Treatment Options for a Patient Experiencing Pruritic Rash Associated with Transdermal Testosterone: A Review of the Literature

Nayahmka J. McGriff, Pharm.D., Gyorgy Csako, M.D., Mahmoud Kabbani, M.D., Long Diep, Pharm.D., George P. Chrousos, M.D., and Frank Pucino, Pharm.D.

Disclosures

Pharmacotherapy. 2001;21(11) 

In This Article

Discussion

Transdermal dosage forms are now available for numerous drugs. This route of administration avoids degradation by gastric enzymes and first-pass metabolism. Whereas patch preparations may improve compliance through relative ease of administration and patient tolerability, application site reactions are relatively common with most transdermal products, including estrogens, nicotine, nitroglycerin, clonidine, scopolamine, and, more recently, testosterone.[5,6,7,8,9,10,11] However, information regarding management of these reactions is limited. In this case report, two major therapeutic issues associated with these site reactions are discussed: management of localized hypersensitivity reactions and evaluation of treatment alternatives. Patients should be monitored, both clinically and with laboratory data, for efficacy and for the development of other side effects.

Application site reactions associated with transdermal testosterone may manifest as skin irritation (including erythema, induration, or burning), allergic contact dermatitis, and/or burn-like blister reactions (vesicles or bullae). The frequency of dermal reactions with any transdermal product may be associated with the presence of system excipients, such as permeation enhancers and specific adhesives.[12] The primary chemical irritants in various transdermal systems are often unknown. According to the product literature, rechallenge in five patients with hypogonadism who were previously intolerant to Androderm patches suggested sensitivity to ethanol in four cases and to testosterone in one case.[13] Ethanol is present in the drug reservoir of both commercially available nonscrotal patch formulations. In addition, occlusive dressings can contribute to hypersensitivity reactions. The hydroalcoholic gel formulation, however, is associated with less skin irritation than the patch formulations.

Cutaneous hypersensitivity reactions may respond to topical steroid creams. Triamcinolone sometimes is used because of its moderate potency, low cost, and compatibility with the hydroalcoholic gel that often is in patch reservoirs. Because triamcinolone is applied to a limited area, the risk for systemic effects is minimal. Studies suggested that pretreatment of the skin with triamcinolone 0.1% cream under a testosterone patch reduces the prevalence and severity of skin irritation without appreciably altering drug bioavailability.[13,14,15] In one study, 65 healthy adult male volunteers wore three patches simultaneously for 6 weeks; patches were changed every 24 hours from Monday through Thursday and left in place for 72 hours from Friday through Sunday. Pretreatment with triamcinolone 0.1% cream was applied under one testosterone patch, one testosterone patch had no pretreatment, and one placebo occlusive dressing was applied.[14] Based on a skin rating system, the prevalence and severity of skin irritation associated with the testosterone patches were decreased by at least one score category in the pretreated areas for 98.6% of subjects. In a 28-day prospective, open-label, randomized, crossover study of 10 men with hypertension, dermal side effects associated with clonidine patches were less frequent after pretreatment with hydrocortisone 0.5% cream than with use of the patch alone.[16] Although plasma clonidine concentrations were decreased in some patients, the pharmacodynamics were unaffected. In our patient, however, a trial of triamcinolone 0.1% cream provided minimal relief of dermal irritation. Ointment corticosteroid formulations are not recommended for pretreatment because of their occlusive nature and concerns about potentially reduced testosterone absorption.[14] To avoid potential systemic effects, oral agents are not typically used for local reactions.

