ISOTRETINOIN

By Gary M. White, MD

Cheilitis caused by isotretinoin Isotretinoin cheilitis


As with all medications, the complete package insert should be consulted. What follows are selected points about isotretinoin use for acne. This discussion does not apply to the higher doses given for myelodysplasia and malignancy.

KEY POINTS ABOUT ISOTRETINOIN

Daily and Total Dose

The standard daily dose is 1 mg/kg/day but can range from 0.5 to 2.0 mg/kg/day. It is common to start at a lower dose initially, e.g. 0.5 mg/kg/day, for a month to get the patient used to the medication, and prevent flaring (called acne Herxheimer-like reaction by Dr. James Leyden). If there are no symptomatic or laboratory issues and no crusted acne flaring at one month, the patient may be advanced to 1 mg/kg/day and stay at that for the rest of the course, till the face is clear. Many advocate calculating a total dose for the course and the typical goal is 120-150 mg/kg, else the risk of relapse is high.

If there is significant inflammation and crusting at the outset, an even lower dose, e.g. 0.1 mg/kg/day is recommended. As the inflammation clears, the dose may be advanced.

Blasiak et al published a study of 180 patients at a single institution [JAMA Derm Dec 2015;149;1392]. At one year follow up, those who had received 220 mg/kg total dose were less likely to have relapsed than those that received less than 220 mg/kg. However, these patients had higher side effects persistent at 1 year e.g. decreased hearing and muscle pains. Also, to get this level of total dose, you either have to give high daily doses, e.g. 120 mg/day as in this study or go for 7-8 months at 1 mg/kg/day.

Going lower dose, but longer time

In one study, the treatment regimen consisted of isotretinoin, fixed 20 mg daily, and duration of treatment-based on the weight of patient, until total cumulative dose of 120 mg/kg was achieved. This lead to a treatment duration from 10-22 months. The relapse (five year follow up) was only 8%. [Adv Biomed Res. 2014; 3: 103]. One significant drawback to this approach is the longer exposure to a highly teratogenic drug for female patients of child-bearing potential.

What predicts patients with acne more likely to relapse?

The key determinant of relapse of acne after a course of isotretinoin is age [Talk at Mauiderm 2017 by Jim Leyden, MD].

Age at Treatment Need for 2nd course
10-11 years 35-40%
12-14 years of age 20%
15 and older 10-15%

Food

All forms of isotretinoin except Absorica should be taken with a fatty meal. Taking isotretinoin with food doubles absorption [J Clin Pharmacol. 1983 Nov-Dec;23(11-12):534-9]. Absorica is isotretinoin combined with a material that improves absorption. Thus, Absorica can be taken with or without food.

Laboratory Measurement

Additional tests should be done if any are abnormal. This is based upon JAAD 2016;75;323.

GGT may be a more useful test for the liver. CK elevations (from muscle, e.g., young athletic men) are relatively common. It may make sense to monitor CK in athletically active patients [Dermatology Online Journal 2017(5)].

Birth Control

Prevention of pregnancy using all the recommendations in the package insert is paramount.

Pharmacokinetics

Serum half life is 18.7 hours. Isotretinoin is not stored in fat, nor does it stimulate its own degradation. Isotretinoin is 99% protein-bound in serum. Isotretinoin is a physiologic compound with a normal concentration of 0.8-2.5 ng/ml. After stopping isotretinoin, it takes 4.4 days to return to physiologic concentration and 9.7 days for its main metabolite oxoisotret. Isotretinoin must be taken with food as its absorption may be doubled (e.g. from 20% to 40%). However there is a new formulation (isotretinoin-Lidose) that need not be taken with food. Mean plasma levels of the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with a fatty meal, and those of the isotretinoin formulation only reached 39.6% of that observed with a fatty meal [J Am Acad Dermatol. 2013 Nov;69(5):762-7].

