Dosage Forms And Strengths

%medicine_name% is available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules.

• 10 mg: Dark yellow, opaque, capsule imprinted with black ink “G 240” on cap and “10” on the body
• 20 mg: Red, opaque, capsule imprinted with black ink “G 241” on cap and “20” on the body
• 25 mg: Green, opaque, capsule imprinted with white ink “G 342” on cap and “25” on the body
• 30 mg: Brown, opaque, capsule imprinted with white ink “G 242” on cap and “30” on the body
• 35 mg: Dark blue, opaque, capsule imprinted with white ink “G 343” on cap and “35” on the body
• 40 mg: Brown and red, capsule imprinted with white ink “G 325” on cap and “40” on the body

%medicine_name% (isotretinoin) Capsules are supplied as follows:

10 mg: Dark yellow, opaque, capsule imprinted with black ink “G 240” on cap and “10” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-115-31

20 mg: Red, opaque, capsule imprinted with black ink “G 241” on cap and “20” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-116-31

25 mg: Green, opaque, capsule imprinted with white ink “G 342” on cap and “25” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-133-31

30 mg: Brown, opaque, capsule imprinted with white ink “G 242” on cap and “30” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-117-31

35 mg: Dark blue, opaque, capsule imprinted with white ink “G 343” on cap and “35” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-134-31

40 mg: Brown and red, capsule imprinted with white ink “G 325” on cap and “40” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-118-31

Storage And Handling

Store at 20° C -25° C (68° F -77° F), excursion permitted between 15° C 30° C (59° F -86° F). Protect from light.

Manufactured for: Ranbaxy Laboratories Inc., Jacksonville, FL 32257 USA GK-244. Revised: September 2015.

%medicine_name% is a retinoid indicated for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, means “many” as opposed to “few or several” nodules. Because of significant adverse reactions associated with its use, %medicine_name% should be reserved for patients with multiple severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, %medicine_name% is indicated only for those female patients who are not pregnant, because %medicine_name% can cause severe birth defects.

Limitations of Use

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience with isotretinoin has shown that patients may continue to improve following treatment with isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth.

As a part of the iPLEDGE program, %medicine_name% may only be administered to patients enrolled in the program .

Healthcare professionals who prescribe %medicine_name% must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of %medicine_name%.

The required laboratory testing must be completed prior to dosing %medicine_name%.

Pregnancy Testing, and Contraceptive measures must be followed prior to dosing %medicine_name%.

Recommended Dosage

The recommended dosage range for %medicine_name% is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.

The safety of once daily dosing with %medicine_name% has not been established. Once daily dosing is not recommended.

Table 1: %medicine_name% Dosing by Body Weight (Based on Administration With or Without Food)

Dosage Range

In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.

Duration Of Use

A normal course of treatment is 15 – 20 weeks. 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 %medicine_name%, even in low doses, has not been studied, and is not recommended. It is important that %medicine_name% be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of %medicine_name% on bone loss is unknown.

Laboratory Testing

Pregnancy Testing

Lipid Profile

Perform a fasting lipid profile including triglycerides prior to use of %medicine_name%.

Liver Function Test

Perform liver function tests prior to use of %medicine_name%.

Pregnancy

%medicine_name% can cause fetal harm when administered to a pregnant woman. Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin in any amount and even for short periods of time. %medicine_name% is contraindicated in females who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus.

Hypersensitivity

Hypersensitivity to this product (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

%medicine_name% must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking %medicine_name% in any amount, even for short periods of time.

%medicine_name% 25 mg contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Embryofetal Toxicity

Teratogenicity

Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin. Females of Reproductive Potential must comply with the pregnancy testing and contraception requirements described in the iPLEDGE program. There are no accurate means of determining whether an exposed fetus has been affected.

No Blood Donation

Patients must be informed not to donate blood during isotretinoin therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to isotretinoin.

iPLEDGE Program

Because of the risk of teratogenicity and to minimize fetal exposure, %medicine_name% is available only through a restricted program under a REMS called iPLEDGE. Under the %medicine_name% REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program. %medicine_name% must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used.

