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ISOTRETINOIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Isotretinoin is the cis isomer of tretinoin, a form of Vitamin A.

Specific Substances

    1) 13-cis-Retinoic Acid
    2) Accutane(R)
    3) cis-Retinoic Acid
    4) RO-4-3780
    5) Vitamin A Acid, cis
    6) CAS 4759-48-2
    1.2.1) MOLECULAR FORMULA
    1) C20H28O2

Available Forms Sources

    A) FORMS
    1) Isotretinoin is available as 10, 20, 30, and 40 mg liquid-filled capsules (Prod Info ABSORICA(TM) oral capsules, 2012; Prod Info ACCUTANE(R) oral capsules, 2010).
    B) USES
    1) Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne (Prod Info ABSORICA(TM) oral capsules, 2012; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne.
    B) PHARMACOLOGY: Isotretinoin (13-cis retinoic acid, RO-43,780) is classified as a retinoid, which is a synthetic analogue of vitamin A. Its exact mechanism of action is not known. When administered in pharmacologic dosages, isotretinoin inhibits sebaceous gland function and keratinization. Retinoids affect the keratinization process, and therefore without specificity exhibit effectiveness in all types of hyperkeratotic conditions.
    C) EPIDEMIOLOGY: Overdose is rare and most cases develop only minor symptoms.
    D) WITH THERAPEUTIC USE
    1) COMMON (5% or greater): Dry mouth and skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, dermatitis, increased blood creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. OTHER EFFECTS: Nausea, vomiting, lethargy, fatigue, pruritus, back pain, and myalgia. RARE: Eruptive xanthomas, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, paronychia, conjunctivitis, corneal opacity, night blindness, tinnitus, vasculitis, mild to moderate increases in liver enzymes, acute allergic reaction, pseudotumor cerebri, papilledema, hypercalcemia, pancreatitis, thrombocytopenia, neutropenia, leukopenia, anemia, agranulocytosis, rhabdomyolysis, seizures, hallucinations, and psychosis. Isotretinoin is a human teratogen (pregnancy category X).
    E) WITH POISONING/EXPOSURE
    1) Isotretinoin is unlike vitamin A in that it is not stored in the liver and is less toxic. Vitamin A and retinoic acid cause more CNS toxicity, GI symptoms, and bone, joint, and muscle pain than isotretinoin. Overdose data are limited. Vomiting, cheilitis, abdominal pain, mild tachycardia, hypertension, tachypnea, facial flushing, abdominal discomfort, headache, dizziness, ataxia, dryness of the lips and scaly patches on the skin, and hallucinations have been reported with overdose.
    0.2.20) REPRODUCTIVE
    A) Isotretinoin is classified as FDA pregnancy category X. Isotretinoin is contraindicated during pregnancy, as numerous cases of isotretinoin-related congenital abnormalities, some fatal, have been reported. If pregnancy occurs during use, the patient should be advised of possible consequences to the fetus and of the risk of miscarriage. Lactation studies with isotretinoin have not been conducted in humans, and it is not known whether it is excreted into human milk. Because of the potential for adverse effects in the infant, nursing mothers should not be treated with isotretinoin.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Monitor CBC with differential with platelet count in symptomatic patients.
    E) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    F) Symptoms of vitamin A toxicity are theoretically possible with isotretinoin, and liver enzymes should be monitored in substantial overdoses. Evaluate patient for clinical evidence of benign increased intracranial pressure (pseudotumor cerebri) such as headache, vomiting, blurred vision, and papilledema. Guidelines for management of Vitamin A overdoses should be followed in such cases when appropriate.
    G) A serum pregnancy test should be performed in any female of childbearing age.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not required.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or persistent seizures.
    E) ANTIDOTE
    1) None.
    F) RHABDOMYOLYSIS
    1) Rhabdomyolysis has been reported rarely with isotretinoin therapy in postmarketing surveillance. Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of isotretinoin.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. If there is any possibility the patient is pregnant she should be referred for a pregnancy test and for counseling if the test is positive.
    2) OBSERVATION CRITERIA: Symptomatic patients, and those with deliberate ingestion should be referred to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, severe abdominal pain, dehydration, electrolyte abnormalities, persistent seizures, severe neutropenia or allergic reaction.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center in patients with severe toxicity or in whom the diagnosis is unclear. Any pregnant patient who is exposed to isotretinoin should be referred to a specialist in teratology.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Acute overdose rarely causes clinical toxicity; avoid over treatment.
    J) PHARMACOKINETICS
    1) Peak plasma level: Oral, multiple-dose, 80 mg: 731.98 nanograms (ng)/mL; single-dose, 80 mg: 573.25 ng/mL. Tmax: oral, 4 hours (range 0 to 12 hours). Absorption: Highly lipophilic. Administration with food more than doubled the isotretinoin bioavailability without altering its disposition. Protein binding: Albumin, 99.9%. Isotretinoin is metabolized in the liver; CYP450 isoenzymes primarily involved in isotretinoin metabolism are CYP2C8, CYP2C9, CYP3A4, and CYP2B6. Metabolites: 4-oxo-isotretinoin (active); tretinoin (active); 4-oxo-tretinoin (active). Excretion: renal: 65% to 83%, changed. fecal: 65% to 83%, changed. Elimination half-life: parent: 15.7 hours; metabolite: 4-oxo-isotretinoin: 23 to 24 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other conditions causing increased intracranial pressure and papilledema (ie, intracranial tumor, malignant hypertension, optic neuropathy, cerebral venous sinus thrombosis). Other disorders causing elevations of liver enzymes (acetaminophen overdose, viral hepatitis).

