ISOTRETINOIN: 34,934 Adverse Event Reports & Safety Profile

ABSORICA ABSORICA (isotretinoin) Capsules contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems:

• 10 mg – iron oxide (yellow) and titanium dioxide;
• 20 mg – iron oxide (red), and titanium dioxide;
• 25 mg – FD&C Blue #1, FD&C Yellow #5 [see Warnings and Precautions (5.14) ] , FD&C Yellow #6 and titanium dioxide;
• 30 mg – iron oxide (black, red and yellow) and titanium dioxide;
• 35 mg – FD&C Blue #2, iron oxide (black, red and yellow) and titanium dioxide;
• 40 mg – iron oxide (black, red and yellow) and titanium dioxide. ABSORICA LD ABSORICA LD (isotretinoin) Capsules contain 8 mg, 16 mg, 20 mg, 24 mg, 28 mg and 32 mg of micronized isotretinoin (a retinoid) in suspension filled in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, USP each capsule contains the following inactive ingredients: butylated hydroxy anisole, gelatin, hard gelatin capsule shell, polysorbate 80 and soybean oil. The gelatin capsules contain the following dye systems:
• 8 mg – D&C Yellow #10, FD&C Blue #1, FD&C Red #40 and titanium dioxide
• 16 mg – FD&C Blue #1, FD&C Red #40, and titanium dioxide
• 20 mg – FD&C Blue #1, FD&C Red #40, and titanium dioxide
• 24 mg – D&C Yellow #10, FD&C Yellow #6 and titanium dioxide
• 28 mg – FD&C Blue #1, FD&C Red #40, and titanium dioxide
• 32 mg – ferrosoferric oxide, ferric oxide (red and yellow) and titanium dioxide The imprinting ink of 8 mg, 16 mg, 24 mg and 32 mg capsules contain the following ingredients: potassium hydroxide, propylene glycol, shellac and titanium dioxide. The imprinting ink of 20 mg and 28 mg capsules contain the following ingredients: ferrosoferric oxide, propylene glycol and shellac glaze.

Isotretinoin

Chemically, isotretinoin is 13- cis -retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is: ABSORICA meets USP Dissolution Test 3. For ABSORICA LD, FDA approved dissolution test differs from the USP. spl-absorica-str.jpg

AND USAGE Isotretinoin capsules are indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, isotretinoin capsules are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. Limitations of Use: If a second course of isotretinoin capsules therapy is needed, it is not recommended before a two month waiting period because the patient's acne may continue to improve following a 15 week to 20 week course of therapy [see Dosage and Administration ( 2.2 )]. Isotretinoin capsules are retinoids indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, isotretinoin capsules are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. ( 1 ) Limitations of Use: If a second course of isotretinoin capsules therapy is needed, it is not recommended before a two month waiting period because the patient's acne may continue to improve following a 15 week to 20 week course of therapy. ( 1 )

AND ADMINISTRATION

• ABSORICA is not substitutable with ABSORICA LD because of different bioavailability and recommended dosage. ( 2.1 , 5.3 )
• Recommended dosage for: o ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks ( 2.1 ) o ABSORICA LD is 0.4 to 0.8 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks ( 2.1 )
• Adult patients with very severe disease (scarring, trunk involvement) may increase dosage to 2 mg/kg/day of ABSORICA (1.6 mg/kg/day of ABSORICA LD) in divided doses. ( 2.1 )
• Once daily dosing is not recommended. ( 2.1 )
• If a dose of ABSORICA/ABSORICA LD is missed, just skip that dose. Do not take two doses of ABSORICA/ABSORICA LD at the same time. ( 2.1 )
• Perform pregnancy tests prior to prescribing, each month during therapy, end of therapy, and one month after discontinuation. ( 2.3 , 8.3 )
• Prior to prescribing, perform fasting lipid profile and liver function tests. ( 2.3 )

2.1 Recommended Dosage ABSORICA is not substitutable with ABSORICA LD <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . The recommended dosage of:

• ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 1).
• ABSORICA LD is 0.4 to 0.8 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 2). To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. During treatment, the dosage may be adjusted according to response of the disease and/or adverse reactions, 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 dosage adjustments up to 2 mg/kg/day for ABSORICA (1.6 mg/kg/day for ABSORICA LD) in divided doses, as tolerated. The safety and effectiveness of once daily dosing with ABSORICA/ABSORICA LD has not been established and is not recommended. If a dose of ABSORICA/ABSORICA LD is missed, just skip that dose. Do not take two doses of ABSORICA/ ABSORICA LD at the same time.

