LIVE BLOG: Isotretinoin and iPledge Update
In this live blog from the 11th annual SDPA conference in Atlanta, Hilary Baldwin, MD, discusses isotretinoin and iPledge Update. She spoke about the new formulation of isotretinoin, gave an iPledge update, and addressed the new isotretinoin procurement program. She also lectured on the question of isotretinoin and inflammatory bowel disease (IBD) and other topics. Here are some highlights.
New formulation of isotretinoin
What’s old = timing of administration
- take with meals
- take BID
Stomach contents and absorption
- absorption of drugs can be altered by presence of food in stomach
- most commonly, food decreases absorption
- highly fat-soluble drugs do better with food in stomach
- early study established the enhanced bioavailability of isotretinoin in the presence of fat
How much fat is enough fat?
- FDA – 50 grams of fat optimal for absorption of lipophilic medication
- 50 grams of fat twice daily? A big mac is 29 gm, donut is 12 gm, 1 cup whole milk is 8 gm, 1 slice pepperoni pizza is 30 gm.
Hilary’s unofficial survey of derm providers:
- most tell patients to take isotretinoin with food
- some tell them to take it with a fatty meal
- no one suggests the supersized meal
- response to elevated triglycerides
reduce fat intake, reduce dose – will isotretinoin work under these circumstances?
Most teenagers skip breakfast, more than 50% of teenage boys, and 66% of teenage girls. 1 in 10 teenage girls often go without breakfast or lunch each day.
So are the only options nodulocystic acne or obesity?
Absorica – option for less fat needed for isotretinoin
- increases bioavailablity
- less food dependence
- less GI irritation
- protection against oxidation
Absorica phase III trial
- phase III randomized, DB, multi-center, non-inferiority trial of 925 patients
- Absorica vs. conventional isotretinoin
- primary endpoints: no difference at 20 weeks
- safety endpoints: no difference in side effects
Has iPledge worked?
- large Kaiser retrospective study
- All FCBP who filled at least one isotretinoin script in 2004-2008
- incidence of fetal exposure before and after iPledge
- no difference in any parameter between pregnancies during SMART and iPledge
- pregnancy statistics remarkably consistent
- year before SMART – 127 pregnancies
- first year of SMART – 120 pregnancies
- first year of iPledge – 122 pregnancies
- no matter what you do there are approximately 120 pregnancies in US on isotretinoin
- non-compliance with birth control
- detect pregnancy earlier to allow time for decision making
iPledge changes in 2012
- numerous changes that simplify efforts
- no more override codes
- no more repopulating demographics
- less need to call contact call center
- instituted a non-compliance action policy
- principles by which non compliance by iPledge stakeholders will be evaluated
- penalties vary (re-education and reinforcement of program requirements and/or permanent deactivation and reporting to the FDA)
Huge iPledge No-No’s
- prescribing directly to patients
- allowing prescriptions to be filled outside the us or over internet
- intentionally falsifying pregnancy test results – including date
- 2 warnings in 60 days
- deactivation of 2 designees for same prescriber within 1 year period
New isotretinoin procurement program:
Zenatane capsules – generic isotretinoin AB rated to Accutane and Amnesteen in 10, 20, 40 mg capsules. It is supported by a dedicated US-based mail order pharmacy.
Does isotretinoin cause inflammatory bowel disease (IBD)?
- 1986: First case report UC suggested association
- no cases during pivotal trial
- several subsequent case reports of GI issues
- 1988: PI modification to include GI warnings
Isotretinoin and IBD
2007 – present
- more than 5000 suits filed – 40-50 to trial
- many dismissals
- roche has lost all 9 cases – $59 mill
- 3 verdicts subsequently reversed on appeal
2009 case control study
- 70 US health plans/55 million patients
- 1.68X increased risk for developing IBD in isotretinoin users compared to non users
- subgroup analysis: strong association for ulcerative colitis, not Crohn’s, increased risk with increased dose and duration prescribed
What does 1.68 mean clinically?
- crocketts odds ration is high
- more interested in absolute risk in practice
- if use an estimate for incidence of UC of 10/100,000 person years and relative risk of 1.68
- number needed to harm = 2977: need to treat 2977 patients with isotretinoin to observe 1 excess case of UC
So where does this leave us?
- three most rigorous studies show conflicting results
- case-controlled studies are designed to show association, not causality
- might the association be between nodulocystic acne and IBD?
- neutrophilic dermatoses similar clinically to acne, pyodermas associated with IBD
- it’s unlikely that the question will be answered conclusively
- extremely low incidence of IBD preclude randomized/controlled or prospective cohort studies
- personal and family history of IBD
- discussion of risks and benefits
- low threshold for discontinuing isotretinoin if GI symptoms arise (weight loss, loss of appetite, abdominal pain, cramping, diarrhea, bloody stool, tenesmus)
- new formation of isotretinoin that is less dependant on stomach contents
- new branded generic isotretinoin with unique delivery system designed to thwart iPledge problems
- IBD and isotretinoin – more data indicating lack of causality
- IBD and tetracyclines – need more data
- more studies showing improvement in mental health following isotretinoin use
- validation of efficacy of topical retinoids post-isotretinoin therapy
Image: Zen Sutherland