Medicine for acne: Isotretinoin Side effects

Isotretinoin Side effects
Side effects occur frequently, are dose-dependent, and are reversible shortly after discontinuing treatment. Patients with side effects can be managed at a lower dosage for a period long enough to reach the 120 mg/kg cumulative dose level. Explain to patients that the long-term benefit is related to the cumulative dosage, not to the duration of therapy.
The incidence of side effects was documented in a large study. Patients in that study stopped isotretinoin for the following reasons: mucous/skin effects (2.5), elevated triglyceride levels (2.0), musculoskeletal effects (1.3), headaches (1.1), elevated liver enzyme levels (0.6), amenorrhea (0.4), and other (0.5).
Teratogenicity--pregnancy prevention program.
Isotretinoin is a potent teratogen primarily involving craniofacial, cardiac, thymic, and central nervous system structures. A number of physicians inadvertently prescribed isotretinoin to pregnant women, which resulted in birth defects. For this reason the FDA considered withdrawing isotretinoin in 1988. Roche Laboratories designed the pregnancy prevention program; as a result, isotretinoin is still available.
The pregnancy prevention program is available from Roche Laboratories in a box containing a qualification checklist for patients, information about treatment, contraception counseling and serum pregnancy testing information, an optional referral form for expert counseling on contraception and patient self-evaluation, consent forms, and a follow-up survey.
Women should be educated about the risks to the fetus and the need for adequate contraception. Sexually active women should have a pregnancy test and postpone therapy until their next normal menstrual period. Some physicians will not prescribe isotretinoin to women of child-bearing age unless they are taking oral contraceptives. Others withhold isotretinoin if abortion is not an option. Isotretinoin is not mutagenic, nor is it stored in tissue. It is recommended that contraception be continued for 1 month after stopping isotretinoin. Patients can be reassured that conception is safe after this 1-month period. One study showed that from the fourth month of treatment onward, a statistically significant increase in the mean sperm density, sperm morphology, and motility were not affected. One year after treatment there was no evidence of any negative influence of 6 months of treatment with isotretinoin on spermatogenesis.
Plasma lipid abnormalities.
Accutane therapy induces an elevation of plasma triglycerides. In one study of patients (ages 14 to 40 years) treated for 20 weeks with 1 mg/kg/day, the maximum mean triglyceride levels rose 46.3 mg/dl in men and 52.3 mg/dl in women. In that study, 2 of 53 patients had a triglyceride elevation over 500 mg/dl, and 8 had elevations of 200 to 500 mg/dl. Triglyceride levels rise after 6 weeks of therapy and continue to rise while therapy continues. Age, sex, and weighted dose do not appear to be risk factors for triglyceride elevations. Overweight subjects are 6 times more likely to develop significant elevations in serum triglyceride, and subjects with elevated baseline triglyceride levels are 4.3 times more likely to develop significant elevations. Plasma lipid and lipoprotein levels return to baseline by 8 weeks after treatment. Liver and lipid abnormalities rarely necessitate dosage reduction and the need for repeat laboratory tests after initial normal values has been questioned.
Hyperostoses.
Asymptomatic hyperostoses (spurs) of the spine and extremities can be documented radiographically in some patients but do not seem to be of concern with a standard course of isotretinoin therapy.
Cheilitis.
Cheilitis is the most common side effect, occurring in virtually all patients. Application of emollients should be started with the initiation of therapy to minimize drying.
Approximately 40% of patients develop an elevated sedimentation rate during treatment. Isotretinoin does not specifically affect skeletal or myocardial muscles, 28% of patients complain of musculoskeletal symptoms. Accutane contains the preservative parabens; those patients with a proven allergy to parabens cannot receive Accutane. Exuberant granulation tissue may occur at the sites of healing acne lesions and is more likely to develop in patients who have preexisting crusted, draining, or ulcerated lesions. Granulation tissue can be controlled with intralesional steroid injections or silver nitrate sticks. Severe dry skin or eczema commonly occurs on the backs of the hands. Routine use of moisturizers and infrequent washing is recommended.

Medicine for acne: Isotretinoin Therapy (2)

Isotretinoin therapy.
Patients are seen frequently during the course of therapy (e.g., every 4 weeks). Isotretinoin is given in two divided doses daily, preferably with meals. Many patients experience a moderate to severe flare of acne during the initial weeks of treatment. This adverse reaction can be minimized by starting at 10 to 20 mg twice each day and gradually increasing the dosage during the first 4 to 6 weeks. Treatment is discontinued at the end of 16 to 20 weeks, and the patient is observed for 2 to 5 months. Those with persistently severe acne may receive a second course of treatment after the posttreatment observation period.
Response to therapy.
At dosages of 1 mg/kg/day, sebum production decreases to approximately 10% of pretreatment values and the sebaceous glands decrease in size. Maximum inhibition is reached by the third or fourth week. Within a week, patients normally notice drying and chapping of facial skin and skin oiliness disappears quickly. These effects persist for an indefinite period when therapy is discontinued.
During the first month, there is usually a reduction in superficial lesions such as papules and pustules. New cysts evolve and disappear quickly. A significant reduction in the number of cysts normally takes at least 8 weeks. Facial lesions respond faster than trunk lesions.
Resistant patients.
Younger patients (14 to 19 years of age) and those who have severe acne relapse more often. [acne relapses more often than facial acne. A return of the reduced sebum excretion rate to within 10% of the pretreatment level is a poor prognostic factor. with microcystic acne (whiteheads) and women with gyneco-endocrinologic problems are resistant to treatment. Women who do not clear after a total cumulative dose of 150 mg/kg need laboratory and clinical evaluation of their endocrinologic status. They may benefit from antiandrogen therapy.
Psychosocial implications.
Patients successfully treated with isotretinoin have significant posttreatment gains in social assertiveness and self-esteem. There is also a significant reduction in anxiety and depression.
Patients with minimal facial acne but with symptoms of dysmorphophobia (inappropriate depression and/or anxiety response to mild acne) are often treated with long-term antibiotic therapy with no perceived improvement. These patients respond to isotretinoin in that they are satisfied with the cosmetic results achieved. The incidence of relapse is greater than that of other acne patients and often requires additional therapy in the form of antibiotics or further isotretinoin.
Laboratory studies.
Pregnancy tests, triglyceride tests, complete blood counts, and liver function tests are performed on patients taking isotretinoin.

