Absorica Ld 16 Mg Oral Capsule

2.1 Evaluations Prior To Prescribing and Use of ABSORICA/ABSORICA LD 

In patients who can get pregnant, only prescribe ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD, see Use in Specific Populations (8.3).

      Prior to ABSORICA/ABSORICA LD use in all patients, complete the following laboratory testing:

2.2 Recommended Dosage 

ABSORICA is not substitutable with ABSORICA LD [see Warnings and Precautions ( 5.3 )].  The recommended dosage of:

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 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.

 ¹ Administer in two divided doses with or without meals

¹ Administer in two divided doses with or without meals

2.3 Recommended 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 treatment, 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 treatment is not recommended before a 2-month waiting period because the patient’s acne may continue to improve after a 15 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 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 [see Warnings and Precautions ( 5.12 )].

5.1 Embryo-Fetal Toxicity

ABSORICA/ABSORICA LD is contraindicated in pregnancy [see Contraindications (4.1) ]. 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 [see Use in Specific Populations (8.1) ].

If a pregnancy occurs during ABSORICA/ABSORICA LD treatment, immediately discontinue ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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).

Patients must be informed not to donate blood during ABSORICA/ABSORICA LD 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.

ABSORICA/ABSORICA LD is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ].

5.2 iPLEDGE REMS

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 [see Warnings and Precautions (5.1) ].

Notable requirements of the iPLEDGE REMS include the following:

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 substitutableon a mg per mg basis.  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 [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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD and promptly contact their health care provider. 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. Avoid concomitant use of ABSORICA/ABSORICA LD 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 for papilledema and, if present, immediately discontinue ABSORICA/ABSORICA LD and refer the patient to a neurologist for further diagnosis and care [see Adverse Reactions ( 6 )].

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 treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.15) ]. 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 treatment 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 [see Adverse Reactions (6)].

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 pediatric subjects 12 years of age and older 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 subjects 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 pediatric 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 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.

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 Abnormalities

Approximately 16% of subjects 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 subjects 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 subjects than male subjects. Arthralgias were experienced in 22% (79/358) of pediatric subjects. Arthralgias were severe in 8% (6/79) of subjects.  Evaluate the musculoskeletal system of 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 treatment with isotretinoin have more of an effect than a single course of treatment on the musculoskeletal system.  It is important to administer ABSORICA/ABSORICA LD 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 treatment at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown.

In a clinical trial of 217 pediatric subjects 12 years of age and older 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 pediatric subjects 12 years of age and older on ABSORICA or another isotretinoin capsule product who had hand radiographs taken to assess bone age, a total of 9 (3%) subjects had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.

5.13 Ocular Abnormalities

Carefully monitor for visual problems. If visual difficulties occur, discontinue ABSORICA/ABSORICA LD 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 subjects 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 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 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:  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 ABSORICA/ABSORICA LD treatment, and 1 month after the discontinuation of ABSORICA/ABSORICA LD (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 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, perform pretreatment and follow-up liver function tests periodically until the response to ABSORICA/ABSORICA LD is known (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 subjects, marked elevations in CPK (≥350 U/L) were observed in approximately 24% of subjects treated with isotretinoin capsules.

In another clinical trial of 217 pediatric subjects 12 years of age and older elevations in CPK were observed in 12% of subjects, 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 subjects, 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 ABSORICA/ABSORICA LD with supplements containing vitamin A.

ABSORICA/ABSORICA LD is closely related to vitamin A. Therefore, concomitant use of ABSORICA/ABSORICA LD with vitamin A may lead to ABSORICA/ABSORICA LD-associated adverse reactions.

7.2 Tetracyclines

Avoid concomitant use of ABSORICA/ABSORICA LD with tetracyclines because isotretinoin use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines [see Warnings and Precautions (5.5) ].

7.3  Oral Contraceptives 

Isotretinoin Capsules did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with a norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology ( 12.3 )]. It is not known if there is an interaction with the concomitant use of ABSORICA/ABSORICA LD with other oral contraceptives.

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 ABSORICA/ABSORICA LD 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

ABSORICA/ABSORICA LD 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. If ABSORICA/ABSORICA LD is used during pregnancy, or if the patient becomes pregnant while taking ABSORICA/ABSORICA LD, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking ABSORICA/ABSORICA LD, immediately discontinue ABSORICA/ABSORICA LD 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 exposure include malformations of the face, eyes, ears, skull, central nervous system, 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: central nervous system (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 ABSORICA/ABSORICA LD, and for at least 8 days after the last dose of ABSORICA/ABSORICA LD.

8.3 Females and Males of Reproductive Potential

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

Pregnancy Testing

All patients who can get 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 ABSORICA/ABSORICA LD treatment.

