254 lines
13 KiB
Plaintext
254 lines
13 KiB
Plaintext
ISOTRETINOINACCUTANEACNEPREGNANCYCYSTICFETALHEALTHMEDICINE
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ISOTRETINOIN (ACCUTANE) TREATMENT OF ACNE
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Isotretinoin (Accutane) treatment of acne
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It has long been known that vitamin A has a regulatory effect
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on growth and differentiation of epithelial tissue. Since the
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1940's, high doses of vitamin A have been employed in the
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treatment of severe acne and various disorders of keratinization.
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Vitamin A's use, however, was limited by its side effects - liver
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toxicity and pseudotumor cerebri in particular. In an attempt to
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find a drug with a better therapeutic index than vitamin A,
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several synthetic retinoids have been developed (1).
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One of these, isotretinoin (13-cis-retinoic acid), was first
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synthesized in 1955. It was largely ignored until the results of
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the first major clinical trial demonstrating its efficacy in the
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treatment of severe recalcitrant cystic acne were published in
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1972 (2). in 1982, isotretinoin was approved in the United States
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for that single indication only. Its trade name is Accutane. A
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major feature of this drug is that it produces a prolonged
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remission in patients with severe cystic acne, many of whom had
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not responded to other therapies. The most striking discovery,
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however, is that the remission is often sustained for months or
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years after the four- to five-month treatment course has been
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completed.
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Transport and metabolism of vitamin A (retinol) and isotretinoin
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Significant differences between vitamin A and isotretinoin
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with regard to their transport and metabolism account for their
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difference in toxicity (3). The major source of vitamin A
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(retinol) is the conversion of dietary plant carotenoids in the
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intestinal mucosa. Retinol is stored in the liver, which contains
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over 90% of body stores. Mobilization from the liver is
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accomplished when retinol is bound to a specific transport
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protein, retinol binding protein, that delivers it to tissues.
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Plasma levels of vitamin A tend to remain constant despite wide
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variations in diet. Extremely high dietary intake (eg. polar bear
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liver, vitamin A tablets) produces hypervitaminosis A.
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Hypervitaminosis A results in greatly increased hepatic stores
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and subsequent toxicity.
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In contrast, isotretinoin binds to serum albumin. Isotretinoin
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is readily absorbed orally and put into circulation via the
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portal system. It is not significantly stored in any organ
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system, and plasma levels vary with the amount ingested.
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Mode of action of isotretinoin in the treatment of acne
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Acne is a disease of the pilosebaceous unit. The pathogenesis
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of acne is believed to include several factors. Among them are
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excessive sebum production, abnormal keratinization of follicular
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epithelium, proliferation of 'Propionibacterium acnes',
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inflammation, and hormonal regulation of sebaceous glands.
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Isotreinoin affects several of these mechanisms, but its exact
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mode of action is not known. Isotretinoin causes pronounced but
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temporary inhibition of sebum production and atrophy of sebaceous
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glands (4). In general, after two weeks of standard therapy
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(1mg/kg/day), sebum production is decreased by more than 50% and
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by the end of a four- to five- month treatment period, it is
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reduced by greater than 90%. While there are some patients who
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continue to have decreased sebum production months to years after
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cessation of therapy, the sebum production of the vast majority
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returns to the baseline level within a few months. Since sebum
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production returns to normal in most patients, this is obviously
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not the sole mechanism for the prolonged remission of acne seen
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in these individuals. Many of these patients continue to improve
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even after therapy is discontinued (5).
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Some investigators believe that isotretinoin inhibits
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follicular keratinization in patients with acne. They postulate
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that this prevents the formation of comedomes (whiteheads and
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blackheads), the precursors of inflammatory acne lesions.
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Isotretinoin does decrease the quantity of 'Propionbacterium
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acnes' in treated patients. This organism is normal flora within
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the follicles. Increased numbers of these bacteria in patients
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with acne produce various chemotactic factors and enzymes that
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may increase inflammation. The decreased number of these bacteria
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in isotretinoin-treated patients is thought to be a result of
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decreased sebum production, producing a poor environment for the
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proliferation of this organism. Therefore, the decreased
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bacterial counts are thought to be secondary, and not the primary
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mechanism of action of Accutane.
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Clinical side effects
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Mucocutaneous side effects are the most common seen in
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isotretinoin treatment (6). More than 90% of people treated
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experience cheilitis, usually within the first two weeks of
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treatment. This is most easily treated with bland emolliation. A
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generalized xerosis is very common, but frequently acne patients
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view this as a beneficial rather than adverse effect. Should
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xerosis become problematic, the use of a noncomedogenic emollient
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lotion can be employed. Frequently patients develop nose bleeds
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and non-infectious conjunctivitis. Symptomatic treatment of these
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problems is all that is indicated. Less than 30% of patients
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notice temporary thinning of the hair. Less than 10% of these
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have clinically apparent hair loss, and hair density returns to
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normal after treatment is discontinued.
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Approximately 20% of patients on isotretinoin have musculo-
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skeletal pains. These tend to be minor, and are relieved by non-
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steroidal anti-inflammatory agents. More worrisome are the
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skeletal abnormalities seen in patients on long term isotretinoin
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treatment for various keratinizing disorders (7). These patients
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however , were usually treated with higher doses of 2mg/kg/day
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for more than two years. The ossification disorder seen in these
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patients resembles diffuse idiopathic skeletal hypostosis.
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Children being treated for these disoreders had x-ray findings
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suggesting premature closure of the epiphyses of the knees.
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More recently, in a small prospective study of patients on
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doses of 2 mg/kg/day of isotretinoin for the treatment of
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keratinizing disorders, radiologically documented skeletal
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changes were noted after only 6-12 months of therapy. These
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changes consisted of slightly increased bone formation in areas
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of ligament attachment. It is not yet known whether this is
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reversible.