Single vs. Divided Dosing

Taking isotretinoin BID does not change efficacy, but can result in fewer side effects compared with QDay dosing [Dermatol Ther. 2015 May-Jun;28(3):151-7]. This is because BID dosing reduces peak serum levels of isotretinoin. Daily dosing is usually recommended for convenience, and BID dosing if symptomatology is problematic.

What follows is only a partial list of potential side effects and should not be considered exhaustive.

Cheilitis

The lips always get dry and chapped. Have the patient carry around a greasy lip balm and apply it multiple times a day. If this fails, one can try hydrocortisone 2.5% ointment to the lips BID. If the lips seem secondarily infected with Staphylococcus, mupirocin (Bactroban) ointment to lips and anterior nares TID for 7 days then off may be tried.

Dry Skin/Eczema

Isotretinoin dries out the skin and facilitates keratinocyte dyscohesion. Many patients develop dry skin and eczematous changes, especially on the arms and hands. Application of a moisturizing cream daily to the arms and hands at the start of isotretinoin helps prevent this.

Hyperlipidemia and Pancreatitis

Isotretinoin may cause hypertriglyceridemia, and patients with baseline elevated triglyceride are at particular risk. Hypertriglyceridemia for 4-5 months is not thought to convey significant cardiac risk. However levels above 800-1000 can trigger pancreatitis, although this is rare. Patients have been known to tolerate triglyceride levels in the 4000's mg/dl without experiencing pancreatitis. In fact, pancreatitis during isotretinoin therapy is more likely idiosyncratic and unassociated with hypertriglyceridemia. In a meta-analysis covering the last 46 years [BJD 2017;177;960], 25 cases of pancreatitis in patients on isotretinoin were found but only four had hypertriglyceridemia associated.

Therefore, baseline fasting triglyceride levels should be measured. If elevated, retesting 4 weeks into isotretinoin therapy is in order. It has been argued that patients with normal baseline triglyceride and no other risks for hypertriglyceridemia do not need further monitoring [BJD 2017;177;960]. In fact, that paper goes further and states that "baseline triglyceride monitoring is unnecessary for typical teenagers if they have no other risk factors for elevated triglycerides." However, the current consensus for all patients on isotretinoin is to measure fasting triglycerides at baseline and if normal, to retest at 2 months. For any patients with significant hypertriglyceridemia, dose reduction, diet modification and rarely, additional medications are in order. For example, gemfibrozil is very effective in treating retinoid induced hyperlipidemia [ADV 1995;75;377]. A typical dose would be 600 mg BID (30 minutes before the morning and evening meals).

Liver

Oral isotretinoin may cause an elevation of liver enzymes, however any changes are typically asymptomatic and transient and can resolve even with continuing therapy. Clinically apparent liver injury due to isotretinoin is exceedingly rare. Elevations in LFTs during isotretinoin therapy may be unrelated and alcohol consumption, the taking of supplements (e.g., protein, creatine, or herbal extracts) or intercurrent illness should be excluded [Pediatrics. 2017 Oct;140(4)]. The isotretinoin should be stopped if LFT levels are greater than 2-3x normal and any abnormalities should be followed until they normalize.

Depression

A recent systematic review and meta-analysis did not find isotretinoin treatment for acne to be associated with any increased risk of depression. Moreover, the treatment of acne appears to ameliorate depressive symptoms [JAAD 2017;76;1068].

Pseudotumor Cerebri

If the patient develops a severe and sustained headache, visual disturbances (e.g. blurry or double vision), and/or ringing in the ears, pseudotumor cerebri (PTC) should be considered. An urgent evaluation including eye exam looking for papilledema by a qualified physician (usually not the dermatologist!) is in order.

Can isotretinoin be considered in patients with a history of PCT from e.g. minocycline? Three patients with recalcitrant acne and a history of PTC were successfully treated with isotretinoin [JAMA Derm 2016;152;582]. Thus, in patients whose acne truly warrants isotretinoin treatment, a history of PTC (unrelated to isotretion) may not absolutely preclude its use. Baseline and subsequent ophthalmology or neurology evaluation is key.

