Isotretinoin is an oral retinoid indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years and older with multiple inflammatory nodules with a diameter of at least 5 mm. 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. It has also been used in the symptomatic management of keratinization disorders such as lamellar ichthyosis, keratosis follicularis, and pityriasis rubra pilaris. Isotretinoin and PUVA (psoralen and UVA light) may be as effective as etretinate and PUVA for the management of severe psoriasis. The antineoplastic effects of isotretinoin may be beneficial in the treatment and prevention of basal cell and squamous cell skin cancer, cervical cancer, head and neck cancer, lung cancer, or prostate cancer. Isotretinoin is the synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid). Isotretinoin is associated with an increased risk of teratogenicity; therefore, the drug is only available through the isotretinoin iPLEDGE REMS program. Prescribers, patients, pharmacies, prescribers, and distributors must be registered in the iPLEDGE program. Female patients of reproductive potential have more restrictive requirements than males or females who cannot get pregnant, including the need for pregnancy tests before the use of the drug and monthly during treatment. For more information see www.ipledgeprogram.com.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH (Draft) 2020 List: Table 2
-Approved by FDA after NIOSH 2016 list published.
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Oral Administration
-Absorica and Absorica LD 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 REMS program when prescribing, dispensing, or receiving isotretinoin.
-PRESCRIBERS must register and be activated in the iPLEDGE REMS program and must agree to 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 the negative pregnancy test results prior to writing each prescription, for no more than a 30-day supply
-follow requirements described in the following booklets:-Guide to Best Practices for the iPLEDGE Program
-Prescriber Contraception Counseling Guide
-Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin
-MALE PATIENTS AND FEMALES OF NON-REPRODUCTIVE POTENTIAL must:-understand the risks and benefits of the drug
-comply with the REMS requirements described in the booklet entitled Guide to Isotretinoin for Patients Who Cannot Get Pregnant
-sign a Patient Information/Informed Consent form
-obtain the prescription within 30 days of the office visit
-FEMALES OF REPRODUCTIVE POTENTIAL WHO ARE NOT PREGNANT must:-understand the risks and benefits of the drug
-comply with the REMS requirements described in the booklet entitled Guide to Isotretinoin for Patients Who Can Get Pregnant and Birth Control Workbook (including the pregnancy testing and contraception requirements)
-sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form
-demonstrate comprehension of the safe-use conditions of the program every month
-obtain the prescription within 7 days of the pregnancy test collection
-PHARMACIES must register and be activated with iPLEDGE, only dispense isotretinoin to patients who are authorized to receive the drug, and agree to comply with REMS requirements described in the booklet entitled Pharmacist Guide; specifically, the "Key Information for Pharmacists" section which includes the following dispensing information:-prescriptions must be obtained no later than the "Do Not Dispense To After" date, if not obtained, then the RMA must be reversed in the iPLEDGE Program system and the product returned to the inventory
-no more than a 30-day supply, with Medication Guide, may be dispensed
-refills require a new prescription and a new authorization from the iPLEDGE system
-WHOLESALERS AND DISTRIBUTORS must register with iPLEDGE and agree to comply with the REMS requirements.
Adverse mucocutaneous and dermatological effects are frequently reported with isotretinoin. Cheilitis (inflammation of the lips) appears to be dose-related. Other mucocutaneous and dermatological effects encountered include xerosis, xerostomia, dry nose, peeling, pruritus, acneiform rash (i.e., acne fulminans), alopecia (which can persist), eczema, flushing, hirsutism, impaired wound healing (including delayed wound healing or exuberant granulation tissue with crusting), palmoplantar desquamation (peeling), photosensitivity, rash (unspecified), seborrhea, skin fragility, skin hyperpigmentation, skin hypopigmentation, urticaria, facial erythema, increased sunburn susceptibility, nail dystrophy, bruising (hematoma), hair abnormalities, paronychia, pyogenic granuloma, sweating (hyperhidrosis), dermatitis, contact dermatitis, and eruptive xanthomas. Post-marketing reports of erythema multiforme and severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)) have been associated with isotretinoin use. Patients should be monitored closely for skin reactions during treatment with isotretinoin. Consider discontinuation of isotretinoin if warranted.