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A small number of patients may have a temporary flare of acne
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at the onset of treatment. Some clinincians feel that this can be
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minimized by the administration of low dose prednisone or oral
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antibiotics.
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Pseudotumor cerebri ( benign intracranial hypertension) has
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occurred in patients treated with isotretinoin. Patients with
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headache, nausea, vomitting or visual disturbances should be
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screened for papilledema. The drug should be stopped immediately
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if papilledema is present.
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Patients with visual disturbances should also be checked for
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corneal opacities. Corneal opacities occur more frequently in
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those patients receiving higher doses of isotretinoin for
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keratinizing disorders but has also been reported in patients
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treated for cystic acne. The opacities resolve six to seven weeks
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after discontinuation of the drug.
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There have been rare reports of inflammatory bowel disease in
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patients treated with isotretinoin. Occasional patients report
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fatigue or lassitude.
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Laboratory abnormalities
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One fourth of patients treated with isotretinoin develop
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elevated serum triglycerides during their four- to five- month
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course of treatment for acne. Approximately one eighth have a
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decrease in the HDL level and one sixteenth have elevated
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chloresterol. These changes usually resolve after therapy is
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discontinued. It is important to monitor blood lipids at the
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onset of therapy and at intervals of two to four weeks until it
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is seen that there are no significant changes. Minor elevations
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in triglycerides are best treated by dietary maneuvres. It is
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not known what role the lipid abnormalities may play in the
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production of coronary heart disease, but the risk is currently
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thought to be low since abnormalities return to normal after
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therapy is stopped. It is perhaps best that patients with high
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triglyceride elevations be treated with the lowest effective
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dosage of isotretinoin for a shorter period of time. Triglyceride
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elevations of greater than 500 mg/dL necessitate discontinuation
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of the drug, as these patients are at risk for developing acute
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pancreatitis. A few patients develop mild leukopenia, anemia, or
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thrombocytosis. Mild pyuria and liver function test abnormalities
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occasionally occur. These changes appear to be reversible after
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discontinuation of the drug and are usually not clinically
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significant.
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Isotretinoin and pregnancy
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The most serious side effect of isotretinoin is its
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teratogenicity. The drug should not be used by women who are
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pregnant or those who plan to become pregnant during treatment.
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Contraception is recommended for women taking the drug, beginning
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one month before treatment, and continuing until one month after
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discontinuation of treatment. Many physicians obtain a pregnancy
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test within two weeks prior to starting therapy.
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Reported fetal abnormalities include hydrocephalus,
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microcephalus, abnormalities of the external ear (micropinna,
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small or absent external auditory canals), Micropthalmia and
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cardiovascular abnormalities. These abnormalities have occured
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only in children born to mothers exposed to the drug during
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pregnancy.
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The package insert recommends that patients who become
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pregnant discuss with their physician the desirability of
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continuing the pregnancy. Since the half-life of isotretinoin is
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less than one to three days, it is believed that there is no risk
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of teratogenicity during subsequent pregnancies occurring at
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least one month after treatment has been stopped.
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While no reproduction studies have been performed on humans
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taking isotretinoin, studies in rats have not revealed impaired
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fertility. No significant changes have been seen in the number or
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mobility of spermatazoa of human males receiving isotretinoin. As
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it is not known whether isotretinoin is secreted into milk, it is
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inadvisable to treat nursing mothers with the drug.
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Dosage and administration
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Isotretinoin is presently approved by the FDA only for the
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treatment of severe recalcitrant nodulocystic acne. While dosages
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of 0.1, 0.5, and 1.0 mg/kg/day orally seem equally effective in
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inducing a remission of acne, there is a significantly higher
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relapse rate in patients rate in patients treated at lower doses.
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As the goal of isotretinoin therapy is not only the clearing of
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active disease but the indefinite maintenance of clearing, it is
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recommended that patients be treated with 1 mg/kg/day for 16-20
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weeks. Extensive truncal lesions, which do not respond as quickly
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or completely as facial lesions, may require dosages of 1.5-2.0
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mg/kg/day. Isotretinoin is supplied in 10,20, and 20 mg capsules.
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Most patients are treated with 40 mg twice daily. Patients should
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be advised not to ingest any vitamin A supplements during their
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treatment course.
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Other indications
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Isotretinoin has also been shown to be effective for a variety
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of other skin disorders, but it is not yet approved by the FDA
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for these indications. These include several variants of acne:
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hidradenitis suppurativa, gram negative folliculitis, and
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rosacea.
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Retinoids also have an antineoplastic effect. Several patients
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with the basal cell nervus syndrome, an autosomal dominant
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disorder in which patients develop multiple basal cell
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carcinomas, have been treated. Isotretinoin resulted in reduction
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in tumor sizes, but usually did not completely destroy the
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tumors. Retinoids are also being studied for possible future
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roles in cancer prevention. Isotretinoin and other retinoids (
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especially etretinate, an aromatic retinoid not yet available in
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the US) have been used to treat a wide variety of keratinizing
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skin disorders, such as psoriasis, keratosis follicularis,
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ichthyosis, pityriasis rubra pilaris, and others (8). Discussion
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of this is beyond the scope of this paper. Although the drug is
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very effective for several of these disorders, the major problem
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is that long-term treatment is required for these chronic
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diseases, and long-term safety of retinoids has not been
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established.
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Conclusion
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Isotretinoin (Accutane) is an exceedingly useful drug,
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producing dramatic prolonged remissions after four to five weeks
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in most patients with severe nodulocystic acne. Because of its
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side effects, teratogenicity, and cost (about $600 for a four- to
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five- month course of treatment), the drug should be reserved for
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the less than 1% of patients with severe acne.
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