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Soriatane (Acitretin)
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Pharmacology
Acitretin is a retinoid, an aromatic analog of vitaminA. The mechanism of action is unknown; however, evidence exists for a wide range of actions at various cellular and subcellular levels. These include: regulation of RNA/DNA synthesis, modulation of factors which influence epidermal proliferation, modification of glycoprotein synthesis and modulation of the immune response. Whatever the exact mechanism of action, the most prominent effect of acitretin is a modulation of cellular differentiation in the epidermis, which re-establishes a more normal pattern of cell growth.
Use of acitretin in psoriatic patients results in improvement manifested by a decrease in scale, erythema and thickness of lesions, and decreased inflammation in the epidermis and dermis.
Oral absorption of acitretin was optimal when given with food. Following administration of a single oral dose of 50mg acitretin to healthy volunteers, maximum plasma acitretin concentrations ranged from 196to 728ng/mL (mean 416ng/mL) and were achieved in 2to 5hours (mean 2.7hours). Following multiple doses, acitretin plasma concentrations reached steady-state conditions within 2weeks. In psoriatic patients who received acitretin (10to 50mg/day) for 8weeks, mean steady-state trough concentrations of acitretin ranged between 6and 25ng/mL in a dose-dependent manner. In patients administered multiple oral doses of acitretin for up to 9months, the range of elimination half-life (t 1/2) values observed was 33to 92hours for acitretin (harmonic mean=48hours) and 28to 123hours for cis-acitretin (harmonic mean=64hours).
In a multiple-dose study in healthy young and elderly subjects, increased acitretin plasma concentrations were seen in elderly subjects. The range of terminal elimination half-lives observed for acitretin were 37to 96hours (harmonic mean=54hours) in elderly and 39to 70hours (harmonic mean=53hours) in young subjects.
Following oral absorption, acitretin undergoes metabolism and interconversion by simple isomerization to its 13-cis form. Both acitretin and its 13-cis isomer are eliminated from the body primarily by metabolism to chain-shortened breakdown products and conjugates. Acitretin is more than 98% bound to plasma proteins, primarily albumin.
Measurable levels of etretinate, of which acitretin is the active metabolite, have been detected in plasma samples of patients administered acitretin. The use of alcohol may have been a factor contributing to the presence of etretinate in these patients. In a 2-way crossover study in healthy volunteers, all 10subjects formed etretinate following the ingestion of a single 100mg oral dose of acitretin in the presence of alcohol (1.4g/kg ethanol over approximately 3hours). Peak concentrations of etretinate measured in these subjects ranged from 22ng/mL to 105ng/mL (mean: 55ng/mL). When acitretin was administered in the absence of ethanol in this study, etretinate was not measurable. However, the formation of etretinate from acitretin in the absence of ethanol cannot be excluded. Etretinate has a long elimination phase. When etretinate has been used as primary therapy, etretinate has been found in the blood of some patients up to 2.9years after discontinuation of treatment. Of 240evaluated psoriatic patients who received treatment with acitretin (5to 60mg/day) with no restrictions on alcohol use, 7.5% were found to have measurable concentrations of etretinate (range: 5to 62ng/mL) and a further 27% had a trace of etretinate in the plasma which was not measurable.
Acitretin is a retinoid, an aromatic analog of vitaminA. The mechanism of action is unknown; however, evidence exists for a wide range of actions at various cellular and subcellular levels. These include: regulation of RNA/DNA synthesis, modulation of factors which influence epidermal proliferation, modification of glycoprotein synthesis and modulation of the immune response. Whatever the exact mechanism of action, the most prominent effect of acitretin is a modulation of cellular differentiation in the epidermis, which re-establishes a more normal pattern of cell growth.
Use of acitretin in psoriatic patients results in improvement manifested by a decrease in scale, erythema and thickness of lesions, and decreased inflammation in the epidermis and dermis.
Oral absorption of acitretin was optimal when given with food. Following administration of a single oral dose of 50mg acitretin to healthy volunteers, maximum plasma acitretin concentrations ranged from 196to 728ng/mL (mean 416ng/mL) and were achieved in 2to 5hours (mean 2.7hours). Following multiple doses, acitretin plasma concentrations reached steady-state conditions within 2weeks. In psoriatic patients who received acitretin (10to 50mg/day) for 8weeks, mean steady-state trough concentrations of acitretin ranged between 6and 25ng/mL in a dose-dependent manner. In patients administered multiple oral doses of acitretin for up to 9months, the range of elimination half-life (t 1/2) values observed was 33to 92hours for acitretin (harmonic mean=48hours) and 28to 123hours for cis-acitretin (harmonic mean=64hours).
In a multiple-dose study in healthy young and elderly subjects, increased acitretin plasma concentrations were seen in elderly subjects. The range of terminal elimination half-lives observed for acitretin were 37to 96hours (harmonic mean=54hours) in elderly and 39to 70hours (harmonic mean=53hours) in young subjects.
Following oral absorption, acitretin undergoes metabolism and interconversion by simple isomerization to its 13-cis form. Both acitretin and its 13-cis isomer are eliminated from the body primarily by metabolism to chain-shortened breakdown products and conjugates. Acitretin is more than 98% bound to plasma proteins, primarily albumin.