Teratogenesis may occur if isotretinoin, in any amount, is given during pregnancy. Major birth defects related to isotretinoin administration have been documented: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, and cranial nerve defects); skull abnormalities; external ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); cardiovascular abnormalities; facial dysmorphia; cleft palate; thymus gland abnormality; and parathyroid hormone deficiency. In some cases, fetal death has occurred. Lowered IQ scores (less than 85) with or without obvious CNS abnormalities have also been reported. There is an increase risk of spontaneous fetal abortion. In addition, premature births have been reported. Prescribers are encouraged to report all cases of pregnancy to the manufacturer or the FDA MedWatch program (800) FDA-1088.
Anaphylactoid reactions and other hypersensitivity reactions have been reported with isotretinoin. Cutaneous allergic reactions and serious cases of allergic vasculitis (including Wegener's granulomatosis), often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal, such as glomerulonephritis), have been reported. Severe allergic reactions necessitate discontinuation of isotretinoin therapy.
Administration of isotretinoin has resulted in alterations in lipid profiles including hypertriglyceridemia (25%, triglycerides less than 800 mg/dl), a decrease in high-density lipoproteins (HDL) (15%), and hypercholesterolemia (7%). Hypertriglyceridemia may be dose related. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported.
Hyperglycemia has been observed in some patients. New cases of diabetes mellitus have been diagnosed during isotretinoin therapy, although no causal relationship has been established.
Approximately 16% of adult patients experience musculoskeletal pain, back pain, arthralgia, and/or myalgia. The incidence of back pain (29%, severe 13.5%) and arthralgias (22%, severe 7.6%) was higher in pediatric patients. These adverse musculoskeletal effects usually resolve upon discontinuing treatment, but have persisted in rare cases. The incidence of arthralgia and myalgia appears to be higher in women. Some patients undergoing vigorous physical activity while receiving isotretinoin have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare post-marketing reports of rhabdomyolysis; some associated with strenuous physical activity. CPK elevations were observed in 24% of patients in a trial of 924 patients. In another trial involving pediatric patients (ages 12 to 17 years), 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. Chest pain (unspecified), arthritis, tendonitis, neck pain, pain in the extremities, musculoskeletal stiffness, and other types of bone abnormalities have also been reported with the use of isotretinoin.
Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of isotretinoin therapy have more of an effect on the musculoskeletal system than a single course of therapy. Premature closure of the epiphyses has been observed in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been observed in isotretinoin-treated patients. While causality to isotretinoin has not been established, an effect cannot be ruled out. In an open-label clinical trial, a single course of isotretinoin therapy for severe recalcitrant nodular acne, bone density measurements at several sites were not significantly decreased (lumbar spine decrease greater than 4% and total hip decrease greater than 5%) or were increased in the majority of patients. Sixteen patients (7.9%) had decreases in lumbar spine bone mineral density greater than 4% and nine patients (4.5%) had a decrease in total hip bone mineral density greater than 5%. Another study of adolescents showed that 8.8% of patients had bone mineral density declines during a 20 week period. 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.
Hematologic effects with isotretinoin include decreases in red blood cell parameters, decreases in white blood cell counts, elevated sedimentation rates, elevated platelet counts, neutropenia, anemia, thrombocytopenia, thrombocytosis, and rare reports of agranulocytosis.
Adverse gastrointestinal effects reported with isotretinoin include weight loss, colitis, decreased appetite, nausea, vomiting, ileus, esophagitis, esophageal ulceration, dry/chapped lips, bleeding/inflammation of gums (gingivitis), constipation, diarrhea, abdominal pain, cheilitis, , and other nonspecific GI symptoms. Isotretinoin has been temporally associated with an inflammatory bowel disease (including regional ileitis). In some cases, these symptoms have persisted after discontinuation of isotretinoin therapy. In a systematic review of all FDA MedWatch reports filed between 1997 and 2002, 85 cases of inflammatory bowel disease (IBD) were reported. The Naranjo ADR probability scale was used to determine the likelihood of an association between the use of isotretinoin and the onset of IBD. According to this scale, the use of isotretinoin was considered to be at least a 'probable' cause of IBD in the majority of the reported cases. Four cases (5%) scored in the 'highly probable' range for isotretinoin as the cause of IBD, 58 cases (68%) were 'probable', 23 cases (27%) were 'possible', and zero cases were doubtful. The median dose of isotretinoin was 40 mg/day. The results of this review suggest there may be an association between the use of isotretinoin and the onset of IBD in some patients. However, it should also be noted that peak age of onset of IBD is also the most common time that isotretinoin is prescribed. Any patient experiencing abdominal pain, severe diarrhea, or rectal bleeding should discontinue use of isotretinoin.
