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Isotretinoin: Drug information

Isotretinoin: Drug information
(For additional information see "Isotretinoin: Patient drug information" and see "Isotretinoin: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
REMS Drugs COVID-19 Safety Alert March 2020

Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.

Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.

ALERT: US Boxed Warning
Pregnancy:

Isotretinoin can cause severe, life-threatening birth defects and is contraindicated in pregnancy. Isotretinoin must not be used by patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin in any amount, even for short periods of time. Potentially, any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected.

Birth defects that have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, CNS, cardiovascular system, and thymus and parathyroid glands. Cases of intelligence quotient (IQ) scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported.

Documented external abnormalities include skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases, death has occurred with some of the abnormalities previously noted.

If pregnancy does occur during treatment of a patient who is taking isotretinoin, isotretinoin must be discontinued immediately and the patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Special prescribing requirements:

Because of isotretinoin's teratogenicity and to minimize fetal exposure, isotretinoin is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This REMS is called iPLEDGE. Isotretinoin must only be prescribed by prescribers who are enrolled and activated with the iPLEDGE REMS. Isotretinoin must only be dispensed by a pharmacy enrolled and activated with iPLEDGE, and must only be dispensed to patients who are enrolled and meet all the requirements of iPLEDGE.

Brand Names: US
  • Absorica;
  • Absorica LD;
  • Accutane;
  • Amnesteem;
  • Claravis;
  • Myorisan;
  • Zenatane
Brand Names: Canada
  • Accutane Roche;
  • ALTI-Isotretinoin;
  • Clarus;
  • Epuris
Pharmacologic Category
  • Acne Products;
  • Antineoplastic Agent, Retinoic Acid Derivative;
  • Retinoic Acid Derivative
Dosing: Adult

Note: Isotretinoin products are available in different formulations: a standard formulation (eg, Amnesteem, Claravis, Myorisan, Zenatane) that requires administration with food and lidose (Absorica) and micronized (Absorica LD) formulations that may be administered with or without food. Standard formulations are not bioequivalent to lidose or micronized formulations. Lidose and micronized formulations are not substitutable with one another due to differences in bioavailability.

Note: All dosing is based on use of a standard or lidose formulation unless otherwise indicated.

Acne vulgaris, moderate to severe

Acne vulgaris, moderate to severe: Oral:

Standard or lidose formulation: 0.5 mg/kg/day in 2 divided doses for 1 month, then increase to 1 mg/kg/day in 2 divided doses as tolerated; alternatively, may administer the total daily dose once daily to increase adherence to therapy (Owen 2022). For patients with severe inflammatory acne (eg, acne conglobata) or deep comedonal acne, consider initial doses <0.5 mg/kg/day (eg, 0.1 mg/kg/day) in combination with an oral glucocorticoid given before or at isotretinoin initiation and continued for the first 2 to 4 weeks of therapy to reduce the risk of severe acne flares (AAD [Zaenglein 2016]; Greywal 2017; Owen 2022). Continue until a total cumulative dose of 120 to 150 mg/kg is reached (AAD [Zaenglein 2016]).

Micronized formulation: 0.4 to 0.8 mg/kg/day in 2 divided doses. Adults with very severe disease/scarring or primarily involving the trunk may require dosage adjustment up to 1.6 mg/kg/day in divided doses, as tolerated. Continue therapy until nodule count has been reduced by at least 70% or for up to 15 to 20 weeks.

Alternative low-dose regimen for moderate acne (off-label use): Standard or lidose formulation: 0.3 to 0.5 mg/kg once daily (AAD [Zaenglein 2016]; Amichai 2006; Lee 2011; Owen 2022). Continue until a total cumulative dose of 120 to 150 mg/kg is reached (AAD [Zaenglein 2016]).

Cutaneous T-cell lymphomas

Cutaneous T-cell lymphomas (off-label use): Oral: Induction: 1 mg/kg/day (in 2 divided doses and in combination with interferon alfa-2b) for 3 to 4 months (Duvic 2003; Knobler 1991). If response occurs, may continue therapy for an additional 3 months; if response continues after 6 months of therapy, may administer isotretinoin and interferon alfa-2b at a 50% reduced dose for an additional 3 months, followed by interferon alfa-2b maintenance therapy (Knobler 1991). Additional trials may be necessary to further define the role of isotretinoin in the management of this condition.

Squamous cell skin cancer, prevention in high-risk patients

Squamous cell skin cancer, prevention in high-risk patients (off-label use): Oral: Initial: 0.25 mg/kg every other day for 1 month, then 0.25 mg/kg daily for one month, then 0.5 mg/kg daily. Adjust dose as needed based on tolerance; higher doses may be more effective for severe skin cancer (Otley 2006). Additional data may be necessary to further define the role of isotretinoin in this setting.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling.

