Drug Safety-related Labeling Changes (SrLC)
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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ABSORICA (NDA-021951)
(ISOTRETINOIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/18/2023 (SUPPL-24)
11/07/2019 (SUPPL-13)
Boxed Warning
Revised; now reads as follows:
WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY
ABSORICA/ABSORICA LD can cause severe life-threatening birth defects and is contraindicated in pregnancy. There is an extremely high risk that severe 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. If pregnancy occurs, discontinue ABSORICA/ABSORICA LD immediately and refer the patient to an Obstetrician- Gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Because of the risk of embryo-fetal toxicity, ABSORICA and ABSORICA LD are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS.
4 Contraindications
Additions and/or revisions underlined:
4.1 Pregnancy
ABSORICA/ABSORICA LD is contraindicated in pregnancy.
4.2 Hypersensitivity
ABSORICA/ABSORICA LD is 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).
5 Warnings and Precautions
Additions and/or revisions underlined:
5.1 Embryo-Fetal Toxicity
ABSORICA/ABSORICA LD is contraindicated in pregnancy. Based on human data, ABSORICA/ABSORICA LD can cause fetal harm when administered to a pregnant patient. There is an extremely high risk that severe 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.
If
a pregnancy occurs during ABSORICA/ABSORICA LD treatment, discontinue
ABSORICA/ABSORICA LD immediately and refer the patient to an
obstetrician/gynecologist experienced in reproductive toxicity for further
evaluation and counseling. Any suspected
fetal exposure during or 1 month after ABSORICA/ABSORICA LD therapy must be
reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088,
and also to the iPLEDGE pregnancy registry at 1-866-495-0654
or via the
internet (www.ipledgeprogram.com).
Patients must be informed not to donate blood during ABSORICA/ABSORICA LD therapy and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin.
ABSORICA/ABSORICA LD is available only through a restricted program under a REMS.
5.2 iPLEDGE Program
ABSORICA/ABSORICA LD are available only through a restricted program under a REMS called the iPLEDGE REMS because of the risk of embryo-fetal toxicity. Notable requirements of the iPLEDGE REMS include the following:
Prescribers must be certified with the program and comply with the following requirements:
Determine reproductive status of all patients prior to initiating treatment.
Provide contraception counseling to patients who can get pregnant prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling
Provide scheduled pregnancy testing, and verify and document the negative pregnancy test result prior to writing each prescription, for no more than a 30-day supply
Patients who can become pregnant must be enrolled by signing an informed consent form and must comply with the following requirements
Comply with the pregnancy testing and contraceptive requirements.
Demonstrate comprehension of the safe-use conditions of the program every month.
Obtain the prescription within 7 days of the pregnancy test collection.
Patients who cannot become pregnant must be enrolled by signing an informed consent form and must obtain the prescription within 30 days of the office visit
Pharmacies that dispense ABSORICA/ABSORICA LD must be certified by being registered and activated in the program, must only dispense to patients who are authorized to receive ABSORICA/ABSORICA LD, and comply with the following requirements:
Only dispense a maximum of a 30-day supply with a Medication Guide.
Do not dispense refills. Dispense only with a new prescription and a new authorization from the program.
Return ABSORICA/ABSORICA LD to inventory if patients do not obtain the prescription by the “Do Not Dispense to After” date
- Wholesalers and distributors must be registered with the program and must only distribute to certified pharmacies.
Further
information, including a list of qualified pharmacies and distributors,
is available at www.ipledgeprogram.com or
1-866-495-0654.
5.4 Psychiatric Disorders
ABSORICA/ABSORICA LD may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.
Healthcare providers should be alert to the warning signs of psychiatric disorders to help ensure patients receive the help they need (Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin). Prior to initiation of ABSORICA/ABSORICA LD therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation is necessary.
Patients should immediately stop ABSORICA/ABSORICA LD and the patient (or caregiver) should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression. Discontinuation of ABSORICA/ABSORICA LD may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare professional.
5.5 Intracranial Hypertension (Pseudotumor Cerebri)
Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided with ABSORICA/ABSORICA LD use. Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue ABSORICA/ABSORICA LD immediately and be referred to a neurologist for further diagnosis and care.
5.6 Serious Skin Reactions
… Patients should be monitored closely for severe skin reactions, and ABSORICA/ABSORICA LD should be discontinued if they occur.
5.7 Pancreatitis
Acute pancreatitis has been reported with isotretinoin use in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. If symptoms of pancreatitis occur, discontinue ABSORICA/ABSORICA LD and seek medical attention.
5.8 Lipid Abnormalities
Elevations of serum triglycerides above 800 mg/dL have been reported with isotretinoin use. In clinical trials, marked elevations of serum triglycerides, decreases in high-density lipoproteins (HDL), and increases in cholesterol levels were reported in 25%, 15%, and 7% of patients treated with isotretinoin capsules, respectively. These lipid changes were reversible upon isotretinoin capsule cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing isotretinoin or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.
