PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 40 mg (Wallet Card)

NDC 59651-636-10

** Rx only**
Isotretinoin Capsules, USP
40 mg

** Attention Pharmacist: Dispense the Medication Guide Provided**
** separately to each patient.**

** Each capsule contains:**Isotretinoin USP 40 mg.

** PATIENT: READ INFORMATION CAREFULLY**
** PHARMACISTS: DISPENSE INTACT**
** PLACE PRESCRIPTION LABEL HERE**

** 10 Capsules**
** Prescription Pack**
AUROBINDO

WARNING: EMBRYO-FETAL TOXICITY - CONTRAINDICATED IN PREGNANCY

1 INDICATIONS 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 to 20-week course of therapy [see Dosage and Administration (2.2)].

4 CONTRAINDICATIONS

4.1 Pregnancy

Isotretinoin capsules are contraindicated in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

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) [see Warnings and Precautions (5.14)].

6 ADVERSE REACTIONS

The following adverse reactions with isotretinoin 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 and 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.

7 DRUG INTERACTIONS

7.1 Vitamin A

Isotretinoin is closely related to vitamin A. Therefore, the use of both vitamin A and isotretinoin at the same time may lead to vitamin A related adverse reactions. Patients treated with isotretinoin should be advised against taking supplements containing Vitamin A to avoid additive toxic effects.

7.2 Tetracyclines

Concomitant treatment with isotretinoin and tetracyclines should be avoided 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 Phenytoin

Phenytoin is known to cause osteomalacia. No formal clinical trials 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.

7.4 Systemic Corticosteroids

Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss with concomitant use of systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together.

7.5 Norethindrone and Ethinyl Estradiol

In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving norethindrone and ethinyl estradiol as an oral contraceptive agent, isotretinoin capsules within the recommended dosage, 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). Although this study did not show any clinically significant interaction between isotretinoin and norethindrone, it is not known if there is an interaction between isotretinoin with other progestins.

15 REFERENCES

1. Cinar SL, Kartal D, Aksoy H, et al. Long-term effect of systemic isotretinoin on female fertility. Cutan Ocul Toxicol. 2017;36(2):132-134.

3 DOSAGE FORMS AND STRENGTHS

Isotretinoin capsules, USPare available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules.

***10 mg:**Dark yellow color cap/dark yellow color body, size ‘3’ hard gelatin band sealed capsule imprinted “ISO” on body and “10” on cap with BLACK TEK ink containing light orange or yellow color medicament. ***20 mg:**Red color cap/red color body, size ‘1’ hard gelatin band sealed capsule imprinted “ISO” on body and “20” on cap with BLACK TEK ink containing light orange or yellow color medicament. ***25 mg:**Green color cap/green color body, size ‘0’ hard gelatin capsule, imprinted “ISO” on body and “25” on cap with WHITE TEK ink containing light orange or yellow color medicament. ***30 mg:**Brown color cap/brown color body, size ‘0EL’ hard gelatin capsule imprinted “ISO” on body and “30” on cap with WHITE TEK ink containing light orange or yellow color medicament. ***35 mg:**Dark blue color cap/dark blue color body, size ‘00’ hard gelatin capsule, imprinted “ISO” on body and “35” on cap with WHITE TEK ink containing light orange or yellow color medicament. ***40 mg:**Brown color cap/red color body, size ‘00EL’ hard gelatin capsule imprinted “ISO” on body and “40” on cap with WHITE TEK ink containing light orange or yellow color medicament.

10 OVERDOSAGE

In humans, isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolved without apparent residual effects.

Patients who can become pregnant who present with an isotretinoin overdosage should be evaluated for pregnancy. Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients treated with isotretinoin should use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for 1 month after the overdose.

All patients with isotretinoin overdose should not donate blood for at least 1 month.

16 HOW SUPPLIED/STORAGE AND HANDLING

Isotretinoin capsules, USP are supplied as follows:

• 10 mg: Dark yellow color cap/dark yellow color body, size ‘3’ hard gelatin band sealed capsule imprinted “ISO” on body and “10” on cap with BLACK TEK ink containing light orange or yellow color medicament.

Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-631-03

• 20 mg: Red color cap/red color body, size ‘1’ hard gelatin band sealed capsule imprinted “ISO” on body and “20” on cap with BLACK TEK ink containing light orange or yellow color medicament.

Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-632-03

• 25 mg: Green color cap/green color body, size ‘0’ hard gelatin capsule imprinted “ISO” on body and “25” on cap with WHITE TEK ink containing light orange or yellow color medicament.

Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-633-03

• 30 mg: Brown color cap/brown color body, size ‘0EL’ hard gelatin capsule imprinted “ISO” on body and “30” on cap with WHITE TEK ink containing light orange or yellow color medicament.

Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-634-03

• 35 mg: Dark blue color cap/dark blue color body, size ‘00’ hard gelatin capsule, imprinted “ISO” on body and “35” on cap with WHITE TEK ink containing light orange or yellow color medicament.

Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-635-03

• 40 mg: Brown color cap/red color body, size ‘00EL’ hard gelatin capsule imprinted “ISO” on body and “40” on cap with WHITE TEK ink containing light orange or yellow color medicament.

Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-636-03

Storage and Handling of Isotretinoin Capsules, USP

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issued: July 2023

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of:

*Isotretinoin capsules is 0.5 to 1 mg/kg/daygiven in two divided doses with or without meals for 15 to 20 weeks (see Table 1).

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 to2 mg/kg/day for isotretinoin capsulesin divided doses, as tolerated.

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.

Table 1: Isotretinoin Capsules Daily Dosage by Body Weight****1

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 isotretinoin capsules.

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 isotretinoin capsules in patients who have completed skeletal growth. The use of another course of isotretinoin capsules 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 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 (5.12)].

2.3 Laboratory Testing Prior to Administration

The following laboratory testingmustbe completed prior to isotretinoin capsules use:

*Pregnancy testing: Ensure patient is not pregnant prior to administering isotretinoin capsules[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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after isotretinoin therapy 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 is 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 isotretinoin is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin, the patient should be apprised of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin, isotretinoin must be discontinued immediately and the patient should be referred 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: 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, and for at least 8 days after the last dose of isotretinoin.

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

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. 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 interval between the two tests must be at least 19 days).

• The first test (a screening test) is obtained by the prescriber when the decision is made to prescribe isotretinoin therapy.
• The second pregnancy test (a confirmation test) is performed after the patient has used 2 forms of contraception for 1 month and during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy (for patients with regular menstrual cycles) or immediately preceding the beginning of isotretinoin therapy (for patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding).

A pregnancy test must be repeated each month, in a CLIA-certified laboratory prior to the patient receiving each prescription. A pregnancy test must also be completed at the end of the entire course of isotretinoin therapy and 1 month after the discontinuation of isotretinoin.

Contraception

Patients who can become 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 isotretinoin therapy, during isotretinoin therapy, and for 1 month after discontinuing isotretinoin therapy. 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 method of contraception during isotretinoin therapy.

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. 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 2 methods of contraception simultaneously.

A clinical drug interaction study did not show any clinically significant interaction between isotretinoin and norethindrone and ethinyl estradiol; however, it is not known if there is an interaction between isotretinoin with other progestins [see Drug Interactions (7.5)]. Prescribers are advised to consult the prescribing information of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients who can become pregnant should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because of a possible interaction 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 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 therapy, the patient must:

a. Stop taking isotretinoin immediately, if on therapy

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 2 forms of contraception simultaneously again for 1 month before resuming isotretinoin therapy

d. Have a second pregnancy test after using 2 forms of contraception for 1 month.

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 (sixth month). However, the values returned to normal at the 18th 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 therapy 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 for the treatment of severe recalcitrant nodular acne have been established in pediatric subjects ages 12 to 17 years. Use of isotretinoin in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use isotretinoin to another isotretinoin capsule product in 397 pediatric subjects (12 to 17 years) [see Clinical Studies (14)] and pharmacokinetic data in pediatric subjects [see Clinical Pharmacology (12.3)].