In rare cases, hepatitis has occurred during isotretinoin treatment. Mild to moderate elevated hepatic enzymes have been observed in approximately 15% of patients in clinical trials. Increases in GGTP, alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, SGOT, and SGPT have been observed. If elevated hepatic enzymes persist or if symptoms attributable to hepatitis develop, isotretinoin should be discontinued.
Adverse central nervous effects include dizziness, drowsiness, fatigue, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, and weakness. Isotretinoin with or without concurrent treatment with tetracyclines has also been associated with pseudotumor cerebri (benign increased intracranial pressure). In some instances, retinal hemorrhage has resulted. Patients exhibiting symptoms of this complication (papilledema, headache, nausea, vomiting, and visual disturbances) should be withdrawn from treatment and referred to a neurologist for further evaluation.
Isotretinoin may cause depression, emotional lability, psychosis, aggression, violent behavior, anxiety, irritability, panic attack, anger, euphoria, auditory hallucinations, and rarely, suicidal ideation, suicide attempts, and suicide. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. A retrospective, cohort study of 5756 patients with severe acne examined the incidence of suicide attempts in isotretinoin-treated patients compared to the general population up to three years before treatment, during treatment, and up to 15 years after treatment. Although not statistically significant, there was a trend toward increased incidence of suicide attempts prior to initiation of therapy. The standardized incidence ratio rose from 0.89 (CI 95% 0.54 to 1.37) 3 years before treatment to 1.36 (0.65 to 2.5) in the year before treatment for first suicide attempts and from 0.99 (0.65 to 1.44) 3 years before isotretinoin treatment to 1.57 (0.86 to 2.63) in the year before treatment for all suicide attempts. The risk peaked to 1.93 (1.08 to 3.18) for first attempts and 1.78 (1.04 to 2.85) for all attempts during and for 6 months after treatment with isotretinoin. Within three years after treatment, the risk returned to normal. Because the risk of suicide was increasing prior to initiation of isotretinoin therapy, clinicians should consider monitoring patients with severe acne for symptoms of depression or suicidal thoughts regardless of the use of isotretinoin therapy. Patients who receive isotretinoin therapy should be closely observed during treatment and for up to 1 year after discontinuation for symptoms of depression or suicidal thoughts, such as sad mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating, or for mood disturbance, psychosis, or aggression. Patients should stop isotretinoin and they or their caregiver should contact their healthcare professional right away if the patient has any of the previously mentioned symptoms. Discontinuation of treatment may be insufficient and further evaluation may be necessary. No mechanism of action has been established for these psychiatric events. Isotretinoin treatment has also been associated with improvement in psychological functions, including mood, as the acne condition improves.
Corneal opacification (diffuse, fine, white to gray, subepithelial deposits) has been reported in patients receiving isotretinoin for acne and in those receiving high dosages for keratinization disorders. This ocular effect is reversible, with either complete resolution or continuing resolution at 6-7 weeks following discontinuance of treatment. Visual disturbances characterized by blurred vision, color vision disorder, potentially sudden decreased night vision (night blindness) that may persist, decreased visual acuity, diplopia (double vision), photophobia, tunnel vision, visual impairment or loss have been observed. Cataracts, keratitis, optic neuritis, xerophthalmia (dry eyes), conjunctivitis, ocular pruritus, ocular irritation, conjunctival hyperemia, asthenopia (symptoms include ocular fatigue, pain in or around the eyes, blurred vision, headache, and sometimes diplopia), eyelid inflammation, and increased lacrimation may also occur during isotretinoin therapy.
Hearing loss or impairment and tinnitus have been reported with isotretinoin therapy. These symptoms may persist after discontinuation of therapy.
Genitourinary adverse reactions reported during treatment with isotretinoin include nonspecific urogenital findings, abnormal menses (menstrual irregularity), impotence (erectile dysfunction), libido decrease, microscopic or gross hematuria, proteinuria, and white cells in the urine (pyuria).
