Personal Injury Law Firms experienced in negligence, malpractice and other types of personal injury actions have taken note of recent product liability actions involving the drug, Duragesic.
Duragesic® is the trade name for a pain-medication patch containing fentanyl, a potent opioid analgesic. Duragesic is a transdermal system-the medicine, fentanyl, is absorbed through the patient's skin and into the bloodstream, providing pain relief for up to three days (72 hours) from a single patch application.
Duragesic is prescribed in five dosage strengths: 12, 25, 50, 75 and 100 mcg of fentanyl per hour. The 50, 75, and 100 ug/h doses are only prescribed for patients who are already on and tolerant to opioid therapy, and require continuous opioid administration. Moreover, the Duragesic label warns that 12 mcg/hour as an initiating dose has not been systematically evaluated; therefore, Duragesic should be used only in patients who are opioid-tolerant.
Fentanyl was found to be a good choice for transdermal application because of its physicochemical properties and high analgesic potency. However, Fentanyl is not without its serious adverse effects. Pharmacologically, fentanyl acts on the central nervous system causing analgesia, sedation, severe respiratory depression, muscle rigidity, seizures, coma, and hypotension. Adverse reactions include mood changes, euphoria, dysphoria, drowsiness, constricted pupils, nausea, and vomiting. The most serious side effect of fentanyl overdose is hypoventilation (respiratory depression), which can be fatal.
Development of Duragesic
Currently, only eleven transdermally administered drugs are on the market; seven of which were developed by ALZA. In 1981, ALZA responded to a plea from a White House-created committee of scientists and physicians to develop more potent analgesics with alternative delivery systems for critically ill and dying patients who were suffering from intractable pain. ALZA began work on a project to develop a fentanyl transdermal patch in late 1982.
In early 1983, ALZA representatives met with agents from the DEA to discuss the handling of fentanyl. Among other issues, the DEA expressed concern that the dosage be kept to an absolute minimum, because of the potential for overdose and abuse.
In 1991, ten years after ALZA proposed the development of a transdermal fentanyl patch, Duragesic was made available for sale in the United States. Originally, Duragesic was approved to treat acute, postoperative and moderate-to-severe pain. However, due to the slow onset of drug levels from the transdermal delivery and three day maintenance of drug levels with Duragesic, the system was more suited for treatment of chronic pain conditions, in particular, cancer patients. By 1998, the World Health Organization (WHO) recommended transdermal fentanyl for treatment of cancer pain in stable patients.
Since receiving FDA approval in 1990, ALZA and Janssen aggressively sought the expansion of Duragesic use beyond cancer patients. For example, transdermal fentanyl has been used to treat rheumatologic pain and severe back pain.
The FDA has also approved an expansion of Duragesic to treat pediatric patients.
Janssen's most recent advertising campaign to expand the use of Duragesic was thwarted by the FDA. In the late 1990s, the company sent a document called Top Ten List to doctors urging physicians to switch their patients to Duragesic patches rather than use more traditional type pain relievers. Among the reasons listed is the phrase "It's not just for end stage cancer any more!" However, in 2000, the Department of Health and Human Services wrote a letter to Janssen informing the company that its promotional pieces concerning the "Broadening of indication" for Duragesic were misleading and contained misrepresentations. The government agency responded, "The suggestion that Duragesic can be used for any type of pain management promotes Duragesic for a much broader use that is recommended by the PI, and thus, is misleading."
Currently, Duragesic is the most widely prescribed transdermal medication. From 2002 to 2003, the total number of fentanyl patch prescriptions within the United States rose from 4.5 million to 5.4 million-a twenty percent increase. And the resulting sales figures for Duragesic have been enormous: total annual sales in the United States have reached one and a half billion ($1,500,000,000.00) dollars annually.
And in 2005, Duragesic sales generated two point one billion ($2,100,000,000.00) dollars worldwide.
Duragesic Defects:
Package Leak-Subsequent Recalls
The design/manufacturing defect most applicable to our case is an improper sealing of one edge of the Duragesic patch, resulting in millions of patches being recalled. During 2004, ALZA (through Janssen) initiated two large Class I recalls of Duragesic for this exact reason. The first was February 17, 2004 at which time Duragesic Control No. 0327192 (75 mcg/hr) was pulled from the market. The cited reason was a potential seal breach on one edge of the patch, which could result in fentanyl leaking from the patch. This recall included about 440,000 patches.
