Version May 2024
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; patients who may become pregnant who relapse must follow the same contraceptive protocol as when initiating therapy.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.
Severe impairment: Use is contraindicated.
Use is contraindicated.
Consider dose reduction to 10 mg once daily for intolerable side effects.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Increased LDL cholesterol (>10%), increased serum triglycerides (30 mg: 35%; 10 mg: 17%)
Hematologic & oncologic: Decreased monocytes (16% to 22%)
Nervous system: Headache (11% to 22%)
1% to 10%:
Cardiovascular: Flushing (2% to 6%), hypertension (1% to 2%)
Dermatologic: Alopecia (2%), cheilitis (1% to 2%), cheilosis (4% to 6%), erythema of skin (2% to 7%), xeroderma (3%)
Endocrine & metabolic: Decreased HDL cholesterol (5% to 10%), decreased serum iron (1% to 5%), decreased thyroid hormones (TSH and T4, reversible: 3% to 10%), high total iron binding capacity (1% to 5%), hot flash (≤1%), hypercholesterolemia (1%), weight gain (1%)
Gastrointestinal: Dyspepsia (1%), nausea (3%), upper abdominal pain (1%), vomiting (1%), xerostomia (3%)
Hematologic & oncologic: Reticulocytopenia (1% to 5%)
Infection: Influenza (2%)
Nervous system: Depression (3%), dizziness (2%)
Neuromuscular & skeletal: Arthralgia (2%), back pain (2%), increased creatine phosphokinase in blood specimen (2% to 3%)
Ophthalmic: Abnormal sensation in eyes (≤1%), conjunctivitis (2%), dry eye syndrome (2% to 3%)
Respiratory: Nasopharyngitis (6%), pharyngitis (1%)
Frequency not defined:
Gastrointestinal: Ileitis
Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin, decreased red blood cells,
Neuromuscular & skeletal: Myalgia
<1%: Ankylosing spondylitis, blurred vision, cataract, eczema (asteatotic), epistaxis, exfoliation of skin, exostosis, idiopathic intracranial hypertension, pruritus, skin rash, vasculitis
Postmarketing: Abnormal hair texture, acute pancreatitis, aggressive behavior, allergic skin rash, anaphylaxis, anxiety, eye irritation, hypersensitivity angiitis, hypersensitivity reaction, increased serum transaminases, inflammatory bowel disease, mood changes, nail disease, night blindness, peripheral edema, psychotic symptoms, skin photosensitivity, suicidal ideation, suicidal tendencies, thrombocythemia, tinnitus
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; breastfeeding; hepatic impairment; severe renal impairment; uncontrolled hypercholesterolemia; uncontrolled hypertriglyceridemia; uncontrolled hypothyroidism; hypervitaminosis A; hereditary fructose intolerance; concurrent use of tetracyclines.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
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.
Not available in the US
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Toctino: 10 mg [DSC], 30 mg [DSC] [contains soybean oil]
Prescriptions must be limited to a 30-day supply for women of childbearing potential; further treatment requires a new prescription. The evaluation of pregnancy test results and the issuance and dispensing of a prescription should preferably occur on the same day. Alitretinoin should be dispensed within 7 days of a medically supervised pregnancy test.
Oral: Administer once daily with a main meal, preferably at the same time each day.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Note: Not approved in the US.
Eczema of the hand: Treatment of severe chronic hand eczema refractory to high-potency topical corticosteroids
Alitretinoin may be confused with altretamine, isotretinoin, tretinoin
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Panretin is a topical preparation of alitretinoin available in the US.
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Substrate of CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
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. Risk D: Consider therapy modification
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with moderate CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a moderate CYP2C9 inhibitor. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Alitretinoin (Systemic). Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Methotrexate: Alitretinoin (Systemic) may enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Progestins (Contraceptive): Retinoic Acid Derivatives may diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Risk D: Consider therapy modification
Tetracyclines: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combination
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Food significantly enhances systemic exposure and decreases variability in exposure. Management: Administer with a meal.
Alitretinoin (Systemic) is contraindicated in females of childbearing potential unless they are able to meet all the requirements of the TOCTINO Pregnancy Prevention Program. [Canadian Boxed Warning]: Alitretinoin should only be prescribed by physicians knowledgeable in the use of systemic retinoids, who have full understanding of the risks of systemic retinoid therapy and the monitoring requirements. In addition, when prescribing alitretinoin to female patients of childbearing potential, physicians must use the TOCTINO Pregnancy Prevention Program, which includes comprehensive information about the potential risks of this drug, a checklist for criteria which must be met prior to prescribing this drug to female patients of childbearing potential, detailed information on birth control options, a patient acknowledgement form for review and signature, and monthly pregnancy reminders for physicians to use at each patient visit during the treatment period. Health care providers can obtain materials for the pregnancy prevention program by calling 800-387-7374.
Evaluate pregnancy status prior to prescribing in females of reproductive potential. Two negative pregnancy tests (sensitivity at least 25 milliunits/mL) performed at least 3 weeks apart are required prior to initiating therapy. Prescriptions should be limited to a 1-month supply. Pregnancy testing should be continued monthly throughout therapy prior to each new prescription; a pregnancy test should also be conducted 1 month after the final dose. Treatment should be initiated on the second or third day of the next normal menstrual period following the second negative pregnancy test.
Women of childbearing potential should use two effective, reliable, and complementary forms of birth control simultaneously for at least 1 month prior to starting therapy, during therapy, and for at least 1 month after treatment is discontinued. Use of microdosed progesterone (minipill) preparations are not recommended. Contraception must be used unless permanent infertility has been medically diagnosed. 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.
[Canadian Boxed Warning]: Alitretinoin is a known teratogen and is contraindicated in pregnancy. Alitretinoin can cause severe birth defects in infants born to women who become pregnant during treatment with alitretinoin in any amount, even for a short period of time. Potentially any exposed fetus can be affected. Fetal abnormalities and spontaneous abortion may occur. Birth defects associated with exposure to retinoids include facial dysmorphia, cleft palate, external ear abnormalities, eye abnormalities, and abnormalities of the central nervous system, cardiovascular system, thymus gland, and parathyroid gland. There are no accurate means of determining whether an exposed fetus has been affected. If pregnancy does occur during treatment with alitretinoin or within 1 month after its discontinuation, alitretinoin treatment must be immediately stopped and a physician and the patient should discuss the desirability of continuing the pregnancy.
It is not known if alitretinoin is present in breast milk; however, it is highly lipophilic and is likely excreted in human breast milk.
Due to the potential for serious adverse reactions in the nursing infant, breastfeeding is contraindicated.
Prior to initiating therapy in patients who may become pregnant, perform 2 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.
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.
Duration: Serum concentrations of endogenous alitretinoin return to normal range within 48 to 72 hours after discontinuation
Absorption: Variable and dose-proportional (not consistently absorbed in fasted state)
Distribution: >14 L
Protein binding: 99%
Metabolism: Hepatic via CYP2C9, 2C8, and 3A4 to metabolites; Major metabolite: 4-oxo-alitretinoin (active)
Bioavailability: Systemic exposure is enhanced by food (Schmitt-Hoffman 2011)
Half-life elimination: Alitretinoin: 9 hours; 4-oxo-alitretinoin: 10 hours
Time to peak: 3 to 4 hours (Weber 1997)
Excretion: Urine (63% as metabolites); feces (~30% as metabolites) (Schmitt-Hoffman 2012)
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