA approval.
In this article, we review important safety warnings that were required in the product labels for dronedarone, prasugrel, dabigatran and rivaroxaban at the time or shortly after these four drugs were approved for marketing.
Dronedarone
In July 2009, the FDA approved dronedarone to reduce the risk of hospitalization for a type of heart rhythm disturbance called atrial fibrillation in patients who have a normal heart rhythm but have a history of uncontrollable intermittent or persistent atrial fibrillation.
The first safety advisory came in January 2011 (18 months after approval), when the FDA issued a statement warning health care professionals and patients about cases of severe liver injury, including two cases of acute liver failure leading to liver transplant, in patients treated with dronedarone.
In July 2011, the FDA stated that it was reviewing data from a new clinical trial conducted in patients with permanent, longstanding atrial fibrillation — a type of abnormal heart rhythm for which dronedarone was not indicated and a condition that is different from having a history of uncontrollable or persistent atrial fibrillation. In that group of patients, there was a two-fold increase in death, stroke and hospitalization for heart failure.
In December 2011, after completing the review of the clinical trial involving patients with permanent atrial fibrillation, the FDA announced a revised dronedarone drug label that alerted health care professionals to avoid prescribing dronedarone to permanent atrial fibrillation patients who cannot be converted (with electrical stimulation: cardioversion) to a normal heart rhythm.
The label also alerted health care professionals that, at least every three months, they should monitor the heart rhythm of all patients using the drug.
These new findings also resulted in a revised label containing an FDA required black box warning and a Medication Guide for dronedarone in late 2011. (See Dronedarone's black box warning.)
Medication Guides are written specifically for patients and can be required for drugs that present serious public health concerns. The FDA approved the Medication Guide for dronedarone and requires that it be distributed with each new or refill prescription.
The dronedarone Medication Guide advises patients about how to recognize worsening heart failure and possible liver toxicity and about what steps to take should the signs and symptoms of liver toxicity develop.
According to the Medication Guide, patients with heart failure whose symptoms have recently worsened or patients with severe heart failure have an increased chance of dying if they take dronedarone. The guide lists the symptoms of heart failure. Call your doctor immediately if you experience:
- shortness of breath or wheezing at rest
- wheezing, chest tightness or the coughing up of frothy sputum at rest, nighttime or after minor exercise
- trouble sleeping or interrupted sleep because of breathing problems
- the need to be propped up by pillows at night to breathe more easily
- rapid weight gain of more than five pounds
- recently increased swelling of the feet or legs
The Medication Guide advises patients to call a doctor immediately if they notice these symptoms of liver disease:
- loss of appetite
- nausea
- vomiting
- fever or ill feeling
- unusual tiredness
- itching
- jaundice (yellowing of the skin or the whites of the eyes)
- unusually dark urine
- pain or discomfort in the right upper stomach area
Prasugrel
The FDA approved the blood thinner prasugrel in July 2009 to lower the risk of another heart attack, stroke, blood clots in a stent or death in patients who have had a heart attack or severe chest pain (stable angina). These risks may occur when the heart does not get enough blood and oxygen or when the patient has been treated with a procedure called angioplasty, with or without stent placement, to open up the arteries.
Prasugrel is one of the few drugs that the FDA required to have a black box warning as well as a Medication Guide at the time of approval.
The manufacturer updated prasugrel’s Medication Guide in September 2011 to warn of serious allergic reactions. Patients who have experienced a serious allergic reaction to clopidogrel (PLAVIX) or ticlopidine (TICLID) may be at a higher risk of serious allergic reactions with prasugrel. The Medication Guide also lists the symptoms of a severe allergic reaction, which require immediate medical help:
- swelling or hives of the face, lips, mouth (inside and around) or throat
- trouble breathing or swallowing
- chest pain or pressure
- dizziness or fainting
Prasugrel also causes a risk of bleeding, which may be higher in the presence of other risk factors, including having recent or recurring stomach or intestinal bleeding; using nonsteroidal anti-inflammatory drugs daily; taking other medications that increase the risk of bleeding (e.g., warfarin [COUMADIN, JANTOVEN]) or that prevent or treat blood clots; or experiencing liver problems, a stomach ulcer, or a traumatic accident or surgery.
