After Accutane

For a woman concerned about the red nodules on her back, acne can ruin a shopping outing with friends. A teenage boy embarrassed about the cystic breakout on his forehead may stay home "sick" the day yearbook photos are taken.

More than a skin condition, acne's emotional toll leaves scars such as low self esteem, social withdrawal and depression in many patients. Studies show even mild outbreaks affect self worth. But for people with disfiguring acne that fails all treatments, acne rules all aspects of their daily lives. The FDA approval of Accutane (oral isotretinoin) in May 1982 came as a near-miraculous cure for these patients.

"Accutane was a godsend," recalls James Herrmann, MD, a dermatologist with the Dermatology Institute of DuPage Medical Group, Wheaton, Ill. More than 13 million patients have used Accutane to clear their acne-usually for the rest of their lives. But isotretinoin also raises concerns about grave side effects, including birth defects if used during pregnancy, bowel disease and depression.

Despite strict government regulation, Accutane proved an unshakable legal burden for Roche Holding AG. Facing thousands of personal injury lawsuits, the company pulled the drug from the U.S. market in July. The company also cited generic competition as cause for discontinuing Accutane.

Dermatologists' reactions are mixed about Accutane's exit. Some say it makes no difference since most patients use generic formulations anyway. Others worry generic drug makers may succumb to the same legal woes plaguing Roche.

Controversial Wonder Drug

Derived from vitamin A, oral isotretinoin regulates cell proliferation and differentiation. It also alters the lipid composition of the skin surface by reducing the size of sebaceous glands and lowering sebum production. This reduces the bacterial skin microflora that cause acne flares.

Patients typically take isotretinoin for 15 weeks to 20 weeks, and many patients continue to improve after ending their course. It permanently clears acne for 80 percent of acne patients. For the remaining 20 percent, it still clears their acne, although breakouts may return later in life.

Patients typically experience uncomfortable dryness of the skin, mouth and eyes while taking isotretinoin. This resolves after patients complete the treatment course.

Isotretinoin also may elevate liver function tests and blood lipids, including triglycerides and cholesterol. Some patients may experience liver inflammation, which resolves when patients stop taking the medication, says Ramzi Saad, MD, a dermatologist with the South Shore Skin Center, in Plymouth, Mass. Dr. Saad says he's never seen permanent liver damage in patients.

Among the most serious side effects is the risk of birth defects if women get pregnant while taking oral isotretinoin. The government set up the iPledge program in 2006 to curb this risk. iPledge requires women of childbearing age to use two forms of birth control and take monthly pregnancy tests while using oral isotretinoin.

Bowel disease is another concern. In recent years, juries awarded $33 million in damages to people who blamed Accutane for bowel disease. However, the link between isotretinoin and inflammatory bowel disease remains controversial.

Canadian researchers recently reported finding no link between isotretinoin and IBD. In their population study, 1.2 percent of patients with Crohn's disease used isotretinoin before diagnosis. But this was statistically similar to the control group, of whom 1.1 percent developed IBD.¹University of North Carolina researchers also found no causal link between isotretinoin and bowel disease in a review of case studies over a 23-year period.²Concerns that oral isotretinoin causes depression and suicidal ideation also have never been substantiated, despite high-profile cases. Congressman Bart Stupak (D-Mich.) and his wife blamed Accutane for their 17-year-old son's suicide in 2000; however the Stupaks lost their case earlier this year.

Losing this case doesn't exonerate Roche or other isotretinoin makers from professional skepticism among some physicians. And the FDA continues to require isotretinoin manufacturers to warn patients on the label about the risk of suicide and depression.

Still, recent research indicates depression improves as acne clears.^3-6 "I haven't had anyone who had depression or major psychological side effects while on oral isotretinoin. It's been the reverse. Patients feel more self confident," says Linda Stein, MD, a dermatologist at the Henry Ford Hospital, Detroit. She adds that patients with a history of suicidal ideation aren't good candidates for the drug.

Accutane's Demise

Accutane's demise says as much about America's fiercely competitive pharmaceutical landscape as it does about the legal climate.

The patent for Accutane expired in 2002, opening doors to the isotretinoin market for generic manufacturers such as Mylan Pharmaceuticals, Barr Laboratories and Ranbaxy Laboratories. As frequently happens when generics appear, name-brand Accutane sales plunged. By the time of Accutane's exit, Roche maintained 5 percent of the isotretinoin market share.

Although patients still have plenty of isotretinoin options, some doctors argue that the generic versions are no substitute for the original formulation.

"The generic forms of oral isotretinoin are not as good as the brand name Accutane," says Alex Khadavi, MD, associate clinical professor of dermatology at the University of Southern California, Los Angeles, and founder of Advanced Skin & Hair Inc. "It's very disappointing that some patients who would have responded in one month to Accutane are taking three months to respond to the generics."

The Food and Drug Administration requires generic drugs to have the same active ingredients, strength, dosage form and route of administration as the brand name product. Generic drugs, however, aren't required to have the same inactive ingredients. These slight variations may affect how quickly a drug is released as well as the size and shape of the pill.

"I'd still be happier to prescribe a product with a 70 percent chance of being the primary cure instead of an 80 percent chance, as long as the side effect profile isn't worse," Dr. Saad says. "There's such variability with response, even with Accutane. It's hard to assess whether it's the patient's response or the generic medication. No great studies prove this one way or another."

Other physicians interviewed say they haven't noticed a difference with the generics. Dr. Stein says the generics are bioequivalent with Accutane. "The majority of my patients were getting generics because of their insurance," she says. "So it really won't make that much of a difference."

