TY - JOUR
AU1 - Ball, Amanda, M.
AU2 - Smith, Kelly, M.
AB - Abstract Purpose. The pharmacokinetics, benefits, risks, and future of transdermal drug products are reviewed. Summary. Transdermal drug delivery capitalizes on an attractive route of drug delivery, as it avoids the need for painful i.v. drug administration, i.v. site access, and syringe disposal and is an option for drug delivery to patients who are unable to swallow oral medications. Specific transdermal drug designs have advantages and disadvantages, including the ability to alter the patch size or readily manipulate the products. Transdermal drug delivery systems currently available include drug reservoir and microreservoir membrane-modulated systems, drug-in-adhesive layer designs, and matrix patches. Maximizing patient response to transdermal drug formulations may also rely on a number of other practical concerns, including patient dexterity, dose reproducibility, storage and stability of the remaining portion, and decreased adhesive efficacy. Adhesives in transdermal precuts may be locally irritating, and prolonged use and high dosages have resulted in dermatological reactions to some patches. Patients may also develop contact sensitization or systemic sensitization to the transdermal formulation itself. When a transdermal product regimen is initiated, caregivers should be mindful of the product’s primary features and educate patients accordingly, specifically addressing where and how to apply the patch, duration of patch use, and procedures for properly changing and storing patches. Conclusion. The increasing complexity of transdermal drug products, the growing number of medications available in such dosage forms, and reports of potential safety concerns contribute to the need for clinicians to understand the principles of transdermal drug delivery, safe usage techniques, and proper patient counseling points. Adhesion, Adhesives, Patches transdermal, Stability, Storage, Toxicity Transdermal drug delivery has greatly advanced since the marketing of scopolamine, the first drug that received labeling approved by the Food and Drug Administration (FDA) for transdermal administration in 1979 to treat motion sickness. Over 25 other transdermal medications are now available to treat a variety of conditions. As the number of transdermal drug options has increased, the number of patients receiving medications through this route has also risen. In 2006, over 4 million women had used the transdermal system containing ethinyl estradiol in fixed combination with norelgestromin (Ortho Evra, Ortho-McNeil) since its release in 2001,1 and over 12 million people worldwide had used transdermal patches.2 In 2004, sales for transdermal products totaled $3.4 billion.1 Transdermal systems have evolved from plastic surrounded with adhesive dipped into a drug dissolved in alcohol to a patch in which drug delivery is enhanced via iontophoresis.3 As the delivery systems have become more sophisticated, so too have the intricacies of product characteristics relevant to patient response. Clinicians must not only be aware that patients are using transdermal medications but also know how to optimize their use. This article reviews the pharmacokinetics, benefits, risks, and future of transdermal drug products. Common medication errors associated with transdermal products and counseling points for patients using transdermal products are also discussed. The case for transdermal drug delivery Transdermal drug administration capitalizes on an attractive route of drug delivery, as it avoids the need for painful i.v. drug administration, i.v. site access, and syringe disposal and is an option for drug delivery to patients who are unable to swallow oral medications. Furthermore, bypassing oral administration obviates first-pass metabolism in the liver and typically decreases the dosage required.4 For example, the oxybutynin transdermal system (Oxytrol, Watson) contains 36 mg of medication and releases approximately 3.9 mg daily; in contrast, the typical oral dosage of oxybutynin is 10 mg daily.5 Many medications administered orally are variably or poorly absorbed in the gastrointestinal tract, and transdermal drug delivery eliminates these absorption issues. Transdermal medications achieve reduced peak plasma drug concentrations, which may translate into fewer dosage-related adverse events. Finally, transdermal medications have a relatively infrequent administration interval compared with that of oral products, as some patches may be worn for up to one week. This decreased administration frequency can increase patient compliance with medication regimens and improve patient satisfaction. Dermal anatomy and pharmacokinetics Just as oral medications must overcome absorption barriers in the gastrointestinal tract, transdermal drugs must overcome absorption barriers through the skin, specifically the stratum corneum (Figure 1). This component of the epidermis, specifically the outermost layer of skin, mostly comprises dead skin cells and sheds approximately every two weeks. The primary functions of the stratum corneum are to prevent molecules from passing in and out of the skin and to protect the lower layers of skin. Drugs that are able to reliably diffuse through this barrier generally have a low molecular weight and are highly lipid soluble.6 Salicylic acid (molecular weight, 138 Da), camphor (152 Da), and menthol (156 Da) have the lowest molecular weights of the available transdermal drugs.7 Oxybutynin (393.9 Da), fentanyl (336 Da), and scopolamine (303 Da) are the highest molecular-weight drugs currently available in transdermal formulations.7,8 In addition to chemical characteristics, drugs that require small doses for efficacy are more suited for transdermal delivery, as current product designs lack the capacity to store and deliver large volumes of drug.6 Advances in transdermal delivery systems are primarily responsible for the increased number of drugs suitable for administration via the stratum corneum. In contrast to the crudely designed first transdermal system, today’s products utilize the more sophisticated designs of embedded active drug in reservoirs, microreservoirs, adhesives, or matrices. The core feature of modern transdermal drug formulation is multiple-layer technology. An impermeable backing is typically used to prevent drug diffusion from both sides of the patch. An additional layer of the patch contains drug, whether embedded in adhesive, stored in reservoirs, or in some other design. A rate-controlling layer slows the release of drug over time through a permeable membrane, provided the integrity of the membrane is maintained. Finally, an adhesive layer is often added to patches to enhance their attachment to the skin; for packaging purposes, a protective liner is placed over the patch until use. Specific transdermal drug designs have advantages and