patients who can become pregnant who use only a single form of contraception. it is not known if hormonal contraceptives differ in their effectiveness when used with zenatane. therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see precautions ). norethindrone/ethinyl estradiol: in a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving ortho-novum ® 7/7/7 tablets as an oral contraceptive agent, zenatane at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (fsh) and luteinizing hormone (lh). prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. st. john’s wort: zenatane use is associated with depression in some patients (see warnings : psychiatric disorders and adverse reactions : psychiatric). patients should be prospectively cautioned not to self-medicate with the herbal supplement st. john’s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting st.john's wort. pregnancies have been reported by users of combined hormonal contraceptives who also used some form of st.john's wort. phenytoin: zenatane has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. these results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the cyp 2c9 human hepatic p450 enzyme. phenytoin is known to cause osteomalacia. no formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and zenatane. therefore, caution should be exercised when using these drugs together. systemic corticosteroids: systemic corticosteroids are known to cause osteoporosis. no formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and zenatane. therefore, caution should be exercised when using these drugs together.

tion of the first course, because experience has shown that patients may continue to improve while off zenatane. the optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see warnings: skeletal: bone mineral density, hyperostosis, premature epiphyseal closure ).

(1394.17) 5082 (2184.23) auc (0-24) (ng⋅hr/ml) 6003.81 (2885.67) – t max (hr)† 6 (1 to 24.6) 4 (0 to12) c ss min (ng/ml) – 352.32 (184.44) t 1/2 (hr) – 15.69 (5.12) cl/f (l/hr) – 17.96 (6.27) *the single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in table 2 . † median (range) in pediatric patients (12 to 15 years), the mean ± sd elimination half-lives (t 1/2 ) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. the accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

ts”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. patients should stop zenatane and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. discontinuation of zenatane therapy may be insufficient; further evaluation may be necessary. while such monitoring may be helpful, it may not detect all patients at risk. patients may report mental health problems or family history of psychiatric disorders. these reports should be discussed with the patient and/or the patient’s family. a referral to a mental health professional may be necessary. the physician should consider whether zenatane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of zenatane therapy. pseudotumor cerebri zenatane use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. concomitant treatment with tetracyclines should therefore be avoided. 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 zenatane immediately and be referred to a neurologist for further diagnosis and care (see adverse reactions: neurological ). serious skin reactions there have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., stevens-johnson syndrome (sjs), toxic epidermal necrolysis (ten)] associated with isotretinoin use. these events may be serious and result in death, life-threatening events, hospitalization, or disability. patients should be monitored closely for severe skin reactions, and discontinuation of zenatane should be considered if warranted. pancreatitis acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. in rare instances, fatal hemorrhagic pancreatitis has been reported. zenatane should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. lipids elevations of serum triglycerides in excess of 800 mg/dl have been reported in patients treated with zenatane. marked elevations of serum triglycerides were reported in approximately 25% of patients receiving zenatane in clinical trials. in addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. in clinical trials, the effects on triglycerides, hdl, and cholesterol were reversible upon cessation of zenatane therapy. 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 zenatane 5 . blood lipid determinations should be performed before zenatane is given and then at intervals until the lipid response to zenatane is established, which usually occurs within 4 weeks. especially careful consideration must be given to risk/benefit for patients who may be at high risk during zenatane therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). if zenatane therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see precautions : laboratory tests ). the cardiovascular consequences of hypertriglyceridemia associated with zenatane are unknown. animal studies: in rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) 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 (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). hearing impairment impaired hearing has been reported in patients taking zenatane; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. mechanism(s) and causality for this event have not been established. patients who experience tinnitus or hearing impairment should discontinue zenatane treatment and be referred for specialized care for further evaluation (see adverse reactions : special senses ). hepatotoxicity clinical hepatitis considered to be possibly or probably related to zenatane therapy has been reported. 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 zenatane, the drug should be discontinued and the etiology further investigated. inflammatory bowel disease zenatane has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. in some instances, symptoms have been reported to persist after zenatane treatment has been stopped. patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue zenatane immediately (see adverse reactions : gastrointestinal ). skeletal bone mineral density effects of multiple courses of zenatane on the developing musculoskeletal system are unknown. there is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. in an open-label clinical trial (n=217) of a single course of therapy with zenatane for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. one patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in five of eight patients (62.5%). in a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of zenatane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see precautions: pediatric use ). spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the zenatane population. while causality to zenatane has not been established, an effect cannot be ruled out. longer term effects have not been studied. it is important that zenatane be given at the recommended doses for no longer than the recommended duration. hyperostosis a high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization. 6 minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. the skeletal effects of multiple zenatane treatment courses for acne are unknown. in a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of zenatane given in two divided doses. hyperostosis may require a longer time frame to appear. the clinical course and significance remain unknown. premature epiphyseal closure there are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of zenatane. the effect of multiple courses of zenatane on epiphyseal closure is unknown. vision impairment visual problems should be carefully monitored. all zenatane patients experiencing visual difficulties should discontinue zenatane treatment and have an ophthalmological examination (see advaerse reactions: special senses ). corneal opacities corneal opacities have occurred in patients receiving zenatane for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. the corneal opacities that have been observed in clinical trial patients treated with zenatane have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see adverse reactions: special senses ). decreased night vision decreased night vision has been reported during zenatane therapy and in some instances the event has persisted after therapy was discontinued. 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.

