On September 26, 2007, the United States Food and Drug Administration (FDA) warned health-care professionals and potential users about risks involving Cephalon Inc.’s cancer drug Fentora (fentanyl buccal) after reports of deaths and dangerous side effects.

Fentora, manufactured by Frazer, Pennsylvania-based Cephalon Inc., is a powerful opioid pain medication approved solely for the treatment of breakthrough pain in cancer patients who have developed a tolerance to their existing opioid pain treatments. Intense, increasing pain occurring at rapid onset is called breakthrough pain.

Breakthrough pain can occur even when opioid medication has been administered. Daily, around the clock usage of narcotic pain medicine by patients can build tolerance to pain medication, making them more resistant to the dangerous side effects of potent opioids like Fentora. Fentora is designed for occasional use in these types of patients. Patients who do not take narcotic pain medications, or take them on a less frequent basis, may not be as resistant to Fentora’s risks.

The Public Health Advisory and Health Care Professional Sheet published September 26, 2007 by the FDA warned health care professionals to follow product label when giving Fentora to patients. The FDA states it is extremely dangerous to administer Fentora for short-term pain ailments such as headaches or migraines.

The FDA also expressed concern over the improper substitution of Fentora for other pain medicines, due to the fact that Fentora is fast-acting. It warns not to substitute Fentora for Actiq, another fentanyl-based cancer drug, as Fentora releases more fentanyl into the blood, posing a risk of potential drug overdose.

The FDA asked Cephalon to improve the warnings and dosing instructions in Fentora’s labeling. The FDA also asked Cephalon to improve healthcare provider education on proper patient selection, dosing and restrictions on Fentora substitutions.

Source: U.S. Food and Drug Administration, “FDA Warns of Potential Serious Side Effects with Breakthrough Cancer Pain Drug,”, September 27, 2007.

Over the week of September 17, 2007, Cephalon Inc., creator of cancer drug [Fentora]/companies/cephalon-inc/fentora.php, sent warning letters to doctors regarding several deaths linked to the drug.

[Fentora]/companies/cephalon-inc/fentora.php is a U.S. Food and Drug Administration (FDA) approved drug to treat acute cancer pain. Although [Fentora]/companies/cephalon-inc/fentora.php is approved by the FDA only to treat cancer patients, some physicians have prescribed the drug “off-label” for unapproved purposes such as headache and back pain relief.

According to Cephalon, [Fentora]/companies/cephalon-inc/fentora.php was linked to a total of four deaths. Cephalon reported that three deaths are the result of apparent [respiratory failure]. The fourth death was a man taking the drug who committed suicide.

Cephalon blamed the deaths on inappropriate prescription of the drug, but the FDA has not addressed fault in the situation. “We have been monitoring this issue. The FDA takes this very seriously, and we are working with the company to assure the safest possible use of this medication,” said FDA spokeswoman Susan Cruzan.

The Connecticut Attorney General began investigating Cephalon in 2004, when an allegation was raised against the company that it was marketing Fentora’s, off-label to doctors to treat headaches.

Cephalon has not released a comment regarding the investigation.

Source: “Cephalon Drug Is Tied to Several Deaths,” WSJ.Com, September 19, 2007.

On June 19, 2007, a federal jury awarded $5.5 million to Lee Hendelson after his 28-year-old son, Adam, died from using Johnson & Johnson’s pain-killing Duragesic patch. The patch contains a powerful painkiller fentanyl, which can be lethal if a person consumes too much.

The Duragesic lawsuit came a year after a jury in Houston awarded $772,500 to the daughter of a woman who died while wearing the patch. The U.S. Food and Drug Administration (FDA) said in 2005 it was investigating 12 deaths among people who used fentanyl.

Source: Birmingham Business Journal, “Gulas and Stuckey attorney wins $5.5 million.” June 20, 2007.

The father of a 28-year-old man who died after an overdose from a Johnson & Johnson pain-killing patch is suing the pharmaceutical giant for damages. Lee Hendelson of West Palm Beach, FL is seeking damages after his son, Adam, died from using the Duragesic patch to relieve lingering pain from a car accident.

The active ingredient in the Duragesic patch, fentanyl, is a pain killer 100 times more potent than morphine.

“Clearly this patch did not perform as designed because it killed Adam Hendelson,” Mr. Hendelson’s personal injury attorney Jim Orr said during closing arguments. “Millions of dollars would be appropriate…Whether it’s $5 million or $3 million or $10 million.”

