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Etretinate (Systemic)


VA CLASSIFICATION
Primary: DE801
Secondary: DE890{39}



Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antipsoriatic (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling. {44}
FOR WOMEN OF CHILD-BEARING POTENTIAL, SEE THE PREGNANCY/REPRODUCTION SECTION OF PRECAUTIONS TO CONSIDER FOR RESTRICTIONS ON THE USE OF ETRETINATE {44}.

Accepted

Psoriasis (treatment)—Etretinate is indicated for the treatment of severe recalcitrant psoriasis, {37} including the erythrodermic and generalized pustular types, in patients who are unresponsive to or intolerant of the standard therapies. {01} {12} {18} {37}
—[Etretinate is also used in combination with {18} {31} psoralens plus ultraviolet light A (PUVA), ultraviolet light B (UVB), selective ultraviolet light, {18} {19} {21} {22} {40} topical adrenocorticoids, {19} {22} anthralin, {19} {22} or coal tar {36} in the treatment of psoriasis. ]

[Lichen planus, oral (treatment)]1—Etretinate is used for the treatment of severe, intractable oral lichen planus. {40}

Etretinate is also used in correcting severe intractable forms of keratinization disorders, such as: {37} {43} {45}
[Dermatoses, ichthyosiform] {38} {37} {45}
[Erythroderma, congenital ichthyosiform] {44} {45}
[Ichthyosis, lamellar, and other ichthyoses] {44} {45}
[Keratosis follicularis (Darier's disease)] {37} {44} {45}
[Keratosis palmaris et plantaris] {44} {45}
[Pityriasis rubra pilaris (PRP)] {44} {45}
[Pustulosis, palmoplantar] {38} {37} {45}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    354.49 {27}

Mechanism of action/Effect:

The mechanism of action of etretinate is not known. {01} However, improvement in psoriatic patients occurs in association with a decrease in scaling, erythema, and thickness of lesions, and there is histological evidence of normalization of epidermal differentiation, decreased stratum corneum thickness, and decreased inflammation in the epidermis and dermis. {01} {12}

Absorption:

Etretinate is absorbed in the small intestine. {12}

Studies in normal volunteers indicate that the absorption of etretinate is greater in patients consuming whole milk or a high-fat diet than in patients in a fasting state. {01}

Distribution:

Etretinate accumulates in high concentrations in adipose tissue, especially in the liver and in subcutaneous fat. {12} {32} {34}

Liver concentrations of etretinate in patients who had received therapy for six months were generally higher than accompanying plasma concentrations and tended to be higher still in livers with a higher degree of fatty infiltration. {01} {12}

Concentrations of etretinate and its active metabolite in epidermal specimens obtained after 1 to 36 months of therapy were a function of location: subcutis much greater than serum greater than epidermis greater than dermis. {01}

Because of the large number of binding sites available for etretinate, displacement from binding sites by other medications is not important. {28} {29}

Protein binding:

Etretinate is more than 99% bound to plasma proteins, predominantly lipoproteins, whereas its active metabolite, acetretin (etretin), {22} {28} {29} {35} is predominantly bound to albumin. {01} {12}

Biotransformation:

Following oral administration, etretinate is extensively metabolized, with significant first-pass metabolism to the pharmacologically active acid form. Subsequent metabolism results in the inactive 13- cis acid form, chain-shortened breakdown products, and conjugates that are ultimately excreted. {01}

Half-life:

In one study, the apparent terminal half-life of etretinate after 6 months of therapy was approximately 120 days. {01}

In another study of 47 patients who had undergone chronic therapy with etretinate, 5 patients had detectable serum drug concentrations (0.5 to 12 nanograms per mL) 2.1 to 2.9 years after therapy was completed. {01}

The long half-life of etretinate appears to be due to its storage in adipose tissue. {01}

Time to peak concentration:

2 to 6 hours {01} during chronic {29} therapy with doses ranging from 25 mg once daily to 25 mg four times daily. {01}

Peak serum concentration:

102 to 389 nanograms per mL {01} during chronic {29} therapy with doses ranging from 25 mg once daily to 25 mg four times daily. {01}

Elimination:
    Primarily {18} biliary; also renal. {01} {12}


Precautions to Consider

Note: Patients receiving etretinate should not donate blood during therapy or for an undetermined length of time (several years or longer) after therapy, because of the possible {29} risk to the developing fetus of a pregnant patient who may receive such blood. {02} {44}


