Transdermal Drug Delivery Systems: The Skinny on Cutaneous Reactions

TDSs have grown in popularity, but side effects that include dermatitis and contact allergic reactions are possible.

Applying topical products to the skin can do 3 things—the product can act locally, pass into the systemic circulation, or do both, either unintentionally as an adverse reaction or intentionally as a transdermal drug delivery system (TDS). Systems that intentionally allow drugs to enter systemic circulation have grown in popularity since the FDA approved the first TDS (scopolamine for motion sickness in 1979).^1-3 TDS benefits include drug delivery unaffected by food or gastrointestinal problems; avoidance of first-pass metabolism in the patient’s liver; diminished likelihood of hepatic induction; and a work-around delivery system for patients who cannot take oral medications. A TDS also requires less frequent dosing and boasts better adherence than traditional dosage forms. One more bonus: a TDS is non-invasive.⁴

In general, TDSs have an outer impermeable membrane, a reservoir containing a drug solution and perhaps a penetration enhancer, a rate-limiting membrane that covers a defined area, and an adhesive frame.^2,4 Today’s TDSs may have matrix, local-action transcutaneous, or reservoir structures. They generally work by diffusion.² These various structures allow the drug to penetrate the hydrophobic stratum corneum and then a lipophobic lipid bilayer, which is the rate-limiting barrier for most drugs. The astute reader will see that since there are 2 hurdles—hydrophobic and lipophobic layers—TDS drugs must have water and fat affinities. So, suitable drugs must have proper polarities, avoid skin protein binding, and be molecularly small and stable.^5,6

Today, many drugs are commercially available as TDS formulations. Although TDS offer many advantages, side effects and adverse reactions are possible. This article addresses potential cutaneous reactions.

Table 1: Available TDS Products

Buprenorphine (Butrans)

Clonidine (Catapres-TTS, generic)

Estradiol (Climara)

Estradiol/levonorgestrel (Climara Pro)

Norelgestromin/ethinyl estradiol (Ortho Evra)

Fentanyl (Duragesic, Novaplus Fentanyl, generic)

Granisetron (Sancuso)

Methylphenidate (Daytrana)

Nicotine (Habitrol, Nicoderm CQ, Nicotrol, generic)

Nitroglycerin (Nitro-Dur)

Oxybutynin (Oxytrol)

Rivastigmine (Exelon)

Rotigotine (Neupro)

Scopalamine (Transderm Scop)

Selegiline (Emsam)

Testosterone (Androderm)

Irritant Dermatitis

Irritant dermatitis is the most common adverse reaction reported with many TDSs, occurring in up to 50% of users. It is generally well-defined, local, transient, and mild to moderate in severity.^7,8 Irritant contact dermatitis, an inflammatory reaction, is non-allergic; memory T cell function and antigen-specific immunoglobulins are uninvolved.^4,9 As the application time increases, the likelihood of irritant dermatitis does, too. TDS, with their long application times, occlude the underlying skin. This increases epidermal and perspiration accumulation, with moisture creating an inviting environment for irritation and bacterial/yeast overgrowth.^10,11 Friction from patch removal may also cause irritant dermatitis.^4,10,12,13 Older patients and patients with histories of eczema are at higher risk of irritant dermatitis, as their skin may be more fragile or react more easily, respectively.¹⁴

Some TDSs include hydrogels to decrease moisture and reduce the potential for irritation.¹⁰ Most patients will find this reaction more of a nuisance than a barrier to use, and will continue to use the product. Cold compresses can relieve some discomfort. Corticosteroids generally will not help.^4,5,15,16

Table 2: Irritant vs Allergic Skin Reactions

Quality or Character

Irritant Reactions

Allergic Reactions

Temporal relationship:

Reaction resolves after TDS is removed

Reaction continues or worsens after TDS is removed

Extent of reaction:

Reaction occurs at current application site

Reaction may occur at previous application sites

Location:

Localized

Diffuse

Vesiculation:

Blistering and swelling rare

Blistering and swelling present

Adapted from references 4 and 15

Allergic Contact Sensitivity

Contact allergic reactions may develop, and TDSs’ occlusive qualities combined with their irritant potential can cause the body to see the system as “other” and mount a chemical allergy response.

¹⁷

The allergy response differs from irritant dermatitis. Usually, sensitization occurs over a week or 2, then re-exposure elicits a reaction within hours or days. The likelihood of sensitization increases with the duration of use, and may occur after years of exposure.