Fasting lipid tests should be performed before ABSORICA/ABSORICA LD treatment and then at intervals until the lipid response to ABSORICA/ABSORICA LD is known, which usually occurs within 4 weeks. Careful consideration should be given to risk/benefit of ABSORICA/ABSORICA LD in patients who are at higher risk of hypertriglyceridemia (e.g., patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If ABSORICA/ABSORICA LD therapy is instituted in such patients, more frequent checks of serum values for lipids are recommended. ABSORICA/ABSORICA LD should be stopped if hypertriglyceridemia cannot be controlled.
5.9 Hearing Impairment
… 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
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.
5.12 Musculoskeletal Abnormalities
Bone Mineral Density Changes, Osteoporosis, and Fractures
Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and another isotretinoin capsule product, 27/306 (9%) of adolescents had BMD declines, defined as greater than or equal to 4% lumbar spine or total hip, or greater than or equal to 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.
This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.
There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin.
Patients in early and late adolescence who participate in sports with repetitive impact may be at an increased risk of spondylolisthesis with and without pars fractures, and hip growth plate injuries have been reported.
Musculoskeletal Abnormalities
Approximately 16% of patients treated with isotretinoin capsules in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of isotretinoin.
In a trial of pediatric patients treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female patients than male patients.
Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 8% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA/ABSORICA LD. Consider discontinuing ABSORICA/ABSORICA LD if any significant abnormality is found …
5.14 Hypersensitivity Reactions
… 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
A pregnancy test must be obtained prior to obtaining a prescription, repeated each month, at the end of the entire course of ABSORICA/ABSORICA LD therapy and 1 month after the discontinuation of ABSORICA/ABSORICA LD.
Pretreatment and follow-up fasting lipid tests should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before testing is performed. It is recommended that these tests be performed periodically until the lipid response to ABSORICA/ABSORICA LD is known. The incidence of hypertriglyceridemia is 25% in patients treated with isotretinoin capsules.
Liver Function Tests
As elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin capsules, pretreatment and follow-up liver function tests should be performed periodically until the response to ABSORICA/ABSORICA LD is known.
6 Adverse Reactions
Revisions underlined to the bulleted line listing:
Embryo-Fetal Toxicity
Intracranial Hypertension (Pseudotumor Cerebri)
Musculoskeletal Abnormalities
Hypersensitivity Reactions
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.
Additions and/or revisions underlined:
Hematologic
Anemia and decreased RBC parameters, thrombocytopenia, increased platelet counts, decreased WBC counts, severe neutropenia, rare reports of agranulocytosis.
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. skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient chest pain, and rare reports of rhabdomyolysis.
Headache, syncope, intracranial hypertension (pseudotumor cerebri), dizziness, drowsiness, lethargy, malaise, nervousness, paresthesia, seizures, stroke, weakness.
Suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability, suicide attempts, suicide, aggression, psychosis and auditory hallucinations. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.
Reproductive System
Abnormal menses, sexual dysfunction, including erectile dysfunction and decreased libido.
Respiratory
Epistaxis, nasal dryness, bronchospasm (with or without a history of asthma), respiratory infection, voice alteration.
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).
Ocular: dry eyes, reduced visual acuity, blurred vision, eye pruritis, eye irritation, asthenopia, decreased night vision …
7 Drug Interactions
Additions and/or revisions underlined:
7.1 Vitamin A
ABSORICA/ABSORICA LD is closely related to vitamin A. Therefore, the use of both vitamin A and ABSORICA/ABSORICA LD at the same time may lead to vitamin A related adverse reactions. Patients treated with ABSORICA/ABSORICA LD should be advised against taking supplements containing Vitamin A to avoid additive toxic effects.
7.2 Tetracyclines
Concomitant treatment with ABSORICA/ABSORICA LD 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.
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.
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
ABSORICA/ABSORICA LD 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
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, the patient should be apprised of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking ABSORICA/ABSORICA LD, ABSORICA/ABSORICA LD 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
… 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.
Revised subsection with table (please refer to label for complete table information):
8.3 Females and Males of Reproductive Potential
ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD therapy (for patients with regular menstrual cycles) or immediately preceding the beginning of ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD therapy and 1 month after the discontinuation of ABSORICA/ABSORICA LD.
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 ABSORICA/ABSORICA LD therapy, during ABSORICA/ABSORICA LD therapy, and for 1 month after discontinuing ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD therapy. TABLE
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: Stop taking ABSORICA/ABSORICA LD immediately, if on therapy
Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy
Start using 2 forms of contraception simultaneously again for 1 month before resuming ABSORICA/ABSORICA LD therapy
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 …
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of ABSORICA/ABSORICA LD for the treatment of severe recalcitrant nodular acne have been established in pediatric subjects ages 12 to 17 years. 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 to 17 years) and pharmacokinetic data in pediatric subjects.
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 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 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 therapy with ABSORICA 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 greater than or equal to 4% lumbar spine or total hip, or greater than or equal to 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.
Subjects replaces patients for the remainder of the subsection:
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEReformatted; please refer to label for complete information.
Extensive changes; please refer to label for complete information.