isotretinoin (Rx)

Brand and Other Names:Amnesteem, Claravis, more...Myorisan, Absorica, Zenatane
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 10mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
  • 20mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
  • 25mg (Absorica)
  • 30mg (Absorica, Claravis, Zenatane)
  • 35mg (Absorica)
  • 40mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)

Severe, Recalcitrant Nodular Acne

Severe nodular acne unresponsive to conventional therapy, including systemic antibiotics

0.5-1 mg/kg/day PO divided BID for 15-20 weeks  

Dose up to 2 mg/kg/day (as tolerated) if disease is very severe with scarring or is primarily manifested on the trunk

Dosing Considerations

>2 months after discontinuation: if warranted by persistent or recurring, severe nodular acne, may initiate a second course of therapy

If total nodule count reduced by >70% before completing 15-20 weeks, may discontinue drug

Dosage Forms & Strengths

capsule

  • 10mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
  • 20mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
  • 25mg (Absorica)
  • 30mg (Absorica, Claravis, Zenatane)
  • 35mg (Absorica)
  • 40mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)

Severe, Recalcitrant Nodular Acne

Severe nodular acne unresponsive to conventional therapy, including systemic antibiotics

<12 years: Safety and efficacy not established

≥12 years: 0.5-1 mg/kg/day PO divided BID for 15-20 weeks  

Dose up to 2 mg/kg/day (as tolerated) if disease is very severe with scarring or is primarily manifested on the trunk

Ichthyosis (Orphan)

Orphan designation for treatment of congenital ichthyosis

Orphan sponsor

  • Patagonia Pharmaceuticals, LLC; 50 Tice Blvd, Suite A35; Woodcliff Lake, NJ 07677
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Interactions

Interaction Checker

and isotretinoin

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Cheilitis (90%)

            Xerosis

            Xerostomia

            Dry nose

            Epistaxis

            Pruritus

            Conjunctivitis (including blepharoconjunctivitis) (40%)

            Irritation (40%)

            Increased erythrocyte sedimentation rates (40%)

            Thinning of hair (which has persisted in rare instances)

            Palmoplantar desquamation

            Skin fragility

            Skin infections (eg, paronychial infections)

            Rash (including erythema, seborrhea, eczema), photosensitivity

            Hypertriglyceridemia (25%)

            Bone or joint pain

            Generalized muscle aches

            Arthralgia

            Decreased HDLs (15%)

            Increased LFTs (15%)

            Increased CPK (12-24%)

            Decreased hemoglobin concentration and hematocrit

            Decreased erythrocyte and leukocyte counts

            Increased platelet count

            1-10%

            Decreased bone mineral density (8.8%)

            Premature epiphyseal closure (3%)

            Frequency Not Defined

            Lethargy

            Fatigue

            Headache

            Anorexia

            Nausea

            Vomiting

            Increased appetite

            Thirst

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            Warnings

            Black Box Warnings

            Embryofetal toxicity

            • Do not use in female patients who are or may become pregnant, because therapy poses an extremely high risk for severe birth effects (with any dose or duration)
            • Documented embryofetal effects include internal and external abnormalities, IQ scores of <85, spontaneous abortion, premature birth, and fetal death
            • Documented external abnormalities include skull abnormality, ear abnormalities (including anotia, micropinna, small or absent external auditory canals), eye abnormalities (including microphthalmia), facial dysmorphia, and cleft palate
            • Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit), cardiovascular abnormalities, thymus gland abnormality, and parathyroid hormone deficiency
            • Discontinue immediately if pregnancy occurs and refer patient to an obstetrician-gynecologist experienced in reproductive toxicity for evaluation
            • Potentially any fetus exposed during pregnancy can be affected, but there are no accurate methods to determine whether an exposed fetus has been affected

            Restricted distribution program

            • Prescribers must register with iPLEDGE, an FDA-approved risk management program designed to minimize pregnancy exposures to isotretinoin (enhancement of earlier riskMAP [risk minimization action plan]); patients must be registered and meet all requirements of iPLEDGE
            • Pharmacies that dispense drug must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive drug, and agree to comply with the REMS requirements described in the booklet entitled Pharmacist Guide, specifically the “Key Information for Pharmacists” section including the following dispensing information:
            • Prescriptions must be obtained no later than the “Do Not Dispense To After” date, and if not obtained, then the RMA must be reversed in the iPLEDGE Program system and the product returned to inventory
            • Patients of childbearing potential must not be pregnant or breastfeeding, must be capable of complying with approved contraceptive methods, and must be reliable in following instructions

            Contraindications

            Pregnancy (see Black Box Warnings)

            Hypersensitivity to isotretinoin or vitamin A

            Cautions

            Significant adverse effects are associated with isotretinoin use

            Embryofetal toxicity; major congenital malformations, spontaneous abortions, and premature births documented (see Black Box Warnings)

            Do not donate blood during therapy and for 1 month after discontinuing treatment, because of embryofetal toxicity risk

            Restricted distribution program (iPLEDGE), a risk management program to minimize pregnancy exposure, has been implemented (see Black Box Warnings)

            Microdosed, progesterone-only preparations (‘minipills’) are an inadequate method of contraception during treatment

            Pseudotumor cerebri reported; some reports involved concomitant tetracycline use; concomitant treatment with tetracyclines should be avoided; early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances; screen patients with these symptoms for papilledema and, if present, discontinue therapy immediately and refer patient to a neurologist for further diagnosis and care