Table

1: ABSORICA Daily Dosage by Body Weight 1 Body Weight Total Daily Dosage (mg) 1 0.5 mg/kg 1 mg/kg 2 mg/kg 40 kg 20 40 80 50 kg 25 50 100 60 kg 30 60 120 70 kg 35 70 140 80 kg 40 80 160 90 kg 45 90 180 100 kg 50 100 200 1 Administer in two divided doses with or without meals Table 2: ABSORICA LD Daily Dosage by Body Weight 1 Body Weight Total Daily Dosage (mg) 1 0.4 mg/kg 0.8 mg/kg 1.6 mg/kg 40 kg 16 32 64 50 kg 20 40 80 60 kg 24 48 96 70 kg 28 56 112 80 kg 32 64 128 90 kg 36 72 144 100 kg 40 80 160 1 Administer in two divided doses with or without meals

2.2 Duration of Use A normal course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue ABSORICA/ABSORICA LD. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, may initiate a second course of ABSORICA/ABSORICA LD in patients who have completed skeletal growth. The use of another course of ABSORICA/ABSORICA LD therapy is not recommended before a two-month waiting period because the patient’s acne may continue to improve after a 15 to 20-week course of therapy. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA/ABSORICA LD, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of ABSORICA/ABSORICA LD on bone loss is unknown <span class="opacity-50 text-xs">[see Warnings and Precautions (5.12) ]</span> .

2.3 Laboratory Testing Prior to Administration The following laboratory testing must be completed prior to ABSORICA/ABSORICA LD use:

• Pregnancy testing: Ensure patient is not pregnant prior to administering ABSORICA/ABSORICA LD [see Contraindications (4) and Use in Specific Populations (8.1 , 8.3) ]
• A fasting lipid profile including triglycerides [see Warnings and Precautions (5.8 , 5.15) ] .
• Liver function tests [see Warnings and Precautions (5.10 , 5.15) ] .

Pregnancy ( 4.1 , 8.1 ) Hypersensitivity to this product or any of its components ( 4.2 , 5.15 )

4.1 Pregnancy Isotretinoin capsules are contraindicated in pregnancy <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]</span> .

4.2 Hypersensitivity Isotretinoin capsules are contraindicated in patients with hypersensitivity to isotretinoin (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.14) ]</span> .

REACTIONS The following adverse reactions with ABSORICA/ABSORICA LD or other isotretinoin capsule products are described in more detail in other sections of the labeling:

• Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.1 )]
• Psychiatric Disorders [see Warnings and Precautions ( 5.4 )]
• Intracranial Hypertension (Pseudotumor Cerebri) [see Warnings and Precautions ( 5.5 )]
• Serious Skin Reactions [see Warnings and Precautions ( 5.6 )]
• Pancreatitis [see Warnings and Precautions ( 5.7 )]
• Lipid Abnormalities [see Warnings and Precautions ( 5.8 )]
• Hearing Impairment [see Warnings and Precautions ( 5.9 )]
• Hepatotoxicity [see Warnings and Precautions ( 5.10 )]
• Inflammatory Bowel Disease [see Warnings and Precautions ( 5.11 )]
• Musculoskeletal Abnormalities [see Warnings and Precautions ( 5.12 )]
• Ocular Abnormalities [see Warnings and Precautions ( 5.13 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.14 )] The following adverse reactions associated with the use of isotretinoin capsules were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dose Relationship

Cheilitis and hypertriglyceridemia were dose related. Body as a Whole Fatigue, irritability, pain, allergic reactions, systemic hypersensitivity, edema, lymphadenopathy, weight loss.

Cardiovascular

Vascular thrombotic disease, stroke, palpitation, tachycardia. Endocrine/Metabolism and Nutritional Decreased appetite, weight fluctuation, alterations in blood sugar.

Gastrointestinal

Dry lips, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting, inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis, esophageal ulceration, ileitis.

Hematologic

Anemia and decreased RBC parameters, thrombocytopenia, increased platelet counts, decreased WBC counts, severe neutropenia, rare reports of agranulocytosis. Infections and Infestations Nasopharyngitis, hordeolum, infections (including disseminated herpes simplex and upper respiratory tract infection).

