R. A. Kunynetz, MD, FRCPC
Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
ABSTRACT
Oral isotretinoin, since its introduction more than 20 years ago, has been and still is the “ gold standard” in the treatment of acne and its variants. This is the only approach to acne with the possibility of a permanent “cure” or long term remission. The role of isotretinoin has evolved with higher dosage schedules and use earlier in the course of the disease. The frequency of laboratory monitoring has diminished along with associated costs based on 2 decades of experience. Pregnancy-associated safeguards have become a more prominent facet of oral retinoid therapy leading to increased safety for its use in females of childbearing potential.
Key Words: acne, isotretinoin, retinoids
Isotretinoin (13 cis-retinoic acid, Accutane®, Roaccutane®, Roche Pharmaceuticals) is a naturally occurring substance which, since its introduction in 1982, has revolutionized acne therapy. It is the only anti-acne agent that affects all four of the known major etiologic mechanisms: sebum production, comedogenesis, Propionobacterium acnes (P. acnes) colonization of ductal and skin surface, and monocyte chemotaxis-induced inflammation. This may explain its unique ability to sustain long term treatment-free remissions and, in some cases, a permanent remission or “cure” can be achieved.1,2
Indications
Initially with the introduction of isotretinoin, only patients with severe nodular cystic acne or severe inflammatory acne, who were not responding to conventional therapy were given the drug. Now, with more than 20 years of treatment experience, expanded guidelines for its use include:3-5
• Moderate acne relapse (<50% improvement) after a single adequately-dosed course of antibiotics or hormonal therapy of 4 months
• Significant psychosocial impairment
• Marked concomitant seborrhea
• Gram negative folliculitis
• Scarring or persistent dyschromia
Not only deep nodular, but also superficial inflammatory acne can result in scarring. Because scarring is frequently missed during examination, proper assessment of scarring is paramount and was well described in a recent publication.5
Isotretinoin is also of benefit for patients with persistent adult acne who have suffered for many years, or whose acne flares when adequate conventional therapy has been discontinued. Acne persisting into the 6th and 7th decades, termed “pensioners’ acne” has been treated with low dose (0.25mg/kg/day) or intermittent 1 week in every 4 schedules.6-8
Acne conglobata is certainly the best indication for isotretinoin therapy; however acne fulminans, after initial “calming” of the exacerbation with oral tapering dose steroids over 4-6 weeks, responds well to the retinoid.9 Gram-negative folliculitis can be effectively treated not only with ampicillin, co-trimoxozole or trimethoprim, but with isotretinoin as well.10,11
Hidradenitis suppurativa and rosacea patients have benefited from isotretinoin therapy as well.3 Isotretinoin is used in pyoderma faciale after initial oral steroids for the first 4 weeks. It has not shown benefit in vasculitic acne, which is usually treated with oral steroids, azathioprine or cyclosporine.12 Acne excoriee is often quelled with a course of isotretinoin. Good results have been reported in its use for granulomatous perioral dermatitis.
Contraindications
Parabens allergy is a contraindication to oral therapy with isotretinoin because parabens is an excipient in the medication. Due to the “retinoid syndrome” of potential birth defects, pregnancy is an absolute contraindication. With this in mind, the manufacturer has developed the Pregnancy Prevention Program™. This program educates the female patient about the need for two effective methods of contraception and avoidance of pregnancy during treatment and for 1 month after therapy termination.
Although the pregnancy rate has decreased to 0.003% in the US according to the 2001 Slone Accutane® Epidemiology Database, the absolute number of pregnancies has not decreased due to increased number of prescriptions. Analysis of the Slone data show that the patient most likely to have an Accutane® exposed pregancy is a 26 year old woman. In order to address these concerns, as of April 2002, in the US, this program has evolved into the SMART™ Program (System to Manage Accutane Related Teratogenicity) developed by the manufacturer and the US FDA.13
Relative contraindications to isotretinoin therapy with appropriate dosage adjustments are outlined by Cunliffe and Stables.12
Dosage
Acne therapy is usually initiated at a dose of 0.5mg/kg daily for the first 2-4 weeks and then increased to 1.0mg/kg/day for the remainder of the 20 week course. Upon initial introduction in 1982, lower dosages of 0.1- 0.5mg/kg/day were given for severe acne with data analysis showing increased rates of recurrence compared to the dosages recommended today.1 The minimum total cumulative dose associated with long term, permanent remission is 120mg/kg. Some patients requiring re-treatment after relapse or partial response may require doses of 1.5- 2.0mg/kg/day.14 Dermatologists often continue treatment until the patient is clinically clear, although there is controversy regarding benefits beyond 150mg/kg.1 Doses must be adjusted in some cases of concomitant systemic disease. (See Table 1).
