Isotretinoin risks in acne treatment

When it comes to isotretinoin, dermatology experts say, pediatricians should advise parents not to believe everything they read online. Furthermore, patients can't always be relied upon to comply with the birth-control requirements for using the drug.

IBD issues

Perhaps the most common misconception about isotretinoin, according to Bernard Cohen, MD, professor of pediatrics and dermatology at Johns Hopkins University School of Medicine, Baltimore, Maryland, is its possible association with inflammatory bowel disease (IBD). "Many people buy into that stuff," states Cohen, "especially people who look on the Internet."

Julie C. Harper, MD, clinical associate professor of dermatology at the University of Alabama at Birmingham, offers an historical rationale for this misconception. "Early on, some large epidemiologic studies showed that perhaps there might be an association between isotretinoin and ulcerative colitis and IBD." However, she continues, those studies did not control for an underlying diagnosis of acne, or for the fact that most people treated with isotretinoin also have been treated with antibiotics. Such factors could act as confounding variables, Harper states.

She adds that later epidemiologic studies attempted to control for these variables. "And the most recent studies have not shown an association between IBD and isotretinoin.”^1,2

Cohen says that when he starts a child on isotretinoin, he alerts patients and parents to the potential connection. "But I also tell them that the best-done studies don't show a connection between use of isotretinoin for acne and IBD."

Elaine Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, Missouri, adds that a well-done recent study actually showed isotretinoin to be protective against IBD.³

Contraceptive conundrum

With birth control pills typically prescribed under the US Food and Drug Administration (FDA)-mandated iPLEDGE risk management program, says Cohen, "People are worried about thromboembolic events. But they forget that pregnancy has a much higher risk than any of the birth control pills we use."

According to the package insert of 1 combined oral contraceptive (COC), a woman's risk of a venous thromboembolic event (VTE) doubles if she takes a COC-rising from approximately 3 per 10,000 women-years to 6 per 10,000 women-years. "If she takes an oral contraceptive pill (OCP) that contains drospirenone, it may triple-up to 9 per 10,000 women-years,” Harper relates, “but if she gets pregnant, it rises to 12 per 10,000 women-years. If someone is sexually active and you give [her] a birth control pill, overall [she is] still choosing to lessen [her] risk of a blood clot. The risk is lower on the pill than if [she gets] pregnant."

Three OCPs-Estrostep (ethinyl estradiol l[EE], norethindrone; Warner Chilcott; Rockaway, New Jersey); Ortho Tri-Cyclen (EE, norgestimate; Janssen Pharmaceuticals; Titusville, New Jersey) and YAZ (EE, drospirenone; Bayer Healthcare, Leverkusen, Germany)-are FDA approved for treating acne.

Cohen says that when he has a patient with moderately inflammatory acne who declines oral antibiotics or who flares without them, "One consideration might be to give her an OCP. Some people will argue that patients who flare during their menstrual periods will be more likely to respond to oral contraceptives" because their acne clearly has a hormonal component.

Cohen believes that, in this setting, it's important to choose a contraceptive-and to counsel patients-carefully. For patients with a family history of thromboembolic events in young people, he avoids drospirenone whether or not the patient goes on isotretinoin. If the family history includes a parent or relative with severe acne who may have used isotretinoin, "The patient is at greater risk for developing more severe, persistent disease,” Cohen emphasizes. “It's important to explain this at the first visit."

Siegfried typically puts postmenarchal females with acne on an OCP (unless contraindicated) after first screening for a family history of clotting and for other risk factors such as smoking. "I also ask the mother if she's ever been on hormonal therapy, and how she tolerated it," she states. If any concern arises, particularly a history of clotting, "I will refer the patient to my hematology colleagues for a thrombophilia evaluation" before prescribing hormonal therapy. 

Assessing abstinence

If a 12-year-old girl needs isotretinoin, has had normal periods for a year, and says she is not sexually active, Harper reflects, "The question is, do you force her to go on an OCP, knowing [its] risks? Or do you allow this person to enter the iPLEDGE program" claiming to be sexually abstinent and reporting no other forms of contraception?

Siegfried states that she has taken the latter route for infants and young children. For women of childbearing age, however, her approach differs. "You do all you can to prevent pregnancy,” she says, “but it is ultimately the patient's responsibility, after you have adequately informed [her]" about the necessity of always using 2 birth-control methods.

The data justify concern about patients’ candor in this regard. In a survey that anonymously asked 75 patients how compliant they were with the birth-control choices they reported for iPLEDGE, Harper relates, "Many were not compliant.⁴ For example, if they said they were going to use OCPs and a condom, they would only really use the OCP and not the condom, and they regularly missed pills. Additionally, in the group of women who said they were going to be abstinent, a fair number were not."

All study participants had reported being sexually active before entering the program, Harper notes. When a patient who previously has been sexually active says she is not currently in a relationship, Harper says, "Perhaps we should strongly encourage her to use a combination such as an OCP and condoms. Age may or may not play a role here. If a person says she's abstinent and has never been sexually active, that person may be a better choice" to rely on abstinence.

Cohen concludes that, for safety's sake, unless proven otherwise, "I have to assume that all patients who are having periods are potentially sexually active."  

Skeletal side effects

Regarding the concern of isotretinoin causing premature closure of epiphyseal plates, Harper says that evidence is scant to support the fears. "There's so much misinformation on the Internet,” she says. “We have moms who come into the clinic with a child who has already been treated with every acne medication, and the child is not responding. In fact, the acne is getting worse, with evidence of scarring."

Yet when staff members begin enrolling the child in the iPLEDGE isotretinoin risk management program, she relates, "The parent says, 'Wait-I've heard that this drug will make children stop growing.'" Harper says that when one looks for data to support this claim, "You'll find that cases where there is premature closure of the epiphyseal plate occur in people who are on extremely high doses for many years for indications other than acne." Examples include disorders of keratinization and some types of ichthyosis, she states.

