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Alitretinoin (Systemic)

Pronunciation

(a li TRET i noyn)

Index Terms

  • 9-cis-Retinoic Acid
  • 9-cis-Tretinoin

Pharmacologic Category

  • Anti-inflammatory Agent
  • Immunomodulator, Systemic
  • Retinoic Acid Derivative

Pharmacology

Binds to both retinoid acid receptor (RAR) and retinoid X receptor (RXR); anti-inflammatory and immunomodulating effects occur through down-regulation of CXCR3 ligands and CCL20 chemokine expression in cytokine-induced dermal cells and suppressed expansion of cytokine-induced leukocytes and antigen presenting cells.

Absorption

Variable and dose-proportional (not consistently absorbed in fasted state)

Distribution

>14 L

Metabolism

Hepatic via CYP2C9, 2C8, and 3A4 to metabolites; Major metabolite: 4-oxo-alitretinoin (active)

Excretion

Urine (63% as metabolites); feces (~30% as metabolites) (Schmitt-Hoffman 2012)

Time to Peak

3 to 4 hours (Weber 1997)

Duration of Action

Serum concentrations of endogenous alitretinoin return to normal range within 48 to 72 hours after discontinuation

Half-Life Elimination

Alitretinoin: 9 hours; 4-oxo-alitretinoin: 10 hours

Protein Binding

99%

Use: Labeled Indications

Note: Not approved in the US.

Eczema of the hand: Treatment of severe chronic hand eczema refractory to high-potency topical corticosteroids

Contraindications

Hypersensitivity to alitretinoin, other retinoids, or any component of the formulation (including allergy to peanut or soya); pregnancy; women of childbearing potential unless all of the conditions of the Pregnancy Prevention Program are met; breast-feeding; hepatic impairment; severe renal impairment; uncontrolled hypercholesterolemia; uncontrolled hypertriglyceridemia; uncontrolled hypothyroidism; hypervitaminosis A; fructose intolerance; concurrent use of tetracyclines

Dosing: Adult

Eczema of the hand (severe, chronic): Oral: Initial: 30 mg once daily; may consider dose reduction to 10 mg once daily for intolerable side effects; usual range: 10 to 30 mg once daily

Therapy duration: 12 to 24 weeks; consider discontinuation of therapy if severe disease is still present after initial 12 weeks of therapy or if clear or almost clear hands occur prior to 24 weeks. Patients who relapse may benefit from additional treatment; females who relapse must follow the same contraceptive protocol as when initiating therapy.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

Dosing: Hepatic Impairment

Use is contraindicated.

Dosing: Adjustment for Toxicity

Consider dose reduction to 10 mg once daily for intolerable side effects.

Administration

Administer once daily with a main meal, preferably at the same time each day. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH, 2014 [group 3]). NIOSH recommends single gloving for administration of intact capsules (NIOSH 2014).

Storage

Store at 15°C to 30°C (59°F to 86°F) in original packaging. Protect from light.

Drug Interactions

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Contraceptives (Progestins): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). 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

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP2C8 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP2C8 inhibitor. Consider therapy modification

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP2C9 inhibitor. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Methotrexate: Alitretinoin (Systemic) may enhance the hepatotoxic effect of Methotrexate. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tetracycline Derivatives: 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

Adverse Reactions

>10%:

Central nervous system: Headache (11% to 22%)

Endocrine & metabolic: Increased LDL cholesterol (>10%)

1% to 10%:

Cardiovascular: Flushing (2% to 6%), hypertension (1% to 2%)

Central nervous system: Depression (3%), dizziness (2%)

Dermatologic: Erythema (2% to 7%), cheilosis (4% to 6%), xeroderma (3%), cheilitis (2%), alopecia (≤2%)

Endocrine & metabolic: Decreased HDL cholesterol (5% to 10%), hypercholesterolemia (1% to 10%), increased serum triglycerides (1% to 10%), decreased serum iron (1% to 5%), high total iron binding capacity (1% to 5%), weight gain (1%), hot flash (≤1%)

Gastrointestinal: Nausea (3%), xerostomia (3%), dyspepsia (1%), upper abdominal pain (1%), vomiting (1%)

Hematologic & oncologic: Reticulocytopenia (1% to 5%)

Infection: Influenza (2%)