Testosterone is available in oral, injectable, implantable, and transdermal formulations (Table 1). Because of the potential for abuse, all commercially available testosterone products have been classified as schedule III controlled substances by the Anabolic Steroids Control Act (21CFR, Federal Control Substances Act, U.S. Congress, 1990). Before testosterone replacement therapy is begun, patients should be screened for a history of polycythemia, fluid overload, migraine headaches, epilepsy, prostate cancer, benign prostatic hyperplasia, and sleep apnea, all of which may be androgen-sensitive conditions. When testosterone is administered orally, it is quickly metabolized in the gastrointestinal mucosa and undergoes extensive first-pass metabolism, which results in variable bioavailability and subtherapeutic serum concentrations. Long-term use of the C-17 alkylated synthetic androgens that are commercially available in the United States, such as methyltestosterone and fluoxymesterone, has been associated with poor androgenic activity, abnormal lipid changes (increased low-density lipoprotein [LDL] cholesterol and decreased high-density lipoprotein [HDL] cholesterol), and liver abnormalities (hemorrhagic cysts, adenomas, cholestasis, peliosis, nodular regenerative hyperplasia, and hepatocellular carcinoma).[3] Because of these limitations, some experts consider these preparations obsolete.[1] Nevertheless, investigational oral formulations, such as buccal[18,19] and sublingual tablets,[20,21] do not undergo first-pass metabolism and therefore may have more favorable safety profiles than older formulations.

Injectable testosterone esters (enanthate, propionate, or cypionate) predate other dosage forms and were once the mainstay of therapy for male hypogonadism.[22] Testosterone propionate is seldom used today because of its short half-life, which requires dose administration every other day. Intramuscular testosterone injections with enanthate or cypionate salts provide a relatively extended duration of action, allowing a dosing frequency of every 2-4 weeks. This dosing regimen does not mimic physiologic testosterone secretion, however; instead, it results in dramatic peak and trough serum testosterone concentrations between doses and a loss of normal diurnal variation.[23] These fluctuations in serum concentrations can result in wide swings in mood and in feelings of well-being, which may be disconcerting to both patients and their partners.[24] Supraphysiologic serum levels near administration time may be associated with breast tenderness and gynecomastia from testosterone conversion to estradiol. If testosterone levels remain elevated throughout the dosing interval, infertility, due to suppression of LH and FSH production,[25] and hepatic adenomas are additional concerns.[24] Although other parenteral testosterone formulations that are under investigation allow for dosing up to 20 weeks, these products also produce sustained, supraphysiologic serum levels (Table 2).[18,19,21,26,27,28,29,30,31,32,33,34,35] In addition, some patients refuse to self-inject because of the need for deep intramuscular administration and therefore require visiting nurses, frequent office visits, or training of family members. Multiple-dose vials allow clinicians to select the appropriate needle gauge and length, but some manufacturers of multiple-dose vials assure stability for up to 1 month of use only, which results in excessive waste. Prefilled syringes are commercially available to improve ease of administration. However, these products often have long (1.5-inch or 3.8-cm), 20-gauge needles that cannot be removed and therefore may be associated with poor compliance because of discomfort.

In a 24-week, randomized study of 66 adult hypogonadal men, 33% of patients experienced at least one local reaction (e.g., pain or soreness, bruising, erythema, swelling, nodules, or furunculosis) to injectable testosterone (needle size unknown).[23] Compared with transdermal testosterone patches, intramuscular administration resulted in a higher frequency of hematocrit elevation (43.85% vs 15.4% of patients) and oversuppression of gonadotropins (31% vs 0% of patients). Although gynecomastia occurred with a greater frequency in patients with transdermal (38%) than intramuscular (28%) administration, it tended to resolve more often in the former group. Injectable testosterone should not be administered to patients who have bleeding disorders or require anticoagulation.

Another option in testosterone replacement therapy is the implantation of cylindrical crystallized testosterone pellets (Testopel; Bartor Pharmaceuticals, Rye, NY) into subdermal tissue. Administration of this product requires a minor, 15-minute surgical procedure every 3-6 months using local anesthesia in sterile office conditions. The number of testosterone pellets inserted depends on patient requirements, diagnosis, and tolerance. Two 75-mg implants are approximately equivalent to a weekly 25-mg dose of testosterone propionate. The preferred application site is the lower abdomen (5 cm from the umbilicus), but the deltoid and gluteal muscles and the upper thigh are alternatives. A trocar, inserted into a 1-cm incision, is used to insert and release each implant into separate fan-like tracks. Steri-strips and water-resistant dressings are usually applied until the incision adequately closes (approximately 1 wk). The testosterone implants form a subdermal depot that dissolves slowly and requires surgical removal only if the therapeutic effect needs to be rapidly terminated. Absorption of testosterone from the pellets follows zero-order release kinetics, with near complete absorption by day 189.[36] This product might prove to be a suitable therapeutic option, but several factors that might limit its use should be considered. Clinician training is required, and an administration device must be obtained from the manufacturer. Trocars are reusable, but they must be sterilized before each procedure and replaced if the beveled edge becomes blunted with frequent use. The most commonly observed adverse event (5-11% of patients) is extrusion of implants through the insertion site, which usually occurs 1-2 months after implantation.[37,38,39] Complications related to any minor surgical procedure, such as bleeding and infection, occur infrequently. A similar subdermal implant of a potent synthetic androgen, 7

