Transdermal drug delivery system exposure outcomes

The Journal of Emergency Medicine, Vol. 18, No. 2, pp. 147–151, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/00 $–see front matter

PII S0736-4679(99)00185-7

Original Contributions

TRANSDERMAL DRUG DELIVERY SYSTEM EXPOSURE OUTCOMES Raymond J. Roberge,

MD, MPH, FAAEM, ACMT,*

Edward P. Krenzelok,

PharmD, FAACT,†

and Rita Mrvos,

BSN†

*Department of Emergency Medicine, Western Pennsylvania Hospital; and †Pittsburgh Poison Center of Children’s Hospital, Pittsburgh, Pennsylvania Reprint Address: Raymond J. Roberge, MD, Department of Emergency Medicine, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224

e Abstract—Transdermal drug delivery systems are increasingly popular, yet few data exist regarding medical outcomes after exposures. Using data collected through a Regional Poison Information System, this retrospective study identified 61 cases of transdermal drug delivery system exposures reported over a recent 5-year period. Exposure routes included dermal (48 patients), oral (10 patients), combined oral and dermal (one patient), parenteral use of gel residue (one patient), and combined oral and parenteral (one patient). Forty-four exposures (72%) were managed by home telephone consultation only. Eleven of 17 patients (18%) evaluated in health care facilities were admitted, including eight (13%) to intensive care units. Hospital admission correlated statistically with clonidine and fentanyl exposures, oral exposures, and drug abuse. Clonidine exposure also correlated statistically with intensive care admission. One fatality was recorded, and all other patients recovered uneventfully. Transdermal drug delivery system exposures are infrequently reported to our regional poison information center but are associated with a significant hospital use and admission rate. © 2000 Elsevier Science Inc.

The era of transdermal drug delivery system (TDDS) use in the United States was ushered in nearly 20 years ago with the introduction of Transderm Scop® (Ciba-Geigy, Summit, NJ), a scopolamine preparation used in the treatment of motion sickness (1). Currently, seven drugs (clonidine, estradiol, fentanyl, nicotine, nitroglycerin, scopolamine, and testosterone) are available as TDDSs (2). A number of other TDDS formulations, including calcium channel blockers (felodipine, diltiazem), nonsteroidal anti-inflammatory drugs (indomethacin), and psychotropic medications (buspirone), are in developmental stages or undergoing field trials (3–5). Occasional singlecase reports of adverse effects after TDDS exposure exist, but case series are few in number and relegated to nicotine TDDSs (6). This study was undertaken to evaluate medical outcomes of TDDS exposures reported to a certified Regional Poison Information Center (RPIC) during a 5-year period and to identify any parameters that were associated with emergency department (ED) use or hospital admission.

e Keywords—transdermal drug delivery systems; exposures; toxicity; outcomes

MATERIALS AND METHODS

Some of the data contained herein were used by Dr. Roberge in a graduate essay as partial fulfillment of requirements for a master of public health degree.

A retrospective case series of TDDS exposures was developed using toxico-surveillance data from the Pittsburgh RPIC, an American Association of Poison Control Centers (AAPCC)-certified RPIC serving a 27-county

INTRODUCTION

Original Contributions is coordinated by John A. Marx,

RECEIVED: 23 March 1999; FINAL

SUBMISSION RECEIVED:

MD,

of Carolinas Medical Center, Charlotte, North Carolina

4 June 1999; ACCEPTED: 16 June 1999 147

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Table 1. Toxic Exposure Surveillance System Medical Outcome Scores Score Outcome 0. No effect (exposure without evident effect). 1. Minor effect (minimally bothersome symptoms that usually resolve rapidly and often are limited to skin or mucous membrane manifestations. Examples are self-limited gastrointestinal symptoms, drowsiness, simple tachycardia without hypotension, first-degree thermal burn). 2. Moderate effect (more pronounced, prolonged, or systemic symptoms for which treatment is, or would be, indicated. Symptoms are not life-threatening, and the patient returns to the pre-exposure state of well-being with no residual disability or disfigurement. Examples are acid-base disturbances, high fever, disorientation, hypotension). 3. Major effect (life-threatening symptoms or significant disability or disfigurement. Examples are patients requiring intubation and mechanical ventilation, cardiac arrest, esophageal stricture, and cyanosis with respiratory depression). 4. Death (patient dies as a result of the exposure or a direct complication of the toxic exposure). 5. Case not followed, judged non-toxic exposure. 6. Case not followed, minimal clinical effects possible. 7. Unable to follow, judged potentially toxic exposure (patient lost to follow-up). 8. Exposure probably not responsible for effect(s).