On June 18, 2007, the case was before a jury in Miami after a two-week-long-trial. There has not yet been a Duragesic patch recall.

Sources: Jane Musgrave, Palm Beach Post, “Jury deliberating in pain-killing patch trial.” June 18, 2007.

A new study by Prime Therapeutics, a pharmacy benefit management company, released data on the use of Actiq lollipops for pain relief that suggested the drug may be misused. The study found that 90 percent of prescriptions written for Actiq are for off-label uses not approved by the FDA. Clients of Prime Therapeutics include Blue Cross/Blue Shield and other major health plans.

The Actiq lollipop, a berry flavored lozenge on a stick, is an orally dissolvable form of fentanyl citrate manufactured by Cephalon. The opiate fentanyl is also available dispensed in patch form or in vials for injection. When taken in excess, or in conjunction with medicines that enhance their effects, opiates may depress respiratory function or even cause breathing to stop. Patients who use alcohol or other sedatives, tranquilizers or pain medications while taking fentanyl in any form are at high risk for respiratory failure. The most threatening danger of the misuse of Actiq is death by respiratory failure.

Prime Therapeutics’ research group consisted of Actiq patients accessed through health plan claims from April 2005 through June 2005. Only 21 of the 95 patients receiving prescriptions for Actiq actually had cancer, the therapeutic use for which Actiq is approved. Ninety percent of the Actiq prescriptions were for other uses. More than 15 percent of the prescriptions exceeded the FDA’s recommended dosage of 120 lollipops per month. These data imply an overuse of the medication by these off-label usage patients.

Many chronic pain patients will need increases in medication dosage over time in order to cover their pain. The off-label use of the Actiq lollipop and its overuse suggests that some patients using this medication may be at risk for drug abuse.

In 2006 Prime Therapeutics offered their clients a program for promoting the safe use of Actiq. The program recommendations included:

• prior authorization from doctors for use of Actiq,
• a limit of 120 doses of Actiq per patient per month,
• and a limit of one year for using Actiq.

Chronic pain can be caused by many different disorders. Anyone suffering from chronic pain should consult their doctor about the dangers of using Actiq. For all patients using Actiq, it is imperative to keep Actiq lollipops, which a child could mistake for candy, stored in a safe, childproof area of the home.

Sources: “Study: Most pain lollipops given off-label,” United Press International, January 16, 2007; “Study finds 90 Percent of Actiq “˜Lollipop’ Prescriptions are Off-label,” Prime Therapeutics Release, January 16, 2007.

Duragesic is the leading brand of a narcotic pain patch containing fentanyl, a drug under investigation by the FDA due to reports of adverse respiratory events experienced by patients wearing the patch. Affected patients experienced severe shortness of breath, fatigue, and in some cases their breathing seems to shut down entirely.

An investigation by the Los Angeles Times reported today that the Los Angeles County Coroner’s office alone has investigated more than 230 deaths involving fentanyl. Of those 230-plus cases, 127 were classified as “accidental deaths,” suggesting that the victims had inadvertently received too much of the drug through the pain patch.

Fentanyl patches * were developed for use by cancer patients, who are usually monitored closely by physicians. Increasingly, however, the Duragesic patch* is being prescribed for other conditions, sometimes without close monitoring. The LA Times report cited the case of a 76-year-old retired paralegal with severe back pain who was prescribed the patch and developed shortness of breath and severe fatigue while on the patch.

The LA Times report also cited 115 additional fentanyl deaths from the state of Florida in the year 2004, as well as an alarming rise in emergency-room cases involving the drug. According to the federal Substance Abuse and Mental Health Services Administration, emergency-room admittals involving fentanyl rose from 28 in 1998 to 1506 in 2004.

Duragesic sales have more than doubled between 2000 and 2004, with more than $1.2 billion in sales in 2004, yet reports of adverse events related to the Duragesic patch began occurring as early as 2001, less than a year after the patch was approved for sale in the U.S. The FDA did not issue a safety alert on the Duragesic patch until July 15, 2005. Currently there are more than 4 million prescriptions written for the Duragesic patch annually.

Source: Ricardo Alonso-Zaldivar, “FDA Slow to Sound Alarm on Pain Drug, ” Los Angeles Times, November 25, 2005.

In 1998, the Food and Drug Administration (FDA) approved Actiq, a potent narcotic, for use only in cancer patients who suffer intense bouts of pain that other narcotics don’t relieve.