Range Of Toxicity

    A) TOXICITY: Acute overdoses of 440 mg and 1,600 mg on 2 consecutive days produced minimal symptoms in one patient. An estimated ingestion of 63.3 mg/kg of isotretinoin produced symptoms of facial flushing and mild tachycardia, tachypnea, and hypertension in a 21-month-old, 17.7 kilogram child. THERAPEUTIC DOSE: ADULTS AND CHILDREN 12 YEARS AND OLDER: 0.5 to 1 mg/kg/day given in 2 divided doses; adults with severe scarring acne or trunk acne may require up to 2 mg/kg/day. CHILDREN YOUNGER THAN 12 YEARS: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne.
    B) PHARMACOLOGY: Isotretinoin (13-cis retinoic acid, RO-43,780) is classified as a retinoid, which is a synthetic analogue of vitamin A. Its exact mechanism of action is not known. When administered in pharmacologic dosages, isotretinoin inhibits sebaceous gland function and keratinization. Retinoids affect the keratinization process, and therefore without specificity exhibit effectiveness in all types of hyperkeratotic conditions.
    C) EPIDEMIOLOGY: Overdose is rare and most cases develop only minor symptoms.
    D) WITH THERAPEUTIC USE
    1) COMMON (5% or greater): Dry mouth and skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, dermatitis, increased blood creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. OTHER EFFECTS: Nausea, vomiting, lethargy, fatigue, pruritus, back pain, and myalgia. RARE: Eruptive xanthomas, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, paronychia, conjunctivitis, corneal opacity, night blindness, tinnitus, vasculitis, mild to moderate increases in liver enzymes, acute allergic reaction, pseudotumor cerebri, papilledema, hypercalcemia, pancreatitis, thrombocytopenia, neutropenia, leukopenia, anemia, agranulocytosis, rhabdomyolysis, seizures, hallucinations, and psychosis. Isotretinoin is a human teratogen (pregnancy category X).
    E) WITH POISONING/EXPOSURE
    1) Isotretinoin is unlike vitamin A in that it is not stored in the liver and is less toxic. Vitamin A and retinoic acid cause more CNS toxicity, GI symptoms, and bone, joint, and muscle pain than isotretinoin. Overdose data are limited. Vomiting, cheilitis, abdominal pain, mild tachycardia, hypertension, tachypnea, facial flushing, abdominal discomfort, headache, dizziness, ataxia, dryness of the lips and scaly patches on the skin, and hallucinations have been reported with overdose.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) TACHYPNEA: Mild tachypnea was noted in a 21-month-old child following an estimated ingestion of 63.3 mg/kg of isotretinoin (Munter & Wilkinson, 1988).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTENSION: Mild hypertension was noted in a 21-month-old child following an estimated ingestion of 63.3 mg/kg of isotretinoin (Munter & Wilkinson, 1988).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) TACHYCARDIA: Mild tachycardia was noted in a 21-month-old child following an estimated ingestion of 63.3 mg/kg of isotretinoin (Munter & Wilkinson, 1988).