-Methyl-19-nortestosterone, is in development and will be formulated to last 6-12 months.[34,35]

Because of their overall efficacy and tolerability, transdermal patches are commonly prescribed for testosterone replacement therapy. After our patient refused to continue parenteral therapy, he was started on Androderm patches because other topical testosterone products were not available on the pharmacy formulary. Androderm contains a reservoir of testosterone dissolved in an alcohol-based gel combined with glycerol monooleate and glycerin for enhanced absorption, a permeable polyethylene membrane, and an acrylic adhesive peripheral layer surrounding the central drug delivery area. Because Androderm takes an average of 8 hours to achieve maximum plasma concentrations (Tmax), nightly application generally returns serum testosterone concentration to normal and mimics the diurnal changes observed in healthy men. Application to the back, abdomen, upper arms, or thighs, avoiding prominent bony areas or oily skin, is recommended. Morning serum testosterone concentrations usually return to normal within the first day of dosing, and accumulation is not observed with continued therapy. After patch removal, hypogonadal serum concentrations are observed within 24 hours. According to product information, up to 37% of patients in clinical trials developed pruritus, and 2-12% of patients experienced some form of dermal irritation.[13]

An alternative transdermal testosterone patch, Testoderm TTS, was prescribed for our patient after Androderm was discontinued because of his dermal symptoms. Testoderm TTS contains a reservoir of testosterone and alcohol gelled with hydroxypropyl cellulose, and an ethylene-vinyl acetate membrane coated with a polyisobutylene adhesive. Although Testoderm TTS may be applied at any time of day according to the package insert, morning application is most practical in order to comply with the recommended monitoring 3-4 hours after patch administration. The maximum concentration occurs 2-4 hours after administration, unlike the longer Tmax associated with Androderm. Testoderm TTS should be placed on the arm, back, or upper buttocks. Product labeling reports pruritus in 12% of patients and rash and erythema in 1-3% of patients at the application site.[40] Although therapeutic substitution with an alternative formulation was intended to lessen the localized hypersensitivity reaction that our patient experienced, he reported a worsening of dermal symptoms. In addition, as observed in our patient, Testoderm TTS patches may not adhere well and may fall off when the patient exercises or sweats.

Testosterone scrotal patches (Testoderm; Alza Pharmaceuticals) are another treatment option. This system consists of a testosterone-containing film of ethylene-vinyl acetate copolymer that contacts the skin surface, modulating steroid bioavailability. Patches with adhesive also contain polyisobutylene and colloidal silicon dioxide. Since scrotal skin is approximately 5 times more permeable to testosterone than other skin sites, Testoderm will not produce adequate testosterone concentrations if it is applied to nonscrotal skin. Peak serum testosterone concentrations occur within 2-4 hours after patch application, are typically 15% higher than trough levels, and return toward baseline values within 2 hours of system removal.[40] Steady state is achieved in 3-4 weeks. Unlike nonscrotal patches, Testoderm does not contain an ethanol-based drug reservoir and therefore may be less likely to precipitate hypersensitivity reactions. A randomized, open-label, crossover study of 60 healthy adult men reported that scrotal systems produced lower frequencies of contact allergy (0% vs 12%, p<0.001) and topical irritation (5% vs 32%, p<0.001) than nonscrotal systems.[41] In addition, subjects with contact allergy to nonscrotal systems could use the scrotal system without sensitivity reactions, suggesting that testosterone may not be the primary allergen. According to the product literature, premarketing clinical trials reported a 7% frequency of pruritis and a 2% frequency of irritation.[40] The frequency of all cutaneous reactions decreased with continued use. Because scrotal skin contains high concentrations of 5-a reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT),[42] the use of scrotal patches has been associated with elevated DHT concentrations. The long-term effect of supraphysiologic serum DHT levels is unknown; therefore, careful monitoring of prostate growth is warranted. Poor patient acceptability and problems with patch adhesion, especially when the patient sweats or exercises, may limit the use of this product.