disadvantages, including the ability to alter the patch size or readily manipulate the product, which are often reflective of the distinct manner in which the product is formulated. A primary concern for patients and physicians alike is the potential for a patch to be cut to a different size. Such a feature is attractive for several reasons, including the desire to administer a dose that is less than what is currently available, and financial savings similar to the cost savings associated with tablet splitting. However, information regarding suitability for patch alteration is not commonly the focus of original research and therefore not readily available in the prescribing information or medical literature and may require further investigation, most often communication with the product manufacturer. General efficacy and safety concerns must also be considered, in conjunction with basic patch design principles, before choosing to cut a transdermal formulation. In the absence of clinical outcomes after such interventions, the risks inherent in reducing the efficacy of a birth control patch will likely deter most patients from the practice of altering the patch, even if the general features of the patch design support such a practice. Conversely, there have been several reports of patient overdoses resulting from patch alteration.9,–11 Maximizing patient response to transdermal drug formulations may also rely on a number of other practical concerns, including patient dexterity, dose reproducibility, storage and stability of the remaining portion, and decreased adhesive efficacy. Tables 11 and 22 characterize transdermal patches currently manufactured in the United States by their design, notable features, and manufacturers’ recommendations regarding efficacy and safety of patch alteration.5,8,12,–43 These latter concerns become more apparent with an understanding of the most common patch designs described below. Types of transdermal drug delivery systems Drug reservoir membrane-modulated systems This common transdermal design involves the use of a drug reservoir enclosed between a backing layer and a rate-controlling microporous membrane.44 Choice of polymer, specific drug characteristics (molecular size and lipophilicity), and membrane layer thickness determine the rate of drug release from the reservoir. The backing layer is drug impermeable, allowing the drug to be released solely through the rate-controlling membrane. An adhesive layer is often added to enhance contact between the patch and the skin. Cutting these types of patches is not recommended since the rate-controlling membrane and the reservoir will be altered, which will unpredictably affect the rate of drug delivery. Referred to as a drug-dumping effect, the entire dose is made immediately available instead of a controlled release of drug over time. Such an event could cause a drug overdose or other serious adverse events, especially with agents such as fentanyl.11 Microreservoir The microreservoir differs from the reservoir primarily in the use of multiple, smaller drug reservoirs. Unlike reservoir products, microreservoir systems may be suitable for alteration; cutting the patch destroys some of the microreservoirs but the majority should remain intact. However, the loss of an unknown number of microreservoirs results in a less than proportional relationship between patch area and dose administered. For example, cutting a clonidine patch in half does not necessarily leave the user with exactly half of the remaining dose, yet such an approach may be used in practice.45,46 Drug-in-adhesive layer This design involves homogeneously mixing the drug into a polymer-based adhesive.44 The patch is constructed by attaching a layer of the drug–adhesive mixture to a nonpermeable backing. An additional layer of non-drug-infused adhesive may be added to improve skin contact and act as a rate-controlling layer.13,44 The amount of drug delivered is diffusion controlled and is directly proportional to the surface area of the patch in contact with the skin. Cutting or altering the size of the patch will decrease the amount of drug delivered, but will not generally present a hazard beyond possible decreased drug efficacy. A lidocaine patch (Lidoderm, Endo Pharmaceuticals), which can be safely cut to size, is representative of this transdermal formulation.28 Matrix The design of a matrix patch is similar to that of the drug-in-adhesive layer. Active drug is evenly infused into a layer of a polymer matrix, a nonpermeable backing is added, and a peripheral adhesive or adhesive layer completes the system.13,44 Again, the amount of drug delivered is directly proportional to the surface area of the patch in contact with the skin. Cutting the patch is generally possible but may decrease the efficacy of the adhesive, especially if it is only peripherally applied. Adverse reactions to transdermal drug products The benefits of transdermal drug administration are numerous, yet medication patches do have drawbacks. Adhesives in transdermal products may be locally irritating, with the potential to result in erythema, blistering, scaling, excoriation, or induration, particularly as a result of friction or pressure.4 Thus, manufacturers commonly recommend that the site be rotated with subsequent applications. Topical corticosteroids may be required to alleviate these symptoms, and a patch should not be reapplied to sites that demonstrate extreme hypersensitivity. Prolonged use and high dosages have resulted in dermatological reactions to clonidine patches.46 Other transdermal products (e.g., lidocaine, lidocaine–tetracaine, ethinyl estradiol–norelgestromin) have resulted in changes in skin pigmentation.26,28,29 Other product- or drug-specific reactions to transdermal formulations have also been reported, ranging from patient overdose to serious dermatological conditions. In response to an analysis of adverse reactions (including death and other serious reactions) submitted to MedWatch, FDA’s safety information and adverse-event reporting program, FDA officials launched an investigation into the safety of the fentanyl (Duragesic) transdermal patch in 2005.47 Unintentional overdoses were thought to be due to a number of factors, including high-dose or multiple-patch use, accidental exposure to a discarded patch, patch exposure to heat, and patch malfunction (e.g., leaking). Patients also reported poor patch adhesion to skin. After the investigation, the safety section of the product’s FDA-approved labeling was updated to reflect the corresponding concerns. Plasma fentanyl concentrations may be quickly increased in patients who concurrently receive sedating agents, ingest alcohol, have high body temperatures, expose the patch to heat, or use medications that interfere with the drug’s metabolism (e.g., cytochrome P-450 3A4 inhibitors). The safety alert reminded prescribers to