Heent

    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) HAIR: Dry hair and thinning hair may occur (Reuter, 1984; Windhorst & Nigra, 1982; Farrell et al, 1980).
    B) WITH POISONING/EXPOSURE
    1) FACIAL FLUSHING: A 21-month-old child developed facial flushing following ingestion of approximately 63.3 mg/kg by history (Munter & Wilkinson, 1988).
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) In addition to corneal opacities and decreased night vision, visual disturbances, photophobia, and color vision disorder have been reported in patients who received isotretinoin in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010). Acute transient myopia has been reported with isotretinoin therapy (Palestine, 1984).
    2) CONJUNCTIVITIS may be noted following oral exposure (Reuter, 1984) Windhorst & Nigra, 1988).
    3) CORNEAL OPACITY: A 14-month-old girl developed reversible corneal deposits during treatment with 2.25 mg/kg/day of isotretinoin for a duration of 7 weeks for congenital unilateral ichthyosiform erythroderma (Weiss et al, 1981).
    4) CATARACTS: Anterior subcapsular cataracts in a 45-year-old female were associated with use of isotretinoin 40 mg twice daily for 14 weeks (Herman & Dyer, 1987).
    5) MYOPIA: Acute transient myopia has been reported (Palestine, 1984a).
    6) NIGHT BLINDNESS and excessive glare sensitivity was reported in 3 patients treated with isotretinoin 1 mg/kg per day. It was theorized that isotretinoin may compete for normal retinol binding sites on cell surfaces or transport molecules (JEF Reynolds , 1990).
    7) SUBCONJUNCTIVAL HEMORRHAGE: A 39-year-old male developed subconjunctival hemorrhage in the left eye 6 weeks after beginning isotretinoin therapy to treat acne. The subconjunctival hemorrhage resolved within 3 weeks after reducing the dose of isotretinoin, and the patient was able to complete the 16-week course of therapy without further problems (Azurdia & Sharpe, 1999).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) HEARING IMPAIRMENT: Hearing impairment, sometimes persisting after discontinuation of therapy, has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    2) TINNITUS: Tinnitus has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS may occur (Reuter, 1984; Jones et al, 1983; Windhorst & Nigra, 1982; Azurdia & Sharpe, 1999).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Mild tachycardia was noted in a 21-month-old child following an estimated ingestion of 63.3 mg/kg of isotretinoin (Munter & Wilkinson, 1988).
    B) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) Vasculitis, including allergic vasculitis, has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) CASE REPORT: Necrotizing cutaneous vasculitis occurred in two patients receiving isotretinoin. Appropriate therapy and discontinuance of the drug resulted in gradual resolution of symptoms. Prednisone was a successful adjunctive therapy in one case (Dwyer et al, 1989).
    C) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-month-old, 17.7 kg child ingested an estimated 63.3 mg/kg of isotretinoin and developed minor facial flushing and mild tachycardia, tachypnea, and hypertension which resolved over 24 hours (Munter & Wilkinson, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm (with or without history of asthma) has been reported in patients who received isotretinoin in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010; Anon, 1996).
    b) CASE REPORT: Exercise-induced asthma was associated with therapeutic doses of isotretinoin in a 20-year-old male with a history of atopic dermatitis and hay fever (Fisher, 1985).
    B) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 49-year-old woman developed an eosinophilic pleural effusion following chronic treatment with isotretinoin 1 mg/kg/day. After the drug was discontinued, symptomatic improvement resulted (Bunker et al, 1989).
    C) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Mild tachypnea was noted in a 21-month-old child following an estimated ingestion of 63.3 mg/kg of isotretinoin (Munter & Wilkinson, 1988).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Lethargy and fatigue have been noted with therapeutic doses (Reuter, 1984; Windhorst & Nigra, 1982).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur in overdose (Prod Info ABSORICA(TM) oral capsules, 2012; Lindemayr, 1986; Sutton, 1983).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizure has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010; Perry & McEvoy, 1983; Windhorst & Nigra, 1982a).
    D) BENIGN INTRACRANIAL HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Pseudotumor cerebri has been reported in adult patients following therapeutic doses (40 to 120 mg/day for 21 days to 6 months) (Spector, 1984; FDA, 1983; Bigby & Stern, 1988; Roytman et al, 1988).
    b) CASE REPORT: A 16-year-old girl experienced severe headaches and impaired night vision 2 months after beginning therapy with isotretinoin 40 mg daily (0.7 mg/kg). Bilateral papilledema and narrowing of the lateral ventricles of the brain were reported.
    1) Improvement was noted upon discontinuation of isotretinoin and administration of dexamethasone (Roytman et al, 1988).
    E) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness has been reported with overdose (Prod Info ABSORICA(TM) oral capsules, 2012).
    F) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) Ataxia has been reported with overdose (Prod Info ABSORICA(TM) oral capsules, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been noted with therapeutic doses (Reuter, 1984; Windhorst & Nigra, 1982).
    2) WITH POISONING/EXPOSURE
    a) Vomiting has been reported with overdose (Prod Info ABSORICA(TM) oral capsules, 2012).
    B) COLITIS
    1) WITH THERAPEUTIC USE
    a) Inflammatory bowel syndrome has been reported with therapeutic doses although a definite cause and effect relationship has not been established (Reniers & Howard, 2001).
    b) CASE REPORT: A 17-year-old male presented with a one-week history of rectal bleeding and bloody stools that began one after completing a 5-month course of isotretinoin for treatment of acne. A colonoscopy and colon biopsies confirmed a diagnosis of ulcerative colitis. Infectious diseases were ruled out as a cause of the colitis and there was no family history of inflammatory bowel disease. Despite treatment with 5-aminosalicylic acid, oral iron supplementation, and a steroid retention enema, the patient's condition deteriorated with increasing abdominal pain and increasing number of bloody stools. Five months after the initial onset of rectal bleeding, a repeat colonoscopy showed severe ulcerative colitis involving the entire colon. The patient gradually recovered following a subtotal colectomy and ileostomy (Reniers & Howard, 2001).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain has been reported with overdose (Prod Info ABSORICA(TM) oral capsules, 2012).
