Fentanyl transdermal patch and fatal adverse reactions

This article was forwarded to me by Pharmacy and comes from The Canadian Adverse Reaction Newletter. I thought it might be of interest to you.

The fentanyl transdermal system is indicated for the management of moderate to severe chronic pain that cannot be managed by other means such as opioid combination products or immediate-release opioids.1 The safety of this system is contingent on its use according to the conditions recommended in the Canadian product monograph.1 The fentanyl transdermal system has been marketed in Canada under the brandname Duragesic since 1992. In July 2006, 2 generic products were introduced: Ratio-Fentanyl and Ran-Fentanyl transdermal systems.
Health Canada continues to monitor reports of serious adverse reactions (ARs) suspected of being associated with fentanyl transdermal patches. Fatal outcomes were previously described in this newsletter involving opioid-naive adolescents and adolescents who abused this medication.2,3 The Canadian product monograph for Duragesic was revised in 2005 to emphasize safety information following reports of death related to inappropriate use of this product. Related advisories were issued in September 2005.4,5 Numerous publications have highlighted safety issues related to the use of fentanyl patches.6‑9
From Jan. 1, 1992, to Dec. 31, 2007, Health Canada received 105 reports of ARs suspected of being associated with fentanyl transdermal patches wherein a fatal outcome was reported. Twenty-seven of the reports were received after the last Health Canada risk communications.4,5 As part of the ongoing monitoring of AR reports, the data were analyzed to identify potentially preventable incidents and to increase awareness regarding the safe use of this product. In 33 of the 105 reports, the cause of death was reported to be unrelated to the fentanyl transdermal patches; in 20 cases, insufficient information was provided in the report for evaluation. The remaining 52 reports are summarized in Table 1.
Health care professionals are reminded to follow the directions in the product monographs for fentanyl transdermal patches.1 Guidance on the safe use of this product is essential for patients, caregivers and their families, including the safe storage of fentanyl patches to prevent their accessibility for abuse and prevention of accidental overdose.
Marielle McMorran, BSc, BSc(Pharm); Maria Longo, BScPharm, Health Canada
Acknowledgement: Health Canada acknowledges the collaboration with Sylvia Hyland, RPh, BScPhm, MHSc (Bioethics), of the Institute for Safe Medication Practices Canada (ISMP Canada) and member of the Expert Advisory Committee on the Vigilance of Health Products, in the analysis of this data and preparation of this article.
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Table 1: Summary of reports of 52 adverse reactions with a fatal outcome suspected of being associated with fentanyl transdermal patches submitted to Health Canada from Jan. 1, 1992, to Dec. 31, 2007*,†

Dose initiation and titration (6 Adverse Reactions-AR) Prescribed to opioid-naive patient (3 cases). Initiation dose high (1 case). Dose titration too quick (2 cases) Concomitant use with other central nervous system (CNS) depressants ( 1 case)

Death occurred within 24 hours after initiation of 100-µg/h fentanyl patch. Cause of death reported as probable central nervous system depression due to combination of fentanyl with other CNS depressants. (1 case)

Drug interaction between fentanyl and CYP3A4 inhibitor (1case) Death occurred less than 4 days after initiation of lopinavirBritonavir (Kaletra), a CYP3A4 inhibitor, during fentanyl therapy

Application of patch by patient (6cases total)
Patient applied more patches than prescribed (4 cases). Patient left old patches on when applying new patch (1 case). Patient changed patch every day instead of every 3 days (1 case)

Application of patch by caregiver (3cases)
Health care professional folded patch in half in attempt to reduce dose (1 case). Health care professional left old patches on when applying new patch (1 case). Caregiver damaged patch by pressing on it because it would not stick; fentanyl gel leaked and patient died of accidental overdose overnight (1 case)

Use of patch prescribed for another patient ( 1 case) To treat back pain, a 64-year-old man applied a 50-µg/h fentanyl patch that had been prescribed for his spouse. The patient was found unresponsive, having vomited and aspirated, and died 5 days later from pneumonia and renal failure

Accidental overdose or overdose effect (5 cases) Patient was elderly and had lean body weight
(1 case). Patient died of cardiac arrhythmia due to accidental overdose of fentanyl and elevated levels of antidepressant (1 case). Patient found dead with toxic level of fentanyl after second dose of 25-µg/h patch (1 case). Limited information provided in 2 cases

Intentional overdose or suicide (4 cases)

Intentional drug abuse (25 cases) Cases described abuse of fentanyl patches

* These data cannot be used to determine the incidence of adverse reactions (ARs) because ARs are underreported and neither patient exposure nor the amount of time the drug was on the market has been taken into consideration.
† The analysis is based on the information as reported in the cases.
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References
1. Duragesic (fentanyl transdermal system) [product monograph]. Toronto: Janssen-Ortho Inc; 2007.
2. Raymond B, Morawiecka I. Transdermal fentanyl (Duragesic): respiratory arrest in adolescents. Can Advers Reaction News 2004;14(4):1-2.
3. Raymond B. Trandermal fentanyl (Duragesic): abuse in adolescents. Can Advers Reaction News 2005;15(3):1.
4. Duragesic (fentanyl transdermal system) safety information [Dear Health Care Professional letter]. Ottawa: Health Canada; 2005 Sept 13. (accessed 2008 Jun 3).
5. Duragesic (fentanyl transdermal system) safety information [public advisory]. Ottawa: Health Canada; 2005 Sept 16. (accessed 2008 Jun 3).
6. Transdermal fentanyl: a misunderstood dosage form. ISMP Canada Safety Bull 2006;6(5).
7. Fentanyl patch linked to another death in Canada. ISMP Canada Safety Bull 2007;7(5).
8. Ongoing, preventable fatal events with fentanyl transdermal patches are alarming! Horsham (PA): Institute for Safe Medication Practices; 2007 June 28.
9. Fentanyl transdermal system (marketed as Duragesic and generics) information for Healthcare Professionals. Rockville (MD): US Food and Drug Administration; 2007 Dec 21. (accessed 2008 Jun 3).