Cross-sensitivity and/or related problems

Patients sensitive to isotretinoin, tretinoin, or vitamin A derivatives may be sensitive to this medication also, since etretinate is related to both retinoic acid and retinol (vitamin A). {01}

Carcinogenicity/Tumorigenicity

In a 2-year study, Sprague-Dawley rats given etretinate at doses up to 3 mg per kg of body weight (mg/kg) per day (2 times the maximum recommended human therapeutic dose) had no increase in tumor incidence. {01}

In an 80-week study, the high-dose male group, but not the high-dose female group, of Crl:CD-1 (ICR) BR mice given doses of 4 to 5 mg/kg per day of etretinate had an increased incidence of blood vessel tumors. {01}

Mutagenicity

Except for a weakly positive response in the Ames test when the tester strain TA 100 was used, there was no evidence of genotoxicity when etretinate was evaluated by the Ames test in a host-mediated assay, in the micronucleus test, and in a `treat and plate' test using the diploid yeast strain S. cerevisiae D7. In addition, no differences were noted in the rate of sister chromatid exchange (SCE) in the lymphocytes of patients examined before and after 4 weeks of treatment with etretinate. {01}

Pregnancy/Reproduction
Fertility—
In human males, no adverse effects on sperm production were observed in 12 psoriatic patients who were treated with 75 mg per day of etretinate for 1 month and 50 mg per day for an additional 2 months. {01}

However, in male animal studies, testicular atrophy was observed in subchronic and chronic rat studies and in a chronic dog study, in some cases at doses approaching those recommended for use in humans. In addition, decreased sperm counts were reported in a 13-week dog study at doses as low as 3 mg/kg per day (approximately 2 times the maximum recommended human dose [MRHD]). Also in dogs, spermatogenic arrest was observed with chronic administration of the all- trans metabolite. {01}

In female animal studies, at doses up to 2.5 mg/kg per day, a study of fertility and general reproductive performance in rats showed no etretinate-related effects. In addition, no adverse effects on various parameters of late gestation were noted in rats given doses of etretinate up to 4 mg/kg per day (approximately 3 times the MRHD). However, at 5 mg/kg per day, the readiness of the treated rats to copulate was reduced, although the pregnancy rate was unaffected. In addition, at this higher dose, the number of live young at birth was reduced, their postnatal weight gain and survival were adversely affected, and the pregnancy rate of the untreated first generation rats and postnatal weight gain of the untreated second generation rats were reduced. Furthermore, at doses of 8 mg/kg per day (approximately 5 times the MRHD), the rate of stillbirths was increased and neonatal weight gain and survival rate were markedly reduced. {01} The relevance of these findings to human females is not known. {08}

Pregnancy—
Etretinate is contraindicated during pregnancy, {40} since it has caused major human fetal abnormalities, including meningomyelocoele; meningoencephalocoele; multiple synostoses; facial dysmorphia; syndactyly; {01} {32} {33} absence of terminal phalanges; malformations of hip, ankle, and forearm; abnormalities of the heart and thymus; {29} low set ears; high palate; decreased cranial volume; and alterations of the skull and cervical vertebrae.

In addition, it has not been determined how long pregnancy should be avoided after discontinuation of treatment; {44} patients have been followed for as long as 2 years after treatment was discontinued, and fetal abnormalities associated with etretinate have occurred during this 2-year period. {01} {12} {29} Therefore, etretinate should not be used in women who plan to have children in the future. {18} {29} {40}

In women of childbearing potential, etretinate should not {40} be used until the possibility of pregnancy is ruled out. In addition, etretinate should not {40} be used in women who, while undergoing treatment and for an indefinite period of time thereafter, are deemed unreliable in their use of contraception or who may not use reliable contraception. {01}

It is strongly recommended that a pregnancy test be performed within 2 weeks prior to etretinate therapy. Etretinate therapy should then be initiated on the second or third day of the next normal menstrual period. It is also recommended that an effective form of contraception be used for at least 1 month before therapy, during therapy, and for an indefinite period of time following completion of therapy. {01}

Etretinate imposes serious risks to the fetus for an indefinite period of time following completion of therapy. {44} Etretinate blood concentrations of 0.5 to 12 nanograms per mL have been reported in 5 of 47 patients 2.1 to 2.9 years after treatment was concluded. It has not been determined how long it is necessary to wait after discontinuation of treatment to assure that no drug will be detectable in the blood. In addition, the significance of undetectable blood concentrations relative to the risk of teratogenicity {29} is unknown. {01}

Women of child-bearing potential should be fully counseled on the serious risks to the fetus should they become pregnant during therapy and for an indefinite period of time following completion of therapy. {01} {44} If pregnancy does occur, patients should be counseled about the risks {29} of continuing the pregnancy. {08}

FDA Pregnancy Category X.