The topical testosterone gel preparation was recently introduced to the market as a therapeutic alternative for patients who cannot tolerate intramuscular injections or patches, like our patient. In a randomized, multicenter, parallel study of 227 hypogonadal men, the gel formulation produced clinical end points comparable with testosterone patches, with a 5.5% frequency of skin irritation compared with a 66% frequency in patients using testosterone patches.[43] The clear, colorless hydroalcoholic gel contains 1% testosterone and is available in single-use 2.5-g or 5-g packets. Of the 2.5 or 5 g in a given application, only 25 mg or 50 mg, respectively, are delivered to the skin surface and, on average, approximately 10% of this dose is absorbed during a 24-hour period.[44] Thus, a 5-g dose is expected to deliver a dose of testosterone similar to a 5-mg patch. The gel product should be applied once/day to clean, dry, intact nonscrotal skin, such as the shoulders, upper arms, and abdomen, where it dries quickly. For optimal absorption, patients should wait at least 5-6 hours after application before showering or swimming. The skin serves as a reservoir for sustained release into the systemic circulation. Steady state generally is achieved by the second or third day of administration, although the elimination half-life is variable. The testosterone metabolite DHT is also available as a topical gel in Europe and is under clinical investigation in the U.S.[33]

The risk of testosterone transfer by skin-to-skin contact is a concern with use of the gel formulation. According to the product literature, in some cases, testosterone levels increased to more than double baseline values in partners who engaged in once-daily 15-minute physical contact with patients using the gel product.[44] To minimize the risk of testosterone transfer, the manufacturer recommends that patients wash their hands immediately after application and cover the application site(s) with clothing after the gel dries. If unwashed or uncovered skin comes in contact with another person, the contact area on the other person should be washed immediately.[44]

Despite advantages of the gel product, its cost may limit its use as first-line therapy. In 2001, a monthly supply of AndroGel 1% cost $163.51 compared with $117.79 and $108.24 for Androderm and TestodermTTS, respectively.[17] In practice, the cost difference may be more substantial based on purchase contracts, reimbursement, and formulary restrictions at individual institutions.

Patients who receive testosterone replacement should be followed for changes in libido, sexual function, energy level, mood, sarcopenia, acne, body weight, and, depending on the diagnosis, secondary sexual characteristics (including body hair distribution, muscle strength and mass, gynecomastia, and testis volumes). Full virilization in a patient with hypogonadism may take up to 4 years. Patients should be followed at 4-6-month intervals during this time to assess efficacy, toxicity, and compliance.[45] Because symptoms and physical findings are subjective, variable, and may be related to other medical conditions, patient history and physical examination alone may not be sufficient to ensure proper dosing. Therefore, laboratory monitoring to determine serum free and total testosterone, percentage of free testosterone, and DHT should be performed after steady state is achieved. The therapeutic goal of testosterone replacement therapy should be to improve symptomatology and to maintain physiologic serum androgen levels. Measurement of total testosterone is relatively inexpensive and readily available in many laboratories. However, changes in the concentration of sex hormone-binding globulin -- commonly observed in patients who are obese, have hyperthyroidism or other medical conditions, or take certain drug regimens -- may result in changes of total testosterone levels, making test results difficult to interpret or misleading.[46] Estimation of free testosterone from the ratio of total testosterone and sex hormone-binding globulin (free androgen index) is not valid for adult men.[46,47] Free testosterone, measured by equilibrium dialysis or immunoassay, theoretically should be a better determinant of androgen status than total testosterone, but currently available immunoassays may not always provide correct results.[46,47] Furthermore, technical complexity and economic cost limit the use of these analytical methods. Because albumin weakly and reversibly binds testosterone, measurement of bioavailable testosterone (free plus albumin-bound testos-terone) may predict testosterone availability at target tissue. However, this test is time consuming, not routinely available, and expensive, and its clinical value is debated.[46,47] Variability in methods and reference intervals among different diagnostic laboratories should be considered for correct interpretation of androgen laboratory results, and abnormal results should be confirmed by repeat analysis. In addition, serum LH concentrations should be determined for patients who have hypergonadotropic hypogonadism. Failure to suppress LH within the eugonadal reference range by 3-6 months may suggest inadequate replacement therapy or noncompliance.[48]