^11,18

Intense itching, redness, and blistering are common. The reaction tends to magnify for a few days after the TDS is removed. The reaction may spread beyond the application site and may persist for a few weeks.^11,15,17 Postinflammatory hyperpigmentation may occur,¹⁹ and patients may become less responsive to the active drug or may rarely have a systemic reaction if they switch to an oral drug.^20-25

Potential allergens include the active drug (most frequently), adhesives, enhancers, membrane components, and solvents. Agents most likely to provoke allergic response are clonidine with up to 25% of users becoming allergic; scopolamine with an incidence of 10%; and nicotine with an incidence of 3%.^26-28 Allergic contact sensitivity has also been reported with nitroglycerin, testosterone, estradiol, and fentanyl. Reactions to non-drug components can be addressed by switching to a different TDS if possible. Mild cases may be soothed with oatmeal baths, calamine lotion, and cold compresses.¹⁵ Moderate cases may call for topical corticosteroids for no more than 3 weeks,²⁹ and systemic antihistamines.³⁰ Patients so treated may be able to use the TDS again without reaction, but may react again.¹⁶

Drug-Related Redness and Erythema

TDS products that contain vasodilators (eg, nitroglycerin and nicotine) or pressure-sensitive adhesives can cause a transient reactive hyperemia. With pressure-sensitive adhesives, the redness is more likely to occur after the patient removes the TDS. It is not dermatitis, and should resolve with time.¹²

Burns

TDS that have a metallic component (usually aluminum) in their waterproof layer can cause burns if they absorb heat. Products are not always labeled with a warning if they contain metals. If the adhesive surface is shiny and reflects light, the TDS may contain an aluminum layer. Some cases of microwave oven radiation leading to second-degree burns have been reported. Other heat sources that can cause burns include defibrillation leading to electrical arcing in patients wearing patches, and burns during magnetic resonance imaging.^31-33

Guiding the TDS Patient

When patients begin using a TDS, counseling can improve their experiences and outcomes. Avoiding harsh soaps and detergents at the application site is necessary, since these dry the skin. Using a lipid-rich moisturizer a few hours before application can improve the skin’s hydration and barrier and reduce the possibility of irritation. (Applying moisturizer immediately before can affect adhesion.) Rotating the application site and allowing previous sites to “rest” is crucial.¹⁵

Patients will have the greatest medication exposure when TDSs are applied to the upper back, chest, and upper arm, but with all TDSs, patients should apply systems in locations identified by the manufacturer. Application sites must be clean, dry, and never irritated. Trimming hair (but not shaving) at application sites can improve adhesion and decrease skin reactions.¹⁵ For patients who are cognitively impaired or uncooperative, caregivers should consider applying TDSs to the upper back so the TDS is more difficult to remove. After TDS removal, cleansing gently with water or an oil-based substance will remove leftover adhesive and reduce exposure to irritants or allergens.³⁴

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance clinical writer.

References

• Benard D. Minor burns, sunburn and wounds In: Krinsky D. Berardi R, Ferreri S, et al, eds. Handbook of Nonprescription Drugs. 17th ed. Washington, DC: American Pharmacists Association; 2012.
• Lacerations. Merck Manual for Healthcare Professionals Online. www.merckmanuals.com/professional/sec22/ch328/ch328a.html#v1110280. Accessed March 29, 2013.
• Hollander JE, Singer AJ. Evaluation of wounds. In: Tintinalli JE, Kelen GD, Stapczynski JS, Ma OJ, Cline DM, eds. Emergency Medicine: A Comprehensive Study Guide. 6th ed. Columbus, OH: McGraw-Hill; 2006:Chapter 40.
• Clean, treat, protect: wound care. Band Aid website. http://www.bandaid.com/proper-wound-care/clean-treat-protect. Accessed April 1, 2013.
• Neosporin website. www.neosporin.com/firstaid/pdf/sciencefactsheet.pdf. Accessed April 1, 2013.
• How to care for a minor wound. Centers for Disease Control website. www.bt.cdc.gov/disasters/woundcare.asp. Accessed April 1, 2013.
• Basic burn care/first aid burn treatment. Massachusetts General Hospital website. www2.massgeneral.org/burns/patients/. Accessed March 29, 2013.