Health officials say the increase in overdoses seems to have ended, in part due to law enforcement's shutdown of a Toluca, Mexico Fentanyl operation in May 2006, according to Dr. T. Stephen Jones, the study’s lead author. But some deaths from illegal Fentanyl still occur. "It almost disappeared entirely. The shutting down of the Toluca facility was probably a major factor," said Jones, a consultant retired from the CDC. The new report is being published this week in a CDC's Morbidity and Mortality Weekly report.
Fentanyl is a prescription painkiller typically prescribed via a patch to cancer patients. Because Fentanyl is also ‘a powerful, euphoria-inducing narcotic—30-50 times more potent than heroin—it is often used illegally for it’s street drug effects with heroin addicts possibly unaware that the deadly version of Fentanyl is included in their injections. Illegal Fentanyl is “sold as a powder, often mixed with cocaine or heroin, and sometimes used as a heroin replacement.” As far back as the 1980s there have been reports of isolated Fentanyl-related outbreaks involving deaths in addicts. For instance, the famed “China White" outbreak is best noted for its severe, deadly reactions. That outbreak involved users dropping “dead with needles still in their arms.”
In the more recent outbreak, which seems to have been initiated in Chicago, those patients who recovered from Fentanyl overdoses reported that they had received “free heroin in orange and pink plastic bags by new drug dealers trying to attract more customers. The Chicago cases are summarized in the July issue of Clinical Toxicology.”
It was when an outbreak occurred in Camden, New Jersey in April 2006 that Marcus notified federal officials. Marcus says the investigation was “unusual” because some health officials were reticent to devote resources on illicit drug fatalities. "The response when I deal with public health officials is, 'Drug abuse is a dangerous habit, and drug abusers know it's a dangerous habit, so why are we making a big deal out of it?'" Marcus said.
Meanwhile, the report separates deaths by those due to illegally made Fentanyl and those due to illegal use of pharmaceutical Fentanyl. Because Medical examiners cannot differentiate between the two, investigators used information from the scenes, among other information, to separate the two groups. Also of note, the figures in this week’s report only cover New Jersey and Delaware and the “cities of Chicago, Detroit, Philadelphia, and St. Louis.” "It's an incomplete picture," Jones said.
Fentora was approved in 2006 only for treating pain in cancer patients. It is intended for patients who experience breakthrough pain because they have developed tolerances to other opiate painkillers. Fentora contains fentanyl, a highly addictive opiate that is 80 times more potent than morphine. Fentanyl is considered a Class II substance by the Drug Enforcement Administration, meaning it is associated with a high potential for abuse and a risk for fatal overdose.
While Fentora is only approved for cancer patients, it is known that as many 80 percent of people using it do so “off-label” to headaches and back pain. Once a drug has been approved by the FDA doctors are free to prescribe it as they see fit, but drug companies are legally barred from promoting off-label use. Cephalon has been the subject of several investigations into off-label promotion of Fentora and other narcotic painkillers. In November, the company reached an agreement with the US Department of Justice to pay $425 to settle charges stemming from the illegal marketing of Fentora, as well as another of its narcotic painkiller, Actiq.
Cephalon has reported five patient deaths due to negative reaction or overdose of the drug. In September 2007, the FDA issued a public health advisory, warning that several Fentora-related deaths had occurred in patients who were prescribed the drug for off-label use. The FDA advisory warned that Fentora should not be used for any other conditions including migraines, post operative pain or pain due to injury.
Despite the overdose dangers, Cephalon has continued to push the FDA to expand Fentora's approved uses. At yesterday's advisory panel meeting, however, FDA scientists testified that widening approval of Fentora could have dangerous effects because of the risks for improper prescribing and abuse of the drug, which is more potent than other pain medications.
Patients suffering from ailments like back pain and migraines already have access to many approved narcotics, causing many panelists to question the need for expanded Fentora approval. "How many people are we going to help with the release of this product and how many are we going to hurt?" asked panel member Dr. Charles Cortinovis, of the Veterans Administration Hospital in Pittsburgh. "In my mind it is very scary to release such a large amount of powerful opiate into the American population."
Cephalon tried to ease fears over Fentora misuse by proposing a plan that would require pharmacists to electronically confirm a patient's symptoms before dispensing the drug. While some panelists like that idea, they want Cephalon to perform more studies to prove its plan will help reduce medication errors and abuse of the drug. Several panel members also said Cephalon should conduct more studies to determine if Fentora offers more benefits to non-cancer patients than other painkillers already approved for such conditions.
The FDA is expected to make its final decision on Fentora by mid-September. Though the agency is not bound by the recommendations of advisory panels, it usually follows them.
Last September, Cephalon submitted a request to the FDA seeking approval to market Fentora for breakthrough pain management in opioid-tolerant noncancer patients. Given that Cephalon’s illegal marketing practices have been under constant scrutiny in recent years and the FDA issued a pubic warning over Fentora following reports its use led to breathing problems, deaths, and other serious complications, this was an odd request.
