A new formulation of the powerful acne drug, updated guidelines for the iPledge program and novel research about associated side effects are among the new pieces of information regarding the controversial medication.
A number of recent developments related to the use and distribution of isotretinoin stand to impact the way dermatologists prescribe the powerful acne medication. A recently approved formulation is now available in the US, and a new study evaluates 3 key areas related to the drug’s potential adverse side effects. Additionally, changes have been made to modify the iPledge Program, the mandatory federal program designed to prevent fetal exposure to this teratogenic agent.
Isotretinoin is a strictly controlled pharmaceutical in the US market. It is not a first-choice therapy. Because of cost concerns and risk factors associated with its use, it is considered only after other first-line therapies have been ineffective for treating severe acne.
Isotretinoin was first manufactured as Accutane by Roche. A course of treatment, including topical creams and antibiotics, is usually attempted before isotretinoin therapy is considered. Oral contraceptives are also approved as an acne treatment and can be used in women prior to isotretinoin.
Isotretinoin works by reducing the size of the sebaceous glands and decreasing sebum production. Many patients report lasting results after a therapy regimen that includes the drug – as many as 85%, according to the American Academy of Dermatology.1 Skin that had been inflamed and marked by severe, cystic acne clears within a period of months, the potential for scarring is reduced and many patients report alleviation of symptoms of depression that are associated with poor self-image caused by severe acne.
Before being pulled from the market by Roche in 2009, the company’s formulation of isotretinoin, Accutane, was a popular treatment for difficult, scarring acne; some studies reported a 250% increase in the dispensation of the medication over an 8-year period.2,3 A report submitted to the FDA in 2000 by Roche estimated about 5 million patients were treated with the drug from 1982-2000.4
In 2009, in response to lawsuits over the drug’s side effects and decreased market share due to the introduction of several generic brands, Roche withdrew and delisted its brand-name formulation of isotretinoin from the market. Since then, reports of the medication’s dispensation and usage practices have largely been anecdotal. However, dermatologists continue to use the product with care and close supervision, particularly when prescribing the medication to patients considered to be at the greatest risk for negative side effects – sexually active women of childbearing age.
Side effects of isotretinoin warrant close supervision when a patient is beginning a course of treatment. Isotretinoin is a teratogen that can lead to stillbirth, miscarriage and serious congenital defects. Serious mental health problems, including depression, psychosis and increased risk of suicide, have been reported. Digestive system impacts also have been reported, with some studies linking use of the drug to Crohn’s disease, ulcerative colitis and inflammatory bowel disease (IBD). Other reported side effects include anemia and thrombocytosis, conjunctivitis and dry eyes, dermatitis and pruritus, myalgia and respiratory problems, particularly in patients with asthma.
Many reports and studies criticizing the drug’s negative side effects have been published over the years, with strong language both for and against use of the medication. The author of a 2002 paper from Harvard Law School wrote: “Accutane also has the potential to destroy lives. Accutane is an extremely dangerous teratogen: It can cause severe birth defects when taken during pregnancy. About one quarter of babies born who have been exposed to Accutane during gestation have major congenital deformities. Those babies born without major malformations frequently develop severe learning disabilities. A whole segment of Accutane babies do not even survive pregnancy: 40% are spontaneously miscarried.”5 The author goes on to compare Accutane to Thalidomide.5
On the other side of the argument, dermatologists praise the drug for its ability to treat severe acne, with current research calling it “a drug of choice” with “immense promise … in reducing dermal irritation and increasing the therapeutic performance, thus resulting in an efficacious and patient-compliant formulation.”6
The iPledge Program
The use of isotretinoin during pregnancy and nursing is strictly contraindicated. One study showed that, among women exposed to isotretinoin who became pregnant, 83% of those pregnancies resulted in spontaneous abortion or infants with birth defects.7 The same study demonstrates that, among pregnancies that led to live births, the most frequently reported severe birth defects involved the central nervous system (microcephaly or hydrocephalus) and the cardiovascular system (anomalies of the great vessels).7 Microtia or absence of external ears were also noted in a majority of cases.7
Since 2006, patients, doctors and pharmacists have been required to use the iPledge system before a prescription for isotretinoin can be dispensed. Under the iPledge program, doctors must enter information about the patient, verify that counseling has occurred into an online system and demonstrate that women of child-bearing potential are following contraceptive guidelines. Currently, 2 parallel methods of contraception are required for women of childbearing potential – for example, an oral contraceptive paired with a barrier method. Additionally, regular pregnancy tests must be administered. Before a prescription can be dispensed, the pharmacist must check the website and verify that the guidelines have been followed. There are also strict guidelines concerning how long prescriptions can be given for – only 30-day supplies are permitted, for example, and there is a 7-day window between when a prescription is filled and when the patient must collect it.