Medicine for acne: Isotretinoin Therapy (1)

Dosage.
The severity of the side effects of isotretinoin is proportional to the daily dose. Start with lower dosages and progressively increase the dosage in accordance with the tolerance.
The cumulative dose may be more important than the duration of therapy. A cumulative dose of greater than 120 mg/kg is associated with significantly better long-term remission. This dosage level can be achieved by either 1 mg/kg/day for 4 months or a smaller dosage for a longer period. The therapeutic benefit from a total cumulative dose of more than 150 mg/kg is virtually nonexistent. Analysis of 9 years of experience demonstrated that 1 mg/kg/day of isotretinoin for 4 months resulted in the longest remissions. Relapse rates in patients receiving 0.5 mg/kg/day were approximately 40% and those receiving 1.0 mg/kg/day were approximately 20%. Younger patients, males, and patients with truncal acne derive maximum benefit from the higher dosages. In these patients, dosages less than 0.5 mg/kg/day for a standard 4-month course are associated with a high relapse rate. Treat older patients with facial acne with a dosage of 0.5 mg/kg/day. Double the dosage if there is no response at the end of 2 months. Side effects depend on the dosage and can be controlled through reduction.
Duration of therapy.
A standard course of isotretinoin therapy is 16 to 20 weeks. Approximately 85% of patients are clear at the end of 16 weeks; 15% require longer treatment. Side effects are related to the dosage. Treat for a longer duration at a lower dosage if mucocutaneous side effects become troublesome. Patients with large, closed comedones may respond slowly and relapse early with inflammatory papules. Another ill-defined group responds slowly and requires up to 9 months until the condition begins to clear.
Relapse and repeat courses of isotretinoin.
Approximately 39% of patients relapse and require oral antibiotics (23%) or additional isotretinoin (16%). Relapse usually occurs within the first 3 years after isotretinoin is stopped; most often during the first 18 months after therapy. Some patients require multiple courses of therapy. The response to repeat therapy is consistently successful, and side effects are similar to those of previous courses. Repeat courses of isotretinoin seem to be safe.

Medicine for acne: Isotretinoin (Accutane)

Isotretinoin (Accutane 10-, 20-, 40-mg capsules)
Isotretinoin (13-cis retinoic acid), an oral retinoid related to vitamin A, is a very effective agent for control of acne and in the induction of long-term remissions, but it is not suitable for all types of acne. Isotretinoin affects all major etiologic factors implicated in acne. It dramatically reduces sebum excretion, follicular keratinization, and ductal and surface Propionibacterium acnes counts. These effects are maintained during treatment and persist at variable levels after therapy. A number of side effects occur during treatment. Isotretinoin is a potent teratogen; pregnancy must be avoided during treatment. Isotretinoin is not mutagenic; female patients should be assured that they may safely get pregnant but should wait for at least 1 month after stopping isotretinoin. Age is not a limiting factor in patient selection.
Indications
Severe, recalcitrant cystic or nodular and inflammatory acne.
A few patients with severe disease respond to oral antibiotics and vigorous drying therapy with a combination of agents such as benzoyl peroxide and sulfacetamide/sulfur lotion. Those who do not respond after a short trial of this conventional therapy should be treated with isotretinoin to minimize scarring.
Moderate acne unresponsive to conventional therapy.
Moderate acne usually responds to antibiotics (e.g., tetracycline or erythromycin 500 mg twice daily) plus topical agents. Change to a different antibiotic (e.g., minocycline 100 mg twice daily) if response is poor after 3 months. Change to a third antibiotic (e.g., ampicillin, a cephalosporin, or trimethoprim/sulfamethoxazole) if response is poor after 3 months on the second antibiotic. Change to isotretinoin if response is unsatisfactory after three consecutive 3-month courses of antibiotics. Patients who have a relapse during or after three courses of antibiotics are also candidates for isotretinoin.
Patients who scar.
Any patient who scars should be considered for isotretinoin therapy. Acne scars leave a permanent mark on the skin and psyche.
Excessive oiliness.
Excessive oiliness is disturbing and can last for years. Antibiotics and topical therapy may provide some relief, but isotretinoin's effect is dramatic. Relief may last for months or years; some patients require a second or third course of treatment.
Severely depressed or dysmorphophobic patients.
Some patients, even with minor acne, are depressed. Those who do not respond to conventional therapy are candidates for isotretinoin. They respond well to isotretinoin, although some may relapse quickly and require repeat courses.