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  • CLASSES

    Oral Anti-Acne Retinoids

    DEA CLASS

    Rx

    DESCRIPTION

    Retinoid; synthetic 13-cis isomer of naturally occurring tretinoin
    Used for severe recalcitrant nodular acne, some keratinization disorders and as an antineoplastic agent for certain cancers
    Due to teratogenicity potential, isotretinoin is only available through iPLEDGE program

    COMMON BRAND NAMES

    Absorica, Accutane, Amnesteem, Claravis, MYORISAN, Sotret, ZENATANE

    HOW SUPPLIED

    Absorica/Accutane/Amnesteem/Claravis/Isotretinoin/MYORISAN/Sotret/ZENATANE Oral Cap: 10mg, 20mg, 25mg, 30mg, 35mg, 40mg

    DOSAGE & INDICATIONS

    For the treatment of severe recalcitrant cystic acne vulgaris (nodular acne).
    NOTE: Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics.
    Oral dosage
    Adults, Adolescents, and Children >= 12 years

    0.5—1 mg/kg/day PO given in 2 divided doses for 15—20 weeks or until the total cyst count decreases by 70% if this occurs sooner than 15—20 weeks. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosages up to 2 mg/kg/day PO given in two divided doses. Dosage may be adjusted according to patient response; however, prior to upward dosage adjustments, patients should be questioned regarding their compliance with food and administration instructions. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 8 weeks following completion of the previous course. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see Precautions). The adult maximum recommended dose is 2 mg/kg/day PO.

    For the treatment of keratinization disorders including keratosis follicularis†, lamellar ichthyosis†, and pityriasis rubra pilaris†.
    Oral dosage
    Adults and Adolescents

    Dosages up to 4 mg/kg/day PO have been used. The specific disease and its severity will determine the appropriate dosage.

    For the treatment of juvenile chronic myelogenous leukemia (CML)†.
    Oral dosage
    Infants and Children

    100 mg/m2/day orally resulted in 2 complete (CR) and 3 partial (PR) responses in 10 patients with juvenile chronic myelogenous leukemia in a multicenter, pilot study. The isotretinoin dosage could be increased by 25% each week after 1 month of therapy and some patients received up to 200 mg/m2/day. CR was defined as white blood cell (WBC) normalization and resolution of organomegaly and PR was defined as a greater than 50% decrease in WBC count and organomegaly. Additionally, one patient had a minimal response (defined as a 26% to 50% decrease in WBC count and organomegaly). The duration of response was 6 to 83 months in responding patients; 3 patients received a bone marrow transplant.

    For the treatment of newly diagnosed, high-risk neuroblastoma† following autologous bone marrow transplantation.
    Oral dosage
    Children and Adolescents

    160 mg/m2/day PO divided in 2 divided doses for 14 days repeated every 28 days for 6 cycles was studied in 258 pediatric patients aged 1 to 18 years with no evidence of progressive disease following 5 cycles of induction chemotherapy and either high-dose chemotherapy followed by autologous bone marrow transplantation or 3 additional cycles of chemotherapy in a randomized, phase III trial. At median follow-up of 36 months, the 3-year event-free survival (EFS) rate (46% vs. 29%; p = 0.027) but not the 3-year overall survival (OS) rate (56% vs. 50%; p = 0.45) was significantly improved in patients who received isotretinoin compared with patients who did not receive isotretinoin. At a median follow-up of 8 years, the 5-year EFS (42% vs. 31%; p = 0.1219) and OS (50% vs. 39%; p = 0.1946) rates were not significantly improved in patients who received isotretinoin compared with no isotretinoin when evaluated using a log-rank comparison, although the 5-year OS rate was statistically superior with isotretinoin therapy when a log (-log(.)) transformation evaluation was used (p = 0.0006). Additionally, the 5-year EFS rate was significantly improved in patients who received ABMT and isotretinoin compared with patients who continued receiving chemotherapy with no isotretinoin (p = 0.0038). Grade 3 or 4 infection occurred in 12% of patients who received isotretinoin.

