2.1 Evaluations Prior to Prescribing and Use of Isotretinoin Capsules

In patients who can get pregnant, only prescribe isotretinoin capsules after verification and documentation that they are not pregnant [see Contraindications (4) and Warnings and Precautions (5.1, 5.2)]. For the detailed requirements prior to prescribing isotretinoin capsules, see [Use in Specific Populations ( 8.3)]

Prior to isotretinoincapsules use in all patients, complete the following laboratory testing:

•   A fasting lipid profile including triglycerides [see Warnings and Precautions (5.7, 5.14)].
•   Liver function tests [see Warnings and Precautions (5.9, 5.14)].

2.2 Recommended Dosage

The recommended dosage range for isotretinoin capsules is 0.5 mg/kg/day to 1 mg/kg/day given in two divided doses with food for 15 weeks to 20 weeks (see Tables 1 and 2, respectively) [see Clinical Pharmacology (12.3)].

To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. Swallow capsules whole. Do not split, crush, chew, or suck on the capsules. 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 isotretinoin capsules in divided doses with food, as tolerated (see Table 3).

The safety and effectiveness of once daily dosing with isotretinoin capsules has not been established and is not recommended.

If a dose of isotretinoin capsules is missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time.

2.3 Recommended Duration of Use

A course of treatment is 15 weeks to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 weeks to 20 weeks of treatment, may discontinue isotretinoin capsules.

After a period of 2 months or more off treatment, and if warranted by persistent or recurring severe nodular acne, may initiate a second course of isotretinoin capsules in patients who have completed skeletal growth. The use of another course of isotretinoin capsules treatment is not recommended before a two-month waiting period because the patient's acne may continue to improve after a 15-week to 20-week course of treatment. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth.

Long-term use of isotretinoin capsules, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of isotretinoin capsules on bone loss is unknown [see Warnings and Precautions (5.11)].

5.1 Embryo-Fetal Toxicity

Isotretinoin capsules is contraindicated in pregnancy [see Contraindications (4)]. Based on human data, isotretinoin capsules 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 isotretinoin capsules 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 [see Use in Specific Populations (8.1)].

If a pregnancy occurs during isotretinoin capsules treatment, immediately discontinue isotretinoin capsules and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Immediately report any suspected fetal exposure during or 1 month after isotretinoin capsules treatment 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).

Inform patients not to donate blood during isotretinoin capsules treatment and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin.

Isotretinoin capsules is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2)].

5.2 iPLEDGE REMS

Because of the risk of embryo-fetal toxicity, isotretinoin capsules are available only through a restricted program under a REMS called the iPLEDGE REMS [see Warnings and Precautions (5.1)]. Notable requirements of the iPLEDGE REMS include the following:

• Prescribers must be certified with the REMS and comply with the REMS requirements, including the following:
• Assess the reproductive status of all patients prior to initiating and during treatment
• Counsel patients who cannot get pregnant on the risk and REMS requirements prior to initiating treatment.
• Counsel patients who can get pregnant on:

• The risk and REMS requirements prior to and during treatment.
• Pregnancy prevention requirements prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling
• Comply with the pregnancy testing requirements.
• Assess the pregnancy status for patients who can get pregnant by reviewing pregnancy tests and documenting a negative result prior to each prescription.
• Report all pregnancies to the REMS.

• Patients who can become pregnant must be enrolled in the REMS and must comply with REMS requirements, including the following:
• Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3)]
• Demonstrate comprehension of the risk and REMS requirements before each prescription is dispensed
• Obtain the prescription within the 7-day prescription window (i.e., within 7 days of the pregnancy test collection)

• Patients who cannot become pregnant must be enrolled in the REMS and must comply with the REMS requirements, including to not share isotretinoin capsules and not donate blood
• Pharmacies that dispense isotretinoin capsules must be certified in the REMS and must comply with the REMS requirements, including the following:
• Obtain authorization to dispense and only dispense to patients who are authorized to receive isotretinoin capsules
• Dispense a maximum of a 30-day supply with a Medication Guide.
• Do not dispense refills.

• Wholesalers and distributors must be registered in the REMS 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 Psychiatric Disorders

Isotretinoin capsules may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors [see Adverse Reactions (6)].