Pregnancy Testing Prior to Prescribing ABSORICA/ABSORICA LD: In patients who can get pregnant,only prescribe ABSORICA/ABSORICA LD after verification and documentation that they are not pregnant:

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 ABSORICA/ABSORICA LD prescription within 7 days of the pregnancy test collection) and has not started ABSORICA/ABSORICA LD treatment, repeat the urine or serum pregnancy test in a medical setting and verify and document that this repeat test is negative prior to prescribing ABSORICA/ABSORICA LD. The confirmatory pregnancy test must be repeated, as needed, until the patient receives ABSORICA/ABSORICA LD.

Pregnancy Testing During Treatment with ABSORICA/ABSORICA LD: In patients who can get pregnant who are being treated with ABSORICA/ABSORICA LD, 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 ABSORICA/ABSORICA LD prescription within 7 days of the pregnancy test collection), repeat the urine or serum pregnancy test within 7 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 prescribing additional ABSORICA/ABSORICA LD treatment.

Pregnancy Testing in Patients Who Have Completed ABSORICA/ABSORICA LD Treatment:  In patients who can get pregnant who have completed ABSORICA/ABSORICA LD 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:

Contraception

Patients who can get pregnant must use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, for at least 1 month prior to initiation of ABSORICA/ABSORICA LD treatment, during ABSORICA/ABSORICA LD treatment, and for 1 month after discontinuing ABSORICA/ABSORICA LD treatment.  However, 2 forms of contraception is 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 ABSORICA/ABSORICA LD 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 get pregnant use two forms of contraception simultaneously.

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

Infertility

In a trial of female acne patients (n = 79) receiving another isotretinoin capsule product, the mean total ovarian volume, the total antral follicle count and mean anti-Mullerian hormone decreased at the end of the treatment (6^th month). However, the values returned to normal at the 18^th month (12 months after the end of treatment). There were no statistically significant changes in terms of follicle-stimulating hormone and luteinizing hormone, both at the end of the treatment and 12 months after the end of treatment. Although the results suggest that possible deteriorative effects of isotretinoin on ovarian reserve may be reversible, the study has important methodological limitations, including a small sample size, lack of a control group, and lack of generalizability.

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 to 32 years) receiving isotretinoin 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 ABSORICA/ABSORICA LD 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 therapy, including systemic antibiotics. Use of ABSORICA/ABSORICA LD in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use ABSORICA to another isotretinoin capsule product in 397 pediatric subjects 12 years of age and older [see Clinical Studies (14) ] and pharmacokinetic data in pediatric subjects [see Clinical Pharmacology (12.3) ].

The safety and effectiveness of ABSORICA/ABSORICA LD in pediatric patients less than 12 years of age have not been established.

Adverse Reactions in Pediatric Subjects

In trials with isotretinoin capsules, adverse reactions reported in pediatric subjects 12 years of age and older 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 subjects. In a trial of pediatric subjects 12 years of age and older 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 subjects than male subjects.  Arthralgias were experienced in 22% (79/358) of pediatric subjects including severe arthralgias in 8% (6/79) of subjects.  Evaluate the musculoskeletal system of pediatric 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 on Bone Mineral Density in Pediatric Subjects

The effect on bone mineral density (BMD) of a 20-week course of treatment with ABSORICA or another isotretinoin capsule product was evaluated in a double-blind, randomized clinical trial involving 396 pediatric subjects with severe recalcitrant nodular acne (mean age 15.4 years old, range 12 to 17 years old, 80% males). Given that there were no statistically significant differences between the two isotretinoin capsule groups following 20 weeks of treatment, the results are presented for the pooled treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 pediatric subjects, 27 (9%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2 to 3 months after the post treatment scan showed no recovery of BMD. Long-term follow-up at 4 to 11 months showed that 3 out of 7 subjects 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. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see Warnings and Precautions (5.12) ].

In an open-label clinical trial (N=217) of a single course of treatment with isotretinoin capsules for pediatric subjects 12 years of age and older with severe recalcitrant nodular acne, BMD at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of subjects. One subject had a decrease in lumbar spine BMD >4% based on unadjusted data. Sixteen (8%) subjects had decreases in lumbar spine BMD >4%, and all the other subjects (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine subjects (5%) had a decrease in total hip BMD >5% based on unadjusted data. Twenty-one (11%) subjects had decreases in total hip BMD >5%, and all the other subjects (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the subjects with decreased BMD for up to 11 months thereafter demonstrated increasing BMD in 5 subjects at the lumbar spine, while the other 3 subjects had lumbar spine BMD measurements below baseline values. Total hip BMD remained below baseline (range −1.6% to −7.6%) in 5 of 8 subjects (63%).