prescribe the lowest effective dosage, refrain from advocating the fentanyl patch for short-term pain relief, and reserve it for opiate-tolerant patients with chronic pain uncontrolled by other methods.47 FDA’s announcement also advised that patients and caregivers be educated about the proper storage and disposal of the patch, including folding a used patch and disposing of it in an area out of the reach of children and pets. A 2007 report of a one-year-old child who died after swallowing a fentanyl patch found on the floor illustrates the importance of proper disposal.48 The risk of venous thromboembolism may be increased twofold with the use of the combination ethinyl estradiol–norelgestromin patch, as noted in a February 2006 preliminary report by the product’s manufacturer.49 Four months earlier, FDA issued a similar warning regarding the potential for an increased risk of adverse effects, including thromboembolic disease, stroke, and myocardial infarction, with transdermal contraceptives versus oral contraceptive products.50 A subsequent analysis found no additional correlation between the risk of ischemic stroke or acute myocardial infarction and the use of the contraceptive patch versus oral norgestimate-containing products.51 These disparate findings demonstrate the need for further investigation; several larger trials are currently underway to elucidate the actual nature and likelihood of such safety concerns. In addition to reacting to the active ingredient, some patients may be intolerant of or react to the transdermal formulation itself. Contact sensitization, with cases of subsequent systemic sensitization, has been linked to a newly approved transdermal methylphenidate product (Daytrana, Shire Pharmaceuticals).33,52 Children receiving the drug for the treatment of attention-deficit/hypersensitivity disorder are likely to develop a mild form of erythema caused by the transdermal formulation of the product, which is known to include a dermal irritant. However, progression to papules or vesicles that diffuse or persist beyond 48 hours may be signs of contact sensitization. Systemic sensitization or other widespread reactions may follow, with some cases so severe as to preclude the future administration of methylphenidate in any route or dosage form. The true extent of such severe reactions has yet to be determined, as the clinical studies during which the reactions were reported were not designed to identify such cases. These and other reports of transdermal drug safety concerns have led to a spate of individual and class-action lawsuits against drug manufacturers.53,54 Promoting safe use of transdermal drug products Variability in patch designs, dosage-strength expression (i.e., units of measure), abbreviations that indicate a patch’s particular delivery system, administration frequency, and administration site increases the potential for confusion on the part of health care professionals, caregivers, and patients. The potential for confusion is apparent when considering that dosage may be expressed as micrograms per hour, milligrams per hour, milligrams per day, milligrams per day per week, or milligrams, depending on the medication. The clonidine patch (Catapres-TTS) has been misinterpreted as a product that should be applied on Tuesdays, Thursdays, and Saturdays.55 The product is not designed to be applied daily, but rather every seven days. Like Catapres-TTS, many transdermal systems are designed similarly to minimize the number of times a new patch must be applied. However, the actual frequency of patch application among transdermal products spans a large range, from several hours to once weekly. Changes in transdermal dosage frequency, particularly dosage reductions, may not be as easily achieved as with oral dosage forms. Most notably, many patches cannot be cut into smaller sizes to reduce the dose delivered to the patient without significantly altering the rate of drug delivery, actual dose delivered, or other pertinent factors. Therefore, clinicians should always consider the actual transdermal system design and manufacturer recommendations before cutting transdermal patches. Medications available in transdermal forms may also be marketed in other delivery systems, and their dosage strengths, frequency, and required monitoring may differ considerably. Prescribers should be aware of these differences rather than assume that the same dose should be delivered, regardless of the dosage form or route of administration. Diagnostic procedures, particularly magnetic resonance imaging (MRI), may place users of transdermal drug products at risk. Because of the strong magnetic pull of the scanner, all magnetic objects must be removed from patients before the procedure.56 While transdermal drug delivery systems are not subject to the strong magnetic force created during MRI, many contain metallic backings that conduct electric currents. Such currents can lead to excessive heat generation and subsequent local tissue damage. Local tissue burns have been reported in two patients wearing nicotine patches during MRI procedures.56 Because the components of the product backing are not readily discernible to the caregiver, temporary patch removal before such procedures may be the safest approach to minimize local reactions. Clonidine products were developed for use in conjunction with an optional overlay—a separate, protective layer of adhesive that is applied (or overlaid) over the entire patch to secure it to the patient’s skin.44 Because overlays are not currently supplied with other transdermal products, both clinicians and patients alike may be unaware of their purpose or proper use. The round, white adhesive covering has been confused with the active transdermal patch, including reports of overlays returned to the pharmacy in health-system settings (in the context of returning unused medications), or applied to patients instead of the actual transdermal system.55 Other reports describe patient application of new clonidine or other patches without removal of the used products or overlaying the new patch on top of an existing one.55 In other cases, overlays were applied to the skin first, followed by the actual patch, thus preventing sufficient drug absorption. Reports also detail the partial removal of the patch backing (protective liner) before application, resulting in erratic or inadequate product absorption.55 The recommended application site may differ among transdermal systems and among different products containing the same active ingredients. Application to alternative sites may result in differing absorption profiles, inadequate adherence to the skin, or other problems. Patches placed on alternative sites may be overlooked by caregivers and remain on the skin for an excessive period of time, placing the patient at risk of adverse effects from supra-therapeutic drug concentrations or