Hepatotoxicity during treatment: Liver enzymes may normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis is suspected.

Dosing: Pediatric

(For additional information see "Isotretinoin: Pediatric drug information")

Note: The product formulation of Absorica LD (micronized) is not bioequivalent to other capsule formulations of isotretinoin (eg, Absorica, or softgel formulations: generics, Amnesteem, Claravis, Myorisan, Zenatane) and should not be substituted on a mg:mg basis.

Acne vulgaris, severe recalcitrant nodular: Children ≥12 years and Adolescents:

Softgel capsule (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane) or hard-gelatin capsule (Absorica):

Initial: Oral: 0.5 mg/kg/day in 2 divided doses for 4 weeks, then increase dose to 1 mg/kg/day in 2 divided doses (AAD [Zaenglein 2016]; AAP [Eichenfield 2013]); for severe extensive cases (involving trunk, nuchal region, lower back, buttocks, thighs) may require higher doses up to 2 mg/kg/day in 2 divided doses (manufacturer labeling).

Duration of therapy: Typically 15 to 20 weeks depending upon daily dose; a target cumulative dose range of 120 to 150 mg/kg has been recommended based on observed lower relapse rates with courses ≥120 mg/kg and the plateau effect observed with higher cumulative total doses of >150 mg/kg (AAD [Zaenglein 2016]).

Repeat course: In older adolescents who have completed skeletal growth, a second course of isotretinoin may be repeated after a period of ≥2 months off therapy for persistent or recurring severe nodular acne; for younger patients who have not completed skeletal growth, the optimal interval before retreatment has not been defined.

Micronized hard-gelatin capsule (eg, Absorica LD): Oral: 0.4 to 0.8 mg/kg/day in 2 divided doses. In adults with severe, extensive cases (involving trunk, nuchal region, lower back, buttocks, thighs), higher doses up to 1.6 mg/kg/day in 2 divided doses have been used; pediatric data specific to the micronized dosage form is lacking. Duration of therapy is typically 15 to 20 weeks, until the total cyst count decreased by 70%, whichever is sooner. Based on experience with other isotretinoin dosage forms, in older adolescents who have completed skeletal growth, a second course of isotretinoin may be repeated after a period of ≥2 months off therapy for persistent or recurring severe nodular acne; for younger patients who have not completed skeletal growth, the optimal interval before retreatment has not been defined.

Acne vulgaris, moderate: Limited data available: Children ≥12 years and Adolescents: Softgel capsule (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane) and hard-gelatin capsule (Absorica): Oral: 0.25 to 0.4 mg/kg/day continued for 6 to 12 months (AAD [Zaenglein 2016]; Amichai 2006).

Neuroblastoma, maintenance: Limited data available: Infants, Children, and Adolescents: Softgel capsule (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane) and hard-gelatin capsule (Absorica): Oral: 80 mg/m2/dose every 12 hours for the last 2 weeks (14 consecutive days) of a 4-week cycle for 6 cycles; dinutuximab therapy is administered during the first week of the 4-week cycle (Yu 2010); begin after continuation chemotherapy or transplantation (Matthay 1999).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

Children and Adolescents:

Baseline hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling.

Hepatotoxicity during treatment: Mild liver enzymes may occur, and generally normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis (eg, transaminases >3 times baseline) is suspected (Brelsford 2008).

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Absorica: 10 mg, 20 mg [contains soybean oil]

Absorica: 25 mg [contains fd&c blue #1 (brilliant blue), fd&c yellow #5 (tartrazine), fd&c yellow #6 (sunset yellow), soybean oil]

Absorica: 30 mg [contains soybean oil]

Absorica: 35 mg [contains fd&c blue #2 (indigo carmine,indigotine), soybean oil]

Absorica: 40 mg [contains soybean oil]

Absorica LD: 8 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10), soybean oil]

Absorica LD: 16 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), soybean oil]

Absorica LD: 24 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10), soybean oil]

Absorica LD: 32 mg [contains soybean oil]

Accutane: 10 mg [contains edetate (edta) disodium, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carmine,indigotine), methylparaben, propylparaben, quinoline (d&c yellow #10) aluminum lake, soybean oil]

Accutane: 20 mg [contains disodium edta, fd&c blue #2 (indigo carmine,indigotine), fd&c red #40(allura red ac)aluminum lake, soybean oil]

Accutane: 30 mg [contains disodium edta, fd&c blue #2 (indigo carmine,indigotine), soybean oil]

Accutane: 40 mg [contains disodium edta, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carmine,indigotine), quinoline (d&c yellow #10) aluminum lake, soybean oil]

Amnesteem: 10 mg, 20 mg, 40 mg [contains soybean oil]

Claravis: 10 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Claravis: 20 mg, 30 mg [contains edetate (edta) disodium, soybean oil]

Claravis: 40 mg [contains edetate (edta) disodium, fd&c yellow #6 (sunset yellow), soybean oil]