area with a population of 3,876,129 (1990 U.S. census). The RPIC is staffed by registered nurses and pharmacists who have passed the examination for Certified Specialist in Poison Information administered by the AAPCC. Study enrollment included any calls to the RPIC about TDDS exposures during the study period (1993–1997). TDDS cases were identified using the AAPCC’s Toxic Exposure Surveillance System (TESS) computerized database. All RPIC calls related to drug categories available as TDDSs were identified. Hospitalized patients were followed throughout their stay by telephone communication originating from the RPIC. A TESS Medical Outcome Score (Table 1) was assigned to each patient, as is routine for the RPIC (7). Institutional Review Board approval was not required as per existing institutional policies. Statistical analysis included ␹2 method for differences in proportions and Fisher’s exact test with associated confidence intervals (CI) and Odds Ratios (OR). A p value of ⬍.05 was considered statistically significant.

RESULTS During the study period, the RPIC averaged 52,200 human toxic exposure calls annually (1,346.7 calls/105 persons/year.). A total of 61 TDDS-related exposures were identified, equating to a reported average incidence of 3.15/106 persons/year for our region. There were 18 pediatric cases (⬍16 years of age) consisting of 13 females and five males, and 43 adults (30 females, 13 males). TDDS exposures consisted of: clonidine (five pediatric, three adults), fentanyl (17 adults, one pediatric), nitroglycerin (nine pediatric, seven adults), nicotine (12 adults, three pediatric), estradiol (three adults), and combined clonidine/nicotine TDDS (one adult). No exposures to testosterone or scopolamine were recorded. Routes of TDDS exposure consisted of oral (seven

adults, three pediatric), combined oral/dermal (one pediatric), parenteral use of gel residue (one adult), combined oral/parenteral (one adult), and dermal (34 adults, 14 pediatric). Intentional exposures consisted of: clonidine (two adults, one pediatric) and fentanyl (eight adults). Unintentional exposure breakdown was clonidine (four pediatric), fentanyl (three adults, one pediatric), nitroglycerin (nine pediatric), nicotine (seven adults, three pediatric), estradiol (one adult), and a mixed clonidine and nicotine exposure (one adult). Therapeutic misuse consisted of clonidine (one adult), fentanyl (six adults), nitroglycerin (seven adults), nicotine (five adults), and estradiol (two adults). Forty-four patients (72%) were managed solely by telephone consultation at home: clonidine (two), fentanyl (nine), nitroglycerin (29), and estradiol (four). Eight persons (13%) exposed to clonidine or fentanyl were admitted to intensive care units (ICU), and three adult patients with fentanyl exposures (5%) with altered mental states but stable vital signs were admitted to regular beds for extended naloxone therapy (additional boluses or continuous infusion) (Table 2). No difference was noted in admission rates between pediatric and adult cases (␹2; p ⫽ N/S). Six patients (10%) (two pediatric clonidine exposures, two adult nicotine exposures, and two adult fentanyl exposures) were treated and released from the ED (Table 2). Relative to all exposures, clonidine was statistically associated with hospital admission (Fisher’s 2-tail test, p ⫽ 0.02; OR 4.19 [CI 0.74 –23.83]), as was fentanyl (Fisher’s 2-tail test; p ⫽ 0.01; OR 6.20 [CI 1.29 –31.91]). Additionally, ICU admission correlated significantly with clonidine exposure (Fisher’s 2-tail test; p ⫽ 0.007; OR 12.25 [CI 1.69 –100.26]). Other identified risk factors for hospital admission included oral TDDS exposures (␹2 3.83; p ⫽ 0.05; OR 4.19 [CI 0.74 –23.83]) and exposures related to intentional drug abuse of TDDSs (␹2 12.20; p ⫽ 0.001; OR 14.0 [CI 2.54 – 87.61]). One adult patient who died after dermal exposure to

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Table 2. Hospital Use After TDDS Exposure Pt.