Breast-feeding

Problems in humans have not been documented. Although it is not known whether etretinate is distributed into breast milk, use is not recommended during breast-feeding or if breast-feeding is anticipated in the future, {29} because of the potential for adverse effects in nursing babies. In addition, studies have shown that etretinate is distributed into the milk of lactating rats, although no adverse effects on various parameters of lactation were noted at doses of etretinate up to 4 mg/kg per day (approximately 3 times the MRHD). {01}

Pediatrics

Because of the shortage of data on etretinate treatment in children and the possibility that children may be more sensitive to the effects of the medication, etretinate should not {18} be used in children unless all alternative therapies have been exhausted. {01}

Ossification of interosseous ligaments and tendons of the limbs has been reported in children. In addition, in at least {29} 2 children there were x-ray changes suggestive of premature epiphyseal closure during treatment with etretinate. It is not known whether these adverse effects occur more commonly in children, but they may be more significant because of the growth process. {01} {12}

Before therapy with etretinate is initiated in children, x-rays for bone age, including x-rays of the knees, should be done, and yearly monitoring thereafter is advised. In addition, during treatment children experiencing pain or limitation of motion should be thoroughly {29} evaluated. {01}


Geriatrics


No information is available on the relationship of age to the effects of etretinate in geriatric patients.


Dental

Gingival bleeding and inflammation and dry mouth have occurred in up to {29} 10% of patients treated with etretinate. {01}

Since use of etretinate decreases or inhibits salivary flow, it contributes to the development of caries, periodontal disease, oral candidiasis, and discomfort. {07}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

{30}
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Abrasive or medicated soaps or cleansers or {02}
Acne preparations or preparations containing a peeling agent, such as: {02} {09}
Benzoyl peroxide
Resorcinol
Salicylic acid
Sulfur
Tretinoin or
Alcohol-containing preparations, topical, such as: {02} {09}
After-shave lotions
Astringents
Perfumed toiletries
Shaving creams or lotions or
Cosmetics or soaps with a strong drying effect or {02}
Medicated cosmetics or “cover-ups” {02}    (may cause a cumulative irritant or drying effect, especially with the application of peeling, desquamating, or abrasive agents, resulting in excessive irritation of the skin {02})


» Alcohol {01}    (consumption during etretinate therapy may result in hypertriglyceridemia, since both alcohol and etretinate may increase plasma triglyceride concentration {01} {02})


High-fat diet or
Milk    (concomitant consumption of milk or a high-fat meal increases the absorption of etretinate; {01} intermittent consumption may make it difficult to accurately titrate the dosage; patients should consistently take each dose of etretinate with milk or high-fat foods {08} {11} {18})


» Isotretinoin or {11}
» Tretinoin or {11}
» Vitamin A {01}    (may result in additive toxic effects {18})


» Methotrexate or {44}
» Hepatotoxic medications, other (See Appendix II )    (concurrent use with other hepatotoxic medications, especially methotrexate, may increase the potential for hepatotoxicity {29} {41} {42} {44})


Photosensitizing medications, other    (concurrent use may cause additive photosensitizing effects {41})


» Tetracyclines    (may increase the potential for pseudotumor cerebri {02} {11} {18})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Acetonuria and {01}
Casts in urine and {01}
Glycosuria and {01}
Hemoglobinuria and {01}
Microscopic hematuria and {01}
Proteinuria and {01}
White blood cells (WBC) in urine {01}    (have occurred; in clinical trials, 1 to 10% [for WBC's in urine, 10 to 25%] of patients treated with etretinate have experienced these effects {01})


» Alanine aminotransferase (ALT [SGPT]) and {01}
» Aspartate aminotransferase (AST [SGOT]) and {01}
» Lactate dehydrogenase (LDH) {01}    (serum values may be increased; in clinical trials, elevations of ALT, AST, and LDH have occurred in 23%, 18%, and 15%, respectively, of patients treated with etretinate; in most cases the elevations were slight to moderate, and concentrations became normal again either during or after cessation of therapy {01})