    For the treatment of recurrent cervical cancer, in combination with interferon alfa†.
    Oral dosage
    Adults

    The dosage has not been established, although 1 mg/kg/day PO (rounded to the nearest 10 mg) divided into 2 doses has been studied in a phase II trial. Isotretinoin (n = 42) or tretinoin (n = 21) plus interferon alfa 3 million units/m2/day subcutaneously was studied in 63 patients; patient accrual was stopped in the tretinoin arm due to a low response in the first 20 patients. Of 39 evaluable patients who received isotretinoin plus interferon alfa, 3 patients (8%) experienced a partial response lasting 17, 22, and 24 weeks. Additionally, the median progression-free survival time was 3 months and the median overall survival time was 8 months in patients who received isotretinoin plus interferon alfa. Grade 3 and 4 toxicities reported in the isotretinoin plus interferon alfa arm included malaise and fatigue (26%), anemia (21%), and granulocytopenia (10%).

    For the adjuvant treatment of advanced squamous cell head and neck cancer†, in combination with interferon alfa and vitamin E.
    Oral dosage
    Adults

    50 mg/m2/day PO with interferon alfa 3 million international units/m2 SC 3 times weekly and alfa-tocopherol 1200 international units/day POfor 12 months following surgery, radiotherapy, or both was studied in 45 patients with locally advanced stage III or IV squamous-cell carcinoma of the head and neck in a nonrandomized, phase II study. Therapy was well tolerated with 86% of patients able to complete the full 12 months of therapy. At a median follow-up of 49.4 months, the 3- and 5-year progression-free survival rates were 82.2% and 80%, respectively, and the 3- and 5-years overall survival rates were 88.9% and 81.3%, respectively. Additionally, only 1 secondary primary tumor (acute promyelocytic leukemia) was reported. Serious toxicities reported in this study include grade 3 arthralgia/myalgia (9%), fatigue (7%), and weight loss (7%) and grade 3 and 4 infection (4%). One patient developed optic neuritis which resolved after withdrawing therapy.

    For the adjuvant treatment of aggressive squamous cell skin carcinoma†, in combination with interferon alfa.
    Oral dosage
    Adults

    Use has not been established, although 1 mg/kg/day PO plus interferon alfa 3 million units subcutaneously 3 times weekly for 6 months (median duration, 4.9 months) has been studied. Isotretinoin/interferon alfa was administered as adjuvant therapy following surgery or radiation therapy (RT) in 31 patients and compared to 34 patients who received no adjuvant therapy following surgery or RT in a randomized, phase III study. All patients had aggressive squamous-cell skin cancer defined as tumor size 2 cm or larger, perineural invasion, evidence of deep invasion, or proven metastases. At a median follow-up of 21.5 months, the primary endpoint of recurrence- and second primary tumor (SPT)-free survival rate was not significantly different in patients who received adjuvant therapy compared with patients who did not receive adjuvant therapy (hazard ratio = 1.13; 95% CI, 0.53 to 2.41). Additionally, the 2-year cumulative recurrence - and SPT-free survival rates were 51.5% and 62.4% for patients who received adjuvant therapy and no adjuvant therapy, respectively. Grade 3 and 4 toxicities reported in the adjuvant treatment arm included fatigue (26%), dry eye or conjunctivitis (19%), dry skin and skin rash (16%), and cheilitis (13%).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2 mg/kg/day PO for cystic acne.

    Elderly

    2 mg/kg/day PO for cystic acne.

    Adolescents

    1 mg/kg/day PO for cystic acne.

    Children

    >= 12 years: 1 mg/kg/day PO for cystic acne.
    < 12 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Absorica may be administered without regard to meals. Administer all other isotretinoin formulations with food to maximize GI absorption. Failure to take certain isotretinoin formulations with food will significantly decrease absorption. Do not crush or open capsules. To minimize the risk of esophageal irritation, all isotretinoin formulations should be swallowed whole with a full glass of liquid.
    All prescribers, patients, and pharmacists must comply with the conditions of the iPLEDGE program when prescribing, dispensing, or receiving isotretinoin:
    Prescribers who are registered in the iPLEDGE program must register patients into the iPLEDGE program via the telephone or the internet and provide monthly confirmation that each patient has received counseling and education. For females of childbearing potential, the prescriber must enter the patients two chosen forms of contraception each month, and enter monthly results from a CLIA-certified laboratory conducted pregnancy test.
    ALL patients must sign a consent form prior to beginning therapy and must be registered in the iPLEDGE program by their prescriber. Sexually active patients must use 2 forms of effective contraception simultaneously for at least one month prior to beginning isotretinoin therapy, during therapy and for 1 month after stopping therapy.
    Women of childbearing potential must have 2 negative pregnancy tests prior to beginning isotretinoin therapy and then monthly during treatment, regardless of sexual activity, and must access the iPLEDGE program via the internet or telephone before starting isotretinoin, on a monthly basis during therapy, and during the one month after the last dose to answer questions on the program requirements and to enter their two chosen forms of contraception.
    Pharmacists may only dispense isotretinoin from an iPLEDGE-registered pharmacy. Pharmacists must obtain authorization from the iPLEDGE program via the internet or telephone for every isotretinoin prescription and must write the risk Management Authorization (RMA) number on the prescription. Pharmacists will dispense a maximum 1-month supply, must dispense prior to the 'do not dispense to a patient after' date provided by the iPLEDGE system, and provide a Medication Guide for patients with each isotretinoin prescription (Note: Separate booklets are available for male and female patients).