Be alert to the warning signs of psychiatric disorders to help ensure patients receive the help they need (Prescribers should read the REMS educational material on recognizing psychiatric disorders). Prior to initiation of isotretinoin capsules treatment, ask patients and family members about any history of psychiatric disorder, and at each visit during treatment assess patients for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation is necessary.

If a patient develops depression, mood disturbance, psychosis, or aggression, instruct patients (or caregivers) to immediately stop isotretinoin capsules and promptly contact their health care provider. Discontinuation of isotretinoin capsules may be insufficient; further evaluation may be necessary such as a referral to a mental health care professional.

5.4 Intracranial Hypertension (Pseudotumor Cerebri)

Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Avoid concomitant use of isotretinoin capsules with tetracyclines [see Drug Interactions (7.2)]. Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances.

Screen patients with these symptoms and, if present, immediately discontinue isotretinoin capsules and refer the patient to a neurologist for further diagnosis and care [see Adverse Reactions (6)].

5.5 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.

Monitor patients closely for severe skin reactions, discontinue isotretinoin capsules if they occur.

5.6 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 isotretinoin capsules and instruct patients to seek medical attention.

5.7 Lipid Abnormalities

Elevations of serum triglycerides above 800 mg/dL have been reported in patients treated with isotretinoin capsules. 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 capsules or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

Perform fasting lipid tests before isotretinoin capsules treatment and then at intervals until the lipid response to isotretinoin capsules is known, which usually occurs within 4 weeks. Carefully consider the risk/benefit of isotretinoin capsules 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 isotretinoin capsules treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.14)].

Discontinue isotretinoin capsules if hypertriglyceridemia cannot be controlled.

5.8 Hearing Impairment

Impaired hearing has been reported in patients taking isotretinoin capsules; in some cases, the hearing impairment has been reported to persist after treatment has been discontinued. Mechanism(s) and causality for this reaction have not been established.

Discontinue isotretinoin capsules treatment in patients who experience tinnitus or hearing impairment and refer them for specialized care for further evaluation.

5.9 Hepatotoxicity

Clinical hepatitis has been reported with isotretinoin capsule treatment. 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.

Discontinue isotretinoin capsules if normalization does not readily occur or if hepatitis is suspected during treatment.

5.10 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 capsules treatment has been stopped.

Discontinue isotretinoin capsules immediately if patients experience abdominal pain, rectal bleeding or severe diarrhea [see Adverse Reactions (6)].

5.11 Musculoskeletal Abnormalities

Osteoporosis and Fractures

There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients treated with isotretinoin capsules or following cessation. Therefore, healthcare providers should use caution when prescribing isotretinoin capsules to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism or patients diagnosed with anorexia nervosa [see Use in Specific Populations (8.4)].

There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients while on treatment with isotretinoin or following cessation of treatment 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 Symptoms

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.

Evaluate the musculoskeletal system in patients who present with these symptoms during or after a course of isotretinoin capsules. Consider discontinuing isotretinoin capsules 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 treatment with isotretinoin have more of an effect than a single course of treatment on the musculoskeletal system. It is important that isotretinoin capsules be given at the recommended dosage 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. 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.

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 treatment at recommended doses. The skeletal effects of multiple isotretinoin capsules treatment courses for acne are 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 capsules on epiphyseal closure is unknown.

5.12 Ocular Abnormalities

Carefully monitor for visual problems . If visual difficulties occur, discontinue isotretinoin capsules treatment and obtain an ophthalmological examination [see Adverse Reactions (6)].

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 capsule treatment and in some instances the event has persisted after treatment was discontinued. Because the onset in some patients was sudden, advise patients of this potential problem and warn patients 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 isotretinoin capsules treatment and afterwards.

5.13 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 of the extremities and extracutaneous involvement (including renal) have been reported.

If a severe allergic reaction occurs, discontinue isotretinoin capsules treatment and initiate appropriate medical management.

5.14 Laboratory Abnormalities and Laboratory Monitoring for Adverse Reactions

Laboratory Monitoring

Pregnancy Testing: Obtain a screening and confirmatory pregnancy test prior to treatment initiation. Repeat a pregnancy test prior to each prescription, at the end of the entire course of isotretinoin capsules treatment and 1 month after the discontinuation of isotretinoin capsules [see Use in Specific Populations (8.3)].