skin irritation. Clear patches, which may be desirable from a cosmetic perspective, may be difficult to locate on a patient’s skin. Printing on clear or translucent patches may rub off during handling or application, making it difficult to locate the patch for its removal. These risks are increased in settings with multiple caregivers for each patient (e.g., health systems, long-term-care facilities). Caregivers should document the timing and location of patch placement, as well as removal of the previous patch. Heat applied to the site of patch placement may increase drug absorption rates. Reports of patient deaths from overdoses of fentanyl related to increased skin temperature have emphasized the need to educate patients about this particular risk.57,58 According to the Institute for Safe Medication Practices, one case readily illustrates this risk.59 A 77-year-old woman applied a heating pad to her buttock, the site of both her sciatic pain and the newly prescribed fentanyl patch. She was subsequently found dead two days later, possibly due to a narcotic-induced respiratory depression. Several other factors appear to have contributed to this patient’s death, including concomitant use of hydrocodone and acetamino-phen and a lack of counseling by a pharmacist regarding proper patch use. Heat in the form of sun exposure has also been linked to hot flashes and skin pigmentation changes at the site of ethinyl estradiol– norelgestromin patch placement in one patient. The patient’s symptoms occurred after several days of sun tanning and subsequent patch exposure to heat; the reaction was thought to be caused by heat-induced elevations in drug release and absorption.56 In June 2006, FDA issued a consumer warning regarding a transdermal patch containing camphor and menthol (Triaminic Vapor Patch), indicated as a cough suppressant in children two years of age or older.38 Cases of accidental ingestion by children included reports of gastrointestinal irritation, headache, and seizures. The product was subsequently recalled by the manufacturer. Children who opened boxes of fentanyl transdermal systems or retrieved discarded patches from an unsecured receptacle have died following application or ingestion of the patch.55,59 These reports illustrate the risks associated with improper transdermal system placement, storage, and disposal. All patients, regardless of their age, should be instructed that the products are for topical use only. Used patches should be folded together and disposed. Simple disposal in a trash receptacle does not destroy the delivery system, allowing absorption during subsequent use by the patient or manipulation by a child who is merely intrigued with an item that resembles a bandage or sticker. Some transdermal systems, including the system used in nicotine patches (Nicoderm CQ), are dispensed with secure disposal units for used patches to minimize retrieval of an active drug compound.39 Proper product storage is also essential. Excessive heat may destroy drug reservoirs in transdermal systems, necessitating storage of patches at room temperature. Products should also remain in their original containers and should not be stored underneath heavy objects, the pressure from which may alter the delivery system. Patient counseling for transdermal products When a transdermal product regimen is initiated, caregivers should be mindful of the product’s primary features and educate patients accordingly. Five key questions should therefore be answered when counseling all patients on the use of transdermal medications. Where can the patches be applied? The manufacturer’s labeling for each transdermal drug product includes recommendations regarding specific areas of the body where the patch may be safely applied. For example, women using estrogen or nicotine-containing patches may not apply these patches to the breasts. The sites recommended in the product labeling for each prescription and nonprescription product should be used. Patches should be applied to hairless, clean, dry, intact skin. Moisturizer, oil, or powder should not be applied to the site before application, as these products may prevent the patch from adhering properly. How is the patch applied? Patients should be instructed to remove the patch from the package without using scissors, which may accidentally puncture the patch and destroy its integrity. The protective liner should be removed; then the adhesive side of the patch should be firmly placed on the skin, with the palm of the hand placed over the patch for 30 seconds. All edges should be adequately attached, and the patient’s hands should be washed after each application. How long should the patch be worn? Patches have variable durations of use, from 12 hours to a week, and it is important to ensure that patients understand how long to wear each patch. Patients should be taught what to do if the patch becomes detached, whether partially or completely, before it is time for replacement. The patient should first attempt to reattach the patch; however, if it does not adhere appropriately, first-aid tape may be used to secure the patch, or a new patch may be applied. Some patches with extended durations (e.g., up to a week) are packaged in single units that can be dispensed as a replacement. How should patches be changed? Patients should remove the patch after wearing it for the prescribed amount of time. Failure to remove the old patch is a very common mistake that patients make.60 Patients should discard the old patch by folding it in half so that children and pets cannot be exposed to it, as residual drug will remain. The same procedure should be followed for application of a new patch, only rotating it to a new appropriate site for application. Soap and water should be used to remove any residual adhesive at the former application site. Many manufacturers recommend that used patches be flushed down the toilet, but concerns about contamination of groundwater systems make this practice controversial. How should patches be stored? Unused patches should be stored away from excessive heat and moisture and remain in the protective liner until just before their use. In the event the patch must be cut, the protective liner should be kept on the patch and the unused portion stored appropriately. The new wave of transdermal delivery systems Just as the number of medications available in transdermal formulations is expanding, so too are the numbers and types of drug delivery systems utilized. Less than five years ago, the majority of transdermal drug products contained active drug embedded in adhesive.3 Such an approach diminishes skin irritation; however, the drug concentration within adhesive directly affects patch adherence to the skin, necessitating increased patch sizes or increased patch reapplication frequency if large drug quantities are required. The next generation of patches