"We are concerned that the sponsor's request to expand the current indication for Fentora ... may greatly increase the prescribing of this product which may increase the availability of the product for diversion, abuse, and misuse," wrote Bob Rappaport, head of the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products. Rappaport added Fentora could "increase the incidence of accidental exposures which, due to the potency of the product, could potentially have devastating effects."
In 2006, the Wall Street Journal investigated Cephalon’s marketing of Actiq—Cephalon's other fentanyl drug sold in a lollipop form—and discovered 80 percent of patients prescribed Actiq were not cancer patients and Cephalon frequently focused marketing of Actiq to noncancer physicians in sports medicine and family practice specialties. That same year, the Connecticut Attorney General discovered Cephalon illegally marketed Actiq for off-label use and set high sales quotas that could only be met through off-label dispensing. Cephalon’s marketing of Fentora had also been under investigation by the US Attorney in Philadelphia as well as by Congress. Actiq has been linked to over 120 deaths. In the case of Fentora, illegal marketing has been linked to four deaths, none of which occurred in cancer patients. Cephalon admitted some of these deaths were due to off-label use.
Fentora and Actiq are FDA-approved only for use in cancer patients for break-through pain—pain that occurs quickly, is severe, and is of short duration. Fentora is contraindicated for noncancer-related pains and for cancer patients intolerant to or not undergoing constant opioid therapy; the drug is indicated for a very specific population, is a faster acting version of Actiq, and is not a generic version of any opioid-containing drug. Because Fentora is dosed to deliver higher amounts of fentanyl—a highly addictive opiate 80 times more powerful than morphine—it is never to be substituted for any other drug since misuse at any dose can—and has—resulted in death.
The FDA is conducting an advisory meeting tomorrow with a panel of external experts regarding whether wider Fentora use should be approved. The FDA said it received reports Fentora was incorrectly prescribed, given at wrong doses, and that tablets were inappropriately substituted by doctors and pharmacists for Actiq. Cephalon told reporters, "There is no evidence that Fentora poses risks of abuse and diversion greater than other opioids." Cephalon said it expects the FDA to make its final decision by September 13.
Dr. Mark J. Pletcher of the University of California, San Francisco led the research. Pletcher and his team based their findings on a review of over 150,000 pain-related emergency room visits nationwide over 13 years and discovered in 1993, 23 percent of patients treated in emergency rooms complaining of pain were given opioids; in 2005, the figure was 37 percent. When nonwhites are treated, figures change. Researchers found if two groups of one dozen patients sought treatment for pain—one group all white; the other all minority—one fewer patient in the minority group would receive medication. Researches said white patients could be given opioids too often, but sounded doubtful, saying, “A more plausible explanation for our findings invokes a true disparity in prescribing, with differential under-treatment of pain in minority patients.”
This is not the only issue of disparate treatment in U.S. hospitals based on. A study published last week revealed that nearly one-third of all patients experiencing misfiring or quivering hearts in U.S. hospitals do not receive life-saving defibrillator shocks within the critical first two minutes of cardiac arrest. This, despite the fact that The American Heart Association recommends stopped hearts be shocked within the first two minutes. The study confirming the importance of the two-minute period for survival was published in the New England Journal of Medicine, which also ran an accompanying editorial piece indicating a person might be better off suffering cardiac arrest in a casino rather than a hospital. Researchers from 369 hospitals in the National Registry of Cardiopulmonary Resuscitation found that being black or having a cardiac arrest outside of regular weekday working hours also significantly delayed the time it took for hospital workers to shock the heart. Paul Chan of the Mid-America Heart Institute in Kansas City, Missouri led the study in the New England Journal of Medicine.
Disparity appears among class groups as well. A recent study found 72 percent of those receiving free drug samples from their physicians had income in excess of 200 percent above the poverty level, while 28 percent had income below poverty level.† William Shrank, a physician at Boston's Brigham and Women's Hospital who studies pharmaceutical use in large populations, said the study helps debunk the assertion that drug samples help the needy.
In 2006, the Wall Street Journal investigated Cephalon’s marketing of Actiq—a pain-management cancer medication—and discovered that 80 percent of patients prescribed Actiq were not cancer patients and that Cephalon frequently focused marketing of Actiq to noncancer physicians in the sports medicine and family practice specialties. That same year, the Connecticut Attorney General discovered that Cephalon marketed Actiq for off-label use—purposes other than the drug’s intention—and set high sales quotas that could only be met through off-label dispensing. Of note since Actiq has been linked to over 120 deaths.
Most recently, Cephalon’s marketing of Fentora—a potent cancer pain management drug—has been under investigation by the US Attorney in Philadelphia, the Connecticut Attorney General, and Congress.
Both Fentora and Actiq are FDA-approved only for use in cancer patients for break-through pain, a type of pain that that occurs quickly, is severe, and is of short duration. Fentora is contraindicated for noncancer-related pains and for cancer patients intolerant to or not undergoing constant opioid therapy. The drug is indicated for a very specific population, is a faster acting version of Actiq, and is not a generic version of any opioid-containing drug. Because Fentora is dosed to deliver higher amounts of the opioid fentanyl—a highly addictive opiate 80 times more powerful than morphine—it is never to be substituted for any other drug since misuse at any dose can and has resulted in death.