    b) CASE REPORT: Vague abdominal discomfort was the only complaint reported by a 15-year-old, 54 kg female following an ingestion of 350 mg isotretinoin (Hepburn, 1990).
    D) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    E) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance. Fatal hemorrhagic pancreatitis has been reported rarely. Acute pancreatitis has occurred in patients with normal serum triglyceride levels as well as in patients with elevated serum triglyceride levels (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) Mild to moderate increases in liver enzymes, including alkaline phosphatase, AST, ALT, LDH and gamma glutamic transpeptidase, were reported in approximately 15% of patients in clinical trials. Some increases normalized with continuation of drug or dosage reduction (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) Hepatitis has been reported with isotretinoin use in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URETHRAL FINDING
    1) WITH THERAPEUTIC USE
    a) During a phase I study, involving patients with head and neck malignancies, doses of greater than 60 mg/m(2) induced urethritis(Reuter, 1984).
    B) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 19-year-old male developed hypercalciuria, hyperuricuria, and nephrolithiasis associated with isotretinoin (1.4 mg/kg) therapy of 16 weeks duration (Bigby & Stern, 1988).
    C) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) CHRONIC TOXICITY: An elevated serum creatinine level, hematuria, proteinuria, and severe bilateral lumbar pains occurred in a 34-year-old male following long-term isotretinoin therapy. An ultrasound showed normal-sized kidneys, an IV pyelogram showed symmetrical kidneys without structural defect and a normal bladder, and an abdominal CT scan showed no evidence of a renal infarction. The patient's signs and symptoms resolved within 7 days after cessation of the isotretinoin (Pavese et al, 1997).
    D) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Gross and microscopic hematuria have been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    E) GLOMERULONEPHRITIS
    1) WITH THERAPEUTIC USE
    a) Glomerulonephritis has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) CASE REPORT: A 15-year-old male developed thrombocytopenia 2 weeks after initiation of isotretinoin 60 mg daily. Platelet count returned to normal upon discontinuation of isotretinoin and recurred when the patient was rechallenged with a single 60 mg dose (Johnson & Rapini, 1987).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia, sometimes severe, has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    D) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia and decreases in red blood cell parameters have been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    E) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis has been reported rarely with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) Dry skin has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) Dry skin (Sutton, 1983), pruritus, eruptive xanthomas, facial dermatitis, general desquamation, skin fragility (Reuter & Hellriegel, 1983), xerosis, or pathological dryness of the skin and mucous membranes may be noted (Reuter, 1984) Windhorst & Nigra, 1988; (Jones et al, 1983; Azurdia & Sharpe, 1999).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: One report described the relative lack of toxicity of isotretinoin following an overdose over a period of 2 days. A 15-year-old, 180 pound male with cystic acne ingested eleven 40 mg capsules 1 day (440 mg) and forty 40 mg capsules (1,600 mg) the next (total dose, 2,040 mg). One day later the patient developed headache and dryness of the extremities and examination revealed dryness of the lips and dry, scaly patches on the arms and shoulders. Laboratory evaluations were normal and no other abnormalities were observed (Sutton, 1983).
    B) ERUPTIVE XANTHOMA
    1) WITH THERAPEUTIC USE
    a) Eruptive xanthomas have occurred with isotretinoin therapy (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    C) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme and severe skin reactions, which may be life-threatening, have been reported with isotretinoin therapy during postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    D) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome, which may be serious and life-threatening, has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    E) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis, which may be serious and life-threatening, has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    F) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    G) PARONYCHIA
    1) WITH THERAPEUTIC USE
    a) Paronychia has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    H) CHEILITIS
    1) WITH THERAPEUTIC USE
    a) Cheilitis (inflammation of the lips) may occur in up to 90% of the patients treated with isotretinoin (Johnson & Rapini, 1987; Reuter & Hellriegel, 1983; Windhorst & Nigra, 1982; Jones et al, 1983).
    2) WITH POISONING/EXPOSURE
    a) Cheilitis has been reported with overdose (Prod Info ABSORICA(TM) oral capsules, 2012).
    I) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Patients treated with isotretinoin may have photosensitizing reactions and an increased susceptibility to sunburn (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    J) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) Vasculitis, including allergic vasculitis, has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) Cutaneous necrotizing vasculitis was reported in two patients taking isotretinoin. Symptoms gradually resolved with appropriate therapy and discontinuance of the drug; prednisone was a successful adjunctive therapy in one case (Dwyer et al, 1989).
    K) INFECTION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Skin infections, including disseminated herpes simplex, have been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    L) ABNORMAL HAIR TEXTURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 46-year-old woman taking 1 mg/kg isotretinoin daily for one year developed progressive curling of the hair. It returned to its normal state 6 months after treatment was discontinued (Bunker et al, 1990).
    M) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) Facial flushing has been reported with overdose (Prod Info ABSORICA(TM) oral capsules, 2012).
    b) CASE REPORT: A 21-month-old child developed facial flushing following ingestion of approximately 63.3 mg/kg by history (Munter & Wilkinson, 1988).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) ACQUIRED MUSCULOSKELETAL DEFORMITY
    1) WITH THERAPEUTIC USE
    a) Skeletal toxicity is known to occur with isotretinoin doses in excess of 2 mg/kg/day. Doses of 0.5 mg/kg/day did not produce significant, long-term musculoskeletal changes (Carey et al, 1988).