Myorisan: 10 mg, 20 mg [contains soybean oil]

Myorisan: 30 mg

Myorisan: 40 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Zenatane: 10 mg [contains edetate (edta) disodium, fd&c blue #1 (brilliant blue), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]

Zenatane: 20 mg [contains edetate (edta) disodium, methylparaben, propylparaben, soybean oil]

Zenatane: 30 mg [contains edetate (edta) disodium, fd&c blue #2(indig carmine)aluminum lake, methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]

Zenatane: 40 mg [contains edetate (edta) disodium, fd&c blue #1 (brilliant blue), fd&c blue #2 (indigo carmine,indigotine), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]

Generic: 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Accutane Roche: 10 mg [contains soybean oil]

Accutane Roche: 40 mg [contains fd&c yellow #6 (sunset yellow), methylparaben, propylparaben, quinoline yellow (d&c yellow #10), soybean oil]

Clarus: 10 mg, 40 mg [contains soybean oil]

Epuris: 10 mg, 20 mg, 30 mg, 40 mg [contains soybean oil]

Generic: 10 mg, 40 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Absorica: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021951s013lbl.pdf#page=32

Accutane: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018662s061MedGuide.pdf

Sotret: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/Sotret.pdf

Administration: Adult

Oral: Administer standard formulation with a meal; lidose (Absorica) or micronized (Absorica LD) formulations may be taken without regard to meals. According to the manufacturer's labeling, capsules should be swallowed whole with a full glass of liquid; do not chew or suck on the capsule. For patients unable to swallow capsule whole, an oral liquid may be prepared (see "Extemporaneously Prepared"); may irritate esophagus if contents are removed from the capsule. Safety of once-daily dosing of isotretinoin has not been established and is not recommended.

Neuroblastoma (off-label use): In a pharmacokinetic study, the end of the capsule was punctured/cut and capsule contents extruded into ice cream or yogurt if patients were unable to swallow capsules whole; if capsule is opened, contents must be consumed immediately to avoid degradation (Veal 2007). Refer to "Extemporaneously Prepared" for additional information.

Administration: Pediatric

Oral:

Softgel (eg, generics, Amnesteem, Claravis, Myorisan, Zenatane): Administer orally with a meal. According to the manufacturers’ labeling, capsules should be swallowed whole with a full glass of liquid. For patients unable to swallow capsule whole, an oral liquid may be prepared (see Extemporaneous Preparations). Contents removed from capsules may irritate esophagus.

Neuroblastoma: In pediatric neuroblastoma trials when patient was unable to swallow capsule, the end of capsule was punctured/cut and capsule's contents extruded into ice cream or yogurt (high-fat food); if capsule is opened, contents must be consumed immediately to avoid degradation of the drug (Matthay 1999; Veal 2007).

Hard-gelatin capsules (Absorica, Absorica LD [micronized]): May be taken without regard to meals.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it meets the criteria for a hazardous drug. Isotretinoin may cause teratogenicity and has a structural or toxicity profile similar to existing hazardous agents.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Acne vulgaris, severe: Treatment of severe recalcitrant nodular acne unresponsive to conventional therapy (including systemic antibiotics).

Use: Off-Label: Adult

Acne vulgaris, moderate; Cutaneous T-cell lymphomas; Squamous cell skin cancer (prevention in high-risk patients)

Medication Safety Issues
Sound-alike/look-alike issues:

Accutane may be confused with Accolate, Accupril.

Claravis may be confused with Cleviprex.

ISOtretinoin may be confused with tretinoin.

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

Isotretinoin may be confused with tretinoin (which is also called all-trans retinoic acid, or ATRA); while both products may have uses in cancer treatment, they are not interchangeable.

Adverse Reactions (Significant): Considerations
Bone and growth effects

Data are conflicting, but decreased bone mineral density (Ref), osteopenia, osteoporosis, bone fracture, and delayed healing of bone fractures have been reported (Ref). Premature epiphyseal closure has been reported (Ref).

Mechanism: Possibly dose-related; related to pharmacologic action (ie, retinoids may lead to impaired bone growth) (Ref).

Onset: Delayed; noted on imaging 6 months after initiation (Ref). Premature epiphyseal closure may occur months to years after initiation (Ref).