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

Epiphyseal Closure

There are reports of premature epiphyseal closure in acne patients who used isotretinoin at recommended doses. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 pediatric subjects 12 years of age and older who had hand radiographs taken to assess bone age, a total of 9 subjects had bone age changes that were clinically significant and for which an isotretinoin-related effect cannot be excluded [see Warnings and Precautions (5.12) ].

8.5 Geriatric Use

Clinical studies of ABSORICA/ABSORICA LD did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adult subjects. The effects of aging may increase some risks associated with ABSORICA/ABSORICA LD treatment.

12.1 Mechanism of Action

The exact mechanism of action of ABSORICA/ABSORICA LD 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. 

ABSORICA/ABSORICA LD is a retinoid, which 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 ABSORICA/ABSORICA LD.

12.3 Pharmacokinetics

No clinically significant differences in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects without acne were reported in published literature.

Absorption Following ABSORICA Administration

The ABSORICA mean T_max was 6.4 hours under fed conditions and 2.9 hours under fasting conditions following administration of a single 40 mg dose.

Effect on Food

No clinically significant differences in ABSORICA pharmacokinetics were observed following administration with a modified high-fat, high-calorie meal (123.2 calories from protein, 265.6 calories from carbohydrates, and 468 calories from fat; total calories 857 calories) with reduced vitamin A content. The mean AUC_0-t and C_max of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg ABSORICA dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, ABSORICA may be given with or without meals [see Dosage and Administration (2.1) ].

Absorption Following ABSORICA LD Administration

The ABSORICA LD median T_max was 5 hours under fed conditions and 3.5 hours under fasting conditions following administration of a single 32 mg dose.

Effect on Food

No clinically significant differences in ABSORICA LD pharmacokinetics were observed following administration with a high-fat, high-calorie meal (150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat; total calories 900 calories). The mean AUC_0-t and C_max of isotretinoin were 10209 ng*hr/mL and 646 ng/mL, respectively, following administration of a single 32 mg ABSORICA LD dose under fed conditions; which were approximately 20% and 6% higher, respectively, compared to fasting conditions. However, ABSORICA LD may be given with or without meals [see Dosage and Administration (2.1) ].

Distribution

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

Elimination

The mean elimination half-lives of isotretinoin and its 4-oxo-isotretinoin metabolite were:

•18 hours and 38 hours, respectively, after a single oral ABSORICA 40 mg dose.

•Approximately 24 hours and 38 hours, respectively, after a single oral ABSORICA LD 32 mg dose.

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

Following oral administration of isotretinoin capsules, at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) have been identified in human plasma. The extent of formation of all metabolites was higher under fed conditions. All of these metabolites possess retinoid activity in vitro. The clinical significance is unknown.

Excretion: Following oral administration of an 80 mg dose 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 significant differences in the pharmacokinetics of isotretinoin were observed based on age (12 to 15 years (n=38), and ≥18 years (n=19)). In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed [see Use in Specific Populations (8.4) ].

Drug Interaction Studies

Phenytoin: No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when used concomitantly with isotretinoin.  

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 1 mg/kg/day with an oral contraceptive in premenopausal female patients with severe recalcitrant nodular acne. Additionally, there were no clinically significant differences in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in these patients.

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 or 5.3 times the recommended clinical ABSORICA dosage of 1 mg/kg/day or the recommended clinical ABSORICA LD dosage of 0.8 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 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, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical ABSORICA dosage of 1 mg/kg/day or the recommended clinical ABSORICA LD dosage of 0.8 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 ABSORICA dosage of 1 mg/kg/day or the recommended clinical ABSORICA LD dosage of 0.8 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.

13.2 Animal Toxicology and/or Pharmacology 

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 or 5.3 times the recommended clinical ABSORICA dosage of 1 mg/kg/day or the recommended clinical ABSORICA LD dosage of 0.8 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 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical ABSORICA dosage of 1 mg/kg/day or the recommended clinical ABSORICA LD dosage of 0.8 mg/kg/day, respectively, after normalization for total body surface area).

Manufactured by:
ABSORICA
Galephar Pharmaceutical Research, Inc.
Humacao, PR 00792

ABSORICA LD
Ohm Laboratories Inc.
New Brunswick, NJ 08901

Distributed by:
Sun Pharmaceutical Industries, Inc.
Cranbury, NJ 08512

ABSORICA and ABSORICA LD are registered trademarks of Sun Pharmaceutical Industries, Inc. All other trademarks are property of their respective owners.

ABSORICA LD 8 mg, 16 mg, 20 mg, 24 mg, 28 mg and 32 mg are protected by US Patent No. US 9,700,535 and US 9,750,711.