    b) Premature closure of the epiphyses in children and hyperostosis with spinal degeneration in adults may be noted with chronic use (DiGiovanna, 2001) Prod Info, 1988).
    c) Five of seven patients treated for keratinizing disorders with 3 mg/kg of isotretinoin for three years demonstrated irreversible skeletal hyperostosis and deformity (Pittsley & Yoder, 1983) Yoder, 1983).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Bone, joint, or muscle symptoms occurred in 15% of patients receiving a mean daily dose of 109 mg for a mean duration of 150 days (Windhorst & Nigra, 1982).
    C) DECREASED BODY GROWTH
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 9-year-old boy on isotretinoin 5 mg/kg/day for fibrodysplasia ossificans progressiva developed dense metaphyseal bands and growth arrest. After therapy was stopped, normal growth resumed and the metaphyseal bands resolved (Marini et al, 1988).
    D) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal symptoms, sometimes severe, have been reported with isotretinoin use in clinical trials or postmarketing reports. Symptoms included back pain, myalgia, and arthralgia (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) Approximately 29% of pediatric patients (n=358) treated with isotretinoin developed back pain. Of the 104 cases of back pain, 13.5% were severe. More female than male patients reported back pain (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    E) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Rhabdomyolysis, sometimes associated with strenuous physical activity, has been reported rarely with isotretinoin therapy in postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) CASE REPORT: A 20-year-old man developed severe generalized rhabdomyolysis and died 3.5 months after starting isotretinoin therapy for acne papulopustulosa, partim conglobata. Initially, he complained of severe myalgia and arthralgia after moderate exercise 6 weeks before death. He discontinued taking isotretinoin 4 weeks before death and prior to travelling abroad. During his first few days of travelling, his muscle pain worsened and he had signs of vitamin A intoxication (eg, chapped lips, dry skin, loss of appetite, fatigue, and myalgia). He developed dyspnea on exertion 6 days before death and was admitted for a fulminant rhabdomyolysis (CK: 82,100 International Units/L; CK-MB: 2038 IU/L; troponin T 0.50 ng/mL) 3 days later. Despite supportive therapy, he died from ventricular fibrillation (Hartung et al, 2012).
    F) INCREASED CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) Elevated CPK levels have been reported in clinical studies and postmarketing reports in patients undergoing vigorous physical activity while on isotretinoin therapy (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    b) In a clinical trial of pediatric patients (n=217; age, 12 to 17 years), transient increases in CPK were reported in 12% of patients. Patients with CPK elevations included those engaging in strenuous physical activity with associated musculoskeletal symptoms, such as back pain, arthralgia, limb injury, or muscle sprain. Rhabdomyolysis was not reported. About half of the CPK elevations normalized within 2 weeks, and half normalized within 4 weeks (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF MENSTRUATION
    1) WITH THERAPEUTIC USE
    a) Amenorrhea and menstrual irregularities have been reported in patients treated with therapeutic doses of isotretinoin (Cox, 1988).
    B) HYPERTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 26-year-old man developed thyrotoxicosis while receiving isotretinoin 40 mg daily. Thyroid function returned to normal within 2 months after isotretinoin therapy had been discontinued (Minuk & Jackson, 1986). No other treatment was required.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions, including systemic hypersensitivity, cutaneous reactions, and serious cases of allergic vasculitis, have been reported with isotretinoin therapy. Purpura of the extremities and extracutaneous involvement, including renal involvement, have been manifestations of allergic vasculitis (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    B) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylactic reactions have been reported with isotretinoin therapy (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Isotretinoin is classified as FDA pregnancy category X. Isotretinoin is contraindicated during pregnancy, as numerous cases of isotretinoin-related congenital abnormalities, some fatal, have been reported. If pregnancy occurs during use, the patient should be advised of possible consequences to the fetus and of the risk of miscarriage. Lactation studies with isotretinoin have not been conducted in humans, and it is not known whether it is excreted into human milk. Because of the potential for adverse effects in the infant, nursing mothers should not be treated with isotretinoin.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Fetal malformations have been reported following maternal use of isotretinoin in the first trimester (Chambers et al, 2000). Malformations may occur with only short periods of use (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Hersh et al, 1985); therefore, no systemic dose of isotretinoin is considered safe during pregnancy. However, if isotretinoin use is discontinued prior to conception, the risk of congenital anomalies may not be higher than that seen in the general population (Schatz et al, 1988).
    2) The risks of adverse events associated with isotretinoin use during pregnancy are: 15% incidence of major malformations, 5% incidence of perinatal mortality, 16% incidence of premature birth, and 40% incidence of spontaneous abortion (Adams, 1996). Abnormalities, some fatal, of the face (ie, facial dysmorphia, cleft palate), eyes (ie, microphthalmia), ears (ie, anotia, micropinna, small or absent external auditory canals), skull, central nervous system (ie, cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit), cardiovascular system, thymus, and parathyroid glands have been reported following isotretinoin exposure (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    3) The Slone Survey was an independent follow-up survey of women of childbearing age who were prescribed isotretinoin between January 1989 through June 2000, and in which 1019 exposed pregnancies were identified (Survey - Slone Epidemiology Unit, 2000). Of the 63 live births for which records were examined, 13% showed major malformations and 30% showed any degree of malformation. Of pregnancies occurring within 30 days after isotretinoin discontinuation, only 10% of live birth records examined showed malformations and none were determined to be major malformations. Manufacturer data collected since product availability in 1982 to March 31, 2000, identify 42% of 383 live births from 1995 exposed pregnancies as having congenital anomalies, a rate much higher than that determined through voluntary survey (Anon, 2000).