            Serious skin reactions reported (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis); discontinue therapy if skin reaction occurs

            Acute pancreatitis reported with either elevated or normal serum triglyceride levels, including rare instances of fatal hemorrhagic pancreatitis; discontinue if unable to control hypertriglyceridemia; discontinue therapy if pancreatitis occurs

            Increased triglycerides and total cholesterol levels reported; whereas, decreased HDL-cholesterol reported

            Hearing impairment reported and may persist after discontinuing therapy; patients who experience tinnitus or hearing impairment should discontinue treatment and be referred for specialized care for further evaluation

            Hepatitis may occur; mild to moderate liver enzymes elevations also reported; some normalized with dosage reduction or continued administration of drug’ if normalization does not readily occur or if hepatitis is suspected during treatment, therapy should be discontinued

            Associated with inflammatory bowel disease (including regional ileitis); discontinue immediately if abdominal pain, rectal bleeding, or severe diarrhea occurs

            Negative effect on bone mineral density reported; caution with childhood osteoporosis, osteomalacia, chronic corticosteroid use, or anorexia nervosa

            Musculoskeletal symptoms, including arthralgia, may occur; consider discontinuing therapy if any significant abnormality found

            Skeletal hyperostosis observed in clinical trial for keratinization disorders

            Premature epiphyseal closure reported spontaneously with normal doses

            Ocular abnormalities observed, including corneal opacities, decreased night vision, and dry eye

            Hypersensitivity reactions (eg, anaphylactic, cutaneous, allergic vasculitis) reported; severe allergic reaction requires discontinuation and medical management

            Healthcare providers should be alert to warning signs of psychiatric disorders to help ensure patients receive help they need (Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of 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 reported

            Psychiatric effects

            • Depression and psychosis reported; rare reports of suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors
            • Prior to initiation of 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 therapy and the patient (or caregiver) should promptly contact their prescriber if patient develops depression, mood disturbance, psychosis, or aggression
            • Discontinuation of treatment may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare professional

            Laboratory monitoring

            • Pretreatment monitoring: LFTs (1 day before starting initiating therapy), 2 pregnancy tests (negative result 2 weeks before), and fasting lipid profile (including triglycerides)
            • During treatment: Monitor LFTs and lipids at weekly or biweekly intervals until response to isotretinoin established
            • Blood glucose, CPK (particularly in those undergoing vigorous physical activity)
            • Ongoing negative pregnancy tests required according to iPLEDGE rules
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            Pregnancy & Lactation

            Preganacy

            Therapy is contraindicated during pregnancy; it can cause fetal harm when administered to a pregnant patient; there is increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans

            If drug is used during pregnancy, or if patient becomes pregnant while receiving therapy, patient should be apprised of potential hazard to a fetus

            If pregnancy occurs during treatment of patient receiving therapy, it must be discontinued immediately and patient should be referred to Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling

            If a pregnancy occurs during treatment, discontinue therapy immediately and refer patient to obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling; any suspected fetal exposure during or 1 month after initiating therapy must be reported immediately to the FDA via 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)

            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 therapy, during therapy, and for 1 month after discontinuing 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 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
            • 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
            • Prescribers are advised to consult the prescribing information of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease effectiveness of these birth control products
            • Patients who can become pregnant should be prospectively cautioned not to self-medicate with 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 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 therapy immediately
            • If had unprotected sexual contact and 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 therapy
              • Have a second pregnancy test after using 2 forms of contraception for 1 month

            Reproductive Potential

            • 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 therapy (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 therapy

            Therapy is available only through a restricted program under a REMS called the iPLEDGE REMS because of the risk of embryo-fetal toxicity

            Under REMS, 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 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 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 the product
              • Must be certified by being registered and activated in the program, must only dispense to patients who are authorized to receive the treatment, 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 product 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

            Lactation

            There are no data on either animal or human milk, effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment and for at least 8 days after the last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Retinoid; inhibits sebaceous gland function and keratinization; clinical improvement of nodular acne associated with sebum secretion reduction

            Absorption

            Bioavailability: Low

            Peak plasma time

            • 5.3 hr (fed); 3.2 hr (fasted)
            • Absorica: 6.4 hr (fed); 2.9 hr (fasted)

            Peak plasma concentration

            • 862 ng/mL (fed); 301 ng/mL (fasted)
            • Absorica: 395 ng/mL (fed); 314 ng/mL (fasted)

            AUC

            • 10,004 ng•hr/mL (fed): 3703 ng•hr/mL (fasted)
            • Absorica: 6095 ng•hr/mL (fed); 4055 ng•hr/mL (fasted); AUC (fasted state) greater than Accutane, and therefore not interchangeable with generic products

            Distribution

            Protein bound: 99.9% (primarily albumin)

            Metabolism

            Metabolized by liver oxidation via hepatic isoenzymes CYP2B6, CYP2C8/9, and CYP3A4

            Metabolites: 4-oxo-isotretinoin, retinoic acid (tretinoin), 4-oxo-retinoic acid

            Elimination

            Half-life: 10-20 hr; 22-24 hr (Absorica)

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            Administration

            Oral Administration

            Swallow capsule whole with full glass of water to reduce esophageal irritation

            Amnesteem, Claravis, Myorisan, Zenatane: Take with food (significantly improves absorption)

            Absorica: May be taken with or without food

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.