isotretinoin (Amnesteem, Claravis, Myorisan, Absorica, Zenatane)

Dosing and uses of Amnesteem, Claravis (isotretinoin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

capsule

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

 

Severe, Recalcitrant Nodular Acne

Severe nodular acne unresponsive to conventional therapy, including systemic antibiotics

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

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

Dosing considerations

• >2 months after discontinuation: If warranted by persistent or recurring, severe nodular acne, may initiate a 2nd course of therapy
• If total nodule count is reduced by >70% prior to completing 15-20 weeks, may discontinue drug

 

Administration

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

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

Absorica: May be taken with or without food

 

Pediatric dosage forms and strengths

capsule

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

 

Severe, Recalcitrant Nodular Acne

Severe nodular acne unresponsive to conventional therapy, including systemic antibiotics

<12 years: Safety and efficacy not established

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

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

Dosing considerations

• >2 months after discontinuation: If warranted by persistent or recurring, severe nodular acne, may initiate a 2nd course of therapy
• If total nodule count is reduced by >70% prior to completing 15-20 weeks, may discontinue drug

 

Ichthyosis (Orphan)

Orphan designation for treatment of congenital ichthyosis

Orphan sponsor

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

 

Administration

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

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

Absorica: May be taken with or without food

 

Amnesteem, Claravis (isotretinoin) adverse (side) effects

>10%

Cheilitis (90%)

Xerosis

Xerostomia

Dry nose

Epistaxis

Pruritus

Conjunctivitis (including blepharoconjunctivitis) (40%)

Irritation (40%)

Increased erythrocyte sedimentation rates (40%)

Thinning of hair (which has persisted in rare instances)

Palmoplantar desquamation

Skin fragility

Skin infections (eg, paronychial infections)

Rash (including erythema, seborrhea, eczema), photosensitivity

Hypertriglyceridemia (25%)

Bone or joint pain

Generalized muscle aches

Arthralgia

Decreased HDLs (15%)

Increased LFTs (15%)

Increased CPK (12-24%)

Decreased hemoglobin concentration and hematocrit

Decreased erythrocyte and leukocyte counts

Increased platelet count

 

1-10%

Decreased bone mineral density (8.8%)

Premature epiphyseal closure (3%)

 

Frequency not defined

Lethargy

Fatigue

Headache

Anorexia

Nausea

Vomiting

Increased appetite

Thirst

 

Warnings

Black box warnings

Embryofetal toxicity

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

Restricted distribution program

• Prescribers must register with iPLEDGE, an FDA-approved risk management program designed to minimize pregnancy exposures to isotretinoin (enhancement of earlier riskMAP [risk minimization action plan]); patients must be registered and meet all requirements of iPLEDGE
• Patients of childbearing potential must not be pregnant or breastfeeding, must be capable of complying with approved contraceptive methods, and must be reliable in following instructions

 

Contraindications

Pregnancy (see Black box warnings)

Hypersensitivity to isotretinoin or vitamin A

 

Cautions

Significant adverse effects are associated with isotretinoin use

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

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

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

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

Depression and psychosis reported; rare reports of suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors

Pseudotumor cerebri reported; some reports involved concomitant tetracycline use

Serious skin reactions reported (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis)

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

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

Hearing impairment reported and may persist after discontinuing therapy

Hepatitis may occur; mild to moderate liver enzymes elevations also reported

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

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

Musculoskeletal symptoms, including arthralgia, may occur

Skeletal hyperostosis observed in clinical trial for keratinization disorders

Premature epiphyseal closure reported spontaneously with normal doses

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

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

Laboratory monitoring

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

 

Pregnancy and lactation

Pregnancy category: X (see Black box warnings)

Lactation: Unknown whether distributed into breast milk; because of potential for serious adverse reactions in nursing infants, do not administer to women who are breastfeeding

 

Pregnancy categories

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

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

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

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

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

NA: Information not available.

 

Pharmacology of Amnesteem, Claravis (isotretinoin)

Mechanism of action

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

 

Absorption

Bioavailability: Low

Peak plasma time

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

Peak plasma concentration

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

AUC

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

 

Distribution

Protein bound: 99.9% (primarily albumin)

 

Metabolism

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

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

 

Elimination

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