ACCUTANE

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WARNING
 
 Contraindications and Warning: Isotretinoin must not be used by females who are pregnant or who may become pregnant while undergoing treatment. Although not every fetus exposed to isotretinoin has resulted in a deformed child, there is an extremely high risk that a deformed infant can result if pregnancy occurs while taking isotretinoin in any amount even for short periods. Potentially any fetus exposed during pregnancy can be affected. Presently, there is no accurate means of determining after isotretinoin exposure which fetus has been affected and which fetus has not been affected.
 
 Isotretinoin is Contraindicated in Women of Childbearing Potential Unless the PATIENT MEETS ALL OF THE
 FOLLOWING CONDITIONS:
 
Has severe disfiguring nodular acne that is recalcitrant to standard therapies (see INDICATIONS AND USAGE
for definition).
Is reliable in understanding and carrying out instructions.
Is capable of complying with the mandatory contraceptive measures.
Has received both oral and written warnings of the hazards of taking isotretinoin during pregnancy and the exposing a fetus to the drug
Has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously, unless abstinence is the chosen method, or the patient has undergone a hysterectomy and has acknowledged in writing her understanding of these warnings and of the need for using dual contraceptive methods
Has had a negative serum pregnancy test with a sensitivity of at least 50 mIU/ml within one week prior to beginning therapy
Will begin therapy only on the second or third day of the next normal menstrual period
 
 It is recommended that a prescription for isotretinoin should not be issued by the physician until a report of a negative
 pregnancy test has been obtained and the patient has begun her menstrual period. It is also recommended that pregnancy testing and contraception counseling be repeated on a monthly basis. To encourage compliance with this recommendation, the physician should prescribe no more than a 1 month supply of the drug.
 
 Major human fetal abnormalities related to isotretinoin administration have been documented: CNS abnormalities (including  cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); skull abnormality;  external ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities  (including microphthalmia); cardiovascular abnormalities; facial dysmorphia; thymus gland abnormality; parathyroid  hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted. Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also been reported. There is an increased risk of  spontaneous abortion. In addition, premature births have been reported.
 
 Effective contraception must be used for at least 1 month before beginning isotretinoin therapy, during therapy and for 1  month following discontinuation of therapy even where there has been a history of infertility, unless due to hysterectomy. It  is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method.
 
 If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the
 pregnancy.
 
 Isotretinoin should be prescribed only by physicians who have special competence in the diagnosis and treatment of severe  recalcitrant nodular acne, are experienced in the use of systemic retinoids and understand the risk of teratogenicity if  isotretinoin is used during pregnancy.
 
CONTRAINDICATIONS
 
Pregnancy Category X
 
See BOXED WARNING. Isotretinoin should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule.
 
WARNINGS
 
 Pseudotumor cerebri: Isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign
 intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and  vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they  should be told to discontinue isotretinoin immediately and be referred to a neurologist for further diagnosis and care.
 
 
 
Decreased Night Vision: A number of cases of decreased night vision have occurred during isotretinoin therapy. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored.
 
Corneal Opacities: Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. All isotretinoin patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination. The corneal opacities that have been observed in patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug. See ADVERSE REACTIONS.
 
Inflammatory Bowel Disease: Isotretinoin has been temporally associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue isotretinoin immediately.
 
Lipids: Blood lipid determinations should be performed before isotretinoin is given and then at intervals until the lipid response to isotretinoin is established, which usually occurs within 4 weeks. See PRECAUTIONS.
 
Approximately 25% of patients receiving isotretinoin experienced an elevation in plasma triglycerides. Approximately 15% developed a decrease in high density lipoproteins and about 7% showed an increase in cholesterol levels. These effects on triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy.
 
Patients with increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake and familial history.
 
The cardiovascular consequences of hypertriglyceridemia are not well understood, but may increase the patient's risk status. In addition, elevation of serum triglycerides in excess of 800 mg/dl has been associated with acute pancreatitis. Therefore, every attempt should be made to control significant triglyceride elevation.
 
Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing isotretinoin.5
 
An obese male patient with Darier's disease developed elevated triglycerides and subsequent eruptive xanthomas.6
 
Hyperostosis: In clinical trials of disorders of keratinization with a mean dose of 2.24 mg/kg/day, a high prevalence of skeletal hyperostosis was noted. Two children showed x-ray findings suggestive of premature closure of the epiphysis. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.7 Minimal skeletal hyperostosis has also been observed by x-rays in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses.
 
Hepatotoxicity: Several cases of clinical hepatitis have been noted which are considered to be possibly or probably related to isotretinoin therapy. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with isotretinoin, the drug should be discontinued and the etiology further investigated.
 
Animal Studies: In rats given 32 or 8 mg/kg/day of isotretinoin for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day.
 
In dogs given isotretinoin chronically at a dosage of 60 mg/kg/day, corneal ulcers and corneal opacities were encountered at a higher incidence than in control dogs. In general, these ocular changes tended to revert toward normal when treatment with isotretinoin was stopped, but did not completely clear during the observation period.
 
In rats given isotretinoin at a dosage of 32 mg/kg/day for approximately 15 weeks, long bone fracture has been observed.
 
PRECAUTIONS
 
Information for the Patient: Women of childbearing potential should be instructed that they must not be pregnant when isotretinoin therapy is initiated, and that they should use effective contraception while taking isotretinoin and for 1 month after isotretinoin has been stopped. They should also sign a consent form prior to beginning isotretinoin therapy. See CONTRAINDICATIONS and BOXED WARNING.
 
Because of the relationship of isotretinoin to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
 
Patients should be informed that transient exacerbation of acne has been seen, generally during the initial period of therapy.
 
Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy.
 
It is recommended that patients not donate blood during therapy and for at least 1 month following discontinuance of the drug.
 
Laboratory Tests: The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin therapy. Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established.
 
Since elevations of liver enzymes have been observed during clinical trials, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to isotretinoin has been established.
 
Certain patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established. Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown.
 
Carcinogenesis, Mutagenesis, and Impairment of Fertility: In Fischer 344 rats given isotretinoin at dosages of 8 or 32 mg/kg/day for greater than 18 months, there was an increased incidence of pheochromocytoma. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage. The relatively high level of spontaneous pheochromocytomas occurring in the Fischer 344 rat makes it a poor model for study of this tumor, since the increase in adrenal medullary proliferative lesions following chronic treatment with relatively high dosages of isotretinoin may be an accentuation of a genetic predisposition in the Fischer 344 rat, and its relevance to the human population is not clear. In addition, a decreased incidence of liver adenomas, liver angiomas and leukemia was noted at the dose levels of 8 and 32 mg/kg/day.
 
The Ames test was conducted in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly-positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay in human-derived lymphocytes and unscheduled DNA synthesis assay) were all negative.
 
No adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at dose levels of 2, 8 or 32 mg/kg/day in male and female rats.
 
In dogs, testicular atrophy was noted after treatment with isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day. In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies in 66 human males, 30 of whom were patients with nodular acne, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
 
Pregnancy Category X: See BOXED WARNING.
 
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive isotretinoin.