Many states have laws requiring pharmacies to automatically fill prescriptions with generic drugs unless specified by the doctor. "Often we as physicians don't know what our patients are getting. Although we write 'Accutane' on the prescription, the medications are substituted at the pharmacy level," Stein says. "Sometimes people will get several different generics within one prescription. So they might get a 40 mg tablet that's one prescription and a 20 mg tablet that's a different brand."

Joel Schlessinger, MD, FAAD, FAACS, president emeritus, American Society of Cosmetic Dermatology and Aesthetic Surgery, worries generic isotretinoin manufacturers could pull out of the market if the legal burden becomes too large.

"The legal system works against the legitimate companies," says Schlessinger, adding that manufacturers with deep pockets become legal targets because they can pay hefty damages. "Roche was getting sued on nearly a daily basis."

With Roche out of the picture, Schlessinger also says the focus of personal injury lawsuits could shift to doctors who prescribe oral isotretinoin, he says. This is already happening. An Illinois patient who took Accutane a decade ago sued his dermatologist in August for failing to warn him about the side effects. The patient later developed Crohn's disease.

Cases such as this make Dr. Schlessinger pause before writing a prescription for oral isotretinoin. "We're on the edge of a precipice," Schlessinger says. "There's a constant drumbeat of lawyers, and we have the added liability of not having a legitimate manufacturer standing behind us."

Lauren Meade is associate editor. She can be reached at lmeade@advanceweb.com.

References

1. Bernstein CN, Nugent Z, Longobardi T, Blanchard JF. Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control Study. Am J Gastroenterol. 2009 Jul 21.

2. Crockett SD, Gulati A, Sandler RS, Kappelman MD. A causal association between isotretinoin and inflammatory bowel disease has yet to be established. Am J Gastroenterol. 2009 Oct;104(10):2387-93.

3. Hahm BJ, Min SU, Yoon MY, Shin YW, Kim JS. Changes of psychiatric parameters and their relationships by oral isotretinoin in acne patients. J Dermatol. 2009 May;36(5):255-61.

4. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg. 2005 Jun;24(2):92-102.

5. Magin P, Pond D, Smith W. Isotretinoin, depression and suicide: a review of the evidence. Br J Gen Pract. 2005 Feb;55(511):134-8.

6. Bozdag KE, Gulseren S, Guven F, Cam B. Evaluation of depressive symptoms in acne patients treated with isotretinoin. J Dermatolog Treat. 2009 Jan 1:1-4. (Epub ahead of print.)

Laser Treatments for Acne

Most doctors agree there's no substitute for oral isotretinoin for severe nodular acne. However, laser and light therapies are increasingly used for mild to moderate acne as well as for diminishing acne scars.

Lasers reported to improve acne include the pulsed-dye laser, intense pulsed light, 1320-nm diode laser, 1450-nm diode laser, Er:YAG laser and light emitting diode.

Lasers shouldn't be used on patients taking isotretinoin. Patients need to wait 6 months after stopping Accutane because of an increased risk of scarring. Those with darker skin types may experience hyperpigmentation of the skin after laser treatments.

"I use lasers for acne, not as the prime treatment, but in conjunction with conventional therapies," says Alex Khadavi, MD, associate clinical professor of dermatology at the University of Southern California and founder of Advanced Skin & Hair Inc. He's currently investigating the effects of 635-nm Zerona diode laser (Erchonia Medical) on cystic acne.

"It's not widely used for acne, but I've been pretty impressed with the results so far," Khadavi says. The Zerona doesn't make the skin peel or become red, he adds.

Paul M. Friedman, MD, clinical assistant professor of dermatology at University of Texas Houston Medical School, has noted significant results¹with the 1450-nm diode laser (Candela, Smoothbeam). The laser heats the sebaceous gland to decrease secretion into the follicle. The long wavelength also heats collagen in the dermis, stimulating new collagen to form and improve depressed scars, Friedman says.

"In a study from our center using the 1450-nm diode laser, the average patient experienced a 38 percent reduction in the number of acne lesions after one treatment and greater than 70 percent reduction in number of lesions after three treatments," says Friedman. Improvements lasted for 12 months after the third treatment.

Photodynamic therapy (PDT) is another option for treating cystic acne. Physicians apply topical 5-aminolevulinic acid (5-ALA). The chemical preferentially goes to sebaceous glands and P. acnes bacteria. The physician uses IPL or blue light to trigger a chemical reaction, which shrinks oil-producing sebaceous glands and eliminates bacteria on the skin.

James Herrmann, MD, a dermatologist with the Dermatology Institute of DuPage Medical Group, Wheaton, Ill., uses the Isolaz (Aesthera) to treat mild to moderate acne. The device suctions black heads while simultaneously emitting broadband light, which destroys acne-causing bacteria. Dr. Herrmann, who also is clinical assistant professor at Northwestern University Medical School in Chicago, recommends at least four treatments every two weeks, with maintenance treatments every three months.

"I use Isolaz in conjunction with conventional treatments such as antibiotics and topical therapy," Dr. Herrmann says. "For a lot of patients, the therapy is very helpful and can minimize the need to go to something like oral isotretinoin."

-Lauren Meade

Reference

1. Jih MH, Friedman PM, Goldberg LH, Robles M, Glaich AS, Kimyai-Asadi A. The 1450-nm diode laser for facial inflammatory acne vulgaris: Dose-response and 12-month follow-up study. J Amer Acad Dermatol. 2006 Jul; 55(1):80-7.