Age

Sex

TDDS

Unit

Signs and Symptoms

1

Adult

F

Fentanyl

ICU

2

29

F

Fentanyl

ICU

3

Adult

M

Clonidine

ICU

4

56

F

Fentanyl

ICU

5

12

M

Clonidine

ICU

6

6

F

Clonidine

ICU

7 8

2 66

F M

Clonidine Fentanyl

ICU ICU

9

76

M

Fentanyl

Reg

10

Adult

F

Fentanyl

Reg

11

31

M

Fentanyl

Reg

12 13 14 15

4 2 39 44

M F M F

Clonidine Clonidine Fentanyl Fentanyl

ED ED ED ED

16

65

F

Nicotine

ED

17

Adult

F

Nicotine

ED

Simultaneous use of 2 TDDSs; altered mentation, respiratory depression, partial response to naloxone Simultaneous use of two TDDSs; confusion, respiratory depression, acidosis Chewed and swallowed one TDDS; profound persistent bradycardia, hypotension, somnolence Simultaneous use of multiple TDDSs; coma, hypoxia, partial responses to repeated doses of naloxone Swallowed TDDS; comatose, hypotensive, bradycardia, partial response to naloxone Applied TDDS to multiple skin sites; coma, miosis, bradycardia, depressed respirations, no response to naloxone or nalmefene Ingested a “spent” TDDS; coma, bradycardia Cardiac arrest with multiple TDDSs; resuscitated, succumbed to anoxic encephalopathy TDDS ⫻ 2 days; hypotensive, lethargic, more alert and improved blood pressure with naloxone Chewed on several TDDSs; coma, respiratory depression, response to naloxone Swallowed TDDS and injected residue; somnolence, depressed respirations, response to naloxone Asymptomatic; parent-to-child skin transfer Asymptomatic; chewed “spent” TDDS Drowsy after applying TDDS that was cut in half Excessive use of TDDS ⫻ 2 weeks; drowsy, weak, dehydrated One-month TDDS use; excited, rapid speech, hypertensive, nausea Used a stronger dose TDDS ⫻ 24 hours; shaky, diaphoresis, lightheaded, nausea, vomiting

TESS MOS* 2 2 3 3 3 2 2 4 2 2 2 0 0 1 1 1 1

* Toxic Exposure Surveillance System Medical Outcome Score.

multiple simultaneous fentanyl TDDSs was the only fatality recorded in this study. All other patients recovered without sequelae.

DISCUSSION A TDDS consists of (from skin layer outward) a protective liner that is peeled away at application, an adhesive layer placed peripherally on the surface side, a ratecontrolling membrane, drug reservoir, and backing (2,8). The rate-controlling membrane is a polymer film of precisely controlled composition, morphology, and dimensions with pore characteristics, membrane thickness, and total contact area determining drug delivery characteristics (9). The increasing popularity of TDDSs is related to several associated favorable characteristics, including improved patient compliance because of ease of use, rate control of absorption resulting in steady blood concentrations, elimination of first-pass biotransformation allowing smaller drug doses to be used with resultant reduced incidences of side effects, elimination of gastric and intestinal irritation, and availability of mul-

tiple skin sites for application (8,10 –12). Disadvantages include lag time from application to therapeutic effect and skin irritation at the site of application (8). This study documented a relatively low number of TDDS exposures reported to an RPIC during a 5-year period. The actual incidence of TDDS-related toxicity in our region cannot be determined from our data because we are unaware of the total number of individuals using TDDSs in this region. Also, our cases may not represent the true number of potentially toxic TDDS exposures in our area since significant underreporting to regional poison centers is well-recognized, with as few as onequarter of actual poisoning cases and associated deaths reported (13,14). By comparison, during 1993, the Food and Drug Administration’s MedWatch program, a voluntary physician reporting system of adverse drug reactions, listed 228 cases and 21 cases, respectively, of nicotine and fentanyl TDDS adverse reactions in Pennsylvania and 223 cases of clonidine TDDS adverse reactions nationally (15). These data suggest that TDDS toxicity may be more common than our study data would indicate, though the overall incidence nationally is still low.