uses an acrylic drug reservoir in combination with a silicon adhesive to create a semisolid suspension of drug cells. This product design is being surpassed by emerging developments in iontophoresis, ultrasound, microneedles, sonophoresis, lasers, and electroporatic methods, which are used to increase skin permeability.61 Delivery timing mechanisms are also being developed to facilitate bolus dosing. Some systems are being combined with electronically controlled micropumps to coordinate the timing of drug delivery. In May 2006, FDA approved the labeling for a fentanyl iontophoretic transdermal system (Ionsys, Ortho-McNeil).27 The patch, which recently reached the U.S. market, is a credit-card-sized device with a self-contained battery that supports on-demand drug release in a manner similar to i.v. patient-controlled analgesia systems. The shorter time to onset of effect of these delivery system advances affords them broader potential uses. Passive delivery models have a typical onset of action ranging from 12 to 24 hours,8,36 making them well suited for chronic conditions, including chronic pain, hormone replacement, Parkinson’s disease, and urinary incontinence. The Ionsys active trans-dermal delivery product delivers the 40-μg dose over 10 minutes, with peak plasma fentanyl concentrations seen 30–45 minutes after activation. Such a profile enables a transdermal product to be used for acute pain management, a therapeutic maneuver not possible with the slower, passive delivery system.27 The next phase of transdermal technology may be evaporative delivery, using a drug solution in a volatile and nonvolatile solvent mixture. The system yields an invisible drug depot in the stratum corneum that is released over two to four days. As with today’s transdermal formulations, these advanced systems are expected to have unique features that require careful consideration by both health care professionals and patients alike to ensure best use. Conclusion The increasing complexity of transdermal drug products, the growing number of medications available in such dosage forms, and reports of potential safety concerns contribute to the need for clinicians to understand the principles of transdermal drug delivery, safe usage techniques, and proper patient counseling points. Table 1. Prescription Transdermal Drug Products Available in the United States Generic Name (Brand Name) Product Designa Application Site(s) Application Frequency Comments aUnless otherwise stated, the manufacturer does not recommend patch alteration. MRI = magnetic resonance imaging, CAT = computed axial tomography, BSA = body surface area. bBecause this product is not yet marketed, there are no manufacturer recommendations regarding patch alteration. cPatch alteration is recommended by the manufacturer. dProduct has been recalled by the manufacturer due to the formation of rotigotine crystals in patches, which may result in variable efficacy. Clonidine (Catapres-TTS) 12 Drug reservoir Upper outer arm or upper chest Every 7 days Cutting patch does not break the reservoir. Dose is directly proportional to BSA covered by patch. No formal studies and cannot ensure exact dose administered if the patch is cut. Anecdotal reports indicate cutting the patch is safe.13 Diclofenac epolamine (Flector patch)14 Matrixb Apply to the most painful area, excluding eyes Twice daily Contraindicated in postoperative coronary artery bypass patients. Remove patch before bathing. Estradiol (Alora)15 Adhesive matrix drug reservoir Lower abdomen, hips, or buttocks Twice weekly . . . Estradiol (Climara)16 Matrix Lower abdomen or upper quadrant of buttocks Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Esclim)19 Drug-in-adhesive matrix Upper arm, buttocks, or upper inner thigh Twice weekly Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Estraderm)20 Drug reservoir Trunk of body including buttocks and abdomen Twice weekly . . . Estradiol (Menostar)21 Drug-in-adhesive matrix Lower abdomen Every 7 days . . . Estradiol (Vivelle)22 Matrix Lower abdomen, upper inner thigh, upper arm, upper buttock, or outer hip Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.18,19 Estradiol (Vivelle-Dot)23 Heat-optimized thermodynamic-release drug in adhesive Lower abdomen only Twice weekly . . . Estradiol/levonorgestrel (ClimaraPro)24 Matrix Lower abdomen only Every 7 days . . . Estradiol/norethindrone (Combipatch)25 Drug in adhesive Lower abdomen only Twice weekly . . . Ethinyl estradiol/norelgestromin (Ortho Evra)26 Matrix Buttocks, abdomen, upper outer arm, or upper torso Every 7 days Change the patch every 7 days for 3 wk, followed by an off week on the 4th wk. Fentanyl (Duragesic)8 Drug reservoir Chest, back, flank, upper arm Every 3 days Increased absorption if patients obtain a fever higher than 102 °F. Fentanyl iontophoretic transdermal system (Ionsys)27 Drug reservoir Chest or upper outer arm Every 24 hr or after 80 doses have been delivered Each time the button is pressed twice firmly over a 3-sec period, 40 μg of fentanyl is released over a 10-min period (maximum, 6 doses/hr); contains metal parts and should be removed prior to MRI, cardioversion, or defibrillation; also contains radiopaque components which may interfere with x-ray or CAT scan; does not interfere with devices such as pacemakers or other electrical monitoring equipment. Lidocaine (Lidoderm)28 Drug in adhesivec Apply to most painful area, excluding eyes Every 12 hr Safe to cut to any size desired (drug delivery is not altered); may apply up to 3 patches. Lidocaine/tetracaine (Synera)29 Drug reservoir covered with a heating system Apply to site of procedure or venipuncture 20–30 min Heating system component is oxygen activated; generates a mild warming once the pouch is exposed to air that enhances drug delivery; do not cover holes in patch. Methylphenidate (Daytrana)33 Matrix Hip area (avoid waistline where clothing may rub patch off) Wear for up to 9 hr daily Apply 2 hr before effect desired; approved in children age 6–12 yr. Nitroglycerin (Minitran)30 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr Patients wearing nitroglycerin patches should have a nitrate-free interval each day of 10–12 hr to ensure tolerance does not develop. Nitroglycerin (Nitro-Dur)31 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr One study of 65 patients found that cutting patch was safe and effective32; dose proportional to BSA covered by patch. Adhesive effectiveness may be altered once patch is cut and handled. Oxybutynin (Oxytrol)5 Matrix Abdomen, hips, or buttocks Twice weekly Do not expose the patch to sunlight. Rivastigmine (Exelon)34 Matrix Upper/lower back, upper arm, or chest Daily Patients weighing <50 kg may experience increased incidence of adverse events. Rotigotine (Neupro)35,d Matrix Abdomen, thigh, hip, flank, shoulder, or upper arm Daily Contains sodium metabisulfite, which may cause allergic