ISOTRETINOIN capsule

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

ISOTRETINOIN (UNII: EH28UP18IF) (ISOTRETINOIN - UNII:EH28UP18IF)

Available from:

Sun Pharmaceutical Industries, Inc.

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

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)]. Isotretinoin capsules are contraindicated in pregnancy [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)]. 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)] . 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 capsules 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 capsules are contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If isotretinoin capsules are used during pregnancy, or if the patient becomes pregnant while taking isotretinoin capsules, the patient should be apprised of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin capsules, isotretinoin capsules 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. Risk Summary There are no data on the presence of isotretinoin in either animal or human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with isotretinoin capsules, and for at least 8 days after the last dose of isotretinoin capsules. All patients who can become pregnant must comply with the iPLEDGE program requirements [see Warnings and Precautions (5.2)]. Pregnancy Testing Isotretinoin capsules 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 capsules 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 capsules 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 capsules therapy (for patients with regular menstrual cycles) or immediately preceding the beginning of isotretinoin capsules 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 capsules therapy and 1 month after the discontinuation of isotretinoin capsules. 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 capsules therapy, during isotretinoin capsules therapy, and for 1 month after discontinuing isotretinoin capsules 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 capsules therapy. Primary forms Secondary forms - Tubal sterilization Barrier: - Male vasectomy - male latex condom with or without spermicide - Intrauterine device - diaphragm with spermicide - Hormonal (combination oral contraceptives, vaginal systems, vaginal inserts, transdermal systems, injections, or implants) - cervical cap with spermicide Other: - Vaginal sponge (contains spermicide) 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 isotretinoin capsules immediately, if on therapy - Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy - Start using 2 forms of contraception simultaneously again for 1 month before resuming isotretinoin capsules 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 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 therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. The safety and effectiveness of isotretinoin capsules for the treatment of severe recalcitrant nodular acne have been established in pediatric subjects ages 12 to 17 years. Use of isotretinoin capsules in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use isotretinoin capsules 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 capsules 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 capsules. Consider discontinuing isotretinoin capsules 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 capsules 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)] . Clinical studies of isotretinoin capsules 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 capsules therapy.

Product summary:

Isotretinoin capsules, USP (opaque) are supplied as follows: Storage and Handling of Isotretinoin Capsules Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Protect from light.

Authorization status:

New Drug Application Authorized Generic

Patient Information leaflet

Sun Pharmaceutical Industries, Inc.
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MEDICATION GUIDE
Isotretinoin (EYE so TRET i noyn) Capsules, USP
Read the Medication Guide that comes with isotretinoin capsules before
you start taking it and each time
you get a prescription. There may be new information. This information
does not take the place of
talking with your healthcare provider about your medical condition or
your treatment.
What is the most important information I should know about
isotretinoin capsules?
•
Isotretinoin capsules can harm your unborn baby, including birth
defects (deformed babies), loss
of a baby before birth (miscarriage), death of the baby, and early
(premature) births.Patients who
are pregnant or who plan to become pregnant must not take isotretinoin
capsules.
•
Patients must not get pregnant:
•
for 1 month before starting isotretinoin capsules
•
during treatment with isotretinoin capsules
•
for 1 month after stopping isotretinoin capsules
•
If you get pregnant during treatment with isotretinoin capsules, stop
taking it right away and call
your healthcare provider.Healthcare providers and patients should
report all cases of pregnancy
during treatment or 1 month after stopping treatment to:
•
FDA MedWatch at 1-800-FDA-1088, and
•
the iPLEDGE Pregnancy Registry at 1-866-495-0654 or
www.ipledgeprogram.com
•
Because isotretinoin capsules can cause birth defects,isotretinoin
capsules are only for patients
who can understand and agree to carry out all of the instructions in
the iPLEDGE Program.
•
Serious mental health problems, including:
•
depression
•
psychosis(seeing or hearing things that are not real)
•
suicide. Some patients taking isotretinoin capsules have had thoughts
about hurting
themselves or putting an end to their own lives (suicidal thoughts).
Some people tried to
end their own lives. Some people have ended their own lives.
Stop taking isotretinoin capsules and call your healthcare provider
right away if you or a family member
notices that you have any of the following signs and symptoms

Summary of Product characteristics

ISOTRETINOIN- ISOTRETINOIN CAPSULE
SUN PHARMACEUTICAL INDUSTRIES, INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
ISOTRETINOIN CAPSULES
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
ISOTRETINOIN CAPSULES.
ISOTRETINOIN CAPSULES, FOR ORAL USE
INITIAL U.S. APPROVAL: 1982
WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
ISOTRETINOIN CAPSULES CAN CAUSE 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 ISOTRETINOIN CAPSULES IN ANY AMOUNT,
EVEN FOR SHORT
PERIODS OF TIME. POTENTIALLY ANY FETUS EXPOSED DURING PREGNANCY CAN BE
AFFECTED.
THERE ARE NO ACCURATE MEANS OF DETERMINING WHETHER AN EXPOSED FETUS
HAS BEEN
AFFECTED. ( 4, 5.1, 8.1)
ISOTRETINOIN CAPSULES ARE AVAILABLE ONLY THROUGH A RESTRICTED PROGRAM
CALLED THE
IPLEDGE REMS. ( 5.2)
INDICATIONS AND USAGE
Isotretinoin capsules are retinoids indicated for the treatment of
severe recalcitrant nodular acne in non-
pregnant patients 12 years of age and older with multiple inflammatory
nodules with a diameter of 5 mm
or greater. Because of significant adverse reactions associated with
its use, isotretinoin capsules are
reserved for patients with severe nodular acne who are unresponsive to
conventional therapy, including
systemic antibiotics. (1)
Limitations of Use:
If a second course of isotretinoin capsules therapy is needed, it is
not recommended before a two-month
waiting period because the patient’s acne may continue to improve
following a 15 to 20-week course of
therapy. (1)
DOSAGE AND ADMINISTRATION
Recommended dosage for:
Isotretinoin capsules is 0.5 to 1 mg/kg/day given in two divided doses
without regard to meals for 15
to 20 weeks (2.1)
Adult patients with very severe disease (scarring, trunk involvement)
may increase dosage to 2
mg/kg/day of isotretinoin capsules in divided doses.