Estradiol Transdermal Systems

For most women, menopause symptoms spontaneously cease within 5 years, yet many still experience hot flashes, sweating, vaginal dryness, and insomnia well past the onset of menopause. Topical administration of estrogens provides a convenient means of replacing one aspect of this steroid deficiency. Estradiol is available in a transdermal form requiring only once-weekly administration.

Pharmacology

Hormone replacement during menopause is indicated for the relief of severe vasomotor symptoms (hot flashes and night sweats); if severe symptoms of vulvar or vaginal atrophy are involved, long-term application of topical patches may be effective, but directly applied vaginal preparations may be preferred to avoid general systemic absorption and possibly reduce side effects.

The use of transdermal estradiol is postulated to reduce the risk for thromboembolitis associated with estrogens by avoiding the hepatic "first-pass effect." Controlled trials have not been performed to confirm this presumption, however.

Dosing and Administration

Once the protective strip on the patch has been removed, the transdermal system is to be applied to a clean and dry area of the intact skin on the trunk of the body, preferably to the abdominal wall or buttocks. The patch should be held in place for about 10 seconds to ensure proper adhesion to the skin. Application to the breasts or waistline should be avoided. To minimize irritation to the skin, application sites should be rotated.

This particular transdermal system of estradiol requires application once weekly. If a patch is not replaced on the designated day, it should be replaced as soon as possible to maintain the established schedule. Used patches should be folded, adhesive side in, and disposed of in an area away from children or pets.

The usual initial dose is one 0.025- mg/d patch applied once weekly. The strongest available dose is the 0.1- mg/d patch.

Side Effect and Interaction Profile

Because other non-estrogen-based therapy is available to treat osteoporosis, the use of supplemental estradiol only for the treatment of osteoporosis should be considered only in the context of risks-benefits for the patient. The use of topical estradiol is accompanied by the same contraindications associated with estrogen use: a history or suspicion of breast cancer or neoplasm, unrelated endometrial hyperplasia, presence or history of thromboembolism or thromboembolic disease (ie, angina or heart attack), untreated hypertension, or active liver disease. Tobacco smoking, obesity, diabetes, and dyslipidemia also increase the likelihood of estrogen-related thromboembolic conditions.

The most common side effect reported from the use of these transdermal patches has been erythema and irritation at the application site, which occurs in nearly a third of women. Mastalgia, abdominal pain with cramps, nausea, and weight gain have also been reported.

Concurrent use of the antituberculin drug rifampin and the herb St. John's wort may diminish the effect of estrogen supplements. The same interaction is possible with the coincident use of the antiseizure drugs phenobarbital and phenytoin.

Clinical Outlook

Although natural therapies such as black cohosh and isoflavones are becoming increasingly popular, traditional estrogen supplements such as estradiol may also help alleviate many of the symptoms associated with menopause, along with diet, calcium supplements, and weight-bearing exercises.

Estradiol is available in transdermal patch strengths of 0.025 mg/d, 0.0375 mg/d, 0.05 mg/d, 0.06 mg/d, 0.075 mg/d, and 0.1 mg/d from Mylan Laboratories Inc.

Sertraline Hydrochloride

Although the selective serotonin reuptake inhibitor (SSRI) sertraline hydrochloride (HCl) is used in the treatment of major depressive disorders, it is also being used for refractory obsessive-compulsive disorders and some anxietyrelated illnesses. Studies indicate that sertraline HCl is more potent than fluvoxamine, fluoxetine, or clomipramine with its effect on serotonin levels. Its Nmethylated metabolite retains selectivity in serotonin reuptake inhibition.

Dosing

For the treatment of adult major depression, the daily dose is 50 mg to 100 mg, with possible weekly increases to a maximum of 200 mg. Sustained dosing over several months is often required to achieve desired effects. Panic disorder, posttraumatic stress disorder, and social phobia are treated with an initial daily dose of 25 mg, again with weekly increases to a daily maximum of 200 mg. Obsessive-compulsive disorders require higher daily doses in the range of 200 mg to 400 mg. Doses at this level, however, carry an 80% rate of adverse reactions. Doses should be discontinued slowly to prevent withdrawal symptoms following prolonged use.

When using the liquid concentrate, the sertraline HCl dose must be carefully measured with the provided calibrated dropper and immediately administered, diluted in 4 ounces of water, ginger ale, lemonade, or orange juice.

Adverse Effects

The sensitivity of the GI tract to serotonin, coupled with the physiologic effects of an SSRI, can result in increased nausea, xerostomia, and diarrhea during treatment with sertraline HCl. Some patients experience treatment-induced sweating. In addition, recent reports suggest that 50% or more of patients using SSRI therapy will describe some form of sexual dysfunction during treatment.

Paradoxically, the use of SSRIs such as sertraline HCl is sometimes associated with a worsening of depression symptoms, or even the emergence of suicidal thoughts and behaviors. While unsupported by controlled trials, empiric observations suggest that treating a major depressive episode with just an antidepressant may unmask an underlying bipolar disorder. A careful psychiatric history and screening are always necessary before initiation of therapy. Children are deemed especially at risk, based on a pooled analysis of data from 24 shortterm studies involving 9 antidepressants, including sertraline HCl. As a result, the FDA has directed all antidepressant manufacturers to include a black-box warning in their package inserts advising of this possibility and has recommended that patient medication guides be dispensed with each fill of an antidepressant prescription.

The rarely occurring "serotonin syndrome" is possible when sertraline HCl is combined with other drugs that may increase serotonin levels. These drugs include lithium, tricyclic antidepressants, trazodone, dextromethorphan, meperidine, monoamine oxidase inhibitors, buspirone, and tramadol.

Since sertraline HCl is extensively metabolized in the liver, doses should be reduced and cautiously employed in the presence of hepatic impairment.

Outlook

Sertraline HCl, in its branded form, represented $3 million in annual sales in 2005. The expense of the branded product resulted in obligatory "pill splitting" to shave pharmacy benefit costs; patients were obliged to take half-tablets of 100-mg strengths to obtain their 50-mg dose. Although this practice is controversial, no apparent medical harm to patients has been determined. The availability of the less-expensive generic form of sertraline HCl should help to temper this mandated routine.

Sertraline HCl is available as an oral solution containing 20 mg/mL from Roxane Laboratories Inc, and in tablet strengths of 25 mg, 50 mg, and 100 mg from Teva Pharmaceuticals USA and from Pfizer Inc's generic unit, Greenstone Ltd.

Mr. Middleton is an instructor of pharmacology at Kellogg Community College in Battle Creek, Mich.