Lipid Tests: Obtain pretreatment and follow-up fasting lipid tests under fasting conditions. Wait 36 hours after consumption of alcohol before testing is performed. It is recommended that these tests be performed periodically until the lipid response to isotretinoin capsules is known. The incidence of hypertriglyceridemia is 25% in patients treated with isotretinoin capsules [see Warnings and Precautions (5.7)].

Liver Function Tests: As elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin capsules, perform pretreatment and follow-up liver function tests periodically until the response to isotretinoin capsules is known [see Warnings and Precautions (5.9)].

Additional Laboratory Abnormalities

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

CPK: Some patients undergoing vigorous physical activity while taking isotretinoin capsules 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 217 pediatric patients (12 to 17 years old) with severe recalcitrant nodular acne, 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.

7.1 Vitamin A

Avoid concomitant use of isotretinoin capsules with supplements containing vitamin A.

Isotretinoin capsules is closely related to vitamin A. Therefore, concomitant use ofisotretinoin capsules with vitamin A may lead to isotretinoin capsules-related adverse reactions.

7.2 Tetracyclines

Avoid concomitant use of isotretinoin capsules with tetracyclines.

Isotretinoin capsules use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use with tetracyclines [see Warnings and Precautions (5.4)].

7.3 Oral Contraceptives

It is not known if there is an interaction between isotretinoin capsules with oral contraceptives that do not contain norethindrone and ethinyl estradiol.

Isotretinoin capsules did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology (12.3)]

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that documents pregnancies in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after isotretinoin capsules treatment 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).

Risk Summary

Isotretinoin capsules are contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans [see Warnings and Precautions (5.1)]. If isotretinoin capsules is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin capsules, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin capsules, immediately discontinue isotretinoin capsules and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Data

Human Data: Major congenital malformations that have been documented following isotretinoin capsule exposure include malformations of the face, eyes, ears, skull, central nervous system (CNS), cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases, death has occurred as a result of the malformations.

Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.

8.2 Lactation

Risk Summary

There are no data on the presence of isotretinoin in either animal or human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with isotretinoin capsules, and for at least 8 days after the last dose of isotretinoin capsules.

8.9 Females and Males of Reproductive Potential

All patients who can become pregnant must comply with the iPLEDGE REMS requirements [see Warnings and Precautions (5.2)].

Pregnancy Testing

In patients who can get pregnant, pregnancy testing is required prior to, during, and after isotretinoin capsules treatment.

Pregnancy Testing Prior to Prescribing Isotretinoin Capsules: In patients who can get pregnant, only prescribe isotretinoin capsules after verification and documentation that they are not pregnant:

1. Complete the first urine or serum pregnancy test (screening test) in a medical setting (e.g., prescriber's office, clinic, laboratory) and verify and document that the test is negative, AND
2. For patients with:

• Regular menstrual cycles, complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and during the first five days of their menstrual period immediately preceding the beginning of isotretinoin capsules treatment, AND (2) after the patient has used their chosen pregnancy prevention methods (i.e., two forms of contraception or committed to abstinence) for at least 30 days. Verify and document that the confirmatory test is negative, OR
• Amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and immediately preceding the beginning of isotretinoin capsules treatment, AND (2) after the patient has used their chosen pregnancy prevention methods (i.e., two forms of contraception or committed to abstinence) for at least 30 days. Verify and document that the confirmatory test is negative.

If a patient who can get pregnant has had negative screening and confirmatory pregnancy tests but they missed the 7-day prescription window (the patient has not obtained their isotretinoin capsules prescription starting from the day of the pregnancy test through six days after the day of the pregnancy test) and have not started isotretinoin capsules treatment, repeat a urine or serum pregnancy test in a medical setting and verify and document that this repeat test is negative prior to prescribing isotretinoin capsules. The confirmatory pregnancy test must be repeated, as needed, until the patient receives isotretinoin capsules.

Pregnancy Testing During Treatment with Isotretinoin Capsules: In patients who can get pregnant who are being treated with isotretinoin capsules, within 7-days before each prescription obtain a urine or serum pregnancy test in a medical setting (e.g., prescriber's office, laboratory, clinic) or instruct patients to use a home pregnancy test. If the patient who can get pregnant missed the 7-day prescription window (the patient has not obtained their isotretinoin capsules prescription starting from the day of the pregnancy test through six days after the day of the pregnancy test), repeat the urine or serum pregnancy test within seven days before the next prescription in a medical setting or instruct patients to use a home pregnancy test. Verify and document the negative pregnancy test result prior to the prescribing additional isotretinoin capsules treatment.