In fact, a recent review culminating in guidelines for pediatric acne⁵ found only one case of premature epiphyseal plate closure associated with isotretinoin use for acne.⁶

For acne treatment, says Cohen, "The recommendations are fairly tight: 120 to 150 mg/kg overall, which, for most people, works out to be about 1 mg/kg for about 5 months." Because isotretinoin's risks are dose and duration dependent, he continues, "In acne, the risks are very low, and may not be any different than in the normal population. We're treating for a finite period, at recommended doses."

Isotretinoin-induced bone abnormalities occur so rarely, adds Siegfried, that she doesn't track these parameters in patients she has on isotretinoin for less than a year, and sometimes 2 years. For the handful of her patients who must be on isotretinoin long term, she says, "I follow bone age and plain (x-ray) films, looking for bony exostoses. I also monitor for osteopenia."

Because parameters for osteopenia in children have not been defined, she advises, "You need an experienced radiologist who can compare the films from year to year for bone loss. And I've never seen that happen." However, she relates, one of her patients with ichthyosis and a history of atopy developed severe headaches caused by bony abnormalities that may have been related to the child's long-term isotretinoin use.

Pseudotumor cerebri

Pseudotumor cerebri (PTC) is not believed to be common, Harper notes. "Yet, it does carry real risk. And the risk we worry most about is permanent blindness. So, we must be aware of the symptoms that go with that." These symptoms include migraine-like headaches (characterized by frontal pressure) accompanied by other symptoms such as nausea, vomiting, and double vision,⁷ she says.

Harper advises that physicians with uncertainty regarding any of these symptoms must refer the affected patient to a neurologist or ophthalmologist for a thorough exam, looking particularly for papilledema. If papilledema is present, she says, "The patient will require neuroimaging to prove that there's not another cause, such as a mass. Once we've excluded mass lesion, the third part of making the diagnosis is lumbar puncture."

For his part, Cohen states that in 30 years of practice, only a handful of his patients have experienced PTC while on isotretinoin. He alerts patients that there's no mistaking the "unbelievably dramatic" and persistent headache that marks this condition. Therefore, he says, "I tell patients if they get headaches that don't go away, stop the drug and call me." Fortunately, he adds, PTC generally resolves just as dramatically. "It's amazing,” he says. “If they stop the drug-even before the eye findings go away-the symptoms go away overnight."

Matters of mood

In the early 2000s, when US Representative Bart Stupak's son committed suicide and a Florida teenager deliberately crashed a private plane, it came out that both individuals had been taking isotretinoin, Siegfried recalls. That’s when the drug’s perceived association with mental health problems spurred the bulk of isotretinoin lawsuits. Now, she says, "That has relatively blown over."

Cohen contends that that perceived link remains controversial. "When you look at some of the bigger surveys that examined the incidence of the risk of suicidal ideation and suicide in adolescents, the risk is about the same" for adolescents on or off oral retinoids, he observes. "Adolescents are a higher-risk group to begin with, and you can make a case for the fact that patients who have horrible acne are at increased risk for depression and suicidal ideations.

Other considerations

Another consideration related to an isotretinoin regimen, says Cohen, is the need to minimize oral antibiotic use. Here, he states, "The only criteria that has changed for me in the last decade is that if I have a kid with severe disease who is at least partially controlled with oral antibiotics, then I probably wouldn't treat with isotretinoin." However, if he can't titrate a patient off oral antibiotics within 6 to 12 months without risking horrible flares, he says, "One of my go-to drugs is isotretinoin."

Acne treatment guidelines recommend using oral antibiotics no longer than 6 months, Cohen says, but in practice, "It's not unusual for us in pediatric dermatology to have patients on and off oral antibiotics for a year or 2. In that group of patients, I will consider isotretinoin earlier than I might have done years ago."

Consent with care

Overall, Cohen concludes, "The best patient or parent is an informed one. So, all these issues-proven or unproven-should be discussed. Be frank with families. If you do that, the patients will be more compliant, the families will help you," and treatment likely will succeed.

However, he notes, some physicians may not have the "luxury" of spending the time to counsel patients and families on their first visit. "If you can't spend more than 5 minutes with a kid with moderately severe acne, you're in trouble," he warns. After you've spent the necessary 15 to 20 minutes, in his opinion, an excellent extender can answer remaining questions.

If anyone who inquires about isotretinoin expresses qualms about its risks, Siegfried states, "I don't put them on it. I will actively discourage them-not because I don't think it's a great drug, but because the perceived risks bother people more than the real [adverse] effects." 

Dr. Harper's comments are from a presentation she made at the American Academy of Dermatology Annual Meeting, March 21-25, 2014, in Denver, Colorado. She and Dr. Cohen report no relevant financial interests. Dr. Siegfried has agreed to serve as an expert witness for Roche, if needed, but had not been called to testify or received any payments as of press time.

REFERENCES

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2. Etminan M, Bird ST, Delaney JA, Bressler B, Brophy JM. Isotretinoin and risk for inflammatory bowel disease: a nested case-control study and meta-analysis of published and unpublished data. JAMA Dermatol. 2013;149(2):216-220.
3. Rashtak S, Khaleghi S, Pittelkow MR, Larson JJ, Lahr BD, Murray JA. Isotretinoin exposure and risk of inflammatory bowel disease. JAMA Dermatol. September 10, 2014. Epub ahead of print.
4. Collins MK, Moreau JF, Opel D, et al. Compliance with pregnancy prevention measures during isotretinoin therapy. J Am Acad Dermatol. 2014;70(1):55-59.
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Mr Jesitus is a medical writer based in Colorado. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.