Laboratory Abnormalities

The following lab tests were increased: creatine phosphokinase (CPK), triglycerides, alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT), gamma-glutamyltransferase (GGTP), cholesterol, low density lipoprotein (LDL), alkaline phosphatase, bilirubin, LDH, fasting blood glucose, uric acid, and sedimentation rate. However, high density lipoprotein (HDL) was decreased. Urine findings included increased white cells, proteinuria, microscopic or gross hematuria. Musculoskeletal and Connective Tissue Decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, arthralgia, musculoskeletal pain, neck pain, extremity pain, myalgia, musculoskeletal stiffness [see Warnings and Precautions (5.12)] , skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient chest pain, and rare reports of rhabdomyolysis.

Neurological

Headache, syncope, intracranial hypertension (pseudotumor cerebri), dizziness, drowsiness, lethargy, malaise, nervousness, paresthesia, seizures, stroke, weakness.

Psychiatric

Suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability, suicide attempts, suicide, aggression, psychosis and auditory hallucinations. 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, sexual dysfunction, including erectile dysfunction, decreased libido, decreased vaginal lubrication, and vaginal dryness.

Respiratory

Epistaxis, nasal dryness, bronchospasm (with or without a history of asthma), respiratory infection, voice alteration. Skin and Subcutaneous Tissue Dry skin, dermatitis, eczema, rash, contact dermatitis, alopecia, pruritus, sunburn, erythema, acne fulminans, alopecia(which in some cases persisted), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, skin fragility, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, increased sunburn susceptibility, sweating, toxic epidermal necrolysis, urticaria,vasculitis (including granulomatosis with polyangiitis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting).

Senses

Hearing: tinnitus and hearing impairment. Ocular : dry eyes, reduced visual acuity, blurred vision, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, conjunctivitis, corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances. Renal and Urinary Glomerulonephritis. Most common adverse reactions (incidence ≥5%) are: dry lips, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, increased creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or iPLEDGE at (1-866-495-0654).

AND PRECAUTIONS

• Psychiatric Disorders (depression, psychosis, suicidal thoughts and behavior, and aggressive and/or violent behaviors): Prior to and during therapy assess for these conditions; stop if these conditions occur on therapy (5.4)
• Intracranial Hypertension (Pseudotumor Cerebri) : Avoid use with concomitant tetracyclines (5.5)
• Serious Skin Reactions : Monitor for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions (5.6)
• Acute Pancreatitis : If occurs, discontinue treatment (5.7)
• Lipid Abnormalities (hypertriglyceridemia, low HDL, and elevation of cholesterol): Monitor lipid levels at regular intervals; stop if hypertriglyceridemia cannot be controlled (5.8)
• Hearing Impairment : Discontinue and refer to specialized care (5.9)
• Hepatotoxicity : Monitor liver function tests prior to and during therapy (5.10 , 5.15)
• Inflammatory Bowel Disease : Discontinue for abdominal pain, rectal bleeding, or severe diarrhea (5.11)
• Musculoskeletal Abnormalities : Arthralgias, back pain, decreases in bone mineral density and premature epiphyseal closure (5.12)
• Ocular Abnormalities e.g., corneal opacities, decreased night vision: If visual symptoms occur, discontinue and refer for an ophthalmological exam (5.13)

5.1 Embryo-Fetal Toxicity ABSORICA/ABSORICA LD is contraindicated in pregnancy <span class="opacity-50 text-xs">[see Contraindications (4.1) ]</span> . Based on human data, ABSORICA/ABSORICA LD can cause fetal harm when administered to a pregnant patient. There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking any amount of ABSORICA/ABSORICA LD even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected. Major congenital malformations, spontaneous abortions, and premature births have been documented following exposure to isotretinoin during pregnancy <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> . If a pregnancy occurs during ABSORICA/ABSORICA LD treatment, discontinue ABSORICA/ABSORICA LD immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA/ABSORICA LD 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). Patients must be informed not to donate blood during ABSORICA/ABSORICA LD therapy and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin. ABSORICA/ABSORICA LD is available only through a restricted program under a REMS <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. 5.2 iPLEDGE Program ABSORICA/ABSORICA LD are available only through a restricted program under a REMS called the iPLEDGE REMS because of the risk of embryo-fetal toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Notable requirements of the iPLEDGE REMS include the following:

• Prescribers must be certified with the program and comply with the following requirements: Determine reproductive status of all patients prior to initiating treatment o Provide contraception counseling to patients who can get pregnant prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling o Provide scheduled pregnancy testing, and verify and document the negative pregnancy test result prior to writing each prescription, for no more than a 30-day supply
• Patients who can become pregnant must be enrolled by signing an informed consent form and must comply with the following requirements o Comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)] o Demonstrate comprehension of the safe-use conditions of the program every month o Obtain the prescription within 7 days of the pregnancy test collection
• Patients who cannot become pregnant must be enrolled by signing an informed consent form and must obtain the prescription within 30 days of the office visit
• Pharmacies that dispense ABSORICA/ABSORICA LD must be certified by being registered and activated in the program, must only dispense to patients who are authorized to receive ABSORICA/ABSORICA LD, and comply with the following requirements: o Only dispense a maximum of a 30-day supply with a Medication Guide. o Do not dispense refills. Dispense only with a new prescription and a new authorization from the program. o Return ABSORICA/ABSORICA LD to inventory if patients do not obtain the prescription by the “Do Not Dispense To After” date
• Wholesalers and distributors must be registered with the program and must only distribute to certified pharmacies. Further information, including a list of qualified pharmacies and distributors, is available at www.ipledgeprogram.com or 1-866-495-0654.

5.3 ABSORICA and ABSORICA LD are Not Substitutable Given that the bioavailability and the recommended dosage of ABSORICA and ABSORICA LD are different, ABSORICA and ABSORICA LD are not substitutable. For example, ABSORICA and ABSORICA LD have a 20 mg strength; however, these strengths have different bioavailability and are not substitutable.

5.4 Psychiatric Disorders ABSORICA/ABSORICA LD may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Healthcare providers should be alert to the warning signs of psychiatric disorders to help ensure patients receive the help they need (Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin ). Prior to initiation of ABSORICA/ABSORICA LD 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 is necessary. Patients should immediately stop ABSORICA/ABSORICA LD and the patient (or caregiver) should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression. Discontinuation of ABSORICA/ABSORICA LD may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare professional.

5.5 Intracranial Hypertension (Pseudotumor Cerebri) Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided with ABSORICA/ABSORICA LD use. Early signs and symptoms of intracranial hypertension 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 ABSORICA/ABSORICA LD immediately and be referred to a neurologist for further diagnosis and care <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> .

5.6 Serious Skin Reactions There have been postmarketing 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 ABSORICA/ABSORICA LD should be discontinued if they occur.

5.7 Pancreatitis Acute pancreatitis has been reported with isotretinoin use in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. If symptoms of pancreatitis occur, discontinue ABSORICA/ABSORICA LD and seek medical attention.

5.8 Lipid Abnormalities Elevations of serum triglycerides above 800 mg/dL have been reported with isotretinoin use. In clinical trials, marked elevations of serum triglycerides, decreases in high-density lipoproteins (HDL), and increases in cholesterol levels were reported in 25%, 15%, and 7% of patients treated with isotretinoin capsules, respectively. These lipid changes were reversible upon isotretinoin capsule cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing isotretinoin or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Fasting lipid tests should be performed before ABSORICA/ABSORICA LD treatment and then at intervals until the lipid response to ABSORICA/ABSORICA LD is known, which usually occurs within 4 weeks. Careful consideration should be given to risk/benefit of ABSORICA/ABSORICA LD in patients who are at higher risk of hypertriglyceridemia (e.g., patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If ABSORICA/ABSORICA LD therapy is instituted in such patients, more frequent checks of serum values for lipids are recommended <span class="opacity-50 text-xs">[see Warnings and Precautions (5.15) ]</span> . ABSORICA/ABSORICA LD should be stopped if hypertriglyceridemia cannot be controlled.

5.9 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 ABSORICA/ABSORICA LD treatment and be referred for specialized care for further evaluation.

5.10 Hepatotoxicity Clinical hepatitis has been reported with isotretinoin use. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with isotretinoin capsules, 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, ABSORICA/ABSORICA LD should be discontinued.

5.11 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 ABSORICA/ABSORICA LD immediately <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> .