ot been established, an effect must not be ruled out. information for patients see precautions and boxed contraindications and warnings . patients must be instructed to read the medication guide supplied as required by law when zenatane is dispensed. the complete text of the medication guide is reprinted at the end of this document. for additional information, patients must also be instructed to read the ipledge rems patient educational materials. all patients must sign the patient enrollment form for patients who cannot get pregnant. patients who can become pregnant must be instructed that they must not be pregnant when zenatane therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting zenatane, while taking zenatane, and for one month after zenatane has been stopped, unless they commit to continuous abstinence from not having any sexual contact with a partner that could result in pregnancy. they should also sign a second patient enrollment form for patients who can get pregnant prior to beginning zenatane therapy. patients who can become pregnant should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a clia-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another zenatane prescription is written (see boxed contraindications and warnings and precautions ). zenatane is found in the semen of male patients taking zenatane, but the amount delivered to a a patient who can become pregnant would be about 1 million times lower than an oral dose of 40 mg. while the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete, and two had other possible explanations for the defects observed. prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. therefore, prior to initiation of zenatane treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment . patients should stop zenatane and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. discontinuation of zenatane treatment may be insufficient; further evaluation may be necessary. while such monitoring may be helpful, it may not detect all patients at risk. patients may report mental health problems or family history of psychiatric disorders. these reports should be discussed with the patient and/or the patient’s family. a referral to a mental health professional may be necessary. the physician should consider whether zenatane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of zenatane therapy. patients must be informed that some patients, while taking zenatane or soon after stopping zenatane, have become depressed or developed other serious mental problems. symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. some patients taking zenatane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). some people tried to end their own lives. and some people have ended their own lives. there were reports that some of these people did not appear depressed. there have been reports of patients on zenatane becoming aggressive or violent. no one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take zenatane. some people have had other signs of depression while taking zenatane. patients must be informed that they must not share zenatane with anyone else because of the risk of birth defects and other serious adverse events. patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant patient whose fetus must not be exposed to zenatane. patients should be reminded to take zenatane with a meal (see dosage and administration ). to decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during zenatane therapy and for at least 6 months thereafter due to the possibility of scarring (see adverse reactions : skin and appendages ). patients should be advised to avoid prolonged exposure to uv rays or sunlight. patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. patients should be informed that approximately 16% of patients treated with zenatane in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. in general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. transient pain in the chest has been reported less frequently. in the clinical trial, these symptoms generally cleared rapidly after discontinuation of zenatane, but in some cases persisted (see adverse reactions: musculoskeletal ). there have been rare post marketing reports of rhabdomyolysis, some associated with strenuous physical activity (see laboratory tests : cpk ). pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with zenatane developed back pain. back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. arthralgias were experienced in 22% (79/358) of pediatric patients. arthralgias were severe in 7.6% (6/79) of patients. appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of zenatane. consideration should be given to discontinuation of zenatane if any significant abnormality is found. neutropenia and rare cases of agranulocytosis have been reported. zenatane should be discontinued if clinically significant decreases in white cell counts occur. patients should be advised that severe skin reactions (stevens-johnson syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. zenatane should be discontinued if clinically significant skin reactions occur. hypersensitivity anaphylactic reactions and other allergic reactions have been reported. cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