Risk factors:

• Higher doses for prolonged durations may be associated with premature epiphyseal closure (Ref)

• Genetic predisposition for bone loss (eg, age-related osteoporosis, history of childhood osteoporosis conditions, osteomalacia, other disorders of bone metabolism)

• Concurrent use of oral contraceptives (Ref)

Cutaneous/hypersensitivity reactions

Cutaneous adverse reactions associated with isotretinoin range from mucocutaneous effects such as cheilitis, xeroderma, dry eye syndrome, conjunctivitis, blepharitis, and episcleritis (Ref) to cases of erythema nodosum (Ref), pityriasis rosea-like eruptions (Ref), pyogenic granuloma (Ref), acne fulminans (Ref), skin photosensitivity (Ref), and pyoderma gangrenosum (Ref). Hypersensitivity reactions have also been reported, including immediate (anaphylaxis, angioedema) (Ref) and delayed reactions (Stevens-Johnson syndrome [SJS] (Ref), toxic epidermal necrolysis, erythema multiforme-like drug eruption, acute generalized exanthematous pustulosis [AGEP], allergic vasculitis, allergic myocardial infarction) (Ref). Inflammatory sacroiliitis has also been described with isotretinoin, in association with a HLA-B27 negative antigen (Ref).

Mechanism:

• Immediate hypersensitivity reactions: Non–dose-related; immunologic (ie, IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure) (Ref).

• Delayed hypersensitivity reactions: Non–dose-related, immunologic. SJS and AGEP are T-cell mediated (Ref). Allergic myocardial infarction occurs due to mast cell degranulation following an allergic insult (Ref).

• Cheilitis: Dose-related (Ref). Isotretinoin and its major metabolite, 4-oxo-isotretinoin, have been shown to have a phototoxic potential (Ref).

Onset:

• Immediate hypersensitivity reactions: Rapid; generally occurs within 1 hour of administration but may occur several hours after exposure (Ref).

• Delayed hypersensitivity reactions: Varied. Severe cutaneous adverse reactions, including SJS and AGEP, usually occur 1 to 8 weeks after initiation (Ref). Allergic vasculitis usually occurs 6 weeks to 5 months after isotretinoin initiation (Ref) and has been reported to occur up to 6 weeks after discontinuation of isotretinoin (Ref). Allergic myocardial infarction can occur within 5 minutes of isotretinoin administration (Ref).

• Cutaneous reactions: Varied, with most reactions occurring 2 to 6 weeks after isotretinoin initiation (Ref).

• Sacroiliitis: Delayed; occurs months to years after initiation of isotretinoin (Ref).

Hepatic effects

Clinical hepatitis and mild to moderate increased liver enzymes have been reported in ~15% of patients receiving isotretinoin (Ref). Reversibility back to baseline has been demonstrated within 4 weeks of discontinuation (Ref).

Mechanism: Unknown; may be related to other comorbidities, concurrent drug therapy, or idiosyncratic (Ref).

Onset: Delayed; occurring 1 to 3 months after initiation (Ref).

Risk factors:

• Concurrent hepatotoxic medications, including alcohol

Hypertriglyceridemia and pancreatitis

Increased serum triglycerides occur in ~5% to 25% of patients receiving isotretinoin (Ref). Rare and potentially fatal acute pancreatitis may occur in patients with normal or elevated triglyceride levels (Ref). Case reports in adolescents (Ref) and adults (Ref) have demonstrated reversibility upon discontinuation.

Mechanism: Retinoids increase apolipoproteins (Ref).

Onset: Varied; seen within 2 weeks to 15 months of initiation (Ref)

Risk factors:

• Elevated baseline triglycerides (Ref)

• Weight >89 kg males or >73 kg females (Ref)

Musculoskeletal effects

Common and potentially fatal (Ref) musculoskeletal symptoms (arthralgia, myalgia, rhabdomyolysis) have been reported in pediatric and adult patients; generally, symptoms were mild to moderate but occasionally required discontinuation of therapy (Ref). Children may experience a higher frequency of myalgia, arthralgia, and back pain. Myalgia symptom resolution occurred with dose reduction, cessation of therapy, or treatment with a non-steroidal anti-inflammatory medication (Ref).

Mechanism: Dose-related; not clearly established. Hypothesized to cause cell membrane damage (Ref).

Onset: Varied; onset can be 1 week to 3 months following initiation (Ref).

Risk factors:

• High cumulative dose (>1,800 mg) (Ref).

• Females (Ref).

Ocular effects

Visual disturbance, night blindness, dry eye syndrome, eye irritation, and conjunctivitis have been reported in 10% to 70% of patients (Ref). Cessation in therapy may reverse ocular effects; however, permanent damage may occur (Ref).

Mechanism: Causes changes in the cornea, tear film composition, and visual process in the retina (Ref).

Onset: Delayed; seen after 3 months of therapy (Ref).

Risk factors:

• Males (Ref)

• Weight <70 kg (Ref)

• Hypovitaminosis A (Ref)

Pseudotumor cerebri

Rare and reversible pseudotumor cerebri (idiopathic intracranial hypertension) has been documented in case reports (Ref) and in large scale adverse drug reporting systems (Ref). Symptoms are reversible with cessation of isotretinoin (Ref).

Mechanism: Unclear (Ref).

Onset: Delayed; onset is typically 2 months (Ref).