    4) Of 14 Californian women who had reported isotretinoin exposure during their pregnancies to either the Boston University Accutane Survey or the California Teratogen Information Service, the following pregnancy outcomes occurred: 4 live births with no major malformations; 1 live birth with major malformations; 4 spontaneous abortions; and 5 induced abortions. The infant born with malformations showed multiple anomalies including congenital heart disease, hydrocephalus, and facial dysmorphism. The infant died at 9 weeks of age (Centers for Disease Control (CDC), 2000).
    5) The pharmacokinetics of isotretinoin 0.47 to 1.7 mg/kg/day were studied in a small number (n=11) of women of childbearing age. The results of this study suggest that the half-life may be more variable and/or longer than previously reported, thus affecting the length of time for safe conception after drug discontinuation (Nulman et al, 1998).
    6) Of 8 children born to mothers who were exposed to isotretinoin beginning after 60 days gestation during pregnancy, 2 were small for their gestational age, 3 had persistent reflux and bowel problems during childhood, and half had below average intelligence or significant learning disabilities (Adams, 1996). The outcome of 154 pregnancies were investigated after documented fetal exposure to isotretinoin 0.5 to 1.5 mg/kg/day. Elective first-trimester abortions terminated 95 pregnancies. Of the remaining 59 pregnancies, 21 resulted in malformed fetuses and 12 in spontaneous abortions; 26 infants were born without major malformations (Lammer et al, 1985).
    7) In a study of 36 cases of isotretinoin defect syndrome in which maternal dosage was known, 34 were exposed 0.8 g/kg/day or more following maternal ingestion. The syndrome includes hydrocephalus, microcephalus, abnormalities of the external ear, microphthalmia, cardiovascular abnormalities, facial dysmorphia, thymus gland abnormalities, parathyroid hormone deficiency, and cerebellum malformations (Rosa, 1987).
    8) Abnormalities have been reported with minimal doses of 0.4 to 1.37 mg/kg/day (Rosa et al, 1986; Howard & Willhite, 1986).
    9) Infants who were exposed during early pregnancy have an estimated relative risk of 25.6 (95% confidence interval = 11.4 to 57.5) for the association between isotretinoin and selected defects (Lammer et al, 1985a).
    B) COGNITIVE IMPAIRMENT
    1) Cases of IQ scores of less than 85 have been reported with prenatal exposure, with or without other abnormalities (Prod Info Absorica(R) oral capsules, 2014).
    C) LACK OF EFFECT
    1) In a prospective study of 79 women who had been treated with isotretinoin for facial acne, gross malformation and neurofunctional abnormality were not found in the 19 infants exposed during the teratogenic risk period. Of the 56 participants who continued their pregnancy, there were 11 spontaneous abortions and 44 healthy full-term babies, 19 of whom were exposed to isotretinoin less than 1 month before conception or during pregnancy (Yook et al, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified isotretinoin as FDA pregnancy category X (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    2) Isotretinoin is contraindicated during pregnancy, as numerous cases of isotretinoin-related congenital abnormalities, some fatal, have been reported. If pregnancy occurs during use, the patient should be advised of possible consequences to the fetus and of the risk of miscarriage. Isotretinoin is also contraindicated in women of childbearing potential unless a number of conditions are met, including 2 forms of effective contraception to be used simultaneously for at least 1 month before beginning therapy, during treatment, and for 1 month following completion of therapy; exceptions may be made for women with a hysterectomy, bilateral oophorectomy, medically confirmed as postmenopausal, or women choosing abstinence. Micro-dosed progesterone preparations are not an acceptable method of contraception during isotretinoin therapy. In addition, female patients of childbearing age are required to have 2 negative pregnancy tests prior to starting isotretinoin and repeated monthly during therapy, upon treatment discontinuation, and 1 month after treatment withdrawal. Isotretinoin is approved for marketing only under a special restricted distribution program, called iPLEDGE, approved by the US Food and Drug Administration. Patients who take isotretinoin are required to register and must comply with all requirements of the iPLEDGE program. If pregnancy occurs during treatment with isotretinoin, discontinue use immediately and report pregnancy to FDA Medwatch at 1-800-FDA-1088 and the iPLEDGE registry 1-866-495-0654 or www.ipledgeprogram.com. Female patients should receive referrals to specialists in obstetrics and gynecology experienced in reproductive toxicity for evaluation and counseling (Prod Info Absorica(R) oral capsules, 2014).
    3) Congenital anomalies have occurred in children born to fathers who received isotretinoin prior to or during conception, but isotretinoin has not been clearly implicated as the causative agent (Pers Comm, 1989). Isotretinoin is found in the semen of male patients taking it, but the amount delivered to a female partner would be approximately 1 million times lower than a 40 mg oral dose (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    B) ABORTION
    1) An increased risk of spontaneous abortion and premature births have been reported (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    2) The Slone Survey was an independent follow-up survey of women of childbearing age who were prescribed isotretinoin between January 1989 and June 2000, and in which 1019 exposed pregnancies were identified. Of these, 117 live births were recorded as were 887 terminations, including 681 elective terminations, 177 spontaneous abortions, and 29 ectopic pregnancies (Survey - Slone Epidemiology Unit, 2000).
    3) Of 14 Californian women who had reported isotretinoin exposure during their pregnancies to either the Boston University Accutane Survey or the California Teratogen Information Service, the following pregnancy outcomes occurred: 4 live births with no major malformations; 1 live birth with major malformations; 4 spontaneous abortions; and 5 induced abortions (Centers for Disease Control (CDC), 2000).