On April 5, 2004, Janssen expanded its recall of Duragesic to include 2.2 million patches (Control Numbers 0327192, 0327193, 0327294, 0327295, and 0330362). Again, the reason cited was the potential for a breach of the seal, which would result in fentanyl leakage. Janssen sent a "Dear Healthcare Professional" letter to inform of the expanded recall.
A leak of fentanyl from a Duragesic patch could cause patients to receive either too much or too little of the drug. If the fentanyl seeps out of the patch before its application to the skin, patients may receive too little medication to adequately treat their pain. In this situation, patients used to a specific does may experience withdrawal effects including sweating, sleeplessness, and abdominal discomfort.
Conversely, fentanyl leaks that occur while the patch is on the skin expose patients to a potentially life-threatening overdose of fentanyl. Duragesic is designed to deliver only a controlled amount of fentanyl into the patient's skin. Patients wearing a defective patch that leaks fentanyl directly onto the skin will receive too much of the medication. If this occurs, patients could experience minor complications such as sedation, drowsiness, and nausea. Fentanyl overdose may result in more serious complications, including fatal hypoventilation (respiratory depression) or cardiac arrest.
When Jansen placed Duragesic on the market in 1991, reports of toxicity due to fentanyl overdosing were fairly common. In fact, one study in California of 112 deaths associated with fentanyl concluded that the general availability of the drug may be responsible for the high incidence of overdoses.
Furthermore, in a recent Duragesic lawsuit filed against Johnson & Johnson, Janssen, and ALZA, the plaintiffs alleged that "despite knowing of this defect, the defendants (Johnson & Johnson, Janssen, ALZA) took inadequate steps to advise physicians, hospitals, nursing homes and other health care professionals of the defect and the significant damages to users of the Duragesic patches."
Heat-Induced Overdose
ALZA and Janssen's knowledge of the overdosing potential caused by external heat dates back to 1986, when ALZA did lab testing on a nitroglycerin-delivering patch using the same co-polymer membrane used in Duragesic patches. ALZA subsequently did lab testing on Duragesic in 1988-that showed that a five degree Centigrade increase in temperature doubled Duragesic's release rate. Dr. Curtis Wright, the FDA Medical Review Officer, was quite concerned in 1989 and again in 1990 that ALZA had not responded to his request for more information on the effects of external heat. After Duragesic hit the market in April of 1991, ALZA and Janssen learned of six reports from healthcare providers that external heat appeared to increase blood fentanyl levels in patients in the hospital setting and at home.
However, the first time Janssen or ALZA made an effort to warn of the effects of external heat came in a January 17, 1994 "Dear Doctor" letter with an attached proposed labeling revision. The labeling contained a new heat warning, which was buried at page 10 of the attachment, but no mention was made in the letter itself to alert physicians that external heat applied to the patch was potentially life-threatening.
GOVERNMENT REGULATION
In 2004, the FDA influenced Janssen and ALZA to issue two Class I Recalls of Duragesic, "due to improper sealing of one of their edges," which could result in a life-threatening overdose of fentanyl. Yet, this was not the first time the FDA encountered problems with the companies' handling of Duragesic. In fact, prior to the recalls in 2004, the FDA has required Duragesic labeling revisions 13 times.
And, as recently as July 2005, the FDA issued a Public Health Advisory concerning the use of Duragesic Patches in response to reports of deaths in patients using the patch.
Beginning in 1994, the FDA sent ALZA a "warning letter" identifying certain violations and deviations from Good Manufacturing Practices (GMP) regulations under the Food and Drug Act. This prompted the company to issue a letter to all health care professionals warning of Duragesic misuse.
In the late 1990s, the Department of Health and Human Services warned Janssen that its promotional materials to expand the use of Duragesic were in direct violation of the Federal Food, Drug, and Cosmetic Act and contained misrepresentations as to the safety and efficacy of the product. The agency determined that the promotional pieces were "false or misleading because they contain misrepresentations of safety information, broaden Duragesic's indication, contain unsubstantiated claims, and lack fair balance."
