Acne Treatment, Systemic Therapy, IsotretinoinISOTRETINOIN
The use of the oral retinoid, isotretinoin, has revolutionized the management of severe treatment-resistant acne. Isotretinoin, like vitamin A, produces side effects, which are not usually severe enough to necessitate interruption of therapy in most cases.
The remarkable aspects of isotretinoin therapy are the completeness of the remission in almost all cases and the longevity of the remission, which lasts for months to years in the great majority of patients.
Isotretinoin therapy, for all practical purposes, is always accompanied by side effects that may mimic those seen in the chronic hypervitaminosis A syndrome. Thus, side effects related to the skin and mucous membranes are most common. Cheilitis of varying degrees is found in almost all cases. Other side effects that are likely to be seen in over 50 percent of patients are dryness of the mucous membranes, xerosis, conjunctivitis, and pruritus. Side effects seen with lesser degrees of frequency include bone and joint pain; thinning of hair; headache and accompanying symptoms associated with increased intracranial pressure; palmoplantar desquamation; and nausea and vomiting.
The laboratory abnormalities that have occurred include elevations in triglycerides, erythrocyte sedimentation rate, platelet count, liver function tests, and white blood cells in the urine and decreases in red blood cell parameters, white cell counts, and high-density lipoprotein levels. The elevation of triglycerides, which is dose-related, is of particular concern because it is often accompanied by a decrease in the high-density lipoprotein levels, which may increase the risk of coronary artery disease.
There are also reports of the development of bony hyperostoses after isotretinoin therapy, but these are more likely to be seen in patients who receive the drug for longer periods of time in higher dosages for diseases of keratinization.
The issue of isotretinoin and psychiatric effects has come to the forefront. From 1982 to May 2000, 37 cases of suicide, 110 cases of hospitalized depression, suicidal ideation or suicide attempt, and 284 cases of nonhospitalized depression in patients on isotretinoin were reported to the FDA's Adverse Event Reporting System. In one population-based cohort study comparing isotretinoin users with oral antibiotic users, the relative risk for development of depression or psychosis was approximately 1.0, indicating no increased risk. Further studies are needed to resolve this issue of causality. Until then, a careful review for signs and symptoms of depression and suicidal ideation should be performed in all patients for whom isotretinoin therapy is considered, and the patients must be carefully monitored during therapy.
Studies show that some of the side effects are dosage related. These same studies demonstrate that clinical results can be obtained with dosages as low as 0.1 mg/kg per day. However, with such dosages, the incidence of relapses after therapy is greater. The recommended daily dosage of isotretinoin is in the range of 0.5 to 1 mg/kg per day. Because back and chest lesions show less of a response than facial lesions, dosages as high as 2 mg/kg per day may be necessary in those patients who have very severe trunk involvement. Patients with severe acne, particularly those with granulomatous lesions, will often develop marked flares of their disease when isotretinoin is started. Therefore, the initial dosing should be low, even below 0.5 mg/kg per day. These patients often need pretreatment for 1 to 2 weeks with prednisone (40 to 60 mg per day), which may have to be continued for the first 2 weeks of therapy. Isotretinoin is usually given for 20 weeks, but the length of the course of treatment is not absolute; in patients who have not shown an adequate response, therapy can be extended, if necessary. Some improvement is usually seen for 1 to 2 months after isotretinoin is discontinued, so that total clearing is not a necessary endpoint for determining when to discontinue therapy. Approximately 10 percent of patients treated with isotretinoin require a second course of the drug. The likelihood for repeat therapy is increased in patients younger than 16 to 17 years of age. It is best to allow at least 2 to 3 months between courses of isotretinoin. Studies suggest that the chances of inducing a long-term remission are greatest if the patient has received a total dose of 120 to 150 mg/kg of isotretinoin during a course of therapy.
Isotretinoin should be used only in those patients with severe acne. Furthermore, laboratory monitoring is indicated. It is appropriate to obtain a baseline complete blood count and liver function tests, but the greatest attention should be paid to following serum triglyceride levels. Baseline values for serum triglycerides should be obtained and repeated at 3 to 4 weeks and 6 to 8 weeks of therapy. If the values are normal at 6 to 8 weeks, there is no need to repeat the test during the remaining course of therapy unless there are risk factors. If serum triglycerides increase above 500 mg/dL, the levels should be monitored frequently. Levels above 700 to 800 mg/dL are a reason for interrupting therapy or treating the patient with a lipid-lowering drug such as gemfibrozil. Eruptive exanthemas or pancreatitis can occur at higher serum triglyceride levels. In rare instances, exuberant granulation tissue has appeared in some lesions. If this occurs, the dosage of drug may have to be decreased or the drug may have to be discontinued. Glucocorticoids may have to be administered either systemically or intralesionally to control the granulation tissue.
The greatest concern during isotretinoin therapy is the risk of the drug being administered during pregnancy and thereby inducing teratogenic effects in the fetus. The drug is not mutagenic; its effect is on organogenesis. Therefore, the production of retinoic embryopathy occurs very early in pregnancy, with a peak near the third week of gestation. Theoretically, based on animal studies and the pharmacokinetics of the drug, there should be more safety in the use of isotretinoin than either vitamin A or etretinate. However, that is not the case, and a significant number of fetal abnormalities have been reported after the use of isotretinoin. For this reason, it should be emphasized that isotretinoin should be given only to patients who have not responded to other therapy. Furthermore, women who are of childbearing age must be fully informed of the risk of pregnancy. The patient must either avoid sexual exposure totally or should employ two highly effective contraception techniques such as the use of an oral contraceptive and condoms with a spermicidal jelly. Contraception must be started at least 1 month before isotretinoin therapy. The patient must have a negative serum pregnancy test at the time when therapy is decided upon and on the second or third day of the next menstrual period or 11 days after the last unprotected intercourse in a woman who is amenorrheic. The woman must thoroughly understand the contraception techniques she is using and continue them throughout the course of isotretinoin and for 1 month after stopping treatment. No more than 1 month's supply of drug should be given to a female patient so that she can be counseled on a monthly basis on the hazards of pregnancy during isotretinoin therapy. The pregnancy test should be repeated monthly to maintain patient awareness. The manufacturer and the FDA have recently instituted a verification process requiring that authorization stickers be affixed to prescriptions to insure that pregnancy-prevention procedures are followed. As stated above, retinoic acid embryopathy results from the effect of isotretinoin on early organogenesis. Therefore, because the drug is not mutagenic, there is no risk to a fetus conceived by a male who is taking isotretinoin. Although it may seem obvious, it is important to remind men who are taking isotretinoin not to give any of their medication to female companions under any circumstances.
The mechanism of action of isotretinoin is not completely known. The drug produces profound inhibition of sebaceous gland activity, and this undoubtedly is of great importance in the initial clearing. In some patients, sebaceous gland inhibition continues for at least a year, but in the majority of patients, sebum production returns to normal after 2 to 4 months. Thus, this action of the drug cannot be used to explain the long-term remissions. The P. acnes population is also decreased during isotretinoin therapy, but this decrease is not often long lasting. Isotretinoin has no inhibitory effect on P. acnes in vitro. Therefore, the effect on the bacterial population is probably indirect, resulting from the decrease in intrafollicular lipids necessary for organism growth. Isotretinoin also has anti-inflammatory activity and probably has an effect on the pattern of follicular keratinization. Once again, it has not been demonstrated that these effects are long lasting. Thus, while the drug may influence the course of severe acne through several different mechanisms, the explanation for the long-term remissions remains obscure.