Inflammatory acne flare is experienced by approximately 6% of patients in the first month of therapy, and is clinically significant in about half.15 Discontinuation of isotretinoin and initiation of therapy with prednisone at 0.5-1.0mg/kg/day for 2-3 months is the treatment of choice.5 Similar doses to those used in acne are given in acne variants such as mature acne, acne conglobata, Gram-negative folliculitis, pyoderma faciale and hidradenitis suppurativa and dissecting cellulitis of the scalp.12
A lower initial dose of 0.25mg/kg/day of isotretinoin, increasing to 1.0mg/kg/day at the end of the 6th week are recommended for acne fulminans, after a course of prednisone of 0.5-1.0mg/kg for 4-6 weeks.16 Rosacea has been shown to respond in doses of 0.5-1.0mg/kg/day in the past, however, more recent studies showed good efficacy in doses as low as 10mg/day.17
Potential Side-Effects of Isotretinoin Therapy
Oral isotretinoin produces predictable manageable side-effects that are, for the most part, reversible on discontinuation of therapy. Most are similar to those seen in high dose vitamin A therapy and are mucocutaneous in nature.5 These include dry cracked lips, xerosis of the skin, mucous membranes and eyes. Musculoskeletal symptoms such as myalgia and arthralgia tend to be transient and dose related to exercise. Skin fragility has been reported and skin surgery should be avoided for 4-6 months. Wax epilation is also not desirable in this timeframe due to risk of skin fragility and dermatitis.5 (See Table 2.)
Elevated levels of lipids and liver enzymes have been associated with therapy, though 20 years of clinical experience shows them to be of little clinical significance. A recent pharmacogenetic study concluded that “ people who develop hypertriglyceridemia during isotretinoin therapy, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.”18 Therefore the physician may take advantage of this side-effect to predict the risk of the patient and their first degree relatives of developing diabetes, high blood pressure and obesity later in life. A full pre-treatment CBC and differential, fasting triglyceride (TG), alanine aminotransferase (ALT) and, in females, beta human chorionic gonatotropin (hCG) in serum or urine are recommended for baseline and should be repeated 4 weeks later. Abnormal results should be repeated as well, as should dosage increases. Monthly pregnancy testing should continue until 1 month after cessation of therapy without exception. Recommendations apply to otherwise healthy individuals and those with prior histories of hyperlipidemias, blood sugar or liver abnormalities may require increased testing frequencies. (See Table 3.)
The Depression Controversy
Isotretinoin has been the subject of negative media coverage. It has been linked with mood alteration and increased suicide risk. Certainly, the high profile incident of the unfortunate suicide of the son of a US
Congressman while taking the drug did promote controversy. There have been a number of recent retrospective studies into this possible link and none have been able to support its existence.20-23 A retrospective data analysis by Jick, et al, of 20,895 acne patients,21 almost one-third of whom had been on isotretinoin, found the estimated relative risk of acne patients for depression and suicidal behavior approximately equal in the oral antibiotic and isotretinoin groups.
In an exhaustive review of the existing literature and MedWatch reports, Jacobs, et al, concluded that there was no evidence to support a causal connection of the drug to depression or suicide, with the reported cases not meeting the established criteria for causality.20 Neither could they establish a molecular mechanism linking the two. Adverse Drug Reaction reports made the regulatory authorities worldwide (1982-2000) suggest that depression and suicide or suicide attempt rates are well below those of the general population from CDC data. (See Table 4.)
As their skin improves, isotretinoin patients’ moods also tend to improve, rather than the opposite.22 To date, no causal relationship between isotretinoin and psychiatric adverse events has been established. Hopefully, ongoing prospective studies will clarify this further.
Expectations of Therapy – Cure?
It has long been recognized that long-term/permanent, treatment-free remissions in patients with acne can most often be achieved with isotretinoin therapy. White, et al reported a long-term remission rate of 39% after one standard course of 1mg/kg in 179 patients at 3 year follow-up.2 Recurrences required further isotretinoin in 19%, topical therapy in 17%, and oral antibiotics in 25%. Alonger term 10-year study in 88 patients by Layton, et al yielded a 40% “cure” rate with further topical therapy, oral antibiotics, and isotretinoin required in 21%, 16% and 23% respectively.1 Data analysis in both studies showed patients that received total cumulative doses >100mg/kg and 120mg/kg had significantly better response than those on lower doses.
Treatment Failures
Non-responding patients to “normal” courses of isotretinoin may have been responders had the following potential pit-falls been adequately addressed during the initial course in assessing response:
• Compliance: check the lips for signs of cheilitis.
• Isotretinoin must be taken with a fat containing food.
• Insufficient dosage: clinical experience has shown that the dosing guidelines given in the product monograph are inadequate to achieve optimal response in most patients.
• Truncal acne, family history, early onset before age 12, long established acne that has been inadequately treated for years: all require more aggressive treatment.
• Ovarian cause (PCOS) may require hormonal therapy.