Risk factors:

• Concurrent use with tetracyclines (Ref)

Psychiatric effects

While data are conflicting, isotretinoin may cause depression, psychosis, mood disturbance (Ref), and rarely, suicidal ideation, suicidal tendencies, death by suicide, aggressive behavior, and/or violent behavior (Ref). Symptoms often resolve with therapy discontinuation (Ref).

Mechanism: Dose-related; the fat solubility of isotretinoin allows for passage through the blood brain barrier, possibly affecting the dopamine and serotonin or hypothalamic regulation (Ref).

Onset: Delayed; occurs between 1 to 4 months after initiation (Ref).

Risk factors:

• Higher doses (Ref)

• Underlying psychiatric diagnosis, in particular bipolar disorder (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are for adults and adolescents unless otherwise indicated.

>10%:

Endocrine & metabolic: Decreased HDL cholesterol (15%), increased serum triglycerides (25%; including cases reported >800 mg/dL)

Hepatic: Increased liver enzymes (15%, including increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin)

Neuromuscular & skeletal: Arthralgia (≤22%; severe arthralgia: adolescents: 2%), back pain (adolescents: 29%)

1% to 10%:

Endocrine & metabolic: Increased serum cholesterol (7%)

Neuromuscular & skeletal: Decreased bone mineral density (adolescents: 9%)

Frequency not defined:

Cardiovascular: Cerebrovascular accident, chest pain (transient), edema, flushing, palpitations, syncope, tachycardia, thrombosis, vasculitis (ten Holder 2002)

Dermatologic: Acne fulminans (Fakih 2020), alopecia (Vallerand 2018), cheilitis (Vallerand 2018), cheilosis (Vallerand 2018), contact dermatitis, dermatitis (Vallerand 2018), diaphoresis, eczema (Vallerand 2018), erythema of skin, facial erythema, fragile skin, hair disease, hyperpigmentation, hypopigmentation, nail disease, paronychia, pruritus (Vallerand 2018), pyogenic granuloma (Simmons 2016), scaling of skin of feet, seborrhea, skin photosensitivity (Vallerand 2018), skin rash, sunburn, superficial peeling of palms, urticaria (Saray 2006), xeroderma (Vallerand 2018)

Endocrine & metabolic: Altered serum glucose, decreased libido, eruptive xanthoma, hirsutism, hyperuricemia, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased LDL cholesterol, increased serum glucose, menstrual disease, weight loss

Gastrointestinal: Abdominal pain, colitis, constipation, decreased appetite, diarrhea (Vallerand 2018), esophageal ulcer, esophagitis, gingival hemorrhage, gingivitis, ileitis, inflammatory bowel disease (Papageorgiou 2009, Passier 2006), nausea (Vallerand 2018), pancreatitis (Opel 2017), vomiting (Vallerand 2018), xerostomia (Vallerand 2018)

Genitourinary: Erectile dysfunction, gross hematuria, microscopic hematuria, proteinuria, pyuria, sexual disorder

Hematologic & oncologic: Anemia, bruise, decreased white blood cell count, increased erythrocyte sedimentation rate, lymphadenopathy, severe neutropenia, thrombocythemia, thrombocytopenia

Infection: Herpes simplex infection (disseminated), infection

Nervous system: Aggressive behavior (Bremner 2012), anxiety, auditory hallucinations (Vallerand 2018), depression (Vallerand 2018), dizziness, drowsiness, emotional lability, euphoria, fatigue (Vallerand 2018), headache (Vallerand 2018), insomnia (Vallerand 2018), irritability, lethargy (Vallerand 2018), malaise, nervousness, outbursts of anger, pain, panic attack, paresthesia, psychosis, seizure, suicidal ideation (Bremner 2012), suicidal tendencies (Bremner 2012), violent behavior, voice disorder

Neuromuscular & skeletal: Arthritis, asthenia, bone fracture (Miziolek 2019), calcification of ligament, calcification of tendon, granulomatosis with polyangiitis (ten Holder 2002), increased creatine phosphokinase in blood specimen, limb pain, musculoskeletal pain (Vallerand 2018), myalgia, neck pain, osteopenia (Miziolek 2019), osteoporosis (Miziolek 2019), premature epiphyseal closure (Alazawi 2011), skeletal hyperostosis, stiffness, tendinopathy

Ophthalmic: Asthenopia, blepharitis, blurred vision (Vallerand 2018), cataract, conjunctivitis (Vallerand 2018), corneal opacity, decreased visual acuity, eye irritation (Vallerand 2018), eye pruritus, hordeolum, increased lacrimation, keratitis, ocular hyperemia, optic neuritis, photophobia (Vallerand 2018), vision color changes, visual disturbance (Vallerand 2018)

Otic: Tinnitus (Rosende 2011)

