ISOtretinoin (Systemic)

(eye soe TRET i noyn)

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

Absorption

Absorption: Enhanced with a high-fat meal; Absorica absorption is ~83% greater than Accutane when administered under fasting conditions; they are bioequivalent when taken with a high-fat meal.

Metabolism

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

Excretion

Urine and feces (equal amounts)

Time to Peak

Serum: 3 to 5 hours

Half-Life Elimination

Terminal: Parent drug: 21 hours; Metabolite: 21 to 24 hours

Protein Binding

99% to 100%; primarily albumin

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

For patients unable to swallow the capsules whole, an oral liquid may be prepared with softgel capsules (not recommended by the manufacturers) by one of the following methods:

Place capsules (softgel formulations only) in small container and add warm (~37°C [97°F]) water or milk to cover capsule(s); wait 2 to 3 minutes until capsule is softened and then drink the milk or water with the softened capsule, or swallow softened capsule.

Puncture capsule (softgel formulations only) with needle or cut with scissors; squeeze capsule contents into 5 to 10 mL of milk or tube feed formula; draw mixture up into oral syringe and administer via feeding tube; flush feeding tube with ≥30 mL additional milk or tube feeding formula.

Puncture capsule (softgel formulations only) with needle or cut with scissors and draw contents into oral syringe; add 1 to 5 mL of medium chain triglyceride, soybean, or safflower oil to the oral syringe; mix gently and administer via feeding tube; flush feeding tube with ≥30 mL milk or tube feeding formula.

Oral: Administer with a meal (except Absorica, which 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.

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

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

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

Estrogen Derivatives (Contraceptive): Retinoic Acid Derivatives may diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Two forms of contraception are recommended in females of child-bearing potential during retinoic acid derivative therapy. Monitor therapy

Mipomersen: ISOtretinoin may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

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

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

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

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. 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. Particularly, microdosed progesterone-only preparations may be inadequately effective. Consider therapy modification

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

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

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

Concerns related to adverse effects:

• Auditory impairment: Hearing impairment, which can continue after therapy is discontinued, may occur. Discontinue therapy if hearing impairment or tinnitus develops.

• Bone mineral density loss: May decrease bone mineral density; osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been reported. Use caution in patients with a genetic predisposition for bone loss (eg, age-related osteoporosis, history of childhood osteoporosis conditions, osteomalacia or other disorders of bone metabolism); including patients diagnosed with anorexia nervosa and those on concomitant medications that may cause drug-induced osteoporosis/osteomalacia and/or affect vitamin D metabolism (eg, systemic corticosteroids, anticonvulsants). Patients may be at increased risk when participating in activities with repetitive impact (such as sports) where the risk of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known.

• Dermatologic effects: Postmarketing reports of erythema multiforme severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatalities, have been reported; monitor for severe skin reactions; discontinue use if severe skin reaction occurs.

• Growth effects: Skeletal hyperostosis and premature epiphyseal closure have also been reported with the use.

• Hematologic effects: Neutropenia and rare cases of agranulocytosis have been reported; discontinue if clinically significant decreases in white cell counts occur.

• Hepatic effects: Clinical hepatitis and mild to moderate elevated liver enzymes have been reported with use; liver enzymes may normalize with dosage reduction or with continued treatment. Discontinue therapy if hepatic enzymes do not normalize or if hepatitis is suspected.

• Hypersensitivity reactions: Anaphylaxis and other types of allergic reactions, including cutaneous reactions and serious cases of allergic vasculitis, often with purpura of the extremities and extracutaneous involvement (including renal) have been reported. Discontinue therapy if a serious allergic reaction occurs and institute appropriate medical management.

• Inflammatory bowel disease: Inflammatory bowel disease, 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).

• Musculoskeletal effects: Musculoskeletal symptoms (including arthralgia) have been reported; generally symptoms were mild to moderate, but occasionally required discontinuation of therapy. Transient pain in the chest has occurred; symptoms generally cleared after discontinuation of therapy, but in some cases persisted. Rhabdomyolysis, some associated with strenuous physical activity, has been reported (rarely).

• Ocular effects: Vision impairment, corneal opacities, decreased tolerance to contact lenses (due to dry eyes), and decreased night vision have been reported with use; discontinue therapy in patients experiencing visual difficulties. Warn patients to be cautious when driving or operating machinery at night.

• Pancreatitis: Acute pancreatitis may occur in patients with normal or elevated triglyceride levels; fatal hemorrhagic pancreatitis (rare) has been reported; discontinue therapy if hypertriglyceridemia cannot be controlled at an acceptable level or symptoms of pancreatitis occurs.

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

• Pseudotumor cerebri: Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances; discontinue immediately and refer patient to a neurologist if papilledema occurs.

• Psychiatric effects: May cause depression, psychosis, mood disturbance, and rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. All patients should be observed closely for symptoms of depression or suicidal thoughts. Discontinue therapy if depression, mood disturbance, psychosis, or aggression develops. Discontinuation of treatment alone may not be sufficient, further evaluation may be necessary. Use with extreme caution in patients with a history of psychiatric disorder.

Disease-related concerns:

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

• Hypertriglyceridemia: Marked elevations of serum triglycerides have been reported; use with caution in patients with hypertriglyceridemia or those who may be at high risk (eg, patients with diabetes, obesity, increased alcohol intake, family history of or those with lipid metabolism disorder). The effects on triglycerides, HDL, and cholesterol have been reversible upon discontinuation of therapy. Instruct patients to avoid or limit ethanol; may increase triglyceride levels if taken in excess.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warnings]: Use of isotretinoin is contraindicated in females who are or may become pregnant. Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus and parathyroid gland abnormalities) have been noted following isotretinoin exposure during pregnancy and the risk for severe birth defects is high, with any dose or even with short treatment duration. Low IQ scores have also been reported. The risk for spontaneous abortion and premature births is increased. Because of the high likelihood of teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE risk evaluation and mitigation strategy (REMS) program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug. If pregnancy occurs during therapy, isotretinoin should be discontinued immediately and the patient referred to an obstetrician-gynecologist specializing in reproductive toxicity.

Dosage form specific issues:

• Absorica: Absorption is ~83% greater than Accutane when administered under fasting conditions; they are bioequivalent when taken with a high-fat meal. Absorica is not interchangeable with other generic isotretinoin products.

• 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 female.

• 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.

• REMS program: [US Boxed Warning]: Because of the high likelihood of teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE risk evaluation and mitigation strategy (REMS) management program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug (see Additional Information or Pharmacotherapy Pearls for details). Women of childbearing potential must be capable of complying with effective contraceptive measures. Patients must select and commit to two forms of contraception. Therapy is begun after two negative pregnancy tests; effective contraception must be used for at least 1 month before beginning therapy, during therapy, and for 1 month after discontinuation of therapy. Prescriptions should be written for no more than a 30-day supply, and pregnancy testing and counseling should be repeated monthly.

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

CBC with differential and platelet count, baseline sedimentation rate, glucose, CPK; signs of depression, mood alteration, psychosis, aggression, severe skin reactions; changes in vision

Pregnancy test (for all female patients of childbearing potential): Two negative tests with a sensitivity of at least 25 milliunits/mL prior to beginning therapy (the second performed at least 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 one month after discontinuation (Absorica).

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.

When used for oncology indications, monitor adherence.