Pregnancy Testing in Patients Who Have Completed Isotretinoin Capsules Treatment: In patients can get pregnant who have completed isotretinoin capsules treatment, complete a urine or serum pregnancy test in a medical setting (e.g., prescriber's office, laboratory, clinic) or instruct patients to use a home pregnancy test:

• At the end of the entire course of isotretinoin capsules treatment, AND
• One month after the discontinuation of isotretinoin capsules.

Contraception

Patients who can get pregnant must use two forms of contraception simultaneously, at least one of which must be a primary form (see Table 4), for at least one month prior to initiation of isotretinoin capsules treatment, during isotretinoin capsules treatment, and for one month after discontinuing isotretinoin capsules treatment. However, two forms of contraception are not required if the patient commits to continuous abstinence from not having any sexual contact with a partner which may result in pregnancy, has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post- menopausal. Micro-dosed progesterone preparations ("minipills" that do not contain an estrogen) are an inadequate form of contraception during isotretinoin capsules treatment. Any birth control method can fail. There have been reports of pregnancy from patients who have used combination oral contraceptives, as well as contraceptive vaginal systems, vaginal inserts, transdermal systems, and injections; these pregnancies occurred while taking isotretinoin capsules. These reports are more frequent for patients who use only a single method of contraception. Therefore, it is critically important that patients who can become pregnant use two methods of contraception simultaneously.

If the patient has unprotected sexual contact with a partner that could result in pregnancy at any time one month before, during, or 1 month after treatment, the patient must:

a.      Stop taking isotretinoin capsules immediately, if on treatment

b.     Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy

c.      Start using two forms of contraception simultaneously again for one month before resuming isotretinoin capsules treatment

d.     Have a second pregnancy test after using two forms of contraception for one month.

Infertility

Sperm Study: In trials 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 years to 32 years) receiving isotretinoin capsules treatment for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

8.4 Pediatric Use

The safety and effectiveness of isotretinoin capsules for the treatment of severe recalcitrant nodular acne have been established in non-pregnant pediatric patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional treatment, including systemic antibiotics. Use of Isotretinoin Capsules in this age group for this indication is supported by evidence from a clinical trial comparing 103 pediatric patients (13 years to 17 years) to 197 adults (both with severe recalcitrant nodular acne). Results from this study demonstrated that isotretinoin capsules, at a dosage of 1 mg/kg/day given in two divided doses, was similarly effective in treating severe recalcitrant nodular acne in both pediatric and adult patients.

The safety and effectiveness of isotretinoin capsules in pediatric patients less than 12 years of age have not been established.

Adverse Reactions in Pediatric Patients

In trials with isotretinoin capsules, adverse reactions reported in pediatric patients aged 12 to 17 years old 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. In a trial of pediatric patients aged 12 to 17 years old 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 occurred in 22% (79/358) of pediatric patients including severe arthralgias in 8% (6/79) of patients. Evaluate the musculoskeletal system in pediatric patients 12 years of age and older who present with these symptoms during or after a course of isotretinoin capsules. Consider discontinuing isotretinoin capsules if any significant abnormality is found.

Effects on Bone Mineral Density in Pediatric Patients

In an open-label clinical trial (N=217) of a single course of treatment with isotretinoin capsules for adolescents with severe recalcitrant nodular acne, BMD at several skeletal sites were assessed:

• One patient had a decrease in lumbar spine BMD >4% based on unadjusted data; 16 (8%) patients had decreases in lumbar spine BMD >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index).
• Nine patients (5%) had a decrease in total hip BMD >5% based on unadjusted data. Twenty-one (11%) patients had decreases in total hip BMD >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index).

Follow-up trials performed in 8 of the patients with decreased BMD for up to 11 months thereafter demonstrated increasing BMD in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine BMD measurements below baseline values. Total hip BMD remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (63%).

In a separate open-label extension trial of 10 patients including those ages 13 to 17 years, who started a second course of isotretinoin capsules 4 months after the first course, two patients showed a decrease in mean lumbar spine BMD up to 3.3%.

Epiphyseal Closure

There have been spontaneous literature reports of premature epiphyseal closure in acne patients who received the recommended dosage of isotretinoin capsules. The effect of multiple courses of isotretinoin capsules on epiphyseal closure is unknown [see Warnings and Precautions (5.11)].