not been established. once daily dosing is not recommended. if the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. after a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. the optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. long-term use of zenatane, even in low doses, has not been studied, and is not recommended. it is important that zenatane be given at the recommended doses for no longer than the recommended duration. the effect of long-term use of zenatane on bone loss is unknown (see warnings : skeletal : bone mineral density , hyperostosis , and premature epiphyseal closure ). contraceptive measures must be followed for any subsequent course of therapy (see precautions ). table 4 zenatane dosing by body weight (based on administration with food) body weight total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg* 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 *see dosage and administration : the recommended dosage range is 0.5 to 1 mg/kg/day. information for pharmacists access the ipledge rems system via the internet (www.ipledgeprogram.com), or telephone (1-866495-0654) to obtain an authorization and the “do not dispense to patient after” date. zenatane must only be dispensed in no more than a 30 day supply. refills require a new prescription and a new authorization from the ipledge system. a zenatane medication guide must be given to the patient each time zenatane is dispensed, as required by law. this zenatane medication guide is an important part of the risk management program for the patient.

scular thrombotic disease, stroke endocrine/metabolic hypertriglyceridemia (see warnings : lipids ), alterations in blood sugar levels (see precautions : laboratory tests ) gastrointestinal inflammatory bowel disease (see warnings : inflammatory bowel disease ), hepatitis (see warnings : hepatotoxicity ), pancreatitis (see warnings : lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms. hematologic allergic reactions (see precautions : hypersensitivity ), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see precautions : information for patients ). see precautions : laboratory tests for other hematological parameters. musculoskeletal skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see warnings : skeletal ), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see precautions : information for patients ), transient pain in the chest (see precautions : information for patients ), arthritis, tendonitis, other types of bone abnormalities, elevations of cpk/rare reports of rhabdomyolysis (see precautions : laboratory tests ). neurological pseudotumor cerebri (see warnings : pseudotumor cerebri ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness psychiatric suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see warnings : psychiatric disorders ), emotional instability. of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. reproductive system abnormal menses. respiratory bronchospasms (with or without a history of asthma), respiratory infection, voice alteration skin and appendages acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, 7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), stevens-johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including wegener’s granulomatosis; see precautions : hypersensitivity ), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see precautions : information for patients ) special senses hearing hearing impairment (see warnings : hearing impairment ), tinnitus. vision corneal opacities (see warnings : corneal opacities ), decreased night vision which may persist (see warnings : decreased night vision ), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances urinary system glomerulonephritis (see precautions : hypersensitivity ), nonspecific urogenital findings (see precautions : laboratory tests for other urological parameters) laboratory elevation of plasma triglycerides (see warnings : lipids ), decrease in serum high-density lipoprotein (hdl) levels, elevations of serum cholesterol during treatment increased alkaline phosphatase, sgot (ast), sgpt (alt), ggtp or ldh (see warnings : hepatotoxicity ) elevation of fasting blood sugar, elevations of cpk (see precautions : laboratory tests ), hyperuricemia. decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; (see precautions : information for patients ), elevated sedimentation rates, elevated platelet counts, thrombocytopenia white cells in the urine, proteinuria, microscopic or gross hematuria

patients who can become pregnant who use only a single form of contraception. it is not known if hormonal contraceptives differ in their effectiveness when used with zenatane. therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see precautions ). norethindrone/ethinyl estradiol: in a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving ortho-novum ® 7/7/7 tablets as an oral contraceptive agent, zenatane at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (fsh) and luteinizing hormone (lh). prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. st. john’s wort: zenatane use is associated with depression in some patients (see warnings : psychiatric disorders and adverse reactions : psychiatric). patients should be prospectively cautioned not to self-medicate with the herbal supplement st. john’s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting st.john's wort. pregnancies have been reported by users of combined hormonal contraceptives who also used some form of st.john's wort. phenytoin: zenatane has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. these results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the cyp 2c9 human hepatic p450 enzyme. phenytoin is known to cause osteomalacia. no formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and zenatane. therefore, caution should be exercised when using these drugs together. systemic corticosteroids: systemic corticosteroids are known to cause osteoporosis. no formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and zenatane. therefore, caution should be exercised when using these drugs together.