Doctors are free to prescribe FDA-approved medications as they see fit, including off-label. It is off-label marketing of FDA-approved medication—marketing for uses not approved by the FDA—which is illegal. Off-label marketing is misleading and, in the case of Fentora, has been linked to four deaths, none of which occurred in cancer patients. Cephalon admitted that some of these deaths were the result of off-label use. The FDA reports that other Fentora deaths have been due to doctors prescribing higher-than-recommended doses of the drug, a dangerous situation in light of the fact that over 80,000 prescriptions have been written for Fentora, a suspiciously large amount given the very limited population able to take the drug.
The FDA has mandated Cephalon to strengthen drug warnings and improve dosing instructions and education plans. And although Cephalon has denied it marketed Fentora and Actiq outside their indication and claims the problems are a result of improper prescribing, they have agreed to pay $425 million to settle the US Justice Department investigation; agreed to a misdemeanor violation of the US Food, Drug, and Cosmetic Act; and will enter into a corporate-integrity agreement with the Department of Health and Human Services.
But, none of this stopped Cephalon from submitting their request to the FDA seeking approval to continue marketing Fentora for noncancer pain management.
Fentora was approved only for treating pain in cancer patients. It is intended for patients who experience breakthrough pain because they have developed tolerances to other opiate painkillers. Fentora contains fentanyl, a highly addictive opiate that is 80 times more potent than morphine. Fentanyl is considered a Class II substance by the Drug Enforcement Administration, meaning it is associated with a high potential for abuse and a risk for fatal overdose.
While Fentora is only approved for cancer patients, it is known that many doctors prescribe the drug “off-label” for headaches and back pain. Once a drug has been approved by the FDA doctors are free to prescribe it as they see fit. The FDA said that several Fentora-related deaths have occurred in patients who were prescribed the drug for off-label use. The FDA advisory warns that Fentora should not be used for any other conditions including migraines, post operative pain or pain due to injury. It should also only be given to patients who have developed opiate tolerance, as others will not be able to handle the high amounts of fentanyl contained in Fentora.
The FDA says that other Fentora deaths have been due to doctors prescribing higher-than-recommended doses of the drug. The FDA advisory says that Fentora contains much higher amounts of fentanyl than other opiate painkillers, including Actiq. For that reason, Fentora is not a suitable substitute for these other painkillers. And the FDA says that doctors must use care in determining the appropriate dose of Fentora for each patient.
Finally, the Public Health Advisory warns people taking Fentora and their caregivers to carefully follow the drug’s label directions. The agency also advises that patients and caregivers become familiar with the signs of fentanyl overdose. These include breathing problems or shallow breathing; tiredness, extreme sleepiness or sedation; inability to think, talk or walk normally; and feeling faint, dizzy or confused. Fentora patients exhibiting these symptoms should be given immediate medical attention.
At least three separate investigations are underway to determine if Cephalon is marketing Fentora for off-label use. Off-label marketing of a drug is illegal, even though off -label use is not. An investigation being conducted by the Connecticut Attorney General’s office has already determined that Cephalon actively promoted off-label use of Fentora’s predecessor, Actiq. The US attorney in Philadelphia and a congressional probe are also looking into Cephalon’s marketing of Fentora.
Fentora and a related medication, Actiq, were approved by the Food and Drug Administration (FDA) only for use in cancer patients. Both contain fentanyl, a highly addictive opiate that is 80 times more potent than morphine. Fentanyl is considered a Class II substance by the Drug Enforcement Administration, meaning it is associated with a high potential for abuse and a risk for fatal overdose. While Fentora and Actiq are only approved for cancer patients, it is known that many doctors prescribe the drugs “off-label” for headaches and back pain. Once a drug has been approved by the FDA, however, doctors are free to prescribe it as they see fit. However, drug companies are prohibited from advertising a drug’s off-label uses.
Now, Fentora has been implicated in the deaths of four people. According to the letter Cephalon sent to physicians, some of those deaths were related to off label use. Cephalon says that two of the patients who died were taking Fentora for headaches. A third death was the result of a patient using the drug to commit suicide, but who hadn’t been prescribed Fentora by a doctor.
Fentora is a fast acting version of Actiq, an earlier pain reliever sold by Cephalon. Actiq, sold as a lozenge on a stick, has been implicated in over 120 fatalities, including the deaths of two children who thought the drug was candy. An investigation by the Wall Street Journal in November found that 80-percent of patients taking Actiq did not have cancer. It appears that many patients are also being prescribed Fentora for ailments that it is not approved to treat.
Now, three separate investigations are underway to determine if Cephalon is marketing Fentora for off-label use. An investigation being conducted by the Connecticut Attorney General’s office has already determined that Cephalon actively promoted off-label use of Actiq. The US attorney in Philadelphia and a congressional probe are also looking into Cephalon’s marketing of Fentora. The Wall Street Journal is reporting that a person familiar with the matter said Cephalon is "in active discussions" about a possible settlement with the Connecticut attorney general and the U.S. attorney in Philadelphia. According to the Journal, any such settlement would involve a large fine and require that Cephalon take remedial measures to reform its aggressive marketing practices.