Respiratory adverse reactions associated with isotretinoin include epistaxis, nasal dryness, bronchospasm (with or without a history of asthma), and voice alteration.
Cardiovascular adverse reaction associated with isotretinoin include vascular thrombotic disease, palpitations, stroke, and sinus tachycardia.
Isotretinoin complications with infection include nasopharyngitis/pharyngitis, hordeolum, disseminated herpes simplex and respiratory infection.
General adverse events noted with isotretinoin therapy include hyperuricemia, edema and lymphadenopathy.
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.
Isotretinoin is contraindicated for use during pregnancy. 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. Documented birth defects associated with isotretinoin include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, thymus, and parathyroid glands. Spontaneous abortion and premature births have also been reported. 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. Patients must 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, use of the drug must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. 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 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.
According to the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), breast-feeding women should not receive isotretinoin due to the potential adverse effects to the nursing infant. Lactating women who are exposed to isotretinoin should avoid breast-feeding during treatment and for at least 30 days after the last dose. It is unknown whether isotretinoin is distributed into breast milk, effects the breast-fed infant, or effects milk production. 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.
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 or 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 younger than 12 years of age. Use of isotretinoin in pediatric patients 12 to 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 delayed healing in patients involved in these activities while receiving isotretinoin treatment or following cessation of treatment. 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.
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.
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.
Isotretinoin should be used cautiously in patients with psychotic disorders. Postmarketing reports show that isotretinoin may cause major depression, psychosis, and rarely, suicidal ideation, suicide attempts, suicide, and aggressive or violent behaviors. Discontinuation of isotretinoin therapy may be insufficient; further evaluation by a mental health professional may be necessary. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults.
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, 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.
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.
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.
Isotretinoin has been associated with an extremely high risk of birth defects if taken during pregnancy in any amount even for a short period of time. Discuss reproductive risk with the patient prior to initiation of therapy. Isotretinoin must not be initiated in females of childbearing potential, regardless of whether they are sexually active, until negative results from 2 urine or serum pregnancy tests are confirmed and the patient or her guardian completes the consent form; the interval between the 2 tests should be at least 19 days. Monthly pregnancy testing during isotretinoin therapy is also required. Discuss contraception requirements with the patient before beginning treatment and monthly during treatment. Women who are, or might become, sexually active with a male partner must select and use 2 forms of effective contraception simultaneously for at least 1 month before beginning, during, and for 1 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.
For the treatment of severe recalcitrant cystic acne vulgaris (nodular acne) in persons with multiple inflammatory nodules with a diameter of at least 5 mm:
Oral dosage (all formulations excluding Absorica LD):
Adults: 0.5 to 1 mg/kg/day PO in 2 divided doses for 15 to 20 weeks or until the total nodule count decreases by more than 70%, whichever occurs first. Doses up to 2 mg/kg/day may be necessary for severe disease (e.g. scarring, trunk involvement). After 2 months or more off therapy, a second course may be initiated in persons who have completed skeletal growth if warranted by persistent or recurring severe nodular acne.
Children and Adolescents 12 to 17 years: 0.5 to 1 mg/kg/day PO in 2 divided doses for 15 to 20 weeks or until the total nodule count decreases by more than 70%, whichever occurs first. The optimal interval before retreatment has not been defined for persons who have not completed skeletal growth. After 2 months or more off therapy, a second course may be initiated in persons who have completed skeletal growth if warranted by persistent or recurring severe nodular acne.
Oral dosage (Absorica LD):
NOTE: Due to different bioavailability and recommended dosage, Absorica LD is not substitutable with other formulations of isotretinoin.
Adults: 0.4 to 0.8 mg/kg/day PO in 2 divided doses for 15 to 20 weeks or until the total nodule count decreases by more than 70%, whichever occurs first. Doses up to 1.6 mg/kg/day may be necessary for severe disease (e.g. scarring, trunk involvement). After 2 months or more off therapy, a second course may be initiated in persons who have completed skeletal growth if warranted by persistent or recurring severe nodular acne.
Children and Adolescents 12 to 17 years: 0.4 to 0.8 mg/kg/day PO in 2 divided doses for 15 to 20 weeks or until the total nodule count decreases by more than 70%, whichever occurs first. The optimal interval before retreatment has not been defined for persons who have not completed skeletal growth. After 2 months or more off therapy, a second course may be initiated in persons who have completed skeletal growth if warranted by persistent or recurring severe nodular acne.