imes severe) and myalgia in pediatric patients (see adverse reactions ). in an open-label clinical trial (n=217) of a single course of therapy with zenatane for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. one patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. total hip bone mineral densities remained below baseline (range −1.6% to −7.6%) in five of eight patients (62.5%). in a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of zenatane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see warnings : skeletal : bone mineral density ).

wing a standardized high-fat meal when compared with zenatane given under fasted conditions (see table 2 ). the observed elimination half-life was unchanged. this lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. the time to peak concentration (t max ) was also increased with food and may be related to a longer absorption phase. therefore, zenatane should always be taken with food (see dosage and administration ). clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin. table 2 pharmacokinetic parameters of isotretinoin mean (%cv), n=74 zenatane 2 x 40 mg capsules auc 0-∞ (ng ⋅ hr/ml) c max (ng/ml) t max (hr) t 1/2 (hr) fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%) fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%) *eating a standardized high-fat meal distribution isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. metabolism following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxotretinoin). retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. the administration of one isomer will give rise to the other. isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. after a single 80 mg oral dose of zenatane to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. all of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. however, the clinical significance of these models is unknown. after multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. in vitro studies indicate that the primary p450 isoforms involved in isotretinoin metabolism are 2c8, 2c9, 3a4, and 2b6. isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. elimination following oral administration of an 80 mg dose of 14 c-isotretinoin as a liquid suspension, 14 c-activity in blood declined with a half-life of 90 hours. the metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). after a single 80 mg oral dose of zenatane to 74 healthy adult subjects under fed conditions, the mean ± sd elimination half-lives (t 1/2 ) of isotretinoin and 4- oxo -isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. after both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne. special patient populations pediatric patients the pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received zenatane for the treatment of severe recalcitrant nodular acne. in both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. the dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in table 3 for pediatric patients. there were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. table 3. pharmacokinetic parameters of isotretinoin following single and multiple dose administration in pediatric patients, 12 to 15 years of age mean ( ± sd), n=38* parameter isotretinoin (single dose) isotretinoin (steady-state) c max (ng/ml) 573.25 (278.79) 731.98 (361.86) auc (0-12) (ng⋅hr/ml) 3033.37 (1394.17) 5082 (2184.23) auc (0-24) (ng⋅hr/ml) 6003.81 (2885.67) – t max (hr)† 6 (1 to 24.6) 4 (0 to12) c ss min (ng/ml) – 352.32 (184.44) t 1/2 (hr) – 15.69 (5.12) cl/f (l/hr) – 17.96 (6.27) *the single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in table 2 . † median (range) in pediatric patients (12 to 15 years), the mean ± sd elimination half-lives (t 1/2 ) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. the accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

ents with nodular acne and healthy subjects with normal skin. table 2 pharmacokinetic parameters of isotretinoin mean (%cv), n=74 zenatane 2 x 40 mg capsules auc 0-∞ (ng ⋅ hr/ml) c max (ng/ml) t max (hr) t 1/2 (hr) fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%) fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%) *eating a standardized high-fat meal distribution isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. metabolism following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxotretinoin). retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. the administration of one isomer will give rise to the other. isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. after a single 80 mg oral dose of zenatane to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. all of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. however, the clinical significance of these models is unknown. after multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. in vitro studies indicate that the primary p450 isoforms involved in isotretinoin metabolism are 2c8, 2c9, 3a4, and 2b6. isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. elimination following oral administration of an 80 mg dose of 14 c-isotretinoin as a liquid suspension, 14 c-activity in blood declined with a half-life of 90 hours. the metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). after a single 80 mg oral dose of zenatane to 74 healthy adult subjects under fed conditions, the mean ± sd elimination half-lives (t 1/2 ) of isotretinoin and 4- oxo -isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. after both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.