But recent studies have shown cancer doctors account for only one percent of the thousands of Actiq prescriptions filled at retail pharmacies in the United States. Data gathered between June 2005 and October 2006 even suggests that more than 80 percent of patients who use the drug do not have cancer.

Instead, doctors are prescribing it “off label” for nonapproved uses, including headaches or back pain.

The FDA prohibits pharmaceutical companies from marketing their drugs for off-label use because, while off-label prescribing isn’t illegal, it is dangerous. Especially for a drug like Actiq.

Actiq contains fentanyl, a highly addictive substance that is 80 times as potent as morphine. The Drug Enforcement Administration (DEA) classifies fentanyl as a Schedule II substance, meaning it has the highest potential for abuse and associated risk of fatal overdose, and puts the substance in the same category as opium, cocaine and methamphetamine.

The drug acts quickly, providing relief within 15 minutes of consuming the fentanyl lozenge.

Actiq has been associated with the following adverse events:

• 127 deaths, including two children who confused the drug for candy
• 47 overdoses or other misuse
• 91 serious, nonfatal incidents, ranging from respiratory distress to severe dehydration

Cephalon Inc., Actiq’s maker based in Pennsylvania, said it does not market the drug for unapproved uses. While acknowledging that the drug is widely used off-label, Cephalon said it cannot control how doctors prescribe the drug.

The company, however, has sent representatives to a broad range of doctors, including sports-medicine specialists and family practitioners, to pitch the drug. It also gave these doctors dozens of coupons for free samples that patients can trade in for six Actiq sticks.

The United States attorney’s office in Philadelphia said it is investigating Cephalon’s marketing practices in connection with Actiq.

Source: John Carreyrou, “Narcotic ‘lollipop’ becomes big seller despite FDA curbs,” Wall Street Journal, November 3, 2006.

The U.S. FDA issued a Public Health Advisory today to warn patients about increasing numbers of reports of death and other serious side effects in patients using fentanyl transdermal skin patches for pain control. Fentanyl is the active ingredient in the brand name pharmaceutical product Duragesic, manufactured by Johnson & Johnson, and is also available in generic form, manufactured by Mylan Laboratories. Fentanyl is an extremely strong narcotic pain killer that can cause death from overdose and may be linked to 120 deaths being investigated by the agency.

Signs of fentanyl overdose include:

• Trouble breathing or shallow breathing
• Tiredness, extreme sleepiness or sedation
• Inability to think, talk, or walk normally
• Feeling faint or dizzy
• Mental confusion

Patients exhibiting signs of overdose should be given medical attention immediately. These patches are normally prescribed for cancer patients, burn victims and others experiencing excruciating and continual pain. It gained notoriety in 2002 when Russian authorities attempted to end a hostage crisis at a Moscow theatre by pumping in a sleeping gas reported to contain fentanyl. Although the authorities meant to put the hostages and their Chechen captors to sleep, 120 of the 750 hostages died from breathing the gas.

Patients overdosing on fentanyl experience a decrease in the lung’s drive to breathe. Patients usually become comatose prior to death. Prescriptions for Duragesic reached 4 million in 2004.

The FDA issues the following strong warnings concerning Fentanyl:

• The Duragesic (fentanyl) skin patch should always be prescribed at the lowest possible dose needed for pain relief
• The Duragesic (fentanyl) skin patch should only be used if a patient has been taking at least 60 mg or oral morphine, at least 30 mg of oral oxycodone, or at least 8 mg of oral hydromorphone daily for a week or longer
• Duragesic (fentanyl) skin patches should not be used to treat short-term pain, pain that is not constant, or for pain after an operation
• Duragesic (fentanyl) skin patches should be stored in a safe place, out of the reach of children
• Potentially fatal effects from Duragesic (fentanyl) can be stronger if the patient drinks alcohol or uses other medications that affect brain function
• Potentially fatal effects from Duragesic (fentanyl) can be stronger if patients have an increase in body temperature or exposed to heat
• Do not use the Duragesic (fentanyl) skin patch if you have acute (sudden) or severe asthma
• Do not use the Duragesic (fentanyl) skin patch if you have a gastrointestinal problem known as paralytic ileus

Sources: Ricardo Alonso-Zaldivar, “Pain-Relief Patch is Investigated in Patient Deaths,” Los Angeles Times, July 16, 2005; “Mylan will work with FDA on Pain Patch Probe,” Reuters, July 18, 2005.