Following Janssen's "voluntary" recall of Duragesic in 2004, the FDA issued a "Safety Alert" warning that the recall was "due to a potential leak in the product seal," which could result in skin exposure to fentanyl. The warning adds that "skin exposure to any leaked medication from a DURAGESIC patch may cause nausea, sedation, drowsiness, or potentially life-threatening complications." Govt Regulation 6. Janssen also wrote a letter to "Healthcare Professional[s]" informing them of the expanded recall in April 2004.
Furthermore, on September 2, 2004 the FDA issued Janssen another "warning letter." This letter states that the latest Duragesic promotional pieces make "false or misleading claims about the abuse potential and other risks of the drug, including unsubstantiated effectiveness claims for Duragesic." The letter states, "By suggesting that Duragesic has a lower potential for abuse compared to other opioid products, the file card could encourage the unsafe use of the drug, potentially resulting in serious or life-threatening hypoventilation."
The Duragesic product label was again updated in June 2005 to add new safety information in several areas of labeling, and Janssen issued another "Dear Healthcare Professional" letter about these changes. Under a section entitled "Hypoventilation (Respiratory Depression)," the letter warns that "Serious or life-threatening hypoventilation may occur at any time during the use of DURAGESIC® especially during the initial 24-72 hours following initiation of therapy and following increases in dose." Janssen also warns of a "potential for temperature-dependant increases in fentanyl released from the system resulting in possible overdose and death." Therefore, the letter instructs all patients to avoid exposing Duragesic to "direct external heat sources, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system."
Finally, on July 15, 2005 the FDA issued a "Public Health Advisory" concerning the use of Duragesic Patches in response to reports of deaths in patients using the patch. The FDA stated it is conducting an investigation into the deaths related to fentanyl overdose in patients using Duragesic. According to the FDA, "Some patients and health care providers may not be fully aware of the dangers of this very strong narcotic painkiller. Therefore, FDA is issuing this public health advisory to alert patients and their caregivers and health care professionals by highlighting the following important safety information."
MEDICAL LITERATURE
Fentanyl Overdose
Since Duragesic hit the marketplace in 1991, studies have shown continued high numbers of overdoses involving transdermal delivery of fentanyl. The most serious side effect is respiratory depression, which can be fatal. One study, published in 1991, examined 112 fentanyl-related deaths in the Eastern United States, mostly in California. Fentanyl deaths appeared to occur rapidly, "probably the result of acute respiratory depression." While acknowledging the extreme potency of fentanyl, the author suggests that "the incidence of fentanyl-related deaths is probably determined by the general availability of the drug, rather than the relative potency of the analogs."
In a study published in 2000, the Los Angeles County Department of the Coroner analyzed 25 cases involving fentanyl-related deaths. The author notes that the Los Angeles County Coroner's Office evaluates nearly one case each month involving fentanyl patch-related death. Another study that same year identified 61 cases of transdermal drug overdoses in a Regional Poison Information System over a five-year period.
Head-Induced Overdose
Heat is expected to increase skin permeability, metabolism and elimination of fentanyl. If drug release from the system is much faster than permeation through the skin, the skin controls the transdermal absorption rate into the patient's systemic circulation, rather than Duragesic's special rate control membrane.
Several case reports have described the development of life-threatening overdose caused by a heating pad or rise in body temperature. Frolich et al. reported a narcotic overdose in a patient that was using a warming blanket to relieve pain following surgery. Medical Literature 17, see M.A. Frolich et al., Opioid Overdose in a Patient Using a Fentanyl Patch During Treatment with a Warming Blanket, 93 ANESTH. ANALG. 647-48 (2001) (unable to obtain hard copy). The increase in absorption may account for other heat-related toxicity associated with transdermal fentanyl. G. Newshan, Heat-Related Toxicity with the Fentanyl Transdermal Patch, 16 J. PAIN SYMPTOM MGMT. 277-78 (1998) (unable to obtain hard copy).
One study, in 2003, examined the effect of heat on transdermal fentanyl absorption. The authors concluded that increases in skin temperature may result in increased systemic absorption of fentanyl. Therefore, warming blankets and heating pads should not be either used in conjunction with, or placed over Duragesic patches.
However, as of 2003, the Duragesic label warned that serum fentanyl concentrations may "theoretically" increase by one third in patients with a body temperature of 40 degrees Celsius because of accelerated drug release and increased skin permeability. The current label warns of a "potential for temperature-dependent increases in fentanyl release from the system."