Renal: Glomerulonephritis

Respiratory: Bronchospasm, dry nose (Vallerand 2018), epistaxis (Vallerand 2018), nasopharyngitis, respiratory tract infection, upper respiratory tract infection

Miscellaneous: Wound healing impairment

Postmarketing:

Cardiovascular: Hypersensitivity angiitis (Vallerand 2018)

Dermatologic: Acute generalized exanthematous pustulosis (da Cunha Filho 2010), allergic skin reaction, erythema multiforme, erythema nodosum (Pasmatzi 2020), pityriasis rosea (Gurel 2018), pyoderma gangrenosum (Wang 2018), Stevens-Johnson syndrome (Vallerand 2018), toxic epidermal necrolysis

Hematologic & oncologic: Agranulocytosis (Ozdemir 2007)

Hepatic: Hepatitis (Kizilyel 2014)

Hypersensitivity: Anaphylaxis (Bamidis 2021), angioedema (Saray 2006)

Nervous system: Idiopathic intracranial hypertension (pseudotumor cerebri) (Tan 2019, Varoglu 2018)

Neuromuscular & skeletal: Rhabdomyolysis (Gutman-Yassky 2003)

Ophthalmic: Dry eye syndrome (Vallerand 2018), eyelid disease (meibomian gland dysfunction/atrophy) (Neudorfer 2012), night blindness (Teo 2014)

Otic: Auditory impairment (Gainville 2021)

Contraindications

Hypersensitivity to isotretinoin or any component of the formulation; pregnancy. Note: Based on the chemical similarity of vitamin A to isotretinoin, the prescribing information of some products (eg, Absorica) lists sensitivity to vitamin A as a contraindication to isotretinoin therapy.

Canadian labeling: Additional contraindications not in the US labeling: Breastfeeding, hepatic or renal insufficiency, hypervitaminosis A, excessive hyperlipidemia, concurrent tetracycline therapy.

Documentation of allergenic cross-reactivity for retinoids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

Concerns related to adverse effects:

• Inflammatory bowel disease: Inflammatory bowel disease (IBD), including regional ileitis, has been reported in patients without a prior history of intestinal disorders; discontinue treatment immediately if abdominal pain, rectal bleeding, or severe diarrhea occurs. Of note, a position statement from the American Academy of Dermatology states that based on currently available data, there is insufficient evidence to prove either an association or a causal relationship between IBD and isotretinoin use (AAD 2016).

• Photosensitivity: Avoid prolonged exposure to UV rays or sunlight.

Disease-related concerns:

• Diabetes: Use with caution in patients with diabetes mellitus; impaired glucose control has been reported.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

• Product interchange: Isotretinoin and tretinoin (which is also known as all-trans retinoic acid, or ATRA) may be confused, while both products may be used in cancer treatment, they are not interchangeable; verify product prior to dispensing and administration to prevent medication errors.

• Tartrazine: Some products may contain tartrazine (FD&C yellow no. 5), which may cause allergic reactions, including bronchial asthma, in certain individuals. Allergy is frequently seen in patients who also have an aspirin hypersensitivity.

Other warnings/precautions:

• Blood donation: Patients should be instructed not to donate blood during therapy and for 1 month following discontinuation of therapy due to risk of donated blood being given to a pregnant patient.

• Experienced health care provider: This medication should only be prescribed by health care providers competent in treating severe recalcitrant nodular acne and experienced with the use of systemic retinoids.

• Long-term use: Safety of long-term use is not established and is not recommended; the effect on bone loss is unknown.

• Skin resurfacing procedures: Avoid skin resurfacing procedures (eg, dermabrasion, laser) and wax epilation during therapy and for ≥6 months after discontinuation of isotretinoin due to the risk of scarring.

Warnings: Additional Pediatric Considerations

Children may experience a higher frequency of some adverse effects including arthralgia (22%) and back pain (29%).

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): May enhance the adverse/toxic effect of ISOtretinoin (Systemic). Specifically, the risk for elevated triglyceride concentrations may be increased. Risk C: Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy

Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

Mipomersen: ISOtretinoin (Systemic) may enhance the hepatotoxic effect of Mipomersen. Risk C: Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination

Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

Progestins (Contraceptive): Retinoic Acid Derivatives may diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Risk D: Consider therapy modification

Tetracyclines: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combination

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy

Vitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination

Food Interactions

Standard formulation isotretinoin bioavailability increased if taken with food or milk. Management: Administer orally with a meal. Note: Also available as lidose (Absorica) and micronized (Absorica LD) formulations that may be administered with or without food.

Reproductive Considerations

[US Boxed Warning]: Isotretinoin must not be used by patients who may become pregnant.

Patients of childbearing potential must be able to comply with the guidelines of the iPLEDGE™ pregnancy prevention program. Females of childbearing potential must have 2 negative pregnancy tests with a sensitivity of ≥25 milliunits/mL prior to beginning therapy, and testing should continue monthly during therapy. Patients of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation of isotretinoin. Upon discontinuation of treatment, patients of childbearing potential should have a pregnancy test after their last dose and again 1 month after their last dose.