Costs in Perspective
It has been determined that long-term therapy in the management of moderate-to-severe acne with rotational oral antibiotics, hormonal and topical therapies have been shown to be less cost-effective than isotretinoin.24-26
Conclusion
Since the introduction of isotretinoin for acne therapy, the usage guidelines for the drug have widened considerably.3-5 Initially, two or three failed courses of adequately dosed oral antibiotics would occasion its use. Now with the known efficacy of isotretinoin, its proven pharmacoeconomic advantage, the realization that even superficial acne can permanently scar, and the psychosocial impact of acne on patients of all ages, it has become the standard of care for not only scarring, but also selected indication-guided cases of non-scarring acne.
| Dosage | Concomitant systemic disease |
| Standard Regimen | Diabetes mellitus, epilepsy, spina bifida, ulcerative colitis and Crohn’s (if significant malabsorption may require higher cumulative dose) |
| 0.25-0.5mg/kg/day. Increase at 2 month intervals to 0.5, and then 1.0mg/kg/day (24 week total) | Chronic renal failure, hypertriglyceridemia, immunosuppression, manic-depressive psychosis, myalgic encephalopathy, motor neuron disease, multiple sclerosis, renal dialysis, renal or cardiac transplant |
| Initial 20mg/week, increase by 20mg/week x 7 weeks until 20mg, b.i.d. | Behçet’s Syndrome, idiopathic thrombocytopenic purpura, leukemia, mitochondrial degeneration, paroxysmal nocturnal hemoglobinuria, polymyalgia rheumatica, cerebellar spongiform encephalopathy |
| Comments | Adverse Effect | Incidence |
| Teratogenicity | Isotretinoin is contraindicated during pregnancy. | |
| Mucocutaneous • Dry Lips • Facial Dermatitis • Dry nose • Dry skin, pruritus, desquamation, irritant dermatitis • Conjunctivitis • Hair loss • Impetiginization • Photosensitivity | 96% | Apply lip salve or petrolatum. |
| 55% | Apply non-comedogenic moisturizer. | |
| 51% | Apply nasal lubricant. Epistaxis usually mild. | |
| 20-50% | Pruritus usually secondary to dry skin; peeling of palms and soles; eczematous changes: moisturize or apply hydrocortisone 1% ointment | |
| 19% | More common in contact lens users. Use artificial tears. | |
| 13% | Dose related and usually reversible. If severe, decrease or stop treatment. Persistent in 0.5% of patients treated. | |
| 7.5% | Staphylococcal impetiginization should be suspected when severe cheilitis, nasal vestibulitis, dermatitis develops. Treat with topical or oral antibiotics. | |
| 1-5% | Minimize sun exposure; majority of patients have no trouble taking isotretinoin during summer. | |
| Arthralgia and Myalgia | 15-20% | Usually transient or episodic and dose related to exercise; nonsteroidal anti-inflammatory agents are rarely required. |
| Headache | 5-16% | Usually mild and requires no treatment. If severe and associated with impaired concentration and blurred vision, check for pseudotumor cerebri (0.5% incidence). Stop and restart at a lower dose when better. Avoid concurrent use of Tetracycline. |
| Depression/Mood swing | Uncommon | Caution is required in patients with a history of severe depression. Patients should be monitored for mood changes during therapy. |
| Ophthalmic • Impaired night vision | Unknown | Rarely persists. Warn patients to be careful when driving at night. |
| Lab Test | Testing Frequency | Possible Effect | Cirteria for Intervention | Incidence of Effect | Recommended Action |
| Complete Blood Count Differential | Baseline and at 4 weeks | Neutropenia Thrombocytopenia | <1,000/ml < 50,000/ml | Uncommon asymptomatic self-limiting | Reduce dose by 50% Repeat test in 4 weeks |
| Fasting Triglyceride (TG) | Baseline and at 4 weeks | Hypertriglyceridemia Pancreatitis | > 8mmol/l or increase of 5mmol/l from baseline | 25% | Stop drug. Repeat test in 2 weeks. Restart at 50% dose. Low fat diet. |
| Alanine Aminotransferase (ALT) | Baseline and at 4 weeks | Increased ALT Hepatocellular injury | 3 x upper limit of normal | 15% | Repeat after 4 weeks. Review medication history. |
| B-hCG (Serum/urine) | Baseline, then monthly | Pregnancy detection | Positive test | N/A | Stop drug. Repeat test. Counsel patient. |
| Blood sugar (known or suspected diabetes | Varies with degree of abnormality | Hyperglycemia | Uncontrolled hyperglycemia | N/A | Closer monitoring + Diet + Medication |
| Depression | Suicide/Suicide Attempt | |
| Isotretinoin use (1982-2000) MedWatch | 10-13/100,000 patients | 1-1.7/100,000 patients |
| USA General Population (1980-92) CDC, aged 15-24 years | 20,000/100,000 patients | 20/100,000 patients |