reactions; falling asleep while engaged in activities of daily life can occur without warning symptoms; patch backing contains aluminum; remove before MRI or cardioversion. Selegiline (Emsam)36 Matrix Upper torso, upper thigh, or outer surface of upper arm Every 24 hr Never cut the patch. Testosterone (Androderm)37 Liquid drug reservoir Back, abdomen, upper arm, or thigh Every 24 hr Decrease incidence and severity of skin irritation by applying a small amount of 0.1% triamcinolone acetonide cream (not ointment) to the skin under the transdermal system; ointment formulation of triamcinolone will significantly reduce testosterone absorption. Generic Name (Brand Name) Product Designa Application Site(s) Application Frequency Comments aUnless otherwise stated, the manufacturer does not recommend patch alteration. MRI = magnetic resonance imaging, CAT = computed axial tomography, BSA = body surface area. bBecause this product is not yet marketed, there are no manufacturer recommendations regarding patch alteration. cPatch alteration is recommended by the manufacturer. dProduct has been recalled by the manufacturer due to the formation of rotigotine crystals in patches, which may result in variable efficacy. Clonidine (Catapres-TTS) 12 Drug reservoir Upper outer arm or upper chest Every 7 days Cutting patch does not break the reservoir. Dose is directly proportional to BSA covered by patch. No formal studies and cannot ensure exact dose administered if the patch is cut. Anecdotal reports indicate cutting the patch is safe.13 Diclofenac epolamine (Flector patch)14 Matrixb Apply to the most painful area, excluding eyes Twice daily Contraindicated in postoperative coronary artery bypass patients. Remove patch before bathing. Estradiol (Alora)15 Adhesive matrix drug reservoir Lower abdomen, hips, or buttocks Twice weekly . . . Estradiol (Climara)16 Matrix Lower abdomen or upper quadrant of buttocks Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Esclim)19 Drug-in-adhesive matrix Upper arm, buttocks, or upper inner thigh Twice weekly Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Estraderm)20 Drug reservoir Trunk of body including buttocks and abdomen Twice weekly . . . Estradiol (Menostar)21 Drug-in-adhesive matrix Lower abdomen Every 7 days . . . Estradiol (Vivelle)22 Matrix Lower abdomen, upper inner thigh, upper arm, upper buttock, or outer hip Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.18,19 Estradiol (Vivelle-Dot)23 Heat-optimized thermodynamic-release drug in adhesive Lower abdomen only Twice weekly . . . Estradiol/levonorgestrel (ClimaraPro)24 Matrix Lower abdomen only Every 7 days . . . Estradiol/norethindrone (Combipatch)25 Drug in adhesive Lower abdomen only Twice weekly . . . Ethinyl estradiol/norelgestromin (Ortho Evra)26 Matrix Buttocks, abdomen, upper outer arm, or upper torso Every 7 days Change the patch every 7 days for 3 wk, followed by an off week on the 4th wk. Fentanyl (Duragesic)8 Drug reservoir Chest, back, flank, upper arm Every 3 days Increased absorption if patients obtain a fever higher than 102 °F. Fentanyl iontophoretic transdermal system (Ionsys)27 Drug reservoir Chest or upper outer arm Every 24 hr or after 80 doses have been delivered Each time the button is pressed twice firmly over a 3-sec period, 40 μg of fentanyl is released over a 10-min period (maximum, 6 doses/hr); contains metal parts and should be removed prior to MRI, cardioversion, or defibrillation; also contains radiopaque components which may interfere with x-ray or CAT scan; does not interfere with devices such as pacemakers or other electrical monitoring equipment. Lidocaine (Lidoderm)28 Drug in adhesivec Apply to most painful area, excluding eyes Every 12 hr Safe to cut to any size desired (drug delivery is not altered); may apply up to 3 patches. Lidocaine/tetracaine (Synera)29 Drug reservoir covered with a heating system Apply to site of procedure or venipuncture 20–30 min Heating system component is oxygen activated; generates a mild warming once the pouch is exposed to air that enhances drug delivery; do not cover holes in patch. Methylphenidate (Daytrana)33 Matrix Hip area (avoid waistline where clothing may rub patch off) Wear for up to 9 hr daily Apply 2 hr before effect desired; approved in children age 6–12 yr. Nitroglycerin (Minitran)30 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr Patients wearing nitroglycerin patches should have a nitrate-free interval each day of 10–12 hr to ensure tolerance does not develop. Nitroglycerin (Nitro-Dur)31 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr One study of 65 patients found that cutting patch was safe and effective32; dose proportional to BSA covered by patch. Adhesive effectiveness may be altered once patch is cut and handled. Oxybutynin (Oxytrol)5 Matrix Abdomen, hips, or buttocks Twice weekly Do not expose the patch to sunlight. Rivastigmine (Exelon)34 Matrix Upper/lower back, upper arm, or chest Daily Patients weighing <50 kg may experience increased incidence of adverse events. Rotigotine (Neupro)35,d Matrix Abdomen, thigh, hip, flank, shoulder, or upper arm Daily Contains sodium metabisulfite, which may cause allergic reactions; falling asleep while engaged in activities of daily life can occur without warning symptoms; patch backing contains aluminum; remove before MRI or cardioversion. Selegiline (Emsam)36 Matrix Upper torso, upper thigh, or outer surface of upper arm Every 24 hr Never cut the patch. Testosterone (Androderm)37 Liquid drug reservoir Back, abdomen, upper arm, or thigh Every 24 hr Decrease incidence and severity of skin irritation by applying a small amount of 0.1% triamcinolone acetonide cream (not ointment) to the skin under the transdermal system; ointment formulation of triamcinolone will significantly reduce testosterone absorption. Table 1. Prescription Transdermal Drug Products Available in the United States Generic Name (Brand Name) Product Designa Application Site(s) Application Frequency Comments aUnless otherwise stated, the manufacturer does not recommend patch alteration. MRI = magnetic resonance imaging, CAT = computed axial tomography, BSA = body surface area. bBecause this product is not yet marketed, there are no manufacturer recommendations regarding patch alteration. cPatch alteration is recommended by the manufacturer. dProduct has been recalled by the manufacturer due to the formation of rotigotine crystals in patches, which may result in variable efficacy. Clonidine (Catapres-TTS) 12 Drug reservoir Upper outer arm or upper chest Every 7 days Cutting patch does not break the reservoir. Dose is directly proportional to BSA covered by patch. No formal studies and cannot ensure exact dose administered if the patch is cut. Anecdotal reports indicate cutting the patch is safe.13 Diclofenac epolamine (Flector patch)14 Matrixb Apply to the most painful area, excluding eyes Twice daily