Muscle

A reversible myopathy has been seen [BMJ 1986;293;425]. In one study of 89 patients with acne treated with isotretinoin [Int J Dermatol. 2008;47:398], elevated CPK levels were found in five patients. Maximum serum CPK values ranged between 292 and 569 IU/l. Only one patient out of five had myalgia and four patients were completely asymptomatic.

Bone

The development of diffuse idiopathic skeletal hyperostosis (DISH) has been associated with chronic (e.g. multi-year) administration of oral retinoids. However, no increased incidence of DISH has been found with one or a few standard courses of isotretinoin.

One study showed that the bone is not demineralized with a 20 week course of isotretinoin [AD 1996;132;769]. Another study however showed that mean bone density was reduced an average of 4.4% after 6 months of isotretinoin 1 mg/kg [AD 1999;135;961]. In order to evaluate for DISH in a patient exposed to retinoids for a prolonged period of time (longer that the standard course of isotretinoin, e.g. > 2 years) a lateral of the cervical and lumbar spine may be obtained. Back and/or neck pain and stiffness are symptoms of DISH.

Taste

Loss of taste has been reported rarely [BJD 1996;134;378].

Night Blindness

Visual complaints are not uncommon among isotretinoin users. Often, the changes result from dryness and frequent use of lubricating eye drops (without any vasoconstriction agents) is helpful. True decreased night vision may occur, but is rare. When it does occur, it usually does so within several weeks of starting the isotretinoin. It has been hypothesized that prior hypovitaminosis A can be a predisposing factor for isotretinoin-induced nyctalopia (night blindness). Any patient with persistent visual complaints should be evaluated by an ophthalmologist. Any patient with nyctalopia should immediately stop all isotretinoin and be seen urgently by an ophthalmologist.

Macrocomedones

Macrocomedones in a patient on isotretinoin

Patients on isotretinoin usually begin to clear after 2-3 months (10-15 weeks). Patients who are slow to clear often have multiple macrocomedones which appear as 2-3 mm white cysts that lie just below the skin. They are best seen when the skin is stretched and begin to be most prominent during 10-15 weeks as the rest of the acne is clearing. Not only do these lesions persist, but they also may rupture, resulting in large inflammatory nodules. Removal during or even prior to instituting isotretinoin therapy can dramatically minimize the amount of isotretinoin needed to clear the acne in these patients. Macrocomedones may be incised with an #11 blade and extracted or cauterized after EMLA-occlusion. [Abstract Clark, Goulden, Cunliffe P-18, Academy SF 1997].

Arthritis

Acute arthritis precipitated by isotretinoin may occur [Dermatology 1999;199;406]. In reported cases, onset has been between the 2nd and 10th weeks of therapy and the knees are the most commonly affected joints. This condition is more severe that the usual aches and pains of isotretinoin. In this case, severe disability may result (e.g. difficulty walking). NSAIDs should be given and the isotretinoin stopped.

Asthma

Asthma has been reported exacerbated by isotretinoin [BJD 2000;142;370]. Indeed, isotretinoin may reduce forced expiratory flow. It is postulated that the drug's drying effect may lead to irritability of the tracheobronchial tree.

Inflammatory Bowel Disease

There has been much controversy as to whether isotretinoin predisposes to IBD. One study did not show any increased risk. In fact, the risk seemed to be decreased [JAMA Derm 2014;150;1322]. Several other recent population studies support no increased risk. There may be some association between acne itself and IBD.

Miscellaneous

Fordyce spots, sebaceous hyperplasia and Tyson's gland's may clear with isotretinoin therapy, but returned soon after.

Should isotretinoin be stopped before surgery?

Although there is concern that isotretinoin could interfere with wound healing, the overall the risk described in the larger and better reported studies is relatively small or absent [British Journal of Dermatology (2014) 170, 239–244] and [JAAD 2017;77;159].

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