Albumin concentration and {01}
Calcium concentration and {01}
Chloride concentration and {01}
Fasting blood sugar (FBS) concentration and {01}
Phosphorus concentration and {01}
Potassium concentration and {01}
Prothrombin time and {01}
Sodium concentration and {01}
Total protein concentration and {01}
Venous CO 2 concentration and {01}
WBC counts {01}    (may be increased or decreased. In clinical trials, changes in calcium, phosphorus, and potassium have occurred in 25 to 50%; changes in chloride, FBS, prothrombin time, sodium, venous CO 2, and WBC's have occurred in 10 to 25%; and changes in albumin and total protein have occurred in 1 to 10% of patients treated with etretinate {01})


Alkaline phosphatase value and {01}
Bilirubin concentration and {01}
Blood urea nitrogen (BUN) concentration and {01}
Creatinine concentration and {01} {03}
Creatine kinase (CK) concentration and {01} {03}
Erythrocyte sedimentation rate (ESR) and {01}
Gamma glutamyl transpeptidase (GGTP) and {01} {04}
Globulin concentration and {01}
Reticulocyte counts {01}    (may be increased. In clinical trials, elevations of ESR and reticulocytes have occurred in 25 to 50%; elevations of GGTP, globulin, and alkaline phosphatase have occurred in 10 to 25%; and elevations of bilirubin, BUN, creatinine, and CK have occurred in 1 to 10% of patients treated with etretinate {01})


Hemoglobin and hematocrit and {01}
Red blood cell counts {01}    (may be decreased or increased, mainly decreased; in clinical trials, decreases have occurred in 10 to 25% and elevations have occurred in 1 to 10% of patients treated with etretinate {01})


» High-density lipoprotein (HDL) {01}    (serum concentrations may be decreased; in clinical trials, decreases in HDL have occurred in about 37% of patients [54% of these had decreases below 36 mg%]; the effect is reversible upon discontinuation of medication {01})


Mean corpuscular hemoglobin (MCH) and {01}
Mean corpuscular hemoglobin concentration (MCHC) and {01}
Partial thromboplastin time (PTT) and {01}
Platelet counts {01}    (may be increased or decreased, mainly increased; in clinical trials, elevations of MCH and MCHC and increases in PTT have occurred in 25 to 50% [elevations of platelets have occurred in 10 to 25%] and decreases have occurred in 1 to 10% of patients treated with etretinate {01})


Mean corpuscular volume (MCV) {01}    (may be decreased; in clinical trials, decreases have occurred in 10 to 25% of patients treated with etretinate {01})


» Triglyceride concentrations, plasma and {01}
» Cholesterol concentrations, serum {01}    (may be increased; in clinical trials, elevated plasma triglyceride concentration has occurred in about 45% of patients [46% of these had elevations above 250 mg per dL and 1 case had a concentration greater than 1000 mg%] and increased cholesterol concentration has occurred in about 16% of patients [19% of these had elevations above 300 mg%]; elevation of serum triglycerides in excess of 800 mg per dL has been associated with acute pancreatitis; these effects are reversible upon discontinuation of medication {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disease, or family history of or {01} {16}
» Cardiovascular risk, history of or family history of {01} {16}    (etretinate may increase plasma triglyceride concentration, possibly increasing patient's cardiovascular risk status)


Diabetes mellitus, or family history of {01} {02}    (possibility of alteration in blood sugar concentration; etretinate may increase plasma triglyceride concentration in patients with diabetes mellitus, possibly increasing their cardiovascular risk status)


Hepatic disease, history of or family history of {16}
» Hypertriglyceridemia or
» Conditions predisposing to hypertriglyceridemia, such as:
High alcohol intake, or history of {02}
Hypertriglyceridemia, family history of {01} {02}
Obesity {01} {02}    (etretinate may increase plasma triglyceride concentration, possibly increasing patient's cardiovascular risk status)


Sensitivity to etretinate

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]) values, serum and {01}
» Aspartate aminotransferase (AST [SGOT]) values, serum and {01}
» Lactate dehydrogenase (LDH) values {01}    (determinations recommended prior to therapy, at 1- to 2-week intervals for the first 1 to 2 months of therapy, and thereafter at 1- to 3-month intervals, depending on the patient's response to etretinate administration; if hepatotoxicity is suspected, etretinate should be discontinued until the etiology of the hepatotoxicity is determined {01})


Bone x-rays, {29} especially of the ankles, pelvis, and knees {01}    (recommended because of the possibility of hyperostosis occurring in patients undergoing long-term or recurrent courses of etretinate therapy {01})


Bone-age determinations, including x-rays of knees {01}    (recommended in children prior to therapy and yearly during therapy to determine effects on epiphyseal centers {01})