8.5 Geriatric Use

Clinical studies of isotretinoin capsules did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. The effects of aging may increase some risks associated with isotretinoin capsules treatment.

12.1 Mechanism of Action

The exact mechanism of action of isotretinoin capsules in 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 who are unresponsive to conventional therapy, including systemic antibiotics is unknown. isotretinoin, a retinoid, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.

12.2 Pharmacodynamics

Decreased sebum secretion is related to the dose and duration of treatment with isotretinoin capsules.

12.3 Pharmacokinetics

The following parameters are presented as mean [coefficient of variation (CV%)] following a single oral dose of 80 mg of isotretinoin capsules in healthy adult subjects unless otherwise stated.

Isotretinoin Cmax is 862 (22%) ng/mL and AUC0-inf is 10,004 (22%) ng*h/mL when isotretinoin capsules was administered with food in healthy adults. Isotretinoin accumulation ratio ranged from 0.90 to 5.43 in patients with cystic acne after multiple doses. No clinically significant differences in the pharmacokinetics of isotretinoin were observed between patients with nodular acne and healthy subjects without acne.

Absorption

Isotretinoin time to maximum concentration (Tmax) is 5.3 hours (77%) when administered with food.

Effect on Food: Isotretinoin AUC0-inf increased 2.7-fold and Cmax increased 2.9-fold relative to the fasted state following a high-fat meal. In addition, the extent of formation of all metabolites was higher, Tmax increased to 5.3 hours (77%), and the elimination half-life was unchanged under fed conditions [see Dosage and Administration (2.1)].

Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily to albumin.

Elimination

The mean ± SD elimination half-life of isotretinoin is 21± 8.2 hours and 24 ± 5.3 hours for its 4-oxo-isotretinoin metabolite.

Metabolism: Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro. Isotretinoin and its metabolites are further metabolized into conjugates.

Isotretinoin is metabolized into at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo- retinoic acid (4-oxo-tretinoin)) which are detected in human plasma. Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. The exposure of adult cystic acne patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. All of these metabolites possess retinoid activity in vitro, however the clinical significance is unknown.

Excretion: Following administration of 80 mg of radiolabeled isotretinoin as a liquid suspension, the metabolites of isotretinoin were excreted in feces and urine in relatively equal amounts (total of 65% to 83%).

Specific Populations

Pediatric Patients: No clinically statistically significant differences in isotretinoin pharmacokinetics were observed based on age (12 years to 15 years, and ≥18 years) in patients who received single and multiple doses of isotretinoin capsules. In both age groups, 4-oxo-isotretinoin was the major metabolite compared to tretinoin and 4-oxo-tretinoin.

Drug Interaction Studies

Clinical Studies:

• Norethindrone and Ethinyl Estradiol: There were no clinically significant differences in the pharmacokinetics of norethindrone and ethinyl estradiol after the concomitant use of isotretinoin capsules (dosage of 1 mg/kg/day) with an oral contraceptive agent in premenopausal female patients with severe recalcitrant nodular acne. Additionally, there was no clinically significant differences in the serum levels of progesterone, follicle- stimulating hormone, and luteinizing hormone in in these patients.
• Phenytoin: There was no clinically significant differences in the pharmacokinetics of phenytoin when used concomitantly with isotretinoin.

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 mg/kg/day or 32 mg/kg/day (1.3 times or 5.3 times the recommended clinical isotretinoin capsules dosage of 1 mg/kg/day, 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 humans is uncertain.

Mutagenesis

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 times 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.

Impairment of Fertility

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2 mg/kg/day, 8 mg/kg/day, or 32 mg/kg/day (0.3 times, 1.3 times, or 5.3 times the recommended clinical isotretinoin capsules dosage of 1 mg/kg/day, 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 mg/kg/day or 60 mg/kg/day (10 times or 30 times the recommended clinical isotretinoin capsules dosage of 1 mg/kg/day, 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.

13.2 Animal Toxicology and/or Pharmacology

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 times or 5.3 times the recommended clinical isotretinoin capsules dosage of 1 mg/kg/day, respectively, after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 months to 7 months of treatment with isotretinoin at a dosage of 60 mg/kg/day to 120 mg/kg/day (30 times to 60 times the recommended clinical isotretinoin capsules dosage of 1 mg/kg/day, after normalization for total body surface area).