Retinoid

Isotretinoin

Approved 29 Sept 2017OralCapsule

The FDA lists this product in 36 strengths and forms.

Indications

Severe Recalcitrant Nodular Acne Isotretinoin capsules are indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, 2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, isotretinoin capsules should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics .

In addition, isotretinoin capsulesare indicated only for those patients who are not pregnant, because isotretinoin capsules can cause life-threatening birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS ). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. 1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off isotretinoin capsules.

The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis, Premature Epiphyseal Closure ).

Contraindications

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS . Allergic Reactions Isotretinoin capsules are contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS, Hypersensitivity ).

Warnings and precautions

Psychiatric Disorders Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS, Psychiatric ). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin . Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need.

Therefore, prior to initiation of isotretinoin 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 may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment.

At a glance

Brand name: Isotretinoin
Pharmacologic class: Retinoid
Route: Oral
Dosage form: Capsule
Applicant: Amneal Pharms Ny
Status: Prescription
FDA approval: 29 Sept 2017
Application: ANDA207792-002

Indications

Warnings and precautions

Interactions

Drug Interactions Vitamin A: Because of the relationship of isotretinoin to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with isotretinoin and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.

Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during isotretinoin therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products.

These reports are more frequent for patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with isotretinoin. Therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS ).

Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Ortho-Novum ® 7/7/7 Tablets as an oral contraceptive agent, isotretinoin at the recommended dose of 1 mg/kg/day, 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).

Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John’s Wort: Isotretinoin use is associated with depression in some patients (see WARNINGS, Psychiatric Disorders and ADVERSE REACTIONS, Psychiatric ). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St.

John’s Wort because a possible interaction has been suggested 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. Phenytoin: Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers.

These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies 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.

Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together. Laboratory Tests 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 first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. - For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. - For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. - Each month of therapy, patients must have a negative result from a urine or serum pregnancy test.

A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the patient who can become pregnant receiving each prescription. Lipids Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established.

The incidence of hypertriglyceridemia is one patient in four on isotretinoin therapy (see WARNINGS, Lipids ). Liver Function Tests Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to isotretinoin has been established (see WARNINGS, Hepatotoxicity ).

Glucose Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established. CPK Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity.

In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks.

No cases of rhabdomyolysis were reported in this trial.

Adverse reactions

Clinical Trials and Postmarketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of isotretinoin, and the postmarketing experience. The relationship of some of these events to isotretinoin therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving isotretinoin are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes).

Dose Relationship Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS ). Body as a Whole Allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS, Hypersensitivity ), edema, fatigue, lymphadenopathy, weight loss.

Cardiovascular Palpitation, tachycardia, vascular thrombotic disease, stroke. Endocrine/Metabolic Hypertriglyceridemia (see WARNINGS, Lipids ), alterations in blood sugar levels (see PRECAUTIONS, Laboratory Tests ). Gastrointestinal Inflammatory bowel disease (see WARNINGS, Inflammatory Bowel Disease ), hepatitis (see WARNINGS, Hepatotoxicity ), pancreatitis (see WARNINGS, Lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

Hematologic Allergic reactions (see PRECAUTIONS, Hypersensitivity ), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see P RECAUTIONS, Information for Patients ). See PRECAUTIONS, Laboratory Tests for other hematological parameters. Musculoskeletal Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS, Skeletal ), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PRECAUTIONS, Information for Patients ), transient pain in the chest (see PRECAUTIONS, Information for Patients ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS, Laboratory Test s ).

Neurological Pseudotumor cerebri (see WARNINGS, Pseudotumor Cerebri ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness. Psychiatric Suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS, Psychiatric Disorder s ), emotional instability. 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. Respiratory Bronchospasms (with or without a history of asthma), respiratory infection, voice alteration. Skin and Appendages Acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, 7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS, Hypersensitivity ), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS, Information for Patients ).

Special Senses: Hearing: hearing impairment (see WARNINGS, Hearing Impairment ), tinnitus. Vision: corneal opacities (see WARNINGS, Corneal Opacities ), decreased night vision which may persist (see WARNINGS, Decreased Night Visio n ), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances. Urinary System: glomerulonephritis (see PRECAUTIONS, Hypersensitivity ), nonspecific urogenital findings (see PRECAUTIONS, Laboratory Test s for other urological parameters).

Laboratory Elevation of plasma triglycerides (see WARNINGS, Lipids ), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment. Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS, Hepatotoxicity ). Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS, Laboratory Tests ), hyperuricemia. Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; (see PRECAUTIONS, Information for Patients ), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.

White cells in the urine, proteinuria, microscopic or gross hematuria.

Isotretinoin

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Isotretinoin

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

Adverse reactions

Composition

Strengths and forms

Official product information