» Lipid concentrations, blood {01}    (determinations recommended in patients {29} under fasting conditions prior to therapy and at 1- to 2-week intervals during therapy until the lipid response to etretinate is determined [usually within 4 to 8 weeks]. Following consumption of alcohol, 36 hours should elapse before blood lipid determination {01})


Ophthalmologic examinations {01}    (patient should be examined for papilledema if early symptoms of pseudotumor cerebri, such as severe or continuing headache, nausea and vomiting, and blurred vision or other changes in vision, occur {01})


Sugar concentrations, blood {01} {02}    (determinations recommended during therapy in known or suspected diabetics because minor elevations in fasting blood sugar concentrations have been reported {29})




Side/Adverse Effects

Note: Nearly all of the side/adverse effects reported with etretinate to date resemble those of hypervitaminosis A syndrome, which primarily produces signs and symptoms related to the mucocutaneous, musculoskeletal, hepatic, and central nervous systems. {01}
An elevation of plasma triglycerides has occurred in approximately 45% of patients; a decrease in high density lipoproteins (HDL) {29} has occurred in approximately 37% of patients; and an increase in cholesterol concentrations has occurred in approximately 16% of patients receiving etretinate. These effects on triglycerides, HDL, {29} and cholesterol were reversible after therapy was discontinued. Hypertriglyceridemia, hypercholesterolemia, and lowered HDL may increase cardiovascular risk, and elevation of serum triglycerides in excess of 800 mg per dL has been associated with acute pancreatitis. Every attempt should be made to control significant elevations of triglycerides or cholesterol or significant decreases in HDL during therapy with etretinate, possibly through weight reduction or restriction of dietary fat and alcohol. {01}
In clinical trials, 84% of patients receiving etretinate for an average of 60 months had radiographic evidence of extraspinal tendon and ligament calcification. The most common sites of this hyperostosis were the ankles (76%), pelvis (53%), and knees (42%). Spinal changes were uncommon. In 47% of the affected patients, there were no bone or joint symptoms. {01} {18} {29}
Studies in rodents have shown an increased incidence of bone fractures with etretinate use, although no evidence of fractures was observed in a 1-year study in dogs. Other dose-related changes in some animals treated with etretinate at subchronic- or chronic-toxicity doses include alopecia, erythema, reductions in body weight and food consumption, stiffness, altered gait, hematologic changes, elevations in serum alkaline phosphatase, and testicular atrophy with microscopic evidence of reduced spermatogenesis. In general, etretinate toxicity in studies in rats, mice, and dogs was dose-related with respect to incidence, onset, and severity. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bone or joint pain, tenderness, or stiffness{01}
    
cramps or pain in upper abdomen or stomach area{01}{25}
    
eyelid abnormalities {01}(burning, redness, itching, feeling of dryness,{29} pain, tenderness, excessive tearing, or other sign of inflammation or irritation of eyes)
    
muscle cramps{01}{25}{29}
    
unusual bruising{01}{25}

Incidence less frequent
    
Abnormalities of conjunctiva, cornea, lens, retina, extraocular musculature, ocular tension, pupil, or vitreous humor {01}(blurred or double vision or other changes in vision)
    
conjunctivitis or mucous membrane abnormalities {01}(burning, redness, itching, feeling of dryness,{29} pain, tenderness, excessive tearing, or other sign of inflammation or irritation of eyes)
    
hepatitis{01}{12}{16} (dark-colored urine, flu-like symptoms, or yellow eyes or skin)
    
otitis externa{01} (change in hearing; earache or pain in ear; ear drainage)

Note: If visual difficulties occur, etretinate should be discontinued and patient should have an ophthalmologic examination. {01}
Hepatitis occurred in approximately 1.5% of patients treated with etretinate in clinical trials. In addition, pathology findings consisting of hepatic fibrosis, necrosis, and cirrhosis have been reported that may be related to etretinate therapy. {01} If signs and symptoms of hepatitis occur, etretinate should be discontinued and the etiology investigated. {01}


Incidence rare
    
Amnesia, anxiety, confusion{46} , or depression (mood or mental changes{01}{46})
    
bleeding or inflammation of gums{01}
    
blot retinal hemorrhage, iritis, posterior subcapsular cataract, pseudotumor cerebri, or scotoma {01}(blurred or double vision or other changes in vision{01}; pseudotumor cerebri may also cause severe or continuing headache or nausea and vomiting)
    
ear infection{01} (change in hearing; earache or pain in ear; ear drainage)
    
photophobia {01}(burning, redness, itching, feeling of dryness,{29} pain, tenderness, excessive tearing, or other sign of inflammation or irritation of eyes)

