Acitretin (acitretin)

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Acitretin should be administered orally once daily with the main meal. (See Food under Pharmacokinetics: Absorption.)

Acitretin is not metabolized by hepatic microsomal enzymes.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Acitretin/Methotrexate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Additive hepatic toxicity.(1-3)

CLINICAL EFFECTS: Methotrexate has a risk of causing hepatic fibrosis and cirrhosis.(1) Concurrent use with another hepatotoxic agent like acitretin increases the risk of hepatotoxicity.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of acitretin states that the concurrent use of acitretin and methotrexate is contraindicated.(2)

DISCUSSION: Because of the risk of increased hepatotoxicity during concurrent administration of methotrexate and etretinate, the manufacturer of acitretin states that concurrent administration of methotrexate and acitretin is contraindicated.(2)

Selected Retinoids (Systemic)/Growth Hormone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic retinoids(1-8,11) and growth hormones(9-11) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(1-8) with growth hormones(9-10) may increase the risk of intracranial hypertension (pseudotumor cerebri). Early signs of intracranial hypertension include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(12)

PREDISPOSING FACTORS: Women of childbearing age with high body mass may have a higher risk of developing intracranial hypertension.(8)

PATIENT MANAGEMENT: The US manufacturer of tretinoin advises avoiding concomitant use of other products that can cause intracranial hypertension.(1) Patients who present with symptoms of intracranial hypertension should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(1-8)

DISCUSSION: Vitamin A derivatives and growth hormone have both been strongly associated with intracranial hypertension. A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 21 patients who developed intracranial hypertension while taking tretinoin, acitretin, or etretinate at prescribed doses. Symptom onset occurred at an average of 2-3 months after starting retinoid therapy and all except 3 cases resolved within a few months after discontinuing therapy.(8) In a systematic review of 580 reported cases of medication-induced intracranial hypertension between January 1900 and June 2019 found in MEDLINE, EMBASE, and Cochrane Review Databases, there were 259 verifiable cases of intracranial hypertension. Vitamin A derivatives were implicated in 84 cases, though 25 cases occurred with excessive vitamin A supplementation. Growth hormone was implicated in 24 cases, all of which occurred in pediatric patients and involved frequent or higher doses of growth hormone.(12)

Selected Retinoids (Systemic)/Lithium

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic retinoids(1-7) and lithium(8-9) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(1-7) with lithium(8-9) may increase the risk of intracranial hypertension (pseudotumor cerebri). Early signs of intracranial hypertension include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(10)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(10)

PATIENT MANAGEMENT: The US manufacturer of tretinoin advises avoiding concomitant use of other products that can cause intracranial hypertension.(1) Patients who present with symptoms of intracranial hypertension should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(1-7)

DISCUSSION: Vitamin A derivatives and lithium have both been strongly associated with intracranial hypertension. In a systematic review of 580 reported cases of medication-induced intracranial hypertension between January 1900 and June 2019 found in MEDLINE, EMBASE, and Cochrane Review Databases, there were 259 verifiable cases of intracranial hypertension. Vitamin A derivatives were implicated in 84 cases, though 25 cases occurred with excessive vitamin A supplementation. Lithium was implicated in 17 cases with lithium levels in therapeutic range.(10)

Selected Retinoids (Systemic)/Tetracyclines

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic tetracyclines(1-4,14) and systemic retinoids(5-14) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(5-12) with tetracyclines has been associated with pseudotumor cerebri (benign intracranial hypertension). Early signs of pseudotumor cerebri include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(15)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(15)

PATIENT MANAGEMENT: The UK(5) and US(6) manufacturers of acitretin state state that concurrent use with tetracyclines is contraindicated. The UK manufacturer of isotretinoin states that concurrent use with tetracyclines is contraindicated.(7) The US manufacturer of isotretinoin states that the concurrent use of tetracyclines should be avoided.(8) The US manufacturer of minocycline states that the administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy.(2) The UK manufacturers of oral tretinoin and alitretinoin states that concurrent use with tetracyclines is contraindicated.(9,11) The Canadian manufacturer of palovarotene states that coadministration of tetracycline derivatives should be avoided.(12) Patients who present with symptoms of pseudotumor cerebri should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(5-13)

DISCUSSION: The concurrent use of isotretinoin and tetracyclines has been associated with pseudotumor cerebri.(5-13) A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 6 patients who developed intracranial hypertension while taking concurrent minocycline or tetracycline with tretinoin, acitretin, or etretinate.(13)

Selected Retinoids/Vitamin A

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The retinoids are structurally related to vitamin A. (1-6)