5.12 Musculoskeletal Abnormalities Bone Mineral Density Changes, Osteoporosis, and Fractures Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and another isotretinoin capsule product, 27/306 (9%) 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 to 3 months after the post-treatment scan showed no recovery of BMD. Long-term data at 4 to 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, healthcare providers should use caution when prescribing ABSORICA/ABSORICA LD 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> . There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. Patients in early and late adolescence who participate in sports with repetitive impact may be at an increased risk of spondylolisthesis with and without pars fractures, and hip growth plate injuries have been reported.

Musculoskeletal Abnormalities Approximately

16% of patients treated with isotretinoin capsules in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of isotretinoin. In a trial of pediatric patients treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. Back pain was severe in 14% (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 8% (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 ABSORICA/ABSORICA LD. Consider discontinuing ABSORICA/ABSORICA LD if any significant abnormality is found. 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. It is important that ABSORICA/ABSORICA LD be given at the recommended dose 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 capsules (approximately 1.1 times the maximum recommended daily dosage). 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 capsules 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 capsules. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 adolescents on ABSORICA or another isotretinoin capsule product who had hand radiographs taken to assess bone age, a total of 9 (3%) patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.

5.13 Ocular Abnormalities Visual problems should be carefully monitored. If visual difficulties occur, discontinue ABSORICA/ABSORICA LD treatment and obtain an ophthalmological examination <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>.

Corneal Opacities

Corneal opacities have occurred in patients receiving isotretinoin capsules 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 capsules have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of isotretinoin [see Adverse Reactions (6) ].

Decreased Night Vision

Decreased night vision has been reported during isotretinoin use 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 Eyes

Dry eyes has been reported in patients during isotretinoin use. Patients who wear contact lenses may have trouble wearing them while on ABSORICA/ABSORICA LD treatment and afterwards.

5.14 Hypersensitivity Reactions Anaphylactic reactions and other allergic reactions have been reported with isotretinoin use. 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.

Allergic Reactions

Due to the Inactive Ingredient (FD&C Yellow No. 5) in the 25 mg ABSORICA Capsule The 25 mg ABSORICA capsule 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 tartrazine sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

The

10 mg, 20 mg, 30 mg, 35 mg, and 40 mg ABSORICA capsules do not contain FD&C Yellow No. 5 and all of the ABSORICA LD capsules do not contain FD&C Yellow No. 5. Thus, in patients with allergic reactions to tartrazine, avoid using the 25 mg ABSORICA capsules.

5.15 Laboratory Abnormalities and Laboratory Monitoring for Adverse Reactions Laboratory Monitoring Pregnancy Testing A pregnancy test must be obtained prior to obtaining a prescription , repeated each month, at the end of the entire course of ABSORICA/ABSORICA LD therapy and 1 month after the discontinuation of ABSORICA/ABSORICA LD <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span>.

Lipid Tests

Pretreatment and follow-up fasting lipid tests should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before testing is performed. It is recommended that these tests be performed periodically until the lipid response to ABSORICA/ABSORICA LD is known. The incidence of hypertriglyceridemia is 25% in patients treated with isotretinoin capsules [see Warnings and Precautions (5.8) ] .

Liver Function

Tests As elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin capsules, pretreatment and follow-up liver function tests should be performed periodically until the response to ABSORICA/ABSORICA LD is known [see Warnings and Precautions (5.10) ].

Additional Laboratory Abnormalities Glucose

With isotretinoin use, some patients have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin use.

Cpk

Some patients undergoing vigorous physical activity while taking isotretinoin have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis with isotretinoin use, some associated with strenuous physical activity. In a clinical trial of 924 patients, marked elevations in CPK (≥350 U/L) were observed in approximately 24% of patients treated with isotretinoin capsules. In another clinical trial of 217 pediatric patients (12 to 17 years old) 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.