Note: If visual difficulties occur, etretinate should be discontinued and patient should have an ophthalmologic examination. {01}
If signs and symptoms of pseudotumor cerebri occur, etretinate should be discontinued immediately and the patient should be referred for neurologic diagnosis and care. {01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Changes in appetite{01}
    
chapped lips{01}
    
dryness of nose{01}
    
dryness, redness, scaling, itching, rash, or other sign of inflammation or irritation of the skin{01}{13}
    
headache, mild{01}
    
increased sensitivity to contact lenses —may occur during and after therapy{01}
    
increased sensitivity of skin to sunlight{01}{14}{15}
    
nosebleeds{01}
    
peeling of skin on fingertips, palms of hands, or soles of feet{01}
    
thinning of hair {01}
    
unusual thirst {01}
    
unusual tiredness{01}

Incidence less frequent
    
Dizziness{01}
    
dryness of mouth{01}
    
fever{01}
    
nausea, mild{01}
    
onycholysis or paronychia {01}{33}(redness or soreness around fingernails or loosening of the fingernails)
    
soreness, cracking, swelling, or inflammation of lips{01}
    
soreness of tongue{01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Etretinate (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to etretinate, isotretinoin, tretinoin, or vitamin A–like preparations

Pregnancy—Not taking etretinate during pregnancy, because it causes birth defects in humans. In addition, since it is not known how long pregnancy should be avoided after treatment stops, planning on never having children after treatment with etretinate. Not taking etretinate unless an effective form of contraception is used for at least 1 month before beginning treatment. Continuing contraception during treatment and for as long as pregnancy is possible after etretinate is stopped. Discussing this information with doctor





Breast-feeding—Although it is not known whether etretinate passes into the breast milk, etretinate is not recommended during breast-feeding, or if breast-feeding is planned in the future, because it may cause unwanted effects in nursing babies





Use in children—Because of the shortage of data on etretinate treatment in children and the possibility that children may be more sensitive to the effects of the medication, etretinate should not be used in children unless all alternative therapies have been exhausted

Other medications, especially alcohol, methotrexate or other hepatotoxic medications, isotretinoin, tretinoin, vitamin A, and tetracyclines
Other medical problems, especially personal or family history of cardiovascular risk or disease or hypertriglyceridemia or conditions predisposing to hypertriglyceridemia, such as high alcohol intake or history of high alcohol intake, family history of hypertriglyceridemia, or obesity

Proper use of this medication
» Taking each dose with milk or fatty food because fats help medication to be absorbed better; rest of time following low-fat diet because of possible hypertriglyceridemia and consequent cardiovascular risks {18} {46}

» Importance of not taking more medication than the amount prescribed

» Proper dosing
Missed dose: Taking as soon as possible with milk or fatty food {18}; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress during therapy

» Using a reliable form of contraception and not changing contraception method during therapy and for as long as able to become pregnant after therapy ends, since etretinate causes birth defects in humans during its use and for at least several years afterwards (it is not known how long after therapy is discontinued that birth defects may occur) {29}; stopping medication immediately and checking with physician if pregnancy is suspected during therapy; checking with physician as soon as possible if pregnancy occurs anytime in the future after therapy is discontinued; talking to physician in either case about the risks of continuing the pregnancy

» To prevent the possibility of a pregnant patient receiving blood containing etretinate, never donating blood to a blood bank during or after treatment with etretinate, since it is not known how long etretinate stays in the body {44}

» Avoiding concurrent use of vitamin A and vitamin supplements containing vitamin A

» Not drinking, or at least reducing consumption of, alcoholic beverages, because of possible hypertriglyceridemia and consequent cardiovascular risks {44} {46}

Diabetics: May alter blood sugar concentrations

» Caution if decrease in night vision, which may be sudden, occurs; not driving, using machines, or doing other things that could be dangerous if unable to see well; checking with physician if this occurs

Possibility of dryness of eyes; may decrease tolerance to contact lenses during therapy and for several weeks or longer {29} after discontinuation of therapy; checking with physician if inflammation occurs and about using ocular lubricant to relieve dryness of eyes

Possibility of photosensitivity; avoiding unprotected exposure to sunlight and not using sunlamp; checking with physician if severe reaction occurs

Possible dryness of mouth and nose; for relief of mouth dryness, using sugarless gum or candy, ice, or saliva substitute for relief; checking with dentist if dry mouth continues for more than 2 weeks