    STORAGE

    Absorica:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Accutane:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Amnesteem :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Claravis :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    MYORISAN:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sotret:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    ZENATANE:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Paraben hypersensitivity, retinoid hypersensitivity

    Isotretinoin is contraindicated in patients with retinoid hypersensitivity, including hypersensitivity to vitamin A, tretinoin, and etretinate, due to the possibility of cross-sensitivity. Similarly, isotretinoin is contraindicated in patients with paraben hypersensitivity because the drug is prepared with paraben as a preservative.

    Pregnancy

    Isotretinoin is contraindicated in pregnancy (FDA pregnancy risk category X). Although not every exposure to isotretinoin has resulted in a birth defect, there is an extremely high risk that birth defects can occur if pregnancy occurs while taking isotretinoin in any amount even for a short period of time. In order to prevent isotretinoin exposure during pregnancy, the iPLEDGE program has been developed. This program requires prescribers, pharmacists and patients to comply with certain conditions prior to prescribing, dispensing or receiving isotretinoin. Isotretinoin therapy should not be initiated in females of childbearing potential, regardless of whether or not they are sexually active, until negative results from two urine or serum pregnancy tests are confirmed and the patient or her guardian completes the consent form. Monthly pregnancy testing during isotretinoin therapy is also required. Women who are, or might become, sexually active with a male partner must also select and use 2 forms of effective contraception simultaneously for at least one month before beginning, during, and for one month following discontinuation of therapy, even when there has been a history of infertility, unless due to hysterectomy. Low-dose progestins may be an inadequate method of contraception during isotretinoin therapy. In addition, females who are using hormonal contraception as a primary form of birth control should not take St. John's Wort, as it may decrease the effectiveness of hormonal contraceptives. They must also sign a Patient Information/Consent form about isotretinoin and birth defects, in addition to the consent form all patients should receive information about other potentially serious risks. If pregnancy does occur during treatment, the prescriber and patient should discuss the desirability of continuing the pregnancy. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800—FDA—1088 and the iPLEDGE pregnancy registry at 866—495—0654.

    Blood donation

    Blood donation must be avoided while patients are receiving isotretinoin and for 1 month following completion of therapy because the donated blood might be given to a pregnant woman and expose the fetus.

    Breast-feeding

    According to the manufacturer, breast-feeding women should not receive isotretinoin due to the potential adverse effects to the nursing infant. It is unknown whether isotretinoin is distributed into breast milk. Vitamin A, which is structurally related to isotretinoin, is present in breast milk. A topical agent may be preferred (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin, tretinoin) for the treatment of acne in a nursing mother, especially while nursing a neonate or preterm infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Anorexia nervosa, children, corticosteroid therapy, hyperostosis, infants, neonates, osteomalacia, osteoporosis

    Although an effect of isotretinoin on bone loss is not established, prescribers should use caution when treating patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are receiving chronic drug therapy that induces osteoporosis/osteomalacia or that affects vitamin D metabolism (e.g., corticosteroid therapy or anticonvulsant therapy). Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. It is important that isotretinoin be given at the recommended dosage for not longer than the recommended duration. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect on the musculoskeletal system than a single course of therapy. The use of isotretinoin has not been studied in neonates, infants and children < 12 years of age. Use of isotretinoin in pediatric patients 12—17 years of age should be given careful consideration. Limited data suggest that isotretinoin may cause premature epiphyseal closure. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Patients may be at increased risk for adverse effects on the musculoskeletal system when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients involved in these activities while receiving isotretinoin treatment or following cessation of treatment (see Adverse Reactions). A high prevalence of skeletal hyperostosis has been noted in clinical trials for keratinization disorders using a mean isotretinoin dose of 2.24 mg/kg/day. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by X-ray in prospective studies of nodular acne patients treated with a single course of isotretinoin at recommended doses.