150

Eight patients (13%) with Grade 2– 4 symptoms on the TESS Medical Outcome Scores (7) were admitted to ICUs, accounting for 73% of study admissions and 47% of hospital use (combined admissions and ED use) (Table 2). This is a higher proportion of ICU admissions than for all human toxic exposures inclusive reported to our RPIC (4%) or nationally to the AAPCC (11%) in 1997 (16). TDDS-related hospital admissions are included in the general database of the AAPCC but are not subcategorized (e.g., ICU, monitored bed, regular bed), such that direct comparisons with our data could not be made. Clonidine demonstrated a statistically significant association with admission (p ⫽ 0.02) and ICU use (p ⬍ 0.007), a reflection of the drug’s potent pharmacologic effects (e.g., bradycardia, hypotension, central nervous system depression) (2), the exquisite toxic sensitivity of children to even small amounts of clonidine (17), and the possibility of prolonged toxicity from ongoing absorption from skin depot sites after removal of the offending TDDS (8,12). Fentanyl was associated with hospital admission (p ⫽ 0.01), but all the cases were related to intentional drug abuse (p ⫽ 0.007), a reminder of the drug’s abuse potential regardless of the product formulation. Seven of eight ICU patients recovered uneventfully, but one patient with multiple fentanyl TDDSs on his chest wall, who was initially resuscitated from cardiac arrest of unknown duration by prehospital personnel, died of anoxic encephalopathy. Several cases of suicide attempts using nicotine TDDSs have been reported recently, as well as one cardiac arrest in a patient using a nicotine patch while continuing to smoke (6,18,19). Oral exposures to a TDDS led to increased admission (p ⫽ 0.05), an expected finding considering the significant amount of drug incorporated into the TDDS reservoir during manufacture to maintain a concentration gradient across the skin (2). Thus, even a “spent” TDDS can contain significantly more drug than is delivered to the patient over the useful life of the patch. Six patients treated and released from EDs were either asymptomatic at the time of presentation or had mild symptoms as evidenced by their low TESS Medical Outcome Scores (⬍2). In the aggregate, 17 of 61 persons (28%) underwent some form of hospital intervention (regular admission, ICU, ED) (Table 2). Although we did not undertake a cost analysis, the fact that almost half of TDDS-related hospital uses resulted in higher-cost ICU admission suggests that significant health care costs may be incurred after TDDS exposure. Unintentional exposures to a TDDS occurred in a number of ways, including 10 pediatric exposures related to improper disposal of “spent” TDDSs, a recurring problem reported in the pediatric literature but one that is easily preventable through patient education (20). Two

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other children, one of whom has been reported previously (21), applied TDDSs in the mistaken notion that they were adhesive bandages, a recognized pediatric risk factor for poisoning because of similarities in size, shape, and flesh coloration (22). One of these patches had been retrieved from a waste receptacle, and the other had fallen off a caretaker. One woman became mildly toxic after mistakenly applying her roommate’s fentanyl patch for her own nicotine patch, another reminder of the potential for toxicity based upon the presence of multiple look-alike TDDSs in a domestic environment. Three individuals were exposed to a TDDS via person-to-person transfer in shared beds (e.g., child/parent, husband/ wife) or other close physical contact (e.g., lovemaking, wrestling) (22,23). Any alteration of the TDDS rate-limiting membrane can result in enhanced drug exposure and toxic effects, as occurred to one adult who became mildly intoxicated after cutting his fentanyl TDDS in half before application to decrease the dosage he was receiving (9,24). This resulted in spillage of the TDDS contents (fentanyl) onto a wider dermal contact area with resultant increased absorption. Two senile nursing home residents were observed chewing their TDDSs shortly after application to their anterior chest walls. This suggests that it may be prudent to apply TDDSs to difficult-to-reach anatomic areas (e.g., posterior thorax) in persons with altered mental states. One person, at his physician’s request, abruptly ceased using a fentanyl TDDS after 2 months of continuous use and experienced drug withdrawal symptoms. This illustrative case serves as a reminder that patients and physicians alike need to be aware of the possibility of complications such as withdrawal with dermally administered narcotics or rebound hypertension after withdrawal of TDDS clonidine (2). Another individual using two TDDSs (clonidine and nicotine) simultaneously adjacent to one another on the same extremity experienced minor toxic symptoms. Persons requiring the use of concomitant different TDDSs should apply each to a different anatomic region to preclude any local drug-drug interaction. The potential for significant toxicity exists with some TDDSs (most prominently fentanyl and clonidine) as evidenced by the 18% overall admission rate and proportional 73% ICU admission rate. Nonetheless, based on our study experience, we believe that the overall incidence of TDDS exposures is low. Limitations of our study include its retrospective nature, the need for reliance on telephone follow-up for clinical data of hospitalized patients rather than their medical records, and lack of a uniform instrument for determining the need for ICU admission. Significant risk factors for admission after TDDS exposure in this study included fentanyl or clonidine exposure, oral exposure, and intentional drug