All patients (male and female) must be enrolled in the iPLEDGE™ risk management program. Patients of childbearing potential must receive oral and written information reviewing the hazards of therapy and the effects that isotretinoin can have on a fetus. Therapy should not begin without 2 negative pregnancy tests ≥19 days apart. Two forms of contraception (a primary and secondary form as described in the iPLEDGE™ program materials) must be used simultaneously beginning 1 month prior to treatment, during treatment, and for 1 month after therapy is discontinued; limitations to their use must be explained. Micro-dosed progesterone products that do not contain an estrogen ("mini-pills") are not an acceptable form of contraception during isotretinoin treatment. Prescriptions should be written for no more than a 30-day supply, and pregnancy testing and counseling should be repeated monthly. During therapy, pregnancy tests must be conducted by a CLIA-certified laboratory. Prescriptions must be filled and picked up from the pharmacy within 7 days of specimen collection for pregnancy test for patients of childbearing potential. Prescriptions for patients of nonchildbearing potential (male and female) must be filled and picked up within 30 days of prescribing.

Any cases of accidental pregnancy should be reported to the iPLEDGE™ program or FDA MedWatch. All patients (male and female) must read and sign the informed consent material provided in the pregnancy prevention program.

Pregnancy Considerations

Isotretinoin and its metabolites can be detected in fetal tissue following maternal use during pregnancy (Benifla 1995; Kraft 1989).

Use is contraindicated in pregnant women. [US Boxed Warning]: Isotretinoin must not be used by patients who are pregnant. There is an extremely high risk that severe birth defects can result if pregnancy occurs while taking isotretinoin in any amount, even for short periods of time. Potentially, any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects that have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, CNS, cardiovascular system, and thymus and parathyroid glands. Cases of intelligence quotient (IQ) scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases, death has occurred with some of the abnormalities previously noted.

If pregnancy does occur during treatment of a patient who is taking isotretinoin, isotretinoin must be discontinued immediately and the patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Any pregnancies should be reported to the iPLEDGE™ program (www.ipledgeprogram.com or 866-495-0654) and the FDA through MedWatch (800-FDA-1088).

Breastfeeding Considerations

It is not known if isotretinoin is present in breast milk.

A case report describes a green discharge from the breast of a non-breastfeeding woman that was determined to be iatrogenic galactorrhea due to isotretinoin (Larsen 1985). Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment and for 1 month after the last dose of isotretinoin.

Dietary Considerations

Standard formulation should be taken with food; lidose (Absorica) or micronized formulations (Absorica LD) may be taken without regard to meals. Limit intake of vitamin A; avoid use of other vitamin A products. Some formulations may contain soybean oil.

Monitoring Parameters

CBC with differential and platelet count, baseline sedimentation rate, glucose, CPK; signs/symptoms of psychiatric effects (eg, depression, suicidal thoughts, mood alteration, psychosis, aggression); severe skin reactions; changes in vision; signs/symptoms of pseudotumor cerebri (eg, papilledema, headache, nausea, vomiting, visual disturbances).

Pregnancy test (for all patients of childbearing potential): Two negative tests with a sensitivity of ≥25 milliunits/mL prior to beginning therapy (the second performed ≥19 days after the first test and performed during the first 5 days of the menstrual period immediately preceding the start of therapy); monthly tests to rule out pregnancy prior to refilling prescription and 1 month after discontinuation.

Lipids: Prior to treatment and at weekly or biweekly intervals until response to treatment is established. Test should not be performed <36 hours after consumption of ethanol.

Liver function tests: Prior to treatment and at weekly or biweekly intervals until response to treatment is established.

Oncology uses: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up. Also monitor adherence.

Mechanism of Action

Reduces sebaceous gland size and reduces sebum production in acne treatment; in neuroblastoma, decreases cell proliferation and induces differentiation

Pharmacokinetics

Note: Pharmacokinetic parameters in adolescents (12 to 15 years) are similar to adults.

Absorption:

Standard formulation: Enhanced with a high-fat meal.

Lidose formulation (Absorica): AUC0-t and Cmax increased 50% and 26%, respectively, under fed compared to fasting conditions.

Micronized formulation (Absorica LD): AUC0-t and Cmax increased 20% and 6%, respectively, under fed compared to fasting conditions.

Protein binding: 99% to 100%; primarily albumin.

Metabolism: Hepatic via CYP2B6, 2C8, 2C9, 3A4; forms metabolites; major metabolite: 4-oxo-isotretinoin (active).

Half-life elimination:

Standard formulation: Parent drug: 21 ± 8.2 hours; Metabolite: 24 ± 5.3 hours.

Lidose formulation (Absorica): Parent drug: 18 hours; Metabolite: 38 hours.