Neuromuscular & skeletal: Increased creatine phosphokinase (2% to 3%), arthralgia (2%), back pain (2%)

Ophthalmic: Dry eye syndrome (2% to 3%), conjunctivitis (2%), abnormal sensation in eyes (≤1%)

Respiratory: Nasopharyngitis (6%), pharyngitis (1%)

<1% (Limited to important or life-threatening): Aggressive behavior, ankylosing spondylitis, anxiety, blurred vision, cataract, decreased hematocrit, decreased hemoglobin, decreased red blood cells, decreased thyroid hormones (TSH and T4, reversible), epistaxis, exfoliation of skin, exostosis, mood changes, nocturnal amblyopia, pseudotumor cerebri, psychotic symptoms, reduced fertility (male), skin rash, suicidal ideation, suicidal tendencies, vasculitis

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic effects: Retinoids enhance the effects of ultraviolet (UV) light; avoid excessive exposure to sunlight or sun lamp. Instruct patients to apply sun protectant (≥15 SPF), skin moisturizers, and lip balm when necessary.

• Hepatic effects: Transient and reversible transaminase elevations have been observed with systemic retinoids; consider dose reduction or discontinuation of therapy for persistent clinically relevant effects.

• Hypercholesterolemia/hypertriglyceridemia: Associated with hypercholesterolemia and hypertriglyceridemia; discontinue use for uncontrollable hypertriglyceridemia. Obese patients or patients with increased alcohol use, diabetes mellitus, or a family history of hypertriglyceridemia may be at an increased risk of developing hypertriglyceridemia. Patients at high risk for cardiac events should be monitored closely.

• Hypersensitivity: Hypersensitivity reactions (eg, anaphylaxis, allergic cutaneous reactions, allergic vasculitis) have been reported rarely. Interrupt therapy for severe allergic reactions and treat as indicated.

• Inflammatory bowel disease: Onset of inflammatory bowel disease (IBD) in patients with no history of gastrointestinal disorders has been observed with systemic retinoids; discontinue use immediately for abdominal pain, rectal bleeding, or severe diarrhea. Rule out IBD in patients with severe diarrhea.

• Intracranial hypertension: [Canadian Boxed Warning]: Retinoids (including alitretinoin) have been associated with the development of benign intracranial hypertension, and in some cases involving concomitant tetracycline use. Discontinue use immediately for signs/symptoms of benign intracranial hypertension (eg, headache, abnormal vision, papilledema, nausea, vomiting).

• Musculoskeletal effects: Use of alitretinoin has been associated with myalgia and arthralgia. Bone changes (eg, premature epiphyseal closure, hyperostosis, calcification of tendons/ligaments) have been observed with other systemic retinoids.

• Ocular effects: Corneal opacities, keratitis, and conjunctivitis have occurred with systemic retinoids. Dry eyes and/or impaired night vision have also been reported with use; may be reversible upon discontinuation of therapy. Patients with dry eyes should be monitored for keratitis. Caution patients with regard to driving or operating machinery. Intolerance to contact lens (due to dry eyes) may be observed. Ophthalmologic exam may be warranted for ongoing visual disturbances and, if necessary, discontinuation of therapy.

• Pancreatitis: Acute pancreatitis has been reported, usually associated with elevated serum triglycerides. Discontinue if symptoms of pancreatitis occur.

• Psychiatric effects: Systemic retinoid use may cause or aggravate depression, anxiety, psychosis, aggressive or violent behavior, and changes in mood; suicidal thoughts and actions have also been reported (rare). Prior to initiation of therapy and routinely during therapy, all patients should be evaluated for symptoms of depression or suicidal thoughts. Caregivers should be informed of the potential for psychiatric effects. Therapy should be discontinued if patients develop depression, aggression, mood disturbance, or psychosis, although discontinuation of treatment alone may not be sufficient to relieve symptoms; further evaluation may be necessary. Use with extreme caution in patients with a history of psychiatric disorder.

• Thyroid effects: Associated with reversible reductions in thyroid-stimulating hormone (TSH) and T4 (free thyroxine).

Disease-related concerns:

• Diabetes mellitus: Use with caution in patients with diabetes mellitus; impaired glucose control has been reported with other retinoids. Monitor blood glucose periodically in patients with known or suspected diabetes mellitus.

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 handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH, 2014 [group 3]).

