Isotretinoin was approved for use in treating severe, recalcitrant nodular acne in 1982 (Food and Drug Administration [FDA], 2003 , 2007). It was first marketed as Accutane by Hoffmann-La Roche. In 2009, Roche took Accutane off the market, citing competition from generic versions starting from 2002 (Reid, 2009). Today, multiple manufacturers produce generic versions of isotretinoin.
As a known teratogen, isotretinoin was assigned a Category X designation in 1982, soon followed by a black box warning regarding fetal deformity. The FDA mandated the implementation of the Accutane Pregnancy Prevention Program in 1989. This evolved into the System to Manage Accutane Related Teratogenicity program for pregnancy prevention in 2001. The newest program, iPLEDGE, began in 2006 and operates today.
Early studies suggested a possible link between isotretinoin use and two diseases: depression and inflammatory bowel disease (IBD). In 1998, the first studies emerged regarding depression and isotretinoin, and the FDA later required stricter reporting of adverse events (Halvorsen et al., 2011 ; Huang & Cheng, 2017). Despite these early reports, the current literature does not support a causative link between depression and isotretinoin. Early studies also suggested a relationship between isotretinoin and IBD, and civil lawsuits were won by patients starting in 2007 (Alhusayen et al., 2013 ; Bernstein, Nugent, Longobardi, & Blanchard, 2009 ; Etminan, Bird, Delaney, Bressler, & Brophy, 2013). The most recent studies fail to show a relationship between isotretinoin and IBD.
MECHANISM OF ACTION
Isotretinoin is the only medication that affects all four pathogenic factors influencing acne (excess sebum production, bacterial colonization, inflammation, and intrafollicular hyperkeratinization). Isotretinoin directly causes shrinkage of sebaceous glands and a subsequent decrease in sebum secretion (Ward, Brogden, Heel, Speight, & Avery, 1984). This inhibits proliferation of the sebum-dependent inflammation-promoting bacterium Propionibacterium acnes. Keratinocyte normalization allows the follicle to remain unobstructed by material that would otherwise contribute to comedone formation.
Isotretinoin is available in the following strengths: 10, 20, 30, and 40 mg (Lexicomp Online, 2017). It is available in the isotretinoin-Lidose formulation in the additional strengths of 25 and 35 mg. The out-of-pocket cost of isotretinoin is upward of $500 per 30 capsules and tends to double for doses higher than 40 mg.
Isotretinoin is a synthetic Vitamin A analog.
The FDA-approved usage of oral isotretinoin is for severe, recalcitrant nodular acne in patients aged 12 years and older (FDA, 2003). This is defined as acne with multiple inflammatory nodules larger than 5 mm, which is unresponsive to conventional therapy. Isotretinoin is often prescribed off-label for the following variants of acne vulgaris: treatment-resistant acne, acne causing significant psychological distress, and dystrophic scarring acne (Goldsmith et al., 2004 ; Strauss et al., 2007). Isotretinoin is not considered the first-line treatment for these conditions. In our clinic, the most frequent off-label indication is treatment-resistant inflammatory acne. We define this as <50% reduction in lesion count despite a 3-month course of oral antibiotics or acne which relapses soon after the discontinuation of oral antibiotics.
Treatment length is 20–24 weeks. Dosing is based on weight. Usual starting dose is 0.5 mg/kg per day for the first month (Zaenglein et al., 2016). The dose is then increased as tolerated to 1 mg/kg per day. Total dose over the entire course of treatment should be 120–150 mg/kg. There is little evidence to suggest twice-daily dosing over once-daily dosing. Total dose in milligrams and milligrams per kilogram should be documented in the medical record upon completion of treatment.
Isotretinoin is highly lipophilic. Its absorption falls by 60% if taken in the fasting state versus fed (Colburn, Gibson, Wiens, & Hanigan, 1983). It should preferably be taken with a meal that is high in fat (>50% calories from fat; U.S. Department of Health and Human Services, 2002). There is a newer lipid-encased formulation (isotretinoin-Lidose) that can be taken without regard to meals (Webster, Leyden, & Gross, 2013).
CONTRAINDICATIONS AND INTERACTIONS
Contraindications include allergy, pregnancy, and breastfeeding. Oral minocycline and doxycycline should be discontinued because of the associated risk of idiopathic intracranial hypertension (Digre, 2003).
Isotretinoin has several common adverse effects. Up to half of patients get an initial acne flare during the first month, which can be minimized by starting at the initial dose of 0.5 mg/kg per day. Patients are advised to avoid waxing and picking, as skin fragility increases during therapy. Myalgia (muscle pain) may occur, especially among those who engage in vigorous physical activity. The severity of the myalgias is rarely severe enough to require termination of therapy.
Mucocutaneous adverse effects are common and result from shrinkage of the sebaceous glands but can be properly treated through education and intervention. We recommend that patients not sleep near an electric fan and reduce exposure to dehumidified environments. No topical acne medication or scar treatment products should be used. Harsh products containing salicylic acid and benzoyl peroxide should be discontinued, and patients should instead use gentle cleansers and rich moisturizers. Cheilitis (dry lips) can be treated with liberal use of lip balm (Well, 2014). Patients should avoid lip balm that contains irritants such as menthol or camphor. Drying of the anterior nasal membrane can cause nosebleeds. Prevention includes treatment with nasal saline gel applied with a cotton swab. Drying of the upper nasal/sinus membrane can be treated with saline nasal spray. Lubricant eye drops can be used for dry eyes. Dry skin is common on the extremities, especially on the dorsum of the hands. It occasionally requires intermediate-strength topical corticosteroids. Facial erythema tends to worsen during isotretinoin treatment and resolves after treatment ends.