Required components of the iPLEDGE Program are:

• %medicine_name% must only be prescribed by prescribers who are registered and activated with the iPLEDGE program and agree to comply with the REMS requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program, The iPLEDGE Program Prescriber Contraception Counseling Guide, and Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.
• Male patients and Females of non-reproductive potential: To obtain %medicine_name%, these patients must understand the risks and benefits of %medicine_name%, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
• Females of reproductive potential: %medicine_name% is contraindicated in female patients who are or may become pregnant.
• Females of reproductive potential who are not pregnant must understand the risks and benefits, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant and The iPLEDGE Program Birth Control Workbook (including the pregnancy testing and contraception requirements ), and sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form. Additionally, the patient must answer questions about the iPLEDGE program and pregnancy prevention monthly.
• Pharmacies that dispense %medicine_name% must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive %medicine_name%, and agree to comply with the REMS requirements described in the booklet entitled The Pharmacist Guide for the iPLEDGE Program.
• Females of reproductive potential must obtain the prescription within 7 days of the specimen collection for the pregnancy test; male patients and females of non-reproductive potential must obtain the prescription within 30 days of the office visit.
• %medicine_name% must only be dispensed in no more than a 30-day supply with a Medication Guide. Refills require a new prescription and a new authorization from the iPLEDGE system.
• Wholesalers and distributors that distribute %medicine_name% must be registered with iPLEDGE and agree to comply with the REMS requirements.

If a pregnancy does occur during %medicine_name% treatment, %medicine_name% must be discontinued immediately. The patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after %medicine_name% therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

Further information, including a list of qualified pharmacies, is available at www.ipledgeprogram.com or 1-866-495-0654.

Unacceptable Contraception

Micro-dosed Progesterone Preparations

Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during %medicine_name% therapy.

Psychiatric Disorders

Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these reactions. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. 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 %medicine_name% therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy 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, as described in the brochure (Recognizing Psychiatric Disorders in Adolescents and Young Adults), 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 %medicine_name% 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 %medicine_name% 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 %medicine_name% therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of %medicine_name% therapy.

Pseudotumor Cerebri

Isotretinoin use has been associated with 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 %medicine_name% immediately and be referred to a neurologist for further diagnosis and care.

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 reactions 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 %medicine_name% should be considered if warranted.

Pancreatitis

Acute pancreatitis has been reported in isotretinoin-treated patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. %medicine_name% should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipid Abnormalities

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin 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 of triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in the dose while continuing isotretinoin.

Blood lipid determinations should be performed before %medicine_name% is given and then at intervals until the lipid response to %medicine_name% 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 of triglyceridemia during %medicine_name% therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If %medicine_name% therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended.

The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

Hearing Impairment

Impaired hearing has been reported in patients taking isotretinoin; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue %medicine_name% treatment and be referred for specialized care for further evaluation.

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to isotretinoin therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with isotretinoin, 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 %medicine_name%, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

Isotretinoin 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 isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue %medicine_name% immediately.

Skeletal Abnormalities

Bone Mineral Density Changes

Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of %medicine_name% and a generic product of Accutane® (isotretinoin), 27/306 (8.8%) of adolescents had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20 week treatment period. Repeat scans conducted within 2-3 months after the post-treatment scan showed no recovery of BMD. Longer term data at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. Therefore, physicians should use caution when prescribing %medicine_name% to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.

Musculoskeletal Abnormalities

Approximately 16% of patients treated with isotretinoin 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.

In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) 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 %medicine_name%. Consideration should be given to discontinuation of %medicine_name% if any significant abnormality is found.

There have been spontaneous reports of osteoporosis, osteopenia, bone fractures and/or delayed healing of bone fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. While causality to isotretinoin has not been established, an effect cannot be ruled out.

Patients may be at an increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injures in early and late adolescence are known.

Effects of multiple courses of isotretinoin 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.

Longer term effects have not been studied. It is important that %medicine_name% 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 of isotretinoin. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown.

In a clinical trial 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 isotretinoin 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 literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown.

In a 20-week clinical trial that included 289 adolescents on %medicine_name% or a generic product of Accutane® (isotretinoin) who had hand radiographs taken to assess bone age, a total of 9 (3.11%) patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.

Ocular Abnormalities

Visual problems should be carefully monitored. All %medicine_name% patients experiencing visual difficulties should discontinue %medicine_name% treatment and have an ophthalmological examination.

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. The corneal opacities that have been observed in clinical trial patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug.