The Medication Guide instructs patients to call a doctor upon suffering the following symptoms:
- bleeding that is unexpected, long-lasting, severe or uncontrollable
- urine that is pink or brown
- stool that is red or black
- bruises that happen without a known cause or get larger
- blood or blood clots produced upon coughing
- blood in vomit or vomit that looks like coffee grounds
Blood clots in the stent, heart attack and death stand out as other risks for patients who cease using prasugrel too soon and have undergone angioplasty with a stent. Also, those who stop taking the drug because of bleeding may have a higher risk of heart attack
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FDA Black Box Warning: Prasugrel WARNING: BLEEDING RISK EFFIENT can cause significant, sometimes fatal, bleeding. Do not use EFFIENT in patients with active pathological bleeding or a history of transient ischemic attack or stroke. In patients ≥ 75 years of age, EFFIENT is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI [myocardial infarction]) where its effect appears to be greater and its use may be considered. Do not start EFFIENT in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue EFFIENT at least 7 days prior to any surgery. Additional risk factors for bleeding include: Suspect bleeding in any patient who is hypotensive and hAs recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG or other surgical procedures in the setting of EFFIENT.
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG or other surgical procedures in the setting of EFFIENT. If possible, manage bleeding without discontinuing EFFIENT. Discontinuing EFFIENT, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events. |
Dabigatran
The FDA approved the blood thinner dabigatran in October 2010 to reduce the risk of stroke and systemic embolism (blood clots) in patients with atrial fibrillation unrelated to a heart valve problem.
In December 2011, only 14 months after approval, the FDA issued a “Drug Safety Communication” about its review of reports of serious bleeding events with the use of dabigatran. The FDA communication was based on a large clinical trial of 18,000 patients comparing dabigatran to the older anticoagulant warfarin. The results showed major bleeding events occurred at similar rates with the two drugs.
A month later, in January 2012, the FDA required that the “Warnings and Precautions” section of dabigatran’s product label warn that dabigatran can “cause serious and sometimes fatal bleeding.”
Because of dabigatran’s serious public health concerns, the FDA requires an agency-approved Medication Guide to be distributed at the pharmacy with each new and refill prescription. The main warning in the Medication Guide concerns an increased risk of bleeding, which especially affects patients over 75 years, those with kidney problems or recent or recurring stomach or intestinal bleeding, and people taking other medications that increase the risk of bleeding. (See the symptoms of bleeding listed in the “Prasugrel” section.)
Rivaroxaban
The FDA first approved rivaroxaban in July 2011 for the prevention of deep vein thrombosis and pulmonary embolism (blood clots in the lungs) in patients undergoing hip or knee replacement surgery.
In November 2011, rivaroxaban was given a new indication: to reduce the risk of stroke and blood clots in patients with a type of heart rhythm disturbance called nonvalvular (not due to heart valve problems) atrial fibrillation.
Like the labels of dronedarone and prasugrel, however, the product label for rivaroxaban now carries an FDA-required black box warning listing its most dangerous risks. Again, bleeding surfaces among the possible effects, along with an increased chance for stroke if a patient stops taking rivaroxaban.
What You Can Do
You should not discontinue the use of any medication without first consulting your prescribing doctor.
In addition to reading Worst Pills, Best Pills News and checking WorstPills.org for warnings about new drugs, you should always review the product label for any new drug you are prescribed. FDA-approved product labels can be found online at the DailyMed website (http://dailymed.nlm.nih.gov/).
If your drug requires a Medication Guide, it can be found in the product label or at www.fda.gov/drugs/drugsafety/ucm085729.htm but should be distributed to you when you fill or refill your prescription.
Consumers may report serious adverse events with drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.
- Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
- Regular mail: Use postage-paid,pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
- Fax: (800) FDA-0178
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Phone: (800) FDA-1088