Contraindicated in postoperative coronary artery bypass patients. Remove patch before bathing. Estradiol (Alora)15 Adhesive matrix drug reservoir Lower abdomen, hips, or buttocks Twice weekly . . . Estradiol (Climara)16 Matrix Lower abdomen or upper quadrant of buttocks Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Esclim)19 Drug-in-adhesive matrix Upper arm, buttocks, or upper inner thigh Twice weekly Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Estraderm)20 Drug reservoir Trunk of body including buttocks and abdomen Twice weekly . . . Estradiol (Menostar)21 Drug-in-adhesive matrix Lower abdomen Every 7 days . . . Estradiol (Vivelle)22 Matrix Lower abdomen, upper inner thigh, upper arm, upper buttock, or outer hip Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.18,19 Estradiol (Vivelle-Dot)23 Heat-optimized thermodynamic-release drug in adhesive Lower abdomen only Twice weekly . . . Estradiol/levonorgestrel (ClimaraPro)24 Matrix Lower abdomen only Every 7 days . . . Estradiol/norethindrone (Combipatch)25 Drug in adhesive Lower abdomen only Twice weekly . . . Ethinyl estradiol/norelgestromin (Ortho Evra)26 Matrix Buttocks, abdomen, upper outer arm, or upper torso Every 7 days Change the patch every 7 days for 3 wk, followed by an off week on the 4th wk. Fentanyl (Duragesic)8 Drug reservoir Chest, back, flank, upper arm Every 3 days Increased absorption if patients obtain a fever higher than 102 °F. Fentanyl iontophoretic transdermal system (Ionsys)27 Drug reservoir Chest or upper outer arm Every 24 hr or after 80 doses have been delivered Each time the button is pressed twice firmly over a 3-sec period, 40 μg of fentanyl is released over a 10-min period (maximum, 6 doses/hr); contains metal parts and should be removed prior to MRI, cardioversion, or defibrillation; also contains radiopaque components which may interfere with x-ray or CAT scan; does not interfere with devices such as pacemakers or other electrical monitoring equipment. Lidocaine (Lidoderm)28 Drug in adhesivec Apply to most painful area, excluding eyes Every 12 hr Safe to cut to any size desired (drug delivery is not altered); may apply up to 3 patches. Lidocaine/tetracaine (Synera)29 Drug reservoir covered with a heating system Apply to site of procedure or venipuncture 20–30 min Heating system component is oxygen activated; generates a mild warming once the pouch is exposed to air that enhances drug delivery; do not cover holes in patch. Methylphenidate (Daytrana)33 Matrix Hip area (avoid waistline where clothing may rub patch off) Wear for up to 9 hr daily Apply 2 hr before effect desired; approved in children age 6–12 yr. Nitroglycerin (Minitran)30 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr Patients wearing nitroglycerin patches should have a nitrate-free interval each day of 10–12 hr to ensure tolerance does not develop. Nitroglycerin (Nitro-Dur)31 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr One study of 65 patients found that cutting patch was safe and effective32; dose proportional to BSA covered by patch. Adhesive effectiveness may be altered once patch is cut and handled. Oxybutynin (Oxytrol)5 Matrix Abdomen, hips, or buttocks Twice weekly Do not expose the patch to sunlight. Rivastigmine (Exelon)34 Matrix Upper/lower back, upper arm, or chest Daily Patients weighing <50 kg may experience increased incidence of adverse events. Rotigotine (Neupro)35,d Matrix Abdomen, thigh, hip, flank, shoulder, or upper arm Daily Contains sodium metabisulfite, which may cause allergic reactions; falling asleep while engaged in activities of daily life can occur without warning symptoms; patch backing contains aluminum; remove before MRI or cardioversion. Selegiline (Emsam)36 Matrix Upper torso, upper thigh, or outer surface of upper arm Every 24 hr Never cut the patch. Testosterone (Androderm)37 Liquid drug reservoir Back, abdomen, upper arm, or thigh Every 24 hr Decrease incidence and severity of skin irritation by applying a small amount of 0.1% triamcinolone acetonide cream (not ointment) to the skin under the transdermal system; ointment formulation of triamcinolone will significantly reduce testosterone absorption. Generic Name (Brand Name) Product Designa Application Site(s) Application Frequency Comments aUnless otherwise stated, the manufacturer does not recommend patch alteration. MRI = magnetic resonance imaging, CAT = computed axial tomography, BSA = body surface area. bBecause this product is not yet marketed, there are no manufacturer recommendations regarding patch alteration. cPatch alteration is recommended by the manufacturer. dProduct has been recalled by the manufacturer due to the formation of rotigotine crystals in patches, which may result in variable efficacy. Clonidine (Catapres-TTS) 12 Drug reservoir Upper outer arm or upper chest Every 7 days Cutting patch does not break the reservoir. Dose is directly proportional to BSA covered by patch. No formal studies and cannot ensure exact dose administered if the patch is cut. Anecdotal reports indicate cutting the patch is safe.13 Diclofenac epolamine (Flector patch)14 Matrixb Apply to the most painful area, excluding eyes Twice daily Contraindicated in postoperative coronary artery bypass patients. Remove patch before bathing. Estradiol (Alora)15 Adhesive matrix drug reservoir Lower abdomen, hips, or buttocks Twice weekly . . . Estradiol (Climara)16 Matrix Lower abdomen or upper quadrant of buttocks Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Esclim)19 Drug-in-adhesive matrix Upper arm, buttocks, or upper inner thigh Twice weekly Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.17,18 Estradiol (Estraderm)20 Drug reservoir Trunk of body including buttocks and abdomen Twice weekly . . . Estradiol (Menostar)21 Drug-in-adhesive matrix Lower abdomen Every 7 days . . . Estradiol (Vivelle)22 Matrix Lower abdomen, upper inner thigh, upper arm, upper buttock, or outer hip Every 7 days Some case reports indicate estradiol in matrix design is safe to cut. Efficacy of altered patches has not been assessed.18,19 Estradiol (Vivelle-Dot)23 Heat-optimized thermodynamic-release drug in adhesive Lower abdomen only Twice weekly . . . Estradiol/levonorgestrel (ClimaraPro)24 Matrix Lower abdomen only Every 7 days . . . Estradiol/norethindrone (Combipatch)25 Drug in adhesive Lower abdomen only Twice weekly . . . Ethinyl estradiol/norelgestromin (Ortho Evra)26 Matrix Buttocks, abdomen, upper outer arm, or upper torso Every 7 days Change the patch every 7 days for 3 wk, followed by an off week on the 4th wk. Fentanyl (Duragesic)8 Drug reservoir Chest, back, flank, upper arm Every 3 days Increased absorption if patients obtain a fever higher than 102 °F. Fentanyl iontophoretic transdermal system (Ionsys)27 Drug reservoir Chest or upper outer arm Every 24 hr or after 80 doses have been delivered Each time the button is pressed twice firmly over a 3-sec