The safety and effectiveness of isotretinoin 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 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 subjects. In a trial of pediatric subjects 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 subjects than male subjects. Arthralgias were experienced in 22% (79/358) of pediatric subjects including severe arthralgias in 8% (6/79) of subjects. Appropriate evaluation of the musculoskeletal system should be done in adolescents who present with these symptoms during or after a course of isotretinoin. Consider discontinuing isotretinoin 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 therapy with isotretinoin or another isotretinoin capsule product was evaluated in a double-blind, randomized clinical trial involving 396 adolescents 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 adolescents, 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 therapy with isotretinoin capsules for adolescents 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 patient 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 subjects including those ages 13 to 17 years, 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 adolescents 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 isotretinoin did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adults. Although reported clinical experience has not identified differences in responses between geriatric and younger adults, effects of aging may increase some risks associated with isotretinoin therapy.

11 DESCRIPTION

Isotretinoin capsules, USP contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin USP (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin USP, 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 – gelatin, iron oxide yellow and titanium dioxide;
• 20 mg – gelatin, iron oxide red and titanium dioxide;
• 25 mg – D&C Yellow #10, FD&C Blue #1, FD&C Yellow #6, gelatin and titanium dioxide;
• 30 mg – gelatin, iron oxide (black, red and yellow) and titanium dioxide;
• 35 mg – FD&C Blue #1, FD&C Red #3, FD&C Yellow #6, gelatin and titanium dioxide;
• 40 mg – gelatin, iron oxide (black, red and yellow) and titanium dioxide.

The black imprinting ink of 10 mg and 20 mg capsules contain the following ingredients: black iron oxide, potassium hydroxide, propylene glycol and shellac.

The white imprinting ink of 25 mg, 30 mg, 35 mg and 40 mg capsules contain the following ingredients: potassium hydroxide, propylene glycol, shellac and titanium dioxide.

In addition 10 mg and 20 mg capsules contain band sealing composition: gelatin and polysorbate 80.

Isotretinoin

Chemically, isotretinoin USP is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow or light-orange, crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in methylene chloride, slightly soluble in alcohol. The structural formula is:

FDA approved dissolution test specifications differ from USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Isotretinoin is a retinoid, which when administered at the recommended dosage [see Dosage and Administration (2.1)], 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 is related to the dose and duration of treatment with isotretinoin capsules and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of isotretinoin in the treatment of severe recalcitrant nodular acne is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of isotretinoin is unknown.

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 Isotretinoin Administration

The isotretinoin mean Tmax 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 isotretinoin 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 AUC0-t and Cmax of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg isotretinoin dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, isotretinoin 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 isotretinoin 40 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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 isotretinoin 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.

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.

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 isotretinoin 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 or 60 mg/kg/day (10 or 30 times the recommended clinical isotretinoin 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

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

14 CLINICAL STUDIES

The effectiveness of isotretinoin for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older has been established and is based on a double-blind, randomized, parallel group trial (Study 1) in subjects with severe recalcitrant nodular acne who received isotretinoin or another isotretinoin capsule product under fed conditions. A total of 925 subjects were randomized 1:1 to receive isotretinoin or another isotretinoin capsule product. Study subjects ranged from 12 to 54 years of age (including 397 pediatric subjects 12 to 17 years old); 60% were male, 40% were female; and the racial groups included 87% White, 4% Black, 6% Asian, and 3% Other. Enrolled subjects had a weight of 40 to 110 kg and had at least 10 nodular lesions on the face and/or trunk. Subjects were treated with an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks, followed by 1 mg/kg/day in two divided doses for the following 16 weeks.

Change from baseline to Week 20 in total nodular lesion count and proportion of subjects with at least a 90% reduction in total nodular lesion count from baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1. A single course of isotretinoin and another isotretinoin capsule product therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of acne in many patients.

** Table 3: Efficacy Results in Subjects with Severe Recalcitrant Nodular Acne at Week 20 (Study 1)**

** Figure 1: Total Nodular (Facial and Truncal) Lesion Count in Subjects with Severe Recalcitrant Nodular Acne by Visit in Study 1**
****

• Another isotretinoin capsule product.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity

There is an extremely high risk of life-threatening birth defects when isotretinoin is used in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Instruct patients who can become pregnant that they must not be pregnant during or up to one month after isotretinoin therapy. Instruct patients to not donate blood during isotretinoin therapy and for 1 month following discontinuation to avoid blood donation to a pregnant patient.

iPLEDGE

Isotretinoin is available only through a restricted program called iPLEDGE [see Warnings and Precautions (5.2)]. Inform patients who can become pregnant of the following notable requirements. These patients must:

• Sign an informed consent form to be enrolled in the program
• Comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)]
• Demonstrate comprehension of the safe-use conditions of the program every month
• Obtain the prescription within 7 days of the pregnancy test collection

Inform patients who cannot become pregnant of the following notable requirements. These patients must sign an informed consent form to enroll in the program and they must obtain the prescription within 30 days of the office visit.