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abuse. Increasing experience with pediatric exposures suggests that most accidental toxic exposures might be eliminated through proper storage of TDDSs and proper disposal of “spent” TDDSs in secure receptacles not within the reach of children (20,21). Some TDDS package inserts (i.e., fentanyl) suggest methods for

proper disposal (i.e., folding the adhesive end on itself and flushing down a toilet) (2). The devices’ increasing popularity, coupled with the development of newer TDDSs, suggests that intentional and accidental toxic exposures are likely to be reported increasingly in the future.

REFERENCES 1. Shaw JE, Prevo ME, Amkraut AA. Testing of controlled-release transdermal dosage forms. Product development and clinical trials. Arch Dermatol 1987;123:1548 – 66. 2. Physicians’ Desk Reference, 49th edn. Montvale, NJ: Medical Economics; 1995. 3. Myshko D. The little patient. R & D Directions 1997;3:23–30. 4. Rao PR, Diwan PV. Formulation and in vitro evaluation of polymeric films of diltiazem hydrochloride and indomethacin for transdermal administration. Drug Dev Ind Pharm 1998;24:327–36. 5. Diez I, Peraire C, Obach R, Domenech J. Influence of D-limonene on the transdermal penetration of felodipine. Eur J Drug Metab Pharmacokinet 1998;23:7–12. 6. Woolf A, Burkhart K, Caraccio T, Litovitz T. Self-poisoning among adults using multiple transdermal nicotine patches. Clin Toxicol 1996;34:691– 8. 7. Litovitz T. The TESS database. Use in product safety assessment. Drug Safety 1998;18:9 –19. 8. Berti JJ, Lipsky JJ. Transcutaneous drug delivery: a practical review. Mayo Clin Proc 1995;70:581– 6. 9. Balkamy TJ, Babin RW, Arenberg IK. Transdermal delivery of medications. Hosp Physician 1983;19:18 –27. 10. Nimmo WS. The promise of transdermal drug delivery (Editorial). Br J Anaesth 1990;64:7–10. 11. Burris JF. The USA experience with clonidine transdermal therapeutic system (Review). Clin Autonom Res 1993;3:391– 6. 12. Varvel JR, Shafer SL, Hwang SS, Coen PA, Stanski DR. Absorption characteristics of transdermally administered fentanyl. Anaesthesiology 1989;70:928 –34. 13. Blanc PD, Jones MR, Olson KR. Surveillance of poisoning and drug overdose through hospital discharge coding, poison control

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

center reporting, and the Drug Abuse Warning Network. Am J Emerg Med 1992;11:14 –9. Blanc PD, Kearney TE, Olson KR. Underreporting of fatal cases to a regional poison center. West J Med 1995;162:505–9. MedWatch, Rockville, Md: Food and Drug Administration, Public Health Service, Office of Epidemiology and Biostatistics. Litovitz TS, Smilkstein M, Felberg I, et al. 1996 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1997;15:447–500. Bamshad MJ, Wasserman GS. Pediatric clonidine intoxications. Vet Hum Toxicol 1990;32:220 –3. Engel CJ, Parmentier AH. Suicide attempts and the nicotine patch (Letter). JAMA 1993;270:323– 4. Sanchez P, Ducasse J-L, Lapeyre-Mestre M, et al. Nicotine poisoning as a cause of cardiac arrest? (Letter) J Toxicol Clin Toxicol 1996;34:475– 6. Caravati EM, Bennett DL. Clonidine transdermal patch poisoning. Ann Emerg Med 1988;17:175– 6. Killian CA, Roberge RJ, Krenzelok EP. “Cloniderm” toxicity: another manifestation of clonidine overdose. Pediatr Emerg Care 1997;13:340 –1. Reed MT, Hamburg EL. Person-to-person transfer of transdermal drug delivery systems; a case report (Letter). N Engl J Med 1986;314:1120. Roberts JR, Hogan K, Doyon S. Transdermal medication exchange: the case of the light-headed lover (Letter). JAMA 1993; 269:47. Klockgether-Radke A, Hildebrandt J. Opioid intoxication. Inappropriate administration of transdermal fentanyl. (German) Anaesthetist 1997;46:428 –9.