    Alcoholism, diabetes mellitus, hepatic disease, hepatitis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity, pancreatitis

    Caution should be exercised when administering isotretinoin to patients with hyperlipidemia or those with conditions that may predispose them to high serum triglyceride levels (i.e., hypertriglyceridemia) such as alcoholism, other hepatic disease, diabetes mellitus, hypercholesterolemia, or obesity. If isotretinoin therapy is started, more frequent monitoring of serum lipids and/or blood sugar is recommended. Pancreatitis, and in rare instances fatal hemorrhagic pancreatitis, has occurred in patients receiving isotretinoin with elevated or normal levels of triglycerides. Pretreatment serum triglyceride levels should be obtained in all patients, followed by periodic lipid determinations throughout treatment (biweekly until lipid response is determined, followed by monthly monitoring). Isotretinoin should be discontinued if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Clinical hepatitis considered possible or probably related to isotretinoin therapy has been reported. If normalization of liver enzyme levels does not readily occur with dose reduction or continuation of the drug or if hepatitis is suspected during isotretinoin treatment, the drug should be discontinued.

    Inflammatory bowel disease

    Isotretinoin has been temporally associated with inflammatory bowel disease (including regional ileitis). Isotretinoin may exacerbate symptoms and should be used with caution in patients with inflammatory bowel disease.

    Depression, psychosis, suicidal ideation

    Isotretinoin should be used cautiously in patients with psychotic disorders. Post-marketing reports show that isotretinoin may cause major depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. Discontinuation of isotretinoin therapy may be insufficient; further evaluation may be necessary. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults.

    Contact lenses, driving or operating machinery, papilledema, visual disturbance

    Patients should be warned against driving or operating machinery at night while taking isotretinoin. Decreased night vision and other visual disturbance have been reported during isotretinoin therapy; onset of visual changes may be sudden. Patients may experience decreased tolerance to contact lenses during and after isotretinoin therapy. All visual problems reported during isotretinoin treatment should be carefully monitored. All patients experiencing visual difficulties should discontinue isotretinoin therapy and have an ophthalmologic examination. Isotretinoin therapy has been associated with cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved the concomitant use of systemic tetracyclines. Concurrent use of isotretinoin with systemic tetracyclines should be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue isotretinoin therapy immediately and be referred to a neurologist for follow-up and treatment.

    Hearing impairment

    Hearing impairment, which continued after discontinuing the drug, has been reported in patients taking isotretinoin. Patients who experience tinnitus or hearing impairment should discontinue isotretinoin treatment and be referred to for further follow-up.

    Sunlight (UV) exposure

    Retinoids may cause photosensitivity. Patients should avoid prolong sunlight (UV) exposure while receiving isotretinoin. Appropriate protective clothing (e.g., hat) and sunscreen should be used if patients are in the sunlight for an extended period of time. Wax epilation and skin resurfacing procedures (e.g., dermabrasion or laser treatments) should be avoided during isotretinoin therapy and for at least 6 months thereafter due to the possibility of scarring.

    Agranulocytosis, leukopenia, neutropenia

    Neutropenia and rare cases of agranulocytosis have been reported during isotretinoin therapy. Isotretinoin should be discontinued in patients show develop clinically significant leukopenia or neutropenia.

    ADVERSE REACTIONS

    Severe

    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    epiphyseal closure / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    esophageal ulceration / Delayed / Incidence not known
    stroke / Early / Incidence not known
    retinal hemorrhage / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    night blindness / Delayed / Incidence not known
    keratitis / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    corneal opacification / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 25.0-25.0
    elevated hepatic enzymes / Delayed / 15.0-15.0
    hypercholesterolemia / Delayed / 7.0-7.0
    impaired wound healing / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    osteopenia / Delayed / Incidence not known
    hyperostosis / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    inflammatory bowel disease / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    pseudotumor cerebri / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    euphoria / Early / Incidence not known
    psychosis / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    photophobia / Early / Incidence not known
    conjunctival hyperemia / Early / Incidence not known
    cataracts / Delayed / Incidence not known
    pyuria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known