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.
Children: Safety and efficacy have not been established.
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%).
For the treatment of acne rosacea*:
Oral dosage:
Adults: 0.3 mg/kg/day PO or 10 to 20 mg/day PO for 4 to 6 months, then may consider continuous microdose therapy at 0.03 to 0.17 mg/kg/day PO.
Maximum Dosage Limits:
-Adults
2 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 1.6 mg/kg/day PO (Absorica LD) for cystic acne.
-Geriatric
2 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 1.6 mg/kg/day PO (Absorica LD) for cystic acne.
-Adolescents
1 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 0.8 mg/kg/day PO (Absorica LD) for cystic acne.
-Children
12 years: 1 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 0.8 mg/kg/day PO (Absorica LD) for cystic acne.
younger than 12 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adapalene; Benzoyl Peroxide: (Moderate) 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.
Albuterol; Budesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Azelastine; Fluticasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Beclomethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Benzoyl Peroxide: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) 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.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) 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.
Budesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Budesonide; Formoterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Cholestyramine: (Moderate) 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: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Clindamycin; Adapalene; Benzoyl Peroxide: (Moderate) 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.
Colestipol: (Moderate) 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.
Corticosteroids: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Cortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Deflazacort: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Demeclocycline: (Major) 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.
Dexamethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Doxycycline: (Major) 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.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) 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.
Eravacycline: (Major) Avoid the concomitant use of isotretinoin and eravacycline due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.
Ethanol: (Minor) Alcohol consumption can increase the risk for isotretinoin-related hypertriglyceridemia; patients experiencing hyperlipidemia while on isotretinoin should be advised to limit their alcohol intake.
Fludrocortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Flunisolide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone; Salmeterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone; Umeclidinium; Vilanterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fluticasone; Vilanterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Formoterol; Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Fosphenytoin: (Minor) 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: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Levomefolate: (Minor) 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.
Lomitapide: (Moderate) 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.
Methotrexate: (Moderate) 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: (Moderate) 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: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Minocycline: (Major) 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.
Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Olopatadine; Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Omadacycline: (Major) 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.
Orlistat: (Moderate) 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.
Palovarotene: (Major) Avoid concomitant use of palovarotene and other retinoids, such as isotretinoin, due to the risk for hypervitaminosis A.
Phenytoin: (Minor) 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.
Porfimer: (Major) Avoid coadministration of porfimer with retinoids due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.
Prednisolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Prednisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Salicylic Acid: (Moderate) 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.
Sarecycline: (Major) 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.
Sodium Thiosulfate; Salicylic Acid: (Moderate) 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.
Tetracycline: (Major) 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.
Tetracyclines: (Major) 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.
Tretinoin; Benzoyl Peroxide: (Moderate) 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.
Triamcinolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.
Valoctocogene Roxaparvovec: (Major) Avoid concomitant use of isotretinoin and valoctocogene roxaparvovec. Concomitant use may reduce factor VIII activity independent of hepatotoxicity.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with retinoids is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.
Warfarin: (Moderate) Isotretinoin can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed.
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.
Isotretinoin is administered orally. Distribution has not been fully characterized; however, unlike vitamin A, 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, primarily albumin. Isotretinoin is metabolized in the liver by CYP2C8, CYP2C9, CYP3A4, and CYP2B6. At least 3 metabolites [4-oxo-isotretinoin, retinoic acid (tretinoin), 4-oxo-retinoic acid (4-oxo-tretinoin)] have been identified in human plasma. All of three metabolites have retinoid activity in vivo; however, the clinical significance of the metabolites' activity is unknown. The half-lives of isotretinoin and its active metabolite, 4-oxo-isotretinoin, are about 10 to 24 hours and 38 hours, respectively. The metabolites of isotretinoin are eliminated in the feces and urine in relatively equal amounts.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Oral Route
Isotretinoin is highly lipophilic and therefore, oral absorption is enhanced when given with a high-fat meal. With the exception of Absorica and Absorica LD, 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 to 6 hours.
-Special Populations
Pediatrics
Data from one study found no clinically significant differences in the pharmacokinetics of isotretinoin based on the drug recipients age [i.e., 12 to 15 year (n=38) versus 18 years and older (n=19)].