PRECAUTIONS Isotretinoin capsules must only be prescribed by prescribers who are enrolled and activated with the iPLEDGE REMS. Isotretinoin capsules must only be dispensed by a pharmacy enrolled and activated with iPLEDGE, and must only be dispensed to patients who are enrolled and meet all the requirements of iPLEDGE. Enrolled and activated pharmacies must receive isotretinoin capsules only from wholesalers enrolled with iPLEDGE. iPLEDGE REMS requirements for wholesalers, prescribers, and pharmacists are described below: Wholesalers: For the purpose of the iPLEDGE REMS, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute isotretinoin capsules, wholesalers must be enrolled with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must enroll with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include: Enrolling prior to distributing isotretinoin and re-enrolling annually thereafter Distributing only FDA approved isotretinoin product Only shipping isotretinoin to wholesalers enrolled in the iPLEDGE REMS with prior written consent from the manufacturer or pharmacies licensed in the US and enrolled and activated in the iPLEDGE REMS Notifying the isotretinoin manufacturer (or delegate) of any non-enrolled and/or non-activated pharmacy or unenrolled wholesaler that attempts to order isotretinoin Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE REMS by the isotretinoin manufacturer (or delegate) Returning to the manufacturer (or delegate) any undistributed product if the wholesaler is deactivated by the iPLEDGE REMS or if the wholesaler chooses to not re-enroll annually Prescribers To prescribe isotretinoin, the prescriber must be enrolled and activated with the pregnancy risk management program iPLEDGE. Prescribers can enroll by signing and returning the completed enrollment form. Prescribers can only activate their enrollment by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy. I have the expertise to provide the patient with detailed pregnancy prevention counseling, or I will refer the patient to an expert for such counseling, reimbursed by the manufacturer. I will comply with the iPLEDGE REMS requirements described in the booklet entitled iPLEDGE REMS Prescriber Guide. Before beginning treatment of patients who can become pregnant with isotretinoin, and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously for at least one month prior to initiation of isotretinoin treatment, during isotretinoin treatment and for one month after discontinuing isotretinoin treatment, unless the patient commits to continuous abstinence, not having any sexual contact with a partner that could result in pregnancy. I will not prescribe isotretinoin to any patient who can become pregnant until verifying the patient has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test one month later. I will report any pregnancy case that I become aware of while the patient who can become pregnant is on isotretinoin or one month after the last dose to the pregnancy registry. To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet ( www.ipledgeprogram.com ) or telephone (1-866-495-0654) to: Register each patient in the iPLEDGE REMS. Confirm monthly that each patient has received counseling and education . For patients who can become pregnant: Enter patient's two chosen forms of contraception each month. Enter monthly result from CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be prescribed to patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be dispensed by a pharmacy enrolled and activated with the pregnancy risk management program iPLEDGE and only when the enrolled patient meets all the requirements of the iPLEDGE REMS. Meeting the requirements for a patient who can become pregnant signifies that the patient: Has been counseled and has signed a Patient Enrollment Form for Patients who can get Pregnant that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter. Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests should be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month. For patients with amenorrhea, irregular cycles, or using a contraceptive form that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month. Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the patient who can become pregnant receiving each prescription. Has selected and has committed to use two forms of effective contraception simultaneously, at least one of which must be a primary form, unless the patient commits to continuous abstinence not having any sexual contact with a partner that could result in pregnancy, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use two forms of effective contraception for at least one month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for one month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis. If the patient has unprotected sexual contact with a partner that could result in pregnancy at any time one month before, during, or one month after therapy, the patient must: Stop taking isotretinoin capsules immediately, if on therapy Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy Start using two forms of effective contraception simultaneously again for one month before resuming isotretinoin capsules therapy Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether the patient has regular menses or not. Effective forms of contraception include both primary and secondary forms of contraception: Primary forms Secondary forms tubal sterilization male vasectomy intrauterine device hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring) Barrier: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: vaginal sponge (contains spermicide) Any birth control method can fail. There have been reports of pregnancy from patients who can become pregnant who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking isotretinoin capsules. These reports are more frequent for patients who use only a single form of contraception. Therefore, it is critically important that patients who can become pregnant use two effective forms of contraception simultaneously. Patients must receive warnings about the rates of possible contraception failure importance of choosing one primary form and a secondary form of contraception and that the patient must be compliant in use as outlined in the Guide for Patients who can get Pregnant. Using two forms of contraception simultaneously substantially reduces the chances that a patient will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin capsules (see PRECAUTIONS: Drug Interactions ). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. 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. If a pregnancy does occur during isotretinoin capsules treatment, isotretinoin capsules 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 one month after isotretinoin capsules therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE Pregnancy Registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