Possibility that psoriasis may appear to worsen, with increased redness or itching, during initial therapy; checking with physician if irritation or other symptoms of condition become severe; possibly having to take medication for 2 or 3 months before full effects are seen


Side/adverse effects
Signs of potential side effects, especially abnormalities of conjunctiva, cornea, lens, retina, extraocular musculature, ocular tension, pupil, or vitreous humor; amnesia; anxiety; bleeding or inflammation of gums; blot retinal hemorrhage; bone or joint pain, tenderness, or stiffness; conjunctivitis; cramps or pain in upper abdomen or stomach area; depression; ear infection; eyelid abnormalities; hepatitis; iritis; mucous membrane abnormalities; muscle cramps; otitis externa; photophobia; posterior subcapsular cataract; pseudotumor cerebri; scotoma; or unusual bruising


General Dosing Information
It is recommended that etretinate be prescribed only by physicians knowledgeable in the systemic use of retinoids. {01}

Each dose of etretinate should be taken with milk or fatty food. This increases the absorption of the medication and allows smaller doses to be given. {18} However, the rest of the day a low-fat diet should be followed. {44}

During the initial period of etretinate therapy, transient exacerbation of psoriasis commonly occurs. {01}

Clinical improvement has been observed in the majority of patients treated with etretinate. In approximately 10% of all patients treated for severe psoriasis, complete clearing of the disease was observed after 4 to 9 months of therapy; this included complete clearing in 16% of patients with erythrodermic psoriasis and 37% of patients with generalized pustular psoriasis. {01}

Generally, therapy should be terminated in patients whose lesions have adequately resolved. {01}

After therapy with etretinate is discontinued, the majority of patients experience some degree of relapse by the end of 2 months. However, subsequent 4- to 9-month courses of etretinate have resulted in approximately the same clinical response as was experienced during the initial course of therapy. {01} {12}

When treating relapses, the same dosage should be used as was used for the initial therapy. {01}

Various treatment protocols are being used for combination therapy using etretinate and other antipsoriatics: {18}    • Either etretinate or another antipsoriatic is used as initial treatment. If satisfactory results do not occur after a reasonable length of time, another antipsoriatic or etretinate, respectively, is added to the therapy regimen. {18} {19} {21}
   • When etretinate is used in combination with psoralens plus ultraviolet light A (PUVA), ultraviolet light B (UVB), or selective ultraviolet light (SUP), standard phototherapy protocols can be used, a reduced dosage of etretinate can be administered, and the total number of ultraviolet treatments can be reduced. {22}
   • Etretinate is also being administered starting 1 to 2 weeks prior to phototherapy. Some clinicians believe that the reduction in scaling and skin thickness derived from the etretinate therapy improves the efficacy of the subsequent phototherapy. {22}
   • Etretinate is being administered in doses as low as 10 to 20 mg per day initially. Each week thereafter, the daily dose is increased by 10 mg until cheilitis is observed. If satisfactory healing does not occur from this therapy, PUVA, a topical corticosteroid, or anthralin is added to the regimen while maintaining the same dosage of etretinate. After the patient's condition has satisfactorily improved, the additional antipsoriatic is discontinued and the patient is maintained at the same dosage of etretinate. {19} {22}
   • Patients who are successfully treated for psoriasis with a combination of etretinate and up to 18 PUVA treatments are being subsequently treated for an additional year with a maintenance dose of etretinate equal to half of the highest tolerated dose of etretinate used during the combination therapy, which in most patients is reported to be 0.5 mg per kg of body weight (mg/kg) per day. It is reported that 80% of these patients remain clear after one year. However, among patients requiring more than 18 PUVA treatments during the combination therapy, little or no benefit was seen from this maintenance therapy. {19} {22}
   • When etretinate is used in combination with topical adrenocorticoids or anthralin, better therapeutic results are reported to occur and it may be possible to reduce etretinate doses more rapidly than during etretinate therapy alone. In addition, average maintenance doses of etretinate have been reported to be as low as 0.3 mg/kg per day during combination therapy with topical adrenocorticoids or anthralin {29}. Also, when etretinate is used in combination therapy with topical adrenocorticoids, the cutaneous side effects associated with etretinate therapy may be reduced. {22}



Oral Dosage Forms

ETRETINATE CAPSULES

Usual adult and adolescent dose
Antipsoriatic (systemic)
Initial: Oral, 750 mcg (0.75 mg) to 1 mg per kg of body weight per day in divided doses. {01}
Note: Erythrodermic psoriasis may respond to initial doses of 250 mcg (0.25 mg) per kg of body weight a day, increased by 250 mcg (0.25 mg) per kg of body weight per day each week until optimal initial response is attained. {01}



