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