tabolic 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 with human-derived lymphocytes, and unscheduled dna synthesis assay) were all negative. in rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). in dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). 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 of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, 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 zenatane therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

ptical shaped soft gelatin capsule imprinted with “ri” in black colored ink along the length of body on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and in boxes of 100 containing 10 prescription packs of 10 capsules, as unit dose blisters. boxes of 30 (3 prescription packs of 10 capsules) ndc 55111-113-81 boxes of 100 (10 prescription packs of 10 capsules) ndc 55111-113-78 zenatane (isotretinoin capsules usp) 40 mg are opaque green elliptical soft gelatin capsules imprinted with black ink, “r137” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and 100 containing 10 prescription packs of 10 capsules, as unit dose blisters. boxes of 30 (3 prescription packs of 10 capsules) ndc 55111-137-81 boxes of 100 (10 prescription packs of 10 capsules) ndc 55111-137-78

hile taking isotretinoin. initial: ______ 2. i understand that i must not get pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin. initial: ______ 3. i understand that i must avoid having any sexual contact (penis-vaginal) with a partner who could get me pregnant completely, or i must use two separate, effective forms of birth control (contraception) at the same time . the only exceptions are if i have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that i am post-menopausal. initial: ______ 4. i understand that hormonal birth control products are among the most effective forms of birth control. combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (iuds). any method of birth control can fail. that is why i must use two different birth control forms at the same time, starting one month before, during, and for one month after stopping therapy every time i have any sexual contact (penis-vaginal) with a partner who could get me pregnant, even if one of the forms i choose is hormonal birth control. initial: ______ 5. i understand that the following are effective forms of birth control: primary forms secondary forms • tying my tubes (tubal sterilization) barrier: • male vasectomy • male latex condom with or without spermicide • intrauterine device • diaphragm with spermicide • hormonal (combination birth control pills, skin patches, shots, under- the-skin implants, or vaginal ring) • cervical cap with spermicide other: • vaginal sponge (contains spermicide) a diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm i understand that at least one of my two forms of birth control must be a primary form. initial: ______ 6. i will talk with my doctor about any medicines including herbal products i plan to take during my isotretinoin treatment because hormonal birth control forms may not work if i am taking certain medicines or herbal products. initial: ______ 7. i may receive a free birth control counseling session from a doctor or other family planning expert. my isotretinoin doctor can give me an isotretinoin contraception referral form for this free consultation. initial: ______ 8. i must begin using the birth control forms i have chosen as described above at least one month before i start taking isotretinoin. initial: ______ 9.i cannot get my first prescription for isotretinoin unless my doctor has told me that i have two negative pregnancy test results. the first pregnancy test should be done when my doctor decides to prescribe isotretinoin. the second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment, or as instructed by my doctor. i will then have one pregnancy test; in a lab. every month during treatment at the end of treatment and 1 month after stopping treatment i must not start taking isotretinoin until i am sure that i am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab. initial: ______ 10. i have read and understand the materials my doctor has provided to me, including the guide for patients who can get pregnant, and the fact sheet on the ipledge rems. i have received information on emergency birth control. initial: ______ 11. i must stop taking isotretinoin right away and call my doctor if i get pregnant, miss my expected menstrual period, stop using birth control, or have any sexual contact (penis-vaginal) with a partner who could get me pregnant without using my two birth control forms at any time. initial: ______ 12. my doctor provided me information about the purpose and importance of providing information to the ipledge rems should i become pregnant while taking isotretinoin or within one month of the last dose. i understand that if i become pregnant, information about my pregnancy, my health, and my baby’s health may be shared with the makers of isotretinoin, authorized parties who maintain the ipledge rems for the makers of isotretinoin and government health regulatory authorities. initial: ______ 13. i understand that being qualified to receive isotretinoin in the ipledge rems means that i: have had 2 negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. the second test must be done in a lab. i must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before i receive another isotretinoin prescription. have chosen and agreed to use two forms of effective birth control at the same time. at least one form must be a primary form of birth control, unless i have chosen never to have any sexual contact (penis-vaginal) with a partner who could get me pregnant (abstinence) , or i have undergone a hysterectomy or bilateral oophorectomy, or i have been medically confirmed to be post-menopausal. i must use two forms of birth control for at least one month before i start isotretinoin therapy, during therapy, and for one month after stopping therapy. i must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy. have