CLINICAL EFFECTS: Concurrent use of retinoids with vitamin A supplements may result in signs of vitamin A toxicity.(1-6) Symptoms of vitamin A toxicity include nausea, vomiting, loss of appetite, weakness, dry or itchy skin or lips, irritability, and hair loss.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of acitretin states that concomitant use of vitamin A supplements should be avoided.(1) The manufacturer of bexarotene states that patients should be advised to limit vitamin A supplements. In clinical studies, patients were advised to limit their vitamin A intake to less than or equal to 15,000 International Units/day.(2) The manufacturer of isotretinoin states that patients should be advised against taking vitamin A supplements.(3) The manufacturer of palovarotene states that concomitant use of vitamin A must be avoided.(4) The manufacturer of tretinoin states that tretinoin must not be administered in combination with vitamin A.(5) The UK manufacturer of alitretinoin states that tretinoin must not be administered in combination with vitamin A.(6)

DISCUSSION: The retinoids are structurally related to vitamin A. The concurrent use of retinoids with vitamin A may result in signs and symptoms of vitamin A toxicity.(1-6)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Acitretin/Ethyl Alcohol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ethanol trans esterifies acitretin into etretinate,(1-3) which is stored in adipose tissue and slowly eliminated.(1)

CLINICAL EFFECTS: Ingestion of ethanol, even sporadically, during acitretin usage and for 2 months after discontinuation of acitretin may result in formation of etretinate. Etretinate is also highly teratogenic and is slowly eliminated from the body over several years after discontinuation.(4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of acitretin states that use of ethanol during or for 2 months after acitretin therapy in females is contraindicated.(4) Females on acitretin therapy should be counseled to avoid consumption and use of ethanol containing products during and for two months after acitretin use.(4) Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (6): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: In a 2-way cross-over study in 10 subjects, consumption of a single dose of acitretin (100 mg) during ethanol ingestion (1.4 g/kg) resulted in formation of etretinate in all 10 subjects. The levels of etretinate formed were comparable to a 5 mg dose of etretinate. There was no detectable etretinate levels in any subject during administration of acitretin without ethanol.(4) In a study in 10 subjects treated with acitretin (30 mg daily for 3 months), 7 patients had detectable etretinate levels, 4 of which were teratogenic. Consumption of ethanol was linked to the formation of etretinate.(1) In a study in 86 patients treated with acitretin, 30 patients had detectable levels of etretinate. No etretinate was found in 20 subjects who reported no ethanol intake. Etretinate was found in all 16 subjects with an average weekly alcohol consumption of greater than 200 g (approximately 15 servings/week). Etretinate was found in 15 of 50 patients with an average weekly ethanol intake less than 200 g.(5) The half-life of etretinate has been estimated at 120 days (range 84-168 days). In a study of 47 patients treated with etretinate, 5 had detectable etretinate levels 2.1 years to 2.9 years after discontinuation of therapy. However, one patient who reported sporadic ethanol intake had detectable etretinate levels 52 months after discontinuation of acitretin.(4)

Selected Retinoids/Progestin-Only Oral Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use may result in increased progesterone levels and interference with the effect of the contraceptive. Major fetal abnormalities have been reported with the administration of acitretin(1) and isotretinoin.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use of "mini-pill" progestin preparations are not recommended. Patients on acitretin(1) or isotretinoin(2) therapy should be using two reliable methods of contraception and should be advised that progestin-only mini-pills may fail. Consider switching to a combination estrogen-progestin contraceptive agent; intrauterine device (IUD); or injected, implanted, or inserted hormonal birth control products. Two methods of contraception are still required.

DISCUSSION: According to the manufacturer of acitretin, this interaction has been documented in one patient who received concurrent therapy with acitretin and a progestin-only mini-pill.(1) Given the severe consequences of contraceptive failure during acitretin or isotretinoin therapy, caution is warranted. All females of reproductive age should use two reliable forms of contraception unless they have undergone a hysterectomy or practice abstinence.(1,2) In a study in 26 healthy women, concurrent use of isotretinoin and Ortho Novum 7/7/7 (ethinyl estradiol and norethindrone) resulted in small, inconsistent, although statistically significant, decreases in ethinyl estradiol (9%) and norethindrone (11%). However, there was large variability of pharmacokinetic and pharmacodynamic markers and the authors stressed that their results reinforced the need for additional contraceptive measures during therapy.(3)

There are no moderate interactions for this drug.