    Mild

    back pain / Delayed / 29.0-29.0
    arthralgia / Delayed / 22.0-22.0
    musculoskeletal pain / Early / 16.0-16.0
    cheilitis / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    skin hypopigmentation / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    purpura / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known
    gingivitis / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    nausea / Early / Incidence not known
    weakness / Early / Incidence not known
    insomnia / Early / Incidence not known
    headache / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known
    dizziness / Early / Incidence not known
    drowsiness / Early / Incidence not known
    fatigue / Early / Incidence not known
    syncope / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    ocular pruritus / Rapid / Incidence not known
    xerophthalmia / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    lacrimation / Early / Incidence not known
    diplopia / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    nasal dryness / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    Adapalene; Benzoyl Peroxide: Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Azelastine; Fluticasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Beclomethasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Benzoyl Peroxide: Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Benzoyl Peroxide; Clindamycin: Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Benzoyl Peroxide; Erythromycin: Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Benzoyl Peroxide; Hydrocortisone: Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Benzoyl Peroxide; Sulfur: Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Betamethasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Budesonide: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Budesonide; Formoterol: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Cholestyramine: Cholestyramine can bind with and possibly decrease the oral absorption of isotretinoin. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.
    Ciclesonide: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Cod Liver Oil: Patients should avoid or limit supplementation with vitamin A during treatment with retinoids to avoid potential additive toxic effects.
    Colestipol: Colestipol can bind with and possibly decrease the oral absorption of isotretinoin. Administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of colestipol.
    Conjugated Estrogens; Medroxyprogesterone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Corticosteroids: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Corticotropin, ACTH: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Cortisone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Deflazacort: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Dexamethasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Drospirenone; Estradiol: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Drospirenone; Ethinyl Estradiol: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Drospirenone; Ethinyl Estradiol; Levomefolate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Estradiol Cypionate; Medroxyprogesterone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Estradiol; Levonorgestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Estradiol; Norethindrone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethanol: Ethanol can potentiate the hypertriglyceridemic effects of isotretinoin; patients experiencing hyperlipidemia while on isotretinoin should be advised to limit their intake of ethanol.
    Ethinyl Estradiol: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Desogestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Ethynodiol Diacetate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Etonogestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Levonorgestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Ethinyl Estradiol; Norelgestromin: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Norethindrone Acetate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Norethindrone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Norgestimate: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Ethinyl Estradiol; Norgestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Fludrocortisone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Flunisolide: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Fluticasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Fluticasone; Salmeterol: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Fluticasone; Vilanterol: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Folic Acid, Vitamin B9: L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Formoterol; Mometasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Fosphenytoin: Long-term use of fosphenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between fosphenytoin and isotretinoin therapy. Patients receiving fosphenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.
    Hydrocortisone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Leuprolide; Norethindrone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Levomefolate: L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Levonorgestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Lomitapide: Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Medroxyprogesterone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Mestranol; Norethindrone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Methotrexate: Concomitant use of systemic retinoids, such as isotretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy.
    Methoxsalen: Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Methylprednisolone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Mipomersen: Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Mometasone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Norethindrone: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Norgestrel: Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Orlistat: The bioavailability of orally administered retinoids may be decreased during coadministration with isotretinoin. In patients receiving orally-administered retinoids along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogues be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption.
    Phenytoin: Long-term use of phenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between phenytoin and isotretinoin therapy. Patients receiving phenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.
    Photosensitizing agents: Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Porfimer: Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Prednisolone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Prednisone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Salicylic Acid: Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
    Sodium Thiosulfate; Salicylic Acid: Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
    St. John's Wort, Hypericum perforatum: Because of the teratogenic potential of isotretinoin, the coadministration of St. John's wort, Hypericum perforatum and isotretinoin is not recommended in females who are using hormonal contraceptives as their primary form of birth control. St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. Breakthrough bleeding and pregnancies have been reported following coadministration of St. John's Wort and hormonal contraception. It is thought that St. John's wort induces hormone metabolism via induction of the hepatic CYP3A4 isoenzyme. It is possible that, as with other CYP3A4 inducers, St. John's wort could also reduce the therapeutic efficacy of non-oral combination contraceptives or progestin-only contraceptives (i.e., norgestrel, levonorgestrel, and medroxyprogesterone).
    Tetracyclines: Avoid the concomitant use of isotretinoin and systemic tetracyclines due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with both systemic retinoid and tetracycline use alone. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.
    Triamcinolone: Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
    Verteporfin: Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Warfarin: Isotretinoin can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed.