Isotretinoin is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain isotretinoin [see Warnings and Precautions (5.2)].

Lactation

Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with isotretinoin, and for at least 8 days after the last dose of isotretinoin [see Use in Specific Populations (8.2)].

Psychiatric Disorders

Instruct patients and/or their caregivers/families that isotretinoin may cause depression, psychosis, suicidal ideation, suicide attempts, and aggressive or violent behavior. Instruct patients to read the Recognizing Psychiatric Disorders in Adolescents and Young Adults brochure prior to taking isotretinoin. Instruct patients to stop isotretinoin and to contact a healthcare provider if they develop any of these signs or symptoms [see Warnings and Precautions (5.4)].

Important Administration Instructions

To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid [see Dosage and Administration (2.1)].

Intracranial Hypertension (Pseudotumor Cerebri)

Advise patients that intracranial hypertension (pseudotumor cerebri) has occurred with isotretinoin use including concomitant use with tetracyclines. Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue isotretinoin immediately if they have symptoms of intracranial hypertension [see Warnings and Precautions (5.5)].

Serious Skin Reactions

Advise patients that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in patients treated with isotretinoin and to discontinue isotretinoin if clinically significant skin reactions occur [see Warnings and Precautions (5.6)].

Inflammatory Bowel Disease

Advise patients that inflammatory bowel disease (including regional ileitis) have occurred with isotretinoin use including those without a prior history of IBD and if they experience IBD symptoms, they should discontinue isotretinoin immediately [see Warnings and Precautions (5.11)].

Musculoskeletal Abnormalities

Inform patients that:

• There have been reports of osteoporosis and fractures and that isotretinoin may have a negative effect on bone mineral density [see Warnings and Precautions (5.12)].
• Isotretinoin use has been associated with musculoskeletal abnormalities (e.g., arthralgia, back pain) [see Warnings and Precautions (5.12)].

Inform adolescents and their families that isotretinoin use in adolescents who participated in sports with repetitive impact increase their risk of spondylolisthesis or hip growth plate injuries [see Warnings and Precautions (5.12)].

Inform pediatric patients and their caregivers that pediatric patients treated with isotretinoin capsules developed back pain including severe back pain, and arthralgias including severe arthralgias [see Use in Specific Populations (8.4)].

Ocular Abnormalities

Inform patients that they may experience dry eyes, corneal opacities, and decreased night vision and contact lens wearers may experience decreased tolerance to contact lenses during and after therapy [see Warnings and Precautions (5.13)].

Rhabdomyolysis

Inform patients there have been rare postmarketing reports of rhabdomyolysis in patients treated with isotretinoin capsules, some associated with strenuous physical activity [see Warnings and Precautions (5.15)].

Hypersensitivity Reactions

Given that anaphylactic reactions and other allergic reactions have been reported in patients treated with isotretinoin capsules, instruct the patient to discontinue isotretinoin and contact their healthcare provider if they have a severe allergic reaction [see Warnings and Precautions (5.14)].

Lipid Abnormalities

Instruct patients that hypertriglyceridemia, decreased HDL, and increased cholesterol levels were reported in patients treated with isotretinoin capsules [see Warnings and Precautions (5.8)].

Additional Instructions

Inform patients:

• To not share isotretinoin with anyone else because of the risk of birth defects and other serious adverse reactions.
• That transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
• That wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during isotretinoin therapy and for at least 6 months thereafter due to the possibility of scarring.
• To avoid prolonged exposure to UV rays or sunlight.

**Dispense with Medication Guide available at: **www.aurobindousa.com/medication-guides

The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited.

Distributed by:
Aurobindo Pharma USA, Inc.
****279 Princeton-Hightstown Road
East Windsor, NJ 08520

Manufactured by:
Aurobindo Pharma Limited
****Hyderabad-500 032, India

Issued: July 2023

** Dispense with Medication Guide available at: **www.aurobindousa.com/medication-guides