Maintenance: Oral, 500 to 750 mcg (0.5 to 0.75 mg) per kg of body weight per day may be initiated after initial response, generally after 8 to 16 weeks of therapy. {01}

Note: Because of interpatient variation in absorption and metabolism of etretinate, the fact that psoriasis is an unpredictable disease, and the possible concurrent use of other antipsoriatics, the dosage of etretinate and any other antipsoriatic that may be used concurrently should be individualized to achieve the maximal therapeutic response with a tolerable level of side effects. {01} {18}
Patients may respond to doses of etretinate as low as 200 mcg (0.2 mg) per kg of body weight per day {22} when etretinate is administered concurrently with {18} psoralens plus ultraviolet light A (PUVA), ultraviolet light B (UVB), selective ultraviolet light (SUP), {18} {19} {21} {22} topical adrenocorticoids, or {18} {19} {22} anthralin {19} {22}. In addition, it may be possible to reduce the other medication's dosage. {20} {22}



Usual adult prescribing limits
Oral, 1.5 mg per kg of body weight per day. {01}

Usual pediatric dose
Use is not recommended unless all alternative therapies have proven ineffective. {01} {11} {24}

Strength(s) usually available

Note: Withdrawn from the U.S. market in March 1998 and the Canadian market in January 1996.

U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {01} unless otherwise specified by manufacturer. Protect from light. {01}

Auxiliary labeling:
   • Do not take this medication if you are pregnant.
   • Take with milk or fatty food.
   • Avoid too much sun or use of sunlamp.
   • May cause dizziness or blurred vision.

Note: Include patient instructions when dispensing. {16} {17} {29}




Revised: 10/13/2000



References
  1. Tegison package insert (Roche—US), Rev 10/86; Rev 1/87; Rev 8/87.
  1. Writer's comments.
  1. Writer's comments.
  1. Writer's comments.
  1. USAN 1987: 135.
  1. Martindale 28 ed: 494.
  1. Writer's comments.
  1. Writer's comments.
  1. Writer's comments.
  1. Writer's comments.
  1. Writer's comments.
  1. Medical Letter, 1/16/87, Vol 29, Issue 731.
  1. Reactions, 7/26/86: 7.
  1. Etretinate photosensitivity; J Amer Acad Dermatol : 274.
  1. Etretinate photosensitivity; Clin-Alert, 3/28/86, No. 50.
  1. PPI - Tegison leaflet, Things You Should Know About Tegison, copyright 1986, received 1/87. Issued 1/87, received 2/87 Issued 1/87, received 1/88.
  1. American Pharmacy 1986 Dec: 20.
  1. Panel Comments 3/87.
  1. Dubertret L. Etretinate in psoriasis: Advantage of low doses progressively increased, J Amer Acad of Derm 1985 Nov: 830–31.
  1. Tuyp E, et al. Combination therapy for psoriasis with methotrexate and etretinate, J Amer Acad of Derm 1986 Jan: 70–3.
  1. Ekenstam E, et al. Response of secondary amyloidosis in psoriasis to treatment with etretinate and ultraviolet light, B Med J 1986 Sep: 733–4.
  1. Ellis C, et al. Etretinate Therapy—Continuing Medical Education (Therapy), J Amer Acad of Derm 1987 Feb: 267–291.
  1. Writer's comments.
  1. Panel Comments 3/87.
  1. Panel Comments 3/87.
  1. Writer's comments.
  1. Merck Index, 10 Ed, 1983: 3836–7.
  1. Writer's comments.
  1. Panel Comments 5/87, second round, monograph revision date 3/20/87.
  1. Writer's comments.
  1. Writer's comments.
  1. Reviewer Comments, 7/24/87.
  1. Writer's comments.
  1. Writer's comments.
  1. Personal communication, 5/19/87.
  1. Personal communication, 7/24/87.
  1. PI - Tegison, Roche, Canada.
  1. Panel comments,3/88.
  1. USAN-88.
  1. Panel Comments, 7/8/88.
  1. Writer's comments.
  1. Zachariae, Hugh; Letters to Editor, Dangers of Methotrexate/Etretinate Combination Therapy, The Lancet, 2/20/88: 422.
  1. Writer's comments.
  1. Dermatology Panel Meeting, 5/89.
  1. Writer's comments.
  1. Writer's comments.
  1. Writer's comments.
  1. Dorland's 27th Ed: 1382.

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