Micronized formulation (Absorica LD): Parent drug: ~24 hours; Metabolite: ~38 hours.

Time to peak, serum:

Standard formulation: 5.3 hours (fed); 3.2 hours (fasting).

Lidose formulation (Absorica): 6.4 hours (fed); 2.9 hours (fasting).

Micronized formulation (Absorica LD): Median: 5 hours (fed); 3.5 hours (fasting).

Excretion: Urine and feces (equal amounts).

Pricing: US

Capsules (Absorica LD Oral)

8 mg (per each): $46.89

16 mg (per each): $46.89

24 mg (per each): $50.45

32 mg (per each): $50.45

Capsules (Absorica Oral)

10 mg (per each): $44.65

20 mg (per each): $44.65

25 mg (per each): $48.04

30 mg (per each): $48.04

35 mg (per each): $48.04

40 mg (per each): $48.04

Capsules (Accutane Oral)

10 mg (per each): $7.99

20 mg (per each): $7.99

30 mg (per each): $7.99

40 mg (per each): $7.99

Capsules (Amnesteem Oral)

10 mg (per each): $18.02

20 mg (per each): $21.37

40 mg (per each): $24.83

Capsules (Claravis Oral)

10 mg (per each): $20.50

20 mg (per each): $24.31

30 mg (per each): $20.56

40 mg (per each): $28.25

Capsules (ISOtretinoin Oral)

10 mg (per each): $20.50 - $42.42

20 mg (per each): $24.31 - $42.42

25 mg (per each): $36.61 - $45.64

30 mg (per each): $20.56 - $45.64

35 mg (per each): $36.61 - $45.64

40 mg (per each): $28.25 - $45.64

Capsules (Myorisan Oral)

10 mg (per each): $18.02

20 mg (per each): $21.37

30 mg (per each): $12.33

40 mg (per each): $24.82

Capsules (Zenatane Oral)

10 mg (per each): $18.02

20 mg (per each): $21.37

30 mg (per each): $24.83

40 mg (per each): $24.83

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Accotin (DK);
  • Acnal SC (KR);
  • Acnecur (PY);
  • Acnelar (EG);
  • Acnemin (ES);
  • Acnetrex (LK, PH);
  • Acnotin (CL, EC, HK, PE, SG, TH, VN);
  • Acnova (BR);
  • Akinol (KR);
  • Aknenormin (DE);
  • Aknetin (UA);
  • Aknil Gel (BD);
  • Atlacne (AR);
  • Atretin (CO);
  • Ciscutan (AT);
  • Claravis (BM);
  • Contracne (FR);
  • Cosmin (PK);
  • Curacne (AE, JO, KW, LB, QA);
  • Curacne Ge (FR);
  • Curakne (CH);
  • Curatane (IL);
  • Dercutane (ES);
  • Dermatane (AU);
  • Hyndriax (CR, DO, GT, HN, NI, PA, SV);
  • Isocural (BE);
  • Isocutan (AR);
  • Isoface (CO, CR, DO, EC, GT, HN, MX, NI, PA, PE, PY, SV, VE);
  • Isolve (CR, DO, GT, HN, NI, PA, SV);
  • Isosupra (BE);
  • Isotane (NZ, TH);
  • Isotina (KR);
  • Isotinon (KR);
  • Isotren (KR);
  • Isotret-Hexal (DE);
  • Isotrex (AE, BH, BR, CL, CR, CY, DK, DO, GB, GT, HN, HU, ID, IE, LU, MX, NI, PA, PK, SA, SG, SV);
  • Isotrex Gel (DE, ES, FR, HK, IL, IT, MY, PH, PL, TH);
  • Isotroin (IN, LB);
  • LOAC SC (KR);
  • Neotrex (MX);
  • Netlook (EG);
  • Nimegen (MY, SG);
  • Oratane (AE, AU, MY, NZ, SG);
  • Procuta Ge (FR);
  • Reducar (BH, HK);
  • Reticap-5 (BD);
  • Retigel (BD);
  • Roaccutan (AR, CO, FI, HU, IT, MX, PE, PT, PY, UY, VE);
  • Roaccutane (AE, AU, BB, BE, BG, BH, BS, BZ, CH, CU, CY, CZ, EE, EG, GB, GH, GR, GY, HK, HR, IE, IL, IQ, IR, JM, JO, KE, KR, KW, LB, LK, LT, LU, LV, LY, NL, OM, PH, PK, PR, QA, RO, SA, SI, SK, SR, SY, TR, TT, TW, TZ, UA, UG, YE, ZM);
  • Roacnetan (CN);
  • Roacta (TH);
  • Roacutan (BR);
  • Rocta (AU);
  • Sotret (IN, TH);
  • Sotrexe (MX);
  • Tretinex (EC)


For country code abbreviations (show table)
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