Atypical wound healing has been reported, but the recent literature suggests a lack of causation (McDonald, Shelley, & Alavi, 2017 ; Prather, Alam, Poon, Arndt, & Dover, 2017 ; Spring et al., 2017). Common practice has been to delay the timing of elective procedures for 6–12 months after treatment ends. Recent literature suggests removal of this delay for minimally invasive procedures such as superficial chemical peels and laser hair removal. The delay should remain in place for more aggressive interventions such as dermabrasion and fully ablative laser.
PSYCHIATRIC ADVERSE EFFECTS
Reviews have concluded that isotretinoin does not appear to be associated with an increased risk for depression (Huang & Cheng, 2017). Some authors have proposed that psychological distress over severe acne, rather than isotretinoin, could be a contributing factor to suicide or depression (Halvorsen et al., 2011). This is supported by evidence that acne treatment tends to decrease depressive symptoms.
CORRELATION WITH IBD
The position of the American Academy of Dermatology is that the “current evidence is insufficient to prove either an association or causal relationship between isotretinoin use and IBD” (American Academy of Dermatology, 2010). A meta-analysis did not find a statistically significant relationship between isotretinoin therapy and IBD (Etminan et al., 2013). A large case–control study showed a 0.1% increase in IBD risk among those who took isotretinoin (Bernstein et al., 2009). Another study found a similar risk of IBD among those who took isotretinoin and those who took topical treatment only. Research is ongoing to explore the possibility that patients with acne may have a higher risk of IBD, regardless of treatment (Alhusayen et al., 2013). Until additional information is available, during discussions of the potential adverse effects of isotretinoin with patients, it is reasonable to mention that, although an increased risk for IBD and/or psychiatric adverse events has been reported, no cause–effect relationship has been established.
MONITORING AND DISCONTINUATION
A baseline lipid panel and liver function tests (LFTs) should be performed. In healthy patients with normal baseline levels, these studies should be repeated after 2 months of isotretinoin therapy. If findings are normal, no further testing may be required (Hansen et al., 2016). Routine monitoring of complete blood count is not recommended (Zaenglein et al., 2016).
Elevations in lipids and LFTs are common, generally transient and rarely severe enough to warrant termination of therapy. Hypertriglyceridemia occurs in up to 45% of patients on isotretinoin therapy (Zane, Leyden, Marqueling, & Manos, 2006). Increases in low-density lipoprotein are seen in approximately 30%. Mild elevations in liver enzymes occur in 20% of patients (Brelsford & Beute, 2008). Indications for stopping therapy include severe hypertriglyceridemia (above 800 mg/dl), significantly elevated LFTs (above 3–10 times normal), and other marked abnormalities on laboratory testing.
Relapse rate was 20% among those treated with a therapeutic dose of >120 mg/kg (Layton, Knaggs, Taylor, & Cunliffe, 1993). A lower relapse rate was observed in patients who took a cumulative dose of 120 mg/kg compared with <120 mg/kg. Patients who receive isotretinoin as young teenagers (under the age of 16 years) may have an increased risk for relapse (Savage & Layton, 2010).
The most severe safety issue concerning oral isotretinoin is teratogenicity (Cheetham et al., 2006 ; Collins et al., 2014 ; Shin et al., 2011). Among pregnant women exposed to isotretinoin, the risk of spontaneous abortion is approximately 20%. Among pregnancies that progress, the risk of birth defects is 30%. Approximately 150 pregnancies occur annually among women taking isotretinoin (FDA, 2003 , 2007). Pregnancy rates hover around 0.3% or around three fetal exposures per 1,000 treatment courses.
The safe use of isotretinoin requires that every effort be made to prevent individuals of childbearing potential from becoming pregnant during treatment. The current program for managing isotretinoin prescriptions is iPLEDGE. Patients of childbearing potential must have two negative urine or blood pregnancy tests before the initial prescription, 30 days apart. The test must be repeated monthly. The prescription must be filled during 7 days after the test. Two forms of pregnancy prevention are required. In our clinic, abstinence is not available as an option for pregnancy prevention.
Here are some best practices to consider regarding isotretinoin. Prescribers must comply with the many rules of iPLEDGE to ensure that patients of childbearing potential do not become pregnant. Most healthy patients should receive two blood tests, a baseline lipid panel and an LFT, and a repeat after 2 months of treatment. Laboratory values often increase but rarely warrant discontinuing treatment. Mucocutaneous adverse effects are common and can be managed through counseling and intervention, along with discontinuing previous acne interventions (topical retinoids, strong cleansers, and mechanical exfoliation). Dosing with meals is recommended as isotretinoin absorption increases when administered with a fatty meal.
Isotretinoin is a useful drug in the arsenal of the dermatology nurse practitioner. It should not be overprescribed, as it is not considered first-line treatment in most cases. It should also not be underprescribed: Its acceptable indications include off-label use, and the current literature fails to show causation with diseases such as depression and IBD. With knowledgeable prescribers and educated patients, isotretinoin can continue to be a valuable tool in the treatment of acne.
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