    4) In a prospective study of 79 women who had been treated with isotretinoin for facial acne, 56 participants continued their pregnancy. In these 56 participants, there were 11 spontaneous abortions and 44 healthy full-term babies (Yook et al, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Lactation studies with isotretinoin have not been conducted in humans, and it is not known whether it is excreted into human milk. Because of the potential for adverse effects in the infant, nursing mothers should not be treated with isotretinoin (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) MALES: No significant effects on sperm count or motility were seen in a study of 66 men, 30 of whom were patients being treated with isotretinoin for nodular acne. In another study, ejaculate volume, sperm count, total sperm motility, morphology, or seminal plasma fructose were unaffected in 50 men during isotretinoin treatment (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    B) ANIMAL STUDIES
    1) DOGS: Testicular atrophy occurred in dogs treated with 10 or 30 times the recommended human dose of 1 mg/kg/day, respectively based on body surface area for about 30 weeks. There was microscopic evidence for reduced spermatogenesis; however, some sperm were observed in all testes and no completely atrophic tubules were observed (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).
    2) RATS: No adverse effects on gonadal function, fertility, conception rate, gestation or parturition were demonstrated when rats were treated with oral isotretinoin at doses 0.3, 1.3, or 5.3 times the recommended dose based on body surface area (Prod Info Absorica(R) oral capsules, 2014; Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) PHEOCHROMOCYTOMA
    1) RATS orally exposed to isotretinoin at up to 32 mg/kg/day demonstrated an increased incidence of pheochromocytoma (Kamm, 1982).
    B) LACK OF EFFECT
    1) MUTAGENICITY - Isotretinoin was not mutagenic for Salmonella typhimurium (Kamm, 1982).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Monitor CBC with differential with platelet count in symptomatic patients.
    E) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    F) Symptoms of vitamin A toxicity are theoretically possible with isotretinoin, and liver enzymes should be monitored in substantial overdoses. Evaluate patient for clinical evidence of benign increased intracranial pressure (pseudotumor cerebri) such as headache, vomiting, blurred vision, and papilledema. Guidelines for management of Vitamin A overdoses should be followed in such cases when appropriate.
    G) A serum pregnancy test should be performed in any female of childbearing age.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) A serum pregnancy test should be performed in any female of childbearing age taking isotretinoin, particularly if isotretinoin was not prescribed for this patient.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, severe abdominal pain, dehydration, electrolyte abnormalities, persistent seizures, severe neutropenia or allergic reaction.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. If there is any possibility the patient is pregnant she should be referred for a pregnancy test and for counseling if the test is positive.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center in patients with severe toxicity or in whom the diagnosis is unclear. Any pregnant patient who is exposed to isotretinoin should be referred to a specialist in teratology.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, and those with deliberate ingestion should be referred to a healthcare facility for evaluation.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Monitor CBC with differential with platelet count in symptomatic patients.
    E) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    F) Symptoms of vitamin A toxicity are theoretically possible with isotretinoin, and liver enzymes should be monitored in substantial overdoses. Evaluate patient for clinical evidence of benign increased intracranial pressure (pseudotumor cerebri) such as headache, vomiting, blurred vision, and papilledema. Guidelines for management of Vitamin A overdoses should be followed in such cases when appropriate.
    G) A serum pregnancy test should be performed in any female of childbearing age.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not required.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor serum electrolytes in patients with significant vomiting.
    4) Monitor CBC with differential with platelet count in symptomatic patients.
    5) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    6) Symptoms of vitamin A toxicity are theoretically possible with isotretinoin, and liver enzymes should be monitored in substantial overdoses. Evaluate patient for clinical evidence of benign increased intracranial pressure (pseudotumor cerebri) such as headache, vomiting, blurred vision, and papilledema. Guidelines for management of Vitamin A overdoses should be followed in such cases when appropriate.
    7) A serum pregnancy test should be performed in any female of childbearing age.
    B) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    C) RHABDOMYOLYSIS
    1) Rhabdomyolysis, sometimes associated with strenuous physical activity, has been reported rarely with isotretinoin therapy in postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010).
    2) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    3) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    4) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    5) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    6) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    D) SEIZURE
    1) Seizure has been reported with isotretinoin therapy in clinical trials or postmarketing surveillance (Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010; Prod Info Amnesteem(R) oral capsules, 2010; Perry & McEvoy, 1983; Windhorst & Nigra, 1982a).
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of isotretinoin.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) One report described the relative lack of toxicity of isotretinoin following an overdose over a period of 2 days. A 15-year-old, 180 pound male with cystic acne ingested eleven 40 mg capsules 1 day (440 mg) and forty 40 mg capsules (1,600 mg) the next (total dose, 2,040 mg). One day later the patient developed headache and dryness of the extremities and examination revealed dryness of the lips and dry, scaly patches on the arms and shoulders. Laboratory evaluations were normal and no other abnormalities were observed (Sutton, 1983).
    B) INFANT
    1) A 21-month-old, 17.7 kg child ingested an estimated 63.3 mg/kg of isotretinoin and developed minor facial flushing and mild tachycardia, tachypnea, and hypertension which resolved over 24 hours (Munter & Wilkinson, 1988).
    C) ADULT
    1) Ingestion of 800 mg of isotretinoin, oxazepam 500 mg, doxepin 450 mg, 6-methyl prednisolone 60 mg, and erythromycin 5 grams in an 18-year-old man resulted in somnolence, headache, tingling, paraphasia, hallucinations, and vertebral pain. Insignificant itching, dryness, and scaling of the skin were present. All laboratory parameters were normal (Lindemayr, 1986).