Decreased Night Vision

Decreased night vision has been reported during isotretinoin 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.

Dry Eye

Dry eye has been reported in subjects during isotretinoin therapy. Patients who wear contact lenses may have trouble wearing them while on %medicine_name% treatment and afterwards.

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported in isotretinoin-treated patients. 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.

Laboratory Monitoring For Adverse Reactions

Lipids Test

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 %medicine_name% is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin.

Liver Function Test

Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to %medicine_name% has been established.

Glucose

Some 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.

CPK

Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In an isotretinoin clinical trial of 924 patients, marked elevations in CPK ( ≥ 350 U/L) were observed in approximately 24% of patients. In another clinical trial of 217 pediatric patients (12 – 17 years) elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this clinical trial.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide)

Advise the patient that %medicine_name% is only available through a restricted program called iPLEDGE.

• As a component of the iPLEDGE program, prescribers must instruct patients to read the Medication Guide, the iPLEDGE program patient educational booklets, and watch the video with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin”. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes %medicine_name% at any time during pregnancy.
• Male patients and Females of non-reproductive potential must understand the risks and benefits of %medicine_name%, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
• Females of reproductive potential must be instructed that they must not be pregnant when %medicine_name% therapy is initiated or plan to become pregnant while receiving %medicine_name% therapy. Additionally, they must use 2 forms of effective contraception simultaneously for 1 month before starting %medicine_name%, while taking %medicine_name%, and for 1 month after %medicine_name% has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning %medicine_name% therapy. Female patients 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 %medicine_name% prescription is written. Additionally, a pregnancy test must be completed at the end of the entire course of %medicine_name% therapy and 1 month after discontinuation of therapy.
• Advise the patient that isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of post-marketing 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.
• Advise the patient that %medicine_name% is available only from pharmacies that are certified in the iPLEDGE program, and provide them with the telephone number (1-866-495-0654) and website (www.ipledgeprogram.com) for information on how to obtain.
• Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the iPLEDGE program.
• 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 %medicine_name% 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. Inform patients that 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 treatment 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 %medicine_name% 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 %medicine_name% therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of %medicine_name% therapy.
• Patients must be informed 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 have tried to end their own lives, and some 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. There have also been reports of psychotic symptoms, which indicate a loss of contact with reality. Psychotic symptoms include feelings of suspiciousness toward others, strange beliefs, hearing voices or other noises without an obvious source, and seeing unusual objects or people with no explanation. No one knows if isotretinoin caused these behaviors and symptoms or if they would have happened even if the person did not take isotretinoin. If any of these behaviors or symptoms occur, the patient should stop treatment and the patient or family member should contact the prescriber promptly without waiting until the next visit. Some people have had other signs of depression while taking isotretinoin.
• Patients must be informed that they must not share %medicine_name% with anyone else because of the risk of birth defects and other serious adverse reactions.
• Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to %medicine_name%.
• %medicine_name% may be taken without regard to meals. To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
• Patients should be informed that inflammatory bowel disease (including regional ileitis) may occur without a prior history of intestinal disorders. In rare instances, symptoms have been reported to persist after treatment has stopped. Patients should be informed that if they experience abdominal pain, rectal bleeding or severe diarrhea, they should discontinue %medicine_name% immediately.
• 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 %medicine_name% therapy and for at least 6 months thereafter due to the possibility of scarring.
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience dry eye, corneal opacities, and decreased night vision. Contact lens wearers may experience decreased tolerance to contact lenses during and after therapy.
• Patients should be informed that 16% of patients treated with isotretinoin 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 therapy, but in some cases persisted.
• There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity.
• Pediatric patients and their caregivers should be informed that approximately 17% to 29% of pediatric patients treated with isotretinoin developed back pain. In a clinical trial, back pain was severe in 13.5% 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 treatment. Consideration should be given to discontinuation of isotretinoin if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported in patients treated with isotretinoin. %medicine_name% 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 in patients treated with isotretinoin. Treatment with %medicine_name% should be discontinued if clinically significant skin reactions occur.
• Adolescent patients who participate in sports with repetitive impact should be informed that isotretinoin use may increase their risk of spondylolisthesis or hip growth plate injuries. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin while involved in these activities.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis and Impairment Of Fertility

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.

The Ames test was conducted with isotretinoin 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 vitr