Isotretinoin (Page 7 of 9)

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

Isotretinoin

N=464

Another

Isotretinoin

Capsule Product*

N=461

Nodular Lesions

Mean Baseline Count

18.4

17.7

Mean Reduction

-15.68

-15.62

Subjects Achieving 90%

Reduction, n (%)

324 (70%)

344 (75%)

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

1
(click image for full-size original)

* Another isotretinoin capsule product.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Isotretinoin capsules, USP are supplied as follows:

  • 10 mg capsules: White opaque/white opaque size 1 capsules imprinted with WPI and 2433 in black ink and filled with a yellow semi-solid and banded with a blue band.
    Box of 30 capsules (3 x 10 Prescription Packs): NDC 0591-2433-15
  • 20 mg capsules: White opaque/light yellow opaque size 0 capsules imprinted with WPI and 2434 in black ink and filled with a yellow semi-solid and banded with a blue band.
    Box of 30 capsules (3 x 10 Prescription Packs): NDC 0591-2434-15
  • 25 mg capsules: Light green opaque/light green opaque size 0 capsules imprinted with WPI and A128 in black ink and filled with a yellow semi-solid and banded with a blue band.
    Box of 30 capsules (3 x 10 Prescription Packs): NDC 0591-2451-15
  • 30 mg capsules: Orange opaque/orange opaque size 00 capsules imprinted with WPI and 2435 in black ink and filled with a yellow semi-solid and banded with a blue band.
    Box of 30 capsules (3 x 10 Prescription Packs): NDC 0591-2435-15
  • 35 mg capsules: Flesh opaque/flesh opaque size 00 capsules imprinted with WPI and A168 in black ink and filled with a yellow semi-solid and banded with a blue band.
    Box of 30 capsules (3 x 10 Prescription Packs): NDC 0591-2501-15
  • 40 mg capsules: Orange opaque/orange opaque size 00 capsules imprinted with WPI and 2436 in black ink and filled with a yellow semi-solid and banded with a blue band.
    Box of 30 capsules (3 x 10 Prescription Packs): NDC 0591-2436-15

Storage and Handling of Isotretinoin Capsules, USP

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light.

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 severe birth defects when isotretinoin capsules are 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 capsules therapy. Instruct patients to not donate blood during isotretinoin capsules therapy and for 1 month following discontinuation to avoid blood donation to a pregnant patient.

iPLEDGE

Isotretinoin capsules are 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 capsules are 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 capsules [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 capsules, and for at least 8 days after the last dose of isotretinoin capsules [see Use in Specific Populations (8.2)].

Psychiatric Disorders

Instruct patients and/or their caregivers/families that isotretinoin capsules 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 capsules. Instruct patients to stop isotretinoin capsules 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 capsules use including concomitant use with tetracyclines. Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue isotretinoin capsules 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 capsules 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 capsules 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 capsules 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 capsules 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 capsules therapy and for at least 6 months thereafter due to the possibility of scarring.
  • To avoid prolonged exposure to UV rays or sunlight.

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Manufactured For:
Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054

Iss. 9/2020

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