signed a patient enrollment form for patients who can get pregnant that contains warnings about the chance of possible birth defects if i am pregnant or become pregnant and my unborn baby is exposed to isotretinoin. have been informed of and understand the purpose and importance of providing information to the ipledge rems should i become pregnant while taking isotretinoin or within 1 month of the last dose. have interacted with the ipledge rems before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control. initial: ______ my doctor has answered all my questions about isotretinoin and i understand that it is my responsibility not to get pregnant one month before, during isotretinoin treatment, or for one month after i stop taking isotretinoin. initial: ______ i now authorize my doctor ________________ to begin my treatment with isotretinoin. patient signature:_____________________________________ date: ______ parent/guardian signature (if under age 18):________________ date:______ please print: patient name and address____________________ telephone _______________________ i have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to patients who can get pregnant. i have asked the patient if there are any questions regarding the treatment with isotretinoin and have answered those questions to the best of my ability. doctor signature: __________________________________ date: ______ place the original signed documents in the patient’s medical record. please provide a copy to the patient. document patient identification number___________________________________ patient enrollment form for patients who cannot get pregnant to be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor. read each item below and initial in the space provided if you understand each item and agree to follow your doctor’s instructions. a parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement. do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin. 1. i, ______________________________________________________, (patient’s name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. in severe nodular acne, many red, swollen, tender lumps form in the skin. if untreated, severe nodular acne can lead to permanent scars. initials: ______ 2. my doctor has told me about my choices for treating my acne. initials: ______ 3. i understand that there are serious side effects that may happen while i am taking isotretinoin. these have been explained to me. these side effects include serious birth defects in babies of pregnant patients. [note: there is a second patient enrollment form for patients who can get pregnant]. initials: ______ 4. i understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). some people tried to end their own lives. and some people have ended their own lives. there were reports that some of these people did not appear depressed. there have been reports of patients on isotretinoin becoming aggressive or violent. no one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. some people have had other signs of depression while taking isotretinoin (see #7 below). initials: ______ 5. before i start taking isotretinoin, i agree to tell my doctor if i have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there. initials: ______ 6. before i start taking isotretinoin, i agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems. initials: ______ 7. once i start taking isotretinoin, i agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. i: start to feel sad or have crying spells lose interest in activities i once enjoyed sleep too much or have trouble sleeping become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) have a change in my appetite or body weight have trouble concentrating withdraw from my friends or family feel like i have no energy have feelings of worthlessness or guilt start having thoughts about hurting myself or taking my own life (suicidal thoughts) start acting on dangerous impulses start seeing or hearing things that are not real initials: ______ 8. i agree to return to see my doctor every month i take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects. initials: ______ 9. isotretinoin will be prescribed just for me — i will not share isotretinoin with other people because it may cause serious side effects, including birth defects. initials: ______ 10. i will not give blood while taking isotretinoin or for 1 month after i stop taking isotretinoin. i understand that if someone who is pregnant gets my donated blood, their baby may be exposed to isotretinoin and may be born with serious birth defects. initials: ______ 11. i have read the fact sheet for the ipledge rems , and other materials my provider provided me containing important safety information about isotretinoin. i understand all the information i received. initials: ______ 12. my doctor and i have decided i should take isotretinoin. i understand that i must be qualified in the ipledge rems to have my prescription filled each month. i understand that i can stop taking isotretinoin at any time. i agree to tell my doctor if i stop taking isotretinoin. initials: ______ i now allow my doctor ___________________________ to begin my treatment with isotretinoin. patient signature: ____________________________________ date: ______ parent/guardian signature (if under age 18): _______________ date: ______ patient name (print) ___________________________________ patient address ___________________________ telephone (___.___.___) ___________________________________ i have: fully explained to the patient __________________, the nature and purpose of isotretinoin treatment, including its benefits and risks provided the patient with the appropriate educational materials, such as the fact sheet for the ipledge program and asked the patient if there are any questions regarding their treatment with isotretinoin answered those questions to the best of my ability. doctor signature: _________________________________ date: ______ place the original signed documents in the patient’s medical record. please provide a copy to the patient.