Isotretinoin is contraindicated in patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions: Must be enrolled with the iPLEDGE REMS by the prescriber Must understand that life-threatening birth defects can occur with the use of isotretinoin by patients who can become pregnant Must be reliable in understanding and carrying out instructions Must sign a Patient Enrollment Form for Patients who cannot get Pregnant that contains warnings about the potential risks associated with isotretinoin Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for patients who can become pregnant Must obtain the prescription within 30 days of the office visit for patients who cannot become pregnant Must not donate blood while on isotretinoin and for one month after treatment has ended Must not share isotretinoin with anyone, even someone who has similar symptoms Patients Who Can Become Pregnant Isotretinoin is contraindicated in patients who are pregnant. In addition to the requirements for all patients described above, patients who can become pregnant must meet the following conditions: Must NOT be pregnant or breast-feeding Must comply with the required pregnancy testing at a CLIA-certified laboratory Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence not having any sexual contact with a partner that could result in pregnancy, and understand behaviors associated with an increased risk of pregnancy Must understand that it is the patient who can become pregnant responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy Must have signed an additional Patient Enrollment Form for Patients who can get Pregnant, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin Must access the iPLEDGE system via the internet ( www.ipledgeprogram.com ) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and one month after the last dose to answer questions on the program requirements and to enter the patient's two chosen forms of contraception Must have been informed of the purpose and importance of providing information to the iPLEDGE REMS should the patient become pregnant while taking isotretinoin or within one month of the last dose Pharmacists To dispense isotretinoin, pharmacies must be enrolled and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site

Pharmacist must enroll the pharmacy by signing and returning the completed Pharmacy Enrollment Form. After enrolling, the Responsible Site Pharmacist can only activate the pharmacy enrollment by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I will train all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions on the iPLEDGE REMS requirements. I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE REMS requirements described in the booklet entitled Pharmacist Guide, specifically the "Key Information for Pharmacists" section including the following dispensing information: Prescriptions must be obtained no later than the "Do Not Dispense To After" date, and if not obtained, then the RMA must be reversed in the iPLEDGE REMS system and the product returned to inventory. I understand and will comply with Non-Compliance Action Policy. I will only obtain isotretinoin capsules product from only iPLEDGE enrolled wholesalers. I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy. I will return to the manufacturer (or delegate) any unused product if the pharmacy is deactivated by the iPLEDGE REMS or if the pharmacy chooses to not reactivate annually. I will not fill isotretinoin for any party other than a qualified patient. I will comply with the audits by the iPLEDGE Sponsors or third party acting on behalf of the iPLEDGE Sponsors to ensure that all processes and procedures are in place and being followed for the iPLEDGE REMS To dispense isotretinoin, the pharmacist must: be trained by the Responsible Site Pharmacist concerning the iPLEDGE REMS requirements. obtain authorization from the iPLEDGE REMS via the internet (www.ipledgeprogram.com), or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin capsules. write the Risk Management Authorization (RMA) number on the prescription. Isotretinoin capsules must only be dispensed: in no more than a 30-day supply with an isotretinoin capsules Medication Guide after authorization from the iPLEDGE REMS prior to the "do not dispense to patient after" date provided by the iPLEDGE system (within 30 days of the office visit for patients who cannot become pregnant and within 7 days of the date of specimen collection for patients who can become pregnant) with a new prescription for refills and another authorization from the iPLEDGE REMS (No automatic refills are allowed) An isotretinoin capsules Medication Guide must be given to the patient each time isotretinoin capsules is dispensed, as required by law. This isotretinoin capsules Medication Guide is an important part of the risk management program for the patients. Isotretinoin capsules must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE REMS. Only FDA-approved isotretinoin capsules products must be distributed, prescribed, dispensed, and used. Patients must obtain isotretinoin capsules prescriptions only at US licensed pharmacies. A description of the iPLEDGE REMS educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE REMS requirements and to reinforce the educational messages.

Prescriber

Guide includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotretinoin capsules prescription.

Pharmacist

Guide includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription. The iPLEDGE REMS is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE REMS includes information on the risks and benefits of isotretinoin capsules which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.

The Fact

Sheet for the iPLEDGE REMS includes information on the iPLEDGE REMS, the product indications and safety information. This handout is provided to both the patient who can become pregnant and the patient who cannot become pregnant.