Maintenance of trough serum testosterone levels within the eugonadal reference range is suggested as a guide for determining the adequacy of parenteral testosterone replacement.[48] According to the Androderm product literature, the patient's morning serum testosterone concentration (after product application the previous evening) may be used to assess the adequacy of dosing.[13] If the serum concentration is outside the reference interval, sampling should be repeated, ensuring proper system adhesion and appropriate application time. For Testoderm products, testosterone measurements are recommended after the patch has been used for 3-4 weeks and should be performed 2-4 hours after patch application.[40] Trough serum testosterone levels (levels immediately before the next application) should be measured approximately 14 days after the patient begins using Androgel.[44]

In addition to androgen parameters, a lipid panel, including total cholesterol, LDL, HDL, and triglycerides, is recommended before beginning testosterone replacement and after 6-12 months of treatment (Table 3).[13,24,40,44,45,48,49,50,51,52,53,54] Depending on the patient's cardiovascular risks, lipid analyses should be performed routinely during therapy. Unlike oral alkylated androgens, parenteral and transdermal testosterone are aromatized to estrogen. Therefore, they usually are not associated with significant adverse serum lipid changes[49] and may even decrease atherogenic lipoprotein(a) concentrations.[55] For the assessment of possible erythrocytosis, hemoglobin and hematocrit determinations are suggested quarterly,[24] or at least annually,[45] for patients receiving long-term and/or high-dosage therapy. Liver function tests should be performed at regular intervals, especially during therapy with oral methylated agents.

For patients over 40 years old, measurement of serum prostate-specific antigen (PSA) and possibly prostatic acid phosphatase (PAP), as well as a digital rectal examination, should be performed quarterly during the first year of testosterone replacement therapy and annually thereafter.[24] Because the change in PSA levels/year while an individual is receiving testosterone replacement is less than 0.9 ng/ml,[56,57,58] a change of more than 1 ng/ml/year may be considered significant and warrants further evaluation.[50] The relatively low sensitivity and specificity of PAP has led some experts to question the need for its measurement. On the other hand, several refinements in PSA testing that are under investigation may improve its diagnostic accuracy, including age-specific and race-specific PSA reference ranges, PSA density (total PSA divided by volume of the prostate on computed tomography or magnetic resonance imaging scan), PSA velocity (e.g., three serial total PSA values measured during a 2-year period), and quantification of free and protein-bound forms of serum PSA.[51,59,60] It is well established that PSA exists in the serum in several molecular forms. Patients with benign prostatic hyperplasia have more of the free form, whereas those with prostate cancer have more of a complexed form (PSA irreversibly and covalently bound to a-1-antichymotrypsin and, to a lesser degree, to a-2-macroglobulin). Accordingly, the proportion of free to total PSA (% free PSA) may be a more sensitive indicator (i.e., it increases cancer detection) in the normal range of total PSA (2.5 or 3.0 to 4.0 ng/ml), whereas percentage of free PSA is a more specific test (i.e., it eliminates unnecessary prostate biopsies) when total PSA is minimally increased or equivocal (4.1-10.0 ng/ml).

Children and growing adolescents who are taking testosterone replacement should have radiographs of the hand and wrist every 6 months to determine the effects of testosterone on the epiphyses and to assess the rate of bone maturation.[61] Information regarding proper monitoring of bone metabolism during testosterone replacement in adults is limited. If osteopenia or osteoporosis is suspected, however, bone mineral density (particularly vertebral trabecular bone) should be assessed regularly,[62] possibly at 1-2-year intervals.[48]

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