The iPledge system has faced its share of criticism, with some physicians or patients who feel the system is an invasion of privacy and that it is a difficult process and prohibitive to proper, responsible treatment. Current research is calling into question the efficacy of the iPLEDGE system, which replaced an earlier, voluntary program called SMART – the System to Manage Accutane Related Teratogenicity.8
“Seven years after its introduction, this program does not appear to have solved the issue of fetal exposure to isotretinoin,” the authors of an article in the March 2013 issue of The Canadian Medical Association Journal report. The article cites a study from 2011 that reported 29 fetal exposures out of 9,912 courses of treatment with the drug. The authors “found no evidence that iPLEDGE significantly decreased the risk of fetal exposure compared with the SMART program.”2
A New Formulation
While the original formulation of isotretinoin, Accutane, is no longer on the market, several other companies continue to offer the medication: Amnesteem (Mylan Laboratories), Claravis (Teva Pharmaceuticals), Sotret and Absorica (Ranbaxy Laboratories) and Myorisan (VersaPharm Inc.).
On March 29, 2013, Promius Pharma LLC announced its new formulation of isotretinoin, Zenatane, following the drug’s earlier approval by the FDA for the US market. Interestingly, financial analysts still report the demand for isotretinoin is strong enough that the company could stand to gain a 20% market share with its new formulation and could expect revenues of $50 million a year from the sale of the product.9 The company said the total market for the drug was $309 million annually in the U.S.10
The product will be supported by the Promius Promise pharmacy service, which is a result of a partnership between the company and an accredited, iPLEDGE-certified, US-based pharmacy.11 The program is designed to assist with patient education regarding treatment requirements and to deliver Zenatane within 24 hours to US locations for eligible patients.11 For more information, please see the News & Trends section of the April 2013 issue of The Dermatologist.
The requirements of the iPLEDGE program have recently been relaxed in some instances. Men, and women not likely to bear children, for example, no longer have to wait 30 days to fill their prescriptions and are not limited to a 7-day window to fill their prescriptions after a doctor writes it.
Recently, in an effort to make the program stronger, a new Non-Compliance Action Policy (NCAP) was instituted. The policy acts as an evaluation tool for stakeholders. There are 5 tiered levels of punishment in the policy for stakeholders who do not meet all requirements of iPLEDGE.12 Each level includes a category, a description of the incorrect action and, if applicable, corrective steps that can be taken.12
The first category, Notice of Non-Compliance, involves “an action that demonstrates a lack of understanding of program requirements. Notices of non-compliance are not accumulated for further action, but can be considered when assessing additional disciplinary action to be taken against a stakeholder when more serious non-compliance issues occur.”12 The corrective action for a Notice of Non-Compliance requires the offending prescriber to be provided re-education and reinforcement of program requirements.12
The second category, Warning, denotes “failure to comply with one or more fundamental elements of the iPledge program.”12 Each warning will be documented, according to the new NCAP. The provider will also be given a history of other Warnings received and reminded that continued Non-compliance (similar or otherwise) may “lead to reporting to the FDA and/or Permanent Deactivation from the program.”12 The stakeholder must comply with the corrective action that is given to them by the Isotretinoin Products Manufacturing Group (IPMG).12
The third category, Suspension, takes effect when a defined number of Warnings are accumulated over a specified period.”12 The offending physician must then fulfill the corrective action requirements of the IPMG.12 The NCAP states: “Submission, acceptance and effectiveness of a corrective action plan is required prior to stakeholder reinstatement.”12
The fourth and fifth categories are Temporary Deactivation and Permanent Deactivation.12 Temporary Deactivation involves “failure to comply with the iPLEDGE Program leading to receipt of product by a non-qualified patient.”12 The NCAP notes that “failure to submit a corrective action plan by a suspended pharmacy within 30 days of Suspension will result in Temporary Deactivation on Day 31.”12 Permanent Deactivation occurs when the stakeholder “fails to implement corrective action or the iPLEDGE Program Sponsors determine that no future program compliance can be expected.”12 When Permanent Deactivation occurs, no corrective action is available; notice of the Permanent Deactivation is sent to the physician and the FDA.
The hope is to increase accountability and to strengthen the program to prevent pregnancies among women who are prescribed isotretinoin.