period, 40 μg of fentanyl is released over a 10-min period (maximum, 6 doses/hr); contains metal parts and should be removed prior to MRI, cardioversion, or defibrillation; also contains radiopaque components which may interfere with x-ray or CAT scan; does not interfere with devices such as pacemakers or other electrical monitoring equipment. Lidocaine (Lidoderm)28 Drug in adhesivec Apply to most painful area, excluding eyes Every 12 hr Safe to cut to any size desired (drug delivery is not altered); may apply up to 3 patches. Lidocaine/tetracaine (Synera)29 Drug reservoir covered with a heating system Apply to site of procedure or venipuncture 20–30 min Heating system component is oxygen activated; generates a mild warming once the pouch is exposed to air that enhances drug delivery; do not cover holes in patch. Methylphenidate (Daytrana)33 Matrix Hip area (avoid waistline where clothing may rub patch off) Wear for up to 9 hr daily Apply 2 hr before effect desired; approved in children age 6–12 yr. Nitroglycerin (Minitran)30 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr Patients wearing nitroglycerin patches should have a nitrate-free interval each day of 10–12 hr to ensure tolerance does not develop. Nitroglycerin (Nitro-Dur)31 Drug in adhesive Any hairless surface except on extremities below knees or elbows; chest is preferred site 12–14 hr One study of 65 patients found that cutting patch was safe and effective32; dose proportional to BSA covered by patch. Adhesive effectiveness may be altered once patch is cut and handled. Oxybutynin (Oxytrol)5 Matrix Abdomen, hips, or buttocks Twice weekly Do not expose the patch to sunlight. Rivastigmine (Exelon)34 Matrix Upper/lower back, upper arm, or chest Daily Patients weighing <50 kg may experience increased incidence of adverse events. Rotigotine (Neupro)35,d Matrix Abdomen, thigh, hip, flank, shoulder, or upper arm Daily Contains sodium metabisulfite, which may cause allergic reactions; falling asleep while engaged in activities of daily life can occur without warning symptoms; patch backing contains aluminum; remove before MRI or cardioversion. Selegiline (Emsam)36 Matrix Upper torso, upper thigh, or outer surface of upper arm Every 24 hr Never cut the patch. Testosterone (Androderm)37 Liquid drug reservoir Back, abdomen, upper arm, or thigh Every 24 hr Decrease incidence and severity of skin irritation by applying a small amount of 0.1% triamcinolone acetonide cream (not ointment) to the skin under the transdermal system; ointment formulation of triamcinolone will significantly reduce testosterone absorption. Table 2. Nonprescription Transdermal Drug Products Available in the United States Generic Name (Brand Name) Product Design Patch Alteration Recommended by Manufacturer? Application Site(s) Application Frequency Comments Camphor–menthol (Triaminic Vapor Patch) Not disclosed No Throat or chest Up to 3 times daily Under nationwide recall after serious adverse event.38 Nicotine (Nicoderm-CQ, Habitrol)39,40 Drug reservoir No Back, abdomen, arm, or thigh Daily Patients should not smoke while using the nicotine patch. Menthol (Bengay pain-relieving patch)41 Hydrogel matrix, which acts as an adhesive Yes Back, legs, shoulders, arms, or neck Lasts 8 hr . . . Salicylic acid (Duofilm, Trans-ver-sal)42 Not disclosed Yes Apply only to wart Every 24 hr Recommended to cut patch to size of the area to be applied to avoid exposure of the drug to healthy skin. Scopolamine (Transderm-Scop)43 Drug reservoir No Behind the ear Every 3 days Indicated for prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia from surgery. Generic Name (Brand Name) Product Design Patch Alteration Recommended by Manufacturer? Application Site(s) Application Frequency Comments Camphor–menthol (Triaminic Vapor Patch) Not disclosed No Throat or chest Up to 3 times daily Under nationwide recall after serious adverse event.38 Nicotine (Nicoderm-CQ, Habitrol)39,40 Drug reservoir No Back, abdomen, arm, or thigh Daily Patients should not smoke while using the nicotine patch. Menthol (Bengay pain-relieving patch)41 Hydrogel matrix, which acts as an adhesive Yes Back, legs, shoulders, arms, or neck Lasts 8 hr . . . Salicylic acid (Duofilm, Trans-ver-sal)42 Not disclosed Yes Apply only to wart Every 24 hr Recommended to cut patch to size of the area to be applied to avoid exposure of the drug to healthy skin. Scopolamine (Transderm-Scop)43 Drug reservoir No Behind the ear Every 3 days Indicated for prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia from surgery. Table 2. Nonprescription Transdermal Drug Products Available in the United States Generic Name (Brand Name) Product Design Patch Alteration Recommended by Manufacturer? Application Site(s) Application Frequency Comments Camphor–menthol (Triaminic Vapor Patch) Not disclosed No Throat or chest Up to 3 times daily Under nationwide recall after serious adverse event.38 Nicotine (Nicoderm-CQ, Habitrol)39,40 Drug reservoir No Back, abdomen, arm, or thigh Daily Patients should not smoke while using the nicotine patch. Menthol (Bengay pain-relieving patch)41 Hydrogel matrix, which acts as an adhesive Yes Back, legs, shoulders, arms, or neck Lasts 8 hr . . . Salicylic acid (Duofilm, Trans-ver-sal)42 Not disclosed Yes Apply only to wart Every 24 hr Recommended to cut patch to size of the area to be applied to avoid exposure of the drug to healthy skin. Scopolamine (Transderm-Scop)43 Drug reservoir No Behind the ear Every 3 days Indicated for prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia from surgery. Generic Name (Brand Name) Product Design Patch Alteration Recommended by Manufacturer? Application Site(s) Application Frequency Comments Camphor–menthol (Triaminic Vapor Patch) Not disclosed No Throat or chest Up to 3 times daily Under nationwide recall after serious adverse event.38 Nicotine (Nicoderm-CQ, Habitrol)39,40 Drug reservoir No Back, abdomen, arm, or thigh Daily Patients should not smoke while using the nicotine patch. Menthol (Bengay pain-relieving patch)41 Hydrogel matrix, which acts as an adhesive Yes Back, legs, shoulders, arms, or neck Lasts 8 hr . . . Salicylic acid (Duofilm, Trans-ver-sal)42 Not disclosed Yes Apply only to wart Every 24 hr Recommended to cut patch to size of the area to be applied to avoid exposure of the drug to healthy skin. Scopolamine (Transderm-Scop)43 Drug reservoir No Behind the ear Every 3 days Indicated for prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia from surgery. Figure 1. Open in new tabDownload slide Transdermal drug delivery and skin structures. 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TI - Optimizing transdermal drug therapy
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp070554
DA - 2008-07-15
UR - https://www.deepdyve.com/lp/oxford-university-press/optimizing-transdermal-drug-therapy-CKWit4DV21
SP - 1337
VL - 65
IS - 14
DP - DeepDyve
ER -