Other warnings/precautions:

• Appropriate use: Use should be reserved for patients nonresponsive to potent topical corticosteroids and/or other measures (eg, avoidance of irritants/allergens, skin protection).

• Blood donation: Patients should not donate blood during therapy and for 1 month after discontinuing therapy due to the potential risk to the fetus of a pregnant transfusion recipient.

• Pregnancy: [Canadian Boxed Warning]: Alitretinoin is a known teratogen and is contraindicated in pregnancy. Females must avoid becoming pregnant while receiving alitretinoin and for at least 1 month after discontinuation of therapy. Discontinue immediately if pregnancy is discovered during treatment or within 1 month after discontinuation. Fetal abnormalities and spontaneous abortion may occur. The risk for severe birth defects is high, with any dose or even with short treatment duration. Only physicians familiar with systemic retinoid therapy should prescribe alitretinoin. Females of childbearing potential must be able to fulfill all conditions for use prior to initiating therapy (consult manufacturer labeling for further detail). Physicians are required to use the Toctino Pregnancy Prevention Program, which includes comprehensive information regarding conditions that must be met prior to initiating therapy, birth control options, potential risks of therapy, informed consent, and monthly pregnancy reminders. Two effective and reliable means of birth control should be used simultaneously for at least 1 month prior to starting therapy during therapy, and for at least 1 month after treatment. Two negative pregnancy tests (sensitivity at least 25 milliunits/mL) and the onset of next menses for 2 or 3 days are required prior to initiating therapy. Refer to Pregnancy considerations for more detailed discussion.

Monitoring Parameters

Prior to initiating therapy in female patients, perform two pregnancy tests (sensitivity at least 25 milliunits/mL); second test must be performed ≤11 days prior to initiation. Thereafter, perform monthly pregnancy tests during therapy and at 1 month following discontinuation. Serum lipids (particularly if at high risk for cardiac events, obese patients and patients with diabetes) at baseline and then monthly until lipid response is established and again at discontinuation; hepatic function; serum glucose (periodically in patients with known or suspected diabetes mellitus, obese patients, and patients with cardiovascular risk factors); thyroid function. Signs/symptoms of depression, mood alteration, psychosis, aggression, hypersensitivity, and pancreatitis.

Pregnancy Considerations

[Canadian Boxed Warning]: Alitretinoin is a known teratogen and is contraindicated in pregnancy. Females must avoid becoming pregnant while receiving alitretinoin and for at least 1 month after discontinuation of therapy. Discontinue immediately if pregnancy is discovered during treatment or within 1 month after discontinuation. Fetal abnormalities and spontaneous abortion may occur. The risk for severe birth defects is high, with any dose or even with short treatment duration. If treatment with alitretinoin is required in women of childbearing potential, two effective and reliable forms of birth control should be used simultaneously for at least 1 month prior to starting therapy, during therapy, and for at least 1 month after treatment. Two negative pregnancy tests (sensitivity at least 25 milliunits/mL) and onset of next menses for 2 or 3 days are required prior to initiating therapy. Patients should be advised of the potential harm to the fetus and the physician and patient should discuss the desire to maintain the pregnancy.

Only physicians familiar with systemic retinoid therapy should prescribe alitretinoin. Females of childbearing potential must be able to fulfill all conditions for use prior to initiating therapy (consult manufacturer labeling for further detail). Physicians are required to use the Toctino Pregnancy Prevention Program, which includes comprehensive information regarding conditions that must be met prior to initiating therapy, birth control options, potential risks of therapy, informed consent, and monthly pregnancy reminders. Even women with amenorrhea, a history of infertility, or those who claim an absence of sexual activity must comply with these conditions.

Small amounts of alitretinoin have been detected in the semen of some healthy male volunteers, although accumulation in the semen is not anticipated. Systemic exposure of female partners or fetus is expected to be negligible. The manufacturer labeling suggests that there is no apparent fetal risk in pregnant females whose male partners are receiving alitretinoin.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, dry eyes, dry lips, dry mouth, or change in how contact lenses feel. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe headache, dizziness, nausea, vomiting, seizures, muscle pain, muscle weakness, severe bone pain, severe joint pain, eye pain, eye irritation, bruising, bleeding, decreased night vision, or signs of inflammatory bowel disease (severe diarrhea, abdominal pain, rectal bleeding, or rectal pain) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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