Recent Isotretinoin Studies
A recent study published by Wolverton et al in the American Journal of Clinical Dermatology re-examined the use of isotretinoin therapy for acne and the associated controversies.13 Three specific sets of adverse effects were studied: depression and suicide; inflammatory bowel disease; and iPledge and pregnancy.13 The authors concluded that some of the claims of adverse side effects might be over emphasized.13
While these side effects do occur, and must be addressed, they are manageable in many cases, the researchers noted. For example, the number of patients susceptible to developing depression while on isotretinoin is very small, and the risk of depression can be managed “provided there is adequate patient awareness of the possibility, maximum communication between the patient and physician, and cessation of therapy if clinically important depression occurs.”13 Many patients receiving isotretinoin reported an improvement in mental health and depression after the treatment of severe acne; according to the researchers, many patients report rapid resolution of depression a week or less after the drug is stopped.13 The authors further reported reviewing only 1 study that linked IBD and ulcerative colitis to isotretinoin.13
Finally, in regard to iPLEDGE, the researchers acknowledge the desire to prevent isotretinoin-fetal contact but state they could find no evidence that the stringent iPLEDGE system is any more effective than previous methods of prevention.13 They stated it was likely that, as long as women are treated with the drug, a small number of female patients will become pregnant.13
According to the CMAJ article, the occurrence of pregnancy can be due to many factors that are attributed to failure of contraceptives.2 Choi and colleagues note that 7%-59% of women taking isotretinoin use no form of contraception at all, despite acknowledging familiarity of the risks between isotretinoin and birth defects, and as many of 80% of women do not use the recommended 2 parallel methods of birth control while taking isotretinoin.2
Choi and colleagues write: “Improper use of contraceptives, in our experience, is the most common reason for unexpected pregnancies among women using isotretinoin and highlights the need for more comprehensive contraceptive counseling for all women starting treatment with this drug.”2 n
Dr. Crandell is co-owner of Southern Tier Dermatology & Aesthetics. She founded the practice, which specializes in medical, surgical and cosmetic dermatology, in 2006. Dr. Crandell is a Fellow of the American Academy of Dermatology, an active member of the American Society of Dermatologic Surgery and a recognized expert in medical, surgical and cosmetic dermatology.
Dr. Fenkl is co-owner of the practice. He has undergone extensive training and professional development in all areas of medical, surgical and cosmetic dermatology.
Disclosures: The authors have no conflicts of interest to report.
1. American Academy of Dermatology. Isotretinoin: Answers to questions patients often ask. http://www.aad.org/dermatology-a-to-z/diseases-and-treatments/i---l/isotretinoin/questions-patients-ask. Accessed May 21, 2013.
2. Choi JS, Koren G, Nulman I. Pregnancy and isotretinoin therapy. CMAJ. 2013;185(5):411-413.
3. Wysowski DK, Swann J, Vega A. Use of isotretinoin (Accutane) in the United States: Rapid increase from 1992 through 2000. J Am Acad Dermatol. 2002;46:505-509.
4. Roche Pharmaceuticals. Accutane (isotretinoin) capsules. http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1c_05.pdf. Accessed May 20, 2013.
5. Julia Green, Harvard Law School. Babies, blemishes and FDA: A history of Accutane regulation in the United States. http://leda.law.harvard.edu/leda/data/472/Green.html. Accessed May 20, 2013.
6. Raza K, Singh B, Singal P, Wadhwa S, Katare OP. Systematically optimized biocompatible isotretinoin-loaded solid lipid nanoparticles (SLNs) for topical treatment of acne. Colloids Surf B Biointerfaces. 2013;105:67-74.
7. Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol. 1984;10(5 Part 1):851-854.
8. FDA. Accutane (isotretinoin) questions and answers. http://1.usa.gov/18frEML. Accessed May 21, 2013.
9. Yahoo News. Dr. Reddy’s shares gain on Zenatane launch. http://news.yahoo.com/dr-reddys-shares-gain-zenatane-045631811.html. Accessed May 20, 2013.
10. Dr. Reddy’s. Dr. Reddy’s announces the launch of Zenatane™ (Isotretinoin Capsules USP). http://www.drreddys.com/media/popups/28mar-2013.html. Accessed March 29, 2013.
11. The Dermatologist. News & Trends. http://www.the-dermatologist.com/content/news-trends-19. Accessed May 21, 2013.
12. iPledge. iPledge non-compliance action policy. https://www.ipledgeprogram.com/documents/Non-Compliance%20Action%20Policy.pdf. Accessed May 21, 2013.
13. Wolverton SE, Harper JC. Important controversies associated with isotretinoin therapy for acne. Am J Clin Dermatol. 2013;14(2):71-76.