Range Of Toxicity

Summary

    A) TOXICITY: Acute overdoses of 440 mg and 1,600 mg on 2 consecutive days produced minimal symptoms in one patient. An estimated ingestion of 63.3 mg/kg of isotretinoin produced symptoms of facial flushing and mild tachycardia, tachypnea, and hypertension in a 21-month-old, 17.7 kilogram child. THERAPEUTIC DOSE: ADULTS AND CHILDREN 12 YEARS AND OLDER: 0.5 to 1 mg/kg/day given in 2 divided doses; adults with severe scarring acne or trunk acne may require up to 2 mg/kg/day. CHILDREN YOUNGER THAN 12 YEARS: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) NODULOCYSTIC ACNE (SEVERE), RECALCITRANT: Recommended oral dose is 0.5 to 1 mg/kg/day in 2 divided doses for 15 to 20 weeks; severe scarring acne or trunk acne may require up to 2 mg/kg/day (Prod Info ABSORICA(TM) oral capsules, 2012; Prod Info Sotret(R) oral capsules, 2010).
    7.2.2) PEDIATRIC
    A) NODULOCYSTIC ACNE (SEVERE), RECALCITRANT:
    1) CHILDREN 12 YEARS AND OLDER: Recommended oral dose is 0.5 to 1 mg/kg/day in 2 divided doses for 15 to 20 weeks (Prod Info ABSORICA(TM) oral capsules, 2012; Prod Info Sotret(R) oral capsules, 2010).
    2) CHILDREN YOUNGER THAN 12 YEARS: Safety and efficacy have not been established (Prod Info ABSORICA(TM) oral capsules, 2012; Prod Info Sotret(R) oral capsules, 2010).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) TEENS/YOUNG ADULTS
    a) Acute overdoses of 440 mg and 1600 mg on 2 consecutive days produced minimal symptoms (dry lips and skin) in a 15-year-old male (Sutton, 1983).
    b) Ingestion of 800 mg of isotretinoin, oxazepam 500 mg, doxepin 450 mg, 6-methyl prednisolone 60 mg, and erythromycin 5 grams in an 18-year-old man resulted in somnolence, headache, tingling, paraphasia, hallucinations, and vertebral pain. Insignificant itching, dryness, and scaling of the skin were present. All laboratory parameters were normal (Lindemayr, 1986).
    c) Abdominal discomfort was the only effect reported in a 15-year-old girl following an acute overdose of 350 mg of isotretinoin (Hepburn, 1990).
    2) PEDIATRIC
    a) An estimated ingestion of 63.3 mg/kg of isotretinoin produced symptoms of facial flushing and mild tachycardia, tachypnea, and hypertension in a 21-month-old, 17.7 kilogram child (Munter & Wilkinson, 1988).
    B) CHRONIC
    1) SKELETAL TOXICITY: Is known to occur with chronic isotretinoin doses in excess of 2 milligrams per kilogram per day (Carey et al, 1988).
    2) Doses of 0.5 mg/kg/day did not produce significant, long-term musculoskeletal changes (Carey et al, 1988).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 904 mg/kg for 20D
    B) LD50- (ORAL)MOUSE:
    1) 3389 mg/kg for 20D
    C) LD50- (INTRAPERITONEAL)RAT:
    1) 901 mg/kg for 20D
    D) LD50- (ORAL)RAT:
    1) >4000 mg/kg for 20D

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Isotretinoin (13-cis retinoic acid, RO-43,780) is classified as a retinoid, which is a synthetic analogue of vitamin A (Reed et al, 1979). Its exact mechanism of action is not known. When administered in pharmacologic dosages, isotretinoin inhibits sebaceous gland function and keratinization. In nodular acne, clinical improvement is associated with a reduction in sebum secretion which is related to the dose and duration of isotretinoin treatment (Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010). Retinoids affect the keratinization process, and therefore without specificity exhibit effectiveness in all types of hyperkeratotic conditions (Dicken & Connolly, 1982).

Toxicologic Mechanism

    A) The teratogenic mechanism of isotretinoin and its main metabolite, 4-oxo-isotretinoin, is thought to result from an adverse effect on the initial differentiation and migration of cephalic neural crest cells (Briggs et al, 1998).
    B) It is thought that the ophthalmic toxicity associated with isotretinoin (poor night vision and excessive glare sensitivity) may be due to competition for normal retinol binding sites on cell surfaces or transport molecules (JEF Reynolds , 1990).

Physicochemical

Physical Characteristics

    A) Isotretinoin is a yellow to orange crystalline powder (Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010) that is soluble in chloroform, sparingly soluble in ethyl alcohol, isopropyl alcohol, and polyethylene glycol 400, and practically insoluble in water (USPDI, 1988).

Molecular Weight

    A) 300.44 (Prod Info Amnesteem(R) oral capsules, 2010; Prod Info Sotret(R) oral capsules, 2010; Prod Info Claravis(TM) oral capsules, 2010)

References

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    72) Product Information: ABSORICA(TM) oral capsules, isotretinoin oral capsules. Ranbaxy Laboratories, Inc. (per FDA), Jacksonville, FL, 2012.
    73) Product Information: ACCUTANE(R) oral capsules, isotretinoin oral capsules. Roche Laboratories Inc, Nutley, NJ, 2010.
    74) Product Information: Absorica(R) oral capsules, isotretinoin oral capsules. Ranbaxy Laboratories, Inc. (per DailyMed), Jacksonville, FL, 2014.
    75) Product Information: Amnesteem(R) oral capsules, isotretinoin oral capsules. Mylan Pharmaceuticals Inc, Morgantown, WV, 2010.
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