The Patient Enrollment

Form for Patients who cannot get Pregnant is also provided to all patients. Patients who can become pregnant are provided with a Guide for Patients who Can Get Pregnant , which contains information on isotretinoin therapy including precautions and warnings, and a second Patient Enrollment Form for Patients who can get Pregnant concerning birth defects, and a toll-free line which provides isotretinoin capsules information in two languages. The booklet for patients who can become pregnant, Contraception Counseling Guide , includes a referral program that offers patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist and a second Patient Enrollment Form for Patients who can get Pregnant concerning birth defects.

The

Guide for Patients Who Can Get Pregnant outlines the effectiveness of the approved contraception options. (see Information for Patients ).

General

Although an effect of isotretinoin capsules on bone loss is not established, physicians should use caution when prescribing isotretinoin capsules to patients with a genetic predisposition for age-related osteoporosis, 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. Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin capsules or following cessation of therapy with isotretinoin capsules while involved in these activities. While causality to isotretinoin capsules has not 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 isotretinoin capsules are 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 isotretinoin capsules therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting isotretinoin capsules, while taking isotretinoin capsules and for one month after isotretinoin capsules have 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 isotretinoin capsules 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 isotretinoin capsules prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS ). Isotretinoin is found in the semen of male patients taking isotretinoin capsules, but the amount delivered to a patient who can become pregnant 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 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 isotretinoin capsules 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 isotretinoin capsules 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 isotretinoin capsules 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 isotretinoin capsules therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin capsules therapy. Patients must be informed that some patients, while taking isotretinoin capsules or soon after stopping isotretinoin capsules, 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 capsules 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 capsules 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 capsules. Some people have had other signs of depression while taking isotretinoin capsules. Patients must be informed that they must not share isotretinoin capsules 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 isotretinoin capsules. Patients should be reminded to take isotretinoin capsules 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 isotretinoin capsules 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 isotretinoin capsules 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 isotretinoin capsules, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal ). There have been rare postmarketing 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 isotretinoin capsules 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 isotretinoin capsules. Consideration should be given to discontinuation of isotretinoin capsules if any significant abnormality is found. Neutropenia and rare cases of agranulocytosis have been reported. Isotretinoin capsules 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. Isotretinoin capsules 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.

Drug Interactions

Vitamin A: Because of the relationship of isotretinoin capsules to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with isotretinoin capsules and tetracyclines should be avoided because isotretinoin capsules use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations ("minipills" that do not contain an estrogen) may be an inadequate method of contraception during isotretinoin capsules therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for 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 isotretinoin capsules. 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 OrthoNovum ® 7/7/7 Tablets as an oral contraceptive agent, isotretinoin capsules 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: Isotretinoin capsules 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 : Isotretinoin capsules have 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 isotretinoin capsules. 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 isotretinoin capsules. Therefore, caution should be exercised when using these drugs together.

Laboratory Tests Pregnancy

Test: Patients who can become pregnant must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin capsules prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin capsules. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the patient who can become pregnant receiving each prescription. Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established. The incidence of hypertriglyceridemia is one patient in four on isotretinoin therapy (see WARNINGS: Lipids ).

Liver Function

Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to isotretinoin has been established (see WARNINGS: Hepatotoxicity ). 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 a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient 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 trial. 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× background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay 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 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 isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

Pregnancy

Category X See Boxed CONTRAINDICATIONS AND WARNINGS .

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive isotretinoin capsules.

Pediatric Use

The use of isotretinoin capsules in pediatric patients less than 12 years of age has not been studied. The use of isotretinoin capsules for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General ). Use of isotretinoin capsules in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (≥18 years). Results from this study demonstrated that isotretinoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. In studies with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS ). In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin 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 isotretinoin 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 ).

Geriatric Use

Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS ).

Drug Interactions Vitamin A: Because of the relationship of isotretinoin to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with isotretinoin and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during isotretinoin therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for 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 isotretinoin. 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, isotretinoin 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: Isotretinoin 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: Isotretinoin 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 isotretinoin. 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 isotretinoin. Therefore, caution should be exercised when using these drugs together.

Laboratory Tests Pregnancy

Test - Patients who can become pregnant must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. - For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. - For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. - Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the patient who can become pregnant receiving each prescription.

Lipids

Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established. The incidence of hypertriglyceridemia is one patient in four on isotretinoin therapy (see WARNINGS, Lipids ).

Liver Function Tests

Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to isotretinoin has been established (see WARNINGS, Hepatotoxicity ).

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 a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient 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 trial.