Acitretin is contraindicated in females who are or may become pregnant during acitretin therapy or within at least 3 years following discontinuance of the drug. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Acitretin is contraindicated in patients with severely impaired renal or hepatic function. (See Hepatic Effects under Warnings/Precautions: Warnings, in Cautions.) The drug also is contraindicated in patients with chronic, abnormally elevated blood lipids. (See Effects on Lipoproteins under Warnings/Precautions: Warnings, in Cautions.)

Concomitant use of acitretin with methotrexate, tetracyclines, or vitamin A and/or other oral retinoids is contraindicated. (See Drug Interactions.)

The drug is contraindicated in patients with known hypersensitivity to acitretin, any ingredient in the formulation, or other retinoids.

• Acute pancreatitis
• Child-pugh class C hepatic impairment
• Idiopathic intracranial hypertension
• Lactation
• Pregnancy

• Capillary leak syndrome
• Depression
• Disease of liver
• Hyperlipidemia
• Hypertriglyceridemia
• Psychotic disorder
• Skeletal hyperostosis

• Diabetes mellitus
• High density lipoprotein deficiency

Adverse effects reported in 10% or more of patients receiving acitretin in clinical trials include cheilitis, alopecia, skin peeling, rhinitis, dry skin, nail disorder, pruritus, rigors, xerophthalmia, dry mouth, epistaxis, arthralgia, spinal hyperostosis, rash, hyperesthesia, paresthesia, paronychia, and skin atrophy. Many reported adverse effects resemble those associated with hypervitaminosis A.

Laboratory abnormalities reported include increased or decreased electrolytes, hematocrit, hemoglobin, and glucose; increased liver transaminases, uric acid, BUN, and total and LDL-cholesterol; and decreased HDL-cholesterol. (See Hepatic Effects under Warnings/Precautions: Warnings, in Cautions and also see Effects on Lipoproteins under Warnings/Precautions: Warnings, in Cautions.)

More Frequent

• Arthralgia
• Headache disorder
• Hypertonia
• Myalgia
• Nausea
• Spinal hyperostosis
• Vomiting

Less Frequent

• Chills
• Eye tearing
• Eyelid edema
• Ocular irritation
• Ocular pain
• Ocular redness
• Paresthesia
• Paronychia
• Photophobia
• Visual changes

Rare or Very Rare

• Acute myocardial infarction
• Acute pancreatitis
• Allergic dermatitis
• Angioedema
• Capillary leak syndrome
• Cataracts
• Cerebrovascular accident
• Corneal erosion
• Depression
• Exfoliative dermatitis
• Flu-like symptoms
• Hepatitis
• Idiopathic intracranial hypertension
• Infection
• Jaundice
• Laryngitis
• Myopathy
• Night blindness
• Otitis externa eczema
• Pharyngitis
• Psoriasiform eruption
• Purpura
• Pyogenic granuloma
• Skin fissure
• Skin ulcer
• Suicidal ideation
• Thromboembolic disorder
• Vulvovaginitis

More Frequent

• Abnormal hepatic function tests
• Alopecia
• Ceruminosis
• Cheilosis
• Dry eye
• Dry nose
• Eyelid dermatitis
• Gingivitis
• Mixed hyperlipidemia
• Polydipsia
• Pruritus of skin
• Rhinitis
• Skin photosensitivity
• Skin scaling of feet
• Skin scaling of hands
• Stomatitis

Less Frequent

• Aphthous stomatitis
• Blepharitis
• Blurred vision
• Conjunctivitis
• Constipation
• Diarrhea
• Epistaxis
• Fatigue
• Hyperhidrosis
• Nail disorders

Rare or Very Rare

• Aggressive behavior
• Bone pain
• Hordeolum
• Hyperesthesia
• Hyperglycemia
• Hypotrichosis of eyelid lashes
• Skin atrophy
• Symptoms of anxiety
• Urticaria

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Safety and efficacy have not been established in pediatric patients.

Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children receiving other systemic retinoids, including etretinate (no longer commercially available in US). A causal relationship has not been established between the use of acitretin and these effects, and it is unknown whether these occurrences are more severe or appear more frequently in children. However, the manufacturer states that there is special concern because of the implications for growth potential in this population.

Category X. (See Users Guide.) All pregnancies during acitretin therapy or within 3 years following drug discontinuance should be reported to Stiefel Laboratories at 888-500-3376 or to the FDA MedWatch Program at 800-FDA-1088. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Acitretin is distributed into milk; women receiving the drug should not breast-feed.

Acitretin dosage should be selected with caution in geriatric patients (usually starting at the low end of the dosage range) because of possible age-related decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Clinical trial experience in patients 65 years of age or older is insufficient to determine whether geriatric patients respond differently than younger adults. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. (See Geriatric Patients under Dosage and Administration: Special Populations.)