    PREGNANCY AND LACTATION

    Pregnancy

    Isotretinoin is contraindicated in pregnancy (FDA pregnancy risk category X). Although not every exposure to isotretinoin has resulted in a birth defect, there is an extremely high risk that birth defects can occur if pregnancy occurs while taking isotretinoin in any amount even for a short period of time. In order to prevent isotretinoin exposure during pregnancy, the iPLEDGE program has been developed. This program requires prescribers, pharmacists and patients to comply with certain conditions prior to prescribing, dispensing or receiving isotretinoin. Isotretinoin therapy should not be initiated in females of childbearing potential, regardless of whether or not they are sexually active, until negative results from two urine or serum pregnancy tests are confirmed and the patient or her guardian completes the consent form. Monthly pregnancy testing during isotretinoin therapy is also required. Women who are, or might become, sexually active with a male partner must also select and use 2 forms of effective contraception simultaneously for at least one month before beginning, during, and for one month following discontinuation of therapy, even when there has been a history of infertility, unless due to hysterectomy. Low-dose progestins may be an inadequate method of contraception during isotretinoin therapy. In addition, females who are using hormonal contraception as a primary form of birth control should not take St. John's Wort, as it may decrease the effectiveness of hormonal contraceptives. They must also sign a Patient Information/Consent form about isotretinoin and birth defects, in addition to the consent form all patients should receive information about other potentially serious risks. If pregnancy does occur during treatment, the prescriber and patient should discuss the desirability of continuing the pregnancy. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800—FDA—1088 and the iPLEDGE pregnancy registry at 866—495—0654.

    According to the manufacturer, breast-feeding women should not receive isotretinoin due to the potential adverse effects to the nursing infant. It is unknown whether isotretinoin is distributed into breast milk. Vitamin A, which is structurally related to isotretinoin, is present in breast milk. A topical agent may be preferred (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin, tretinoin) for the treatment of acne in a nursing mother, especially while nursing a neonate or preterm infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoids exert their effects through binding to specific nuclear retinoid receptors, which are members of the steroid-thyroid superfamily of nuclear receptors. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Isotretinoin acts primarily on the RAR family of receptors.
     
    The primary action of isotretinoin in the treatment of acne is a reversible inhibition of sebum production through a reduction in the size of sebaceous glands and possible inhibition of follicular keratinization. The latter mechanism may be responsible for its beneficial effects in treating keratinization disorders. Sebum production can be reversibly reduced to 10% of pretreatment levels. Given in high dosages, isotretinoin can indirectly reduce the concentration of Propionibacterium acnes bacteria through decreased sebum production. Isotretinoin may inhibit prostaglandin E2 and collagenase, which would account for its antiinflammatory effect.
     
    The role of retinoids in fetal development is to specify positional information for cells in developing limbs and possibly in the nervous system. In all age groups, retinoids are required for normal growth and proliferation of epithelial tissues. Dysregulation of retinoids may contribute to lung, gastric, uterine, bladder, testicular, breast, prostate, pancreatic, and skin cancers.

    PHARMACOKINETICS

    Isotretinoin is administered orally. Distribution has not been fully characterized. Unlike vitamin A, however, isotretinoin does not accumulate in the liver. It is unknown whether isotretinoin crosses the placenta or is excreted into breast milk. The drug is 99.9% bound to plasma proteins.
     
    Isotretinoin is metabolized in the liver primarily via oxidation to 4-oxo-isotretinoin. It is unknown whether this metabolite has pharmacologic activity. The half-life of isotretinoin is about 10—20 hours. The metabolites are eliminated via renal pathways, while unchanged drug and metabolites appear to be excreted in the feces through biliary elimination.

    Oral Route

    Isotretinoin is highly lipophilic and therefore, oral absorption is enhanced when given with a high-fat meal. With the exception of Absorica, isotretinoin formulations should be administered with a meal to enhance bioavailability; however, in general, foods high in cholesterol or fat should be avoided to reduce the risk of developing hypertriglyceridemia. Compared to Accutane, Absorica is bioequivalent when taken with a high-fat meal. However, under fasting conditions, the Absorica AUC is approximately 83% higher and therefore, this formulation is not interchangeable with Accutane or its generic equivalents. Peak plasma concentrations are attained within approximately 3 hours under fasted conditions. Under fed conditions, the peak plasma concentrations are reached in approximately 5—6 hours.