Measurable levels of etretinate, of which acitretin is the active metabolite, have been detected in plasma samples of patients administered acitretin. The use of alcohol may have been a factor contributing to the presence of etretinate in these patients. In a 2-way crossover study in healthy volunteers, all 10subjects formed etretinate following the ingestion of a single 100mg oral dose of acitretin in the presence of alcohol (1.4g/kg ethanol over approximately 3hours). Peak concentrations of etretinate measured in these subjects ranged from 22ng/mL to 105ng/mL (mean: 55ng/mL). When acitretin was administered in the absence of ethanol in this study, etretinate was not measurable. However, the formation of etretinate from acitretin in the absence of ethanol cannot be excluded. Etretinate has a long elimination phase. When etretinate has been used as primary therapy, etretinate has been found in the blood of some patients up to 2.9years after discontinuation of treatment. Of 240evaluated psoriatic patients who received treatment with acitretin (5to 60mg/day) with no restrictions on alcohol use, 7.5% were found to have measurable concentrations of etretinate (range: 5to 62ng/mL) and a further 27% had a trace of etretinate in the plasma which was not measurable.
Indications
Acitretin Is A Retinoid, An Aromatic Analog Of VitaminA. The Mechanism Of Action Is Unknown; However, Evidence Exists For A Wide Range Of Actions At Various Cellular And Subcellular Levels. These Include: Regulation Of RNA/DNA Synthesis, Modulation Of Factors Which Influence Epidermal Proliferation, Modification Of Glycoprotein Synthesis And Modulation Of The Immune Response. Whatever The Exact Mechanism Of Action, The Most Prominent Effect Of Acitretin Is A Modulation Of Cellular Differentiation In The Epidermis, Which Re-establishes A More Normal Pattern Of Cell Growth.
Use Of Acitretin In Psoriatic Patients Results In Improvement Manifested By A Decrease In Scale, Erythema And Thickness Of Lesions, And Decreased Inflammation In The Epidermis And Dermis.
Oral Absorption Of Acitretin Was Optimal When Given With Food. Following Administration Of A Single Oral Dose Of 50mg Acitretin To Healthy Volunteers, Maximum Plasma Acitretin Concentrations Ranged From 196to 728ng/mL (mean 416ng/mL) And Were Achieved In 2to 5hours (mean 2.7hours). Following Multiple Doses, Acitretin Plasma Concentrations Reached Steady-state Conditions Within 2weeks. In Psoriatic Patients Who Received Acitretin (10to 50mg/day) For 8weeks, Mean Steady-state Trough Concentrations Of Acitretin Ranged Between 6and 25ng/mL In A Dose-dependent Manner. In Patients Administered Multiple Oral Doses Of Acitretin For Up To 9months, The Range Of Elimination Half-life (t 1/2) Values Observed Was 33to 92hours For Acitretin (harmonic Mean=48hours) And 28to 123hours For Cis-acitretin (harmonic Mean=64hours).
In A Multiple-dose Study In Healthy Young And Elderly Subjects, Increased Acitretin Plasma Concentrations Were Seen In Elderly Subjects. The Range Of Terminal Elimination Half-lives Observed For Acitretin Were 37to 96hours (harmonic Mean=54hours) In Elderly And 39to 70hours (harmonic Mean=53hours) In Young Subjects.
Following Oral Absorption, Acitretin Undergoes Metabolism And Interconversion By Simple Isomerization To Its 13-cis Form. Both Acitretin And Its 13-cis Isomer Are Eliminated From The Body Primarily By Metabolism To Chain-shortened Breakdown Products And Conjugates. Acitretin Is More Than 98% Bound To Plasma Proteins, Primarily Albumin.
Measurable Levels Of Etretinate, Of Which Acitretin Is The Active Metabolite, Have Been Detected In Plasma Samples Of Patients Administered Acitretin. The Use Of Alcohol May Have Been A Factor Contributing To The Presence Of Etretinate In These Patients. In A 2-way Crossover Study In Healthy Volunteers, All 10subjects Formed Etretinate Following The Ingestion Of A Single 100mg Oral Dose Of Acitretin In The Presence Of Alcohol (1.4g/kg Ethanol Over Approximately 3hours). Peak Concentrations Of Etretinate Measured In These Subjects Ranged From 22ng/mL To 105ng/mL (mean: 55ng/mL). When Acitretin Was Administered In The Absence Of Ethanol In This Study, Etretinate Was Not Measurable. However, The Formation Of Etretinate From Acitretin In The Absence Of Ethanol Cannot Be Excluded. Etretinate Has A Long Elimination Phase. When Etretinate Has Been Used As Primary Therapy, Etretinate Has Been Found In The Blood Of Some Patients Up To 2.9years After Discontinuation Of Treatment. Of 240evaluated Psoriatic Patients Who Received Treatment With Acitretin (5to 60mg/day) With No Restrictions On Alcohol Use, 7.5% Were Found To Have Measurable Concentrations Of Etretinate (range: 5to 62ng/mL) And A Further 27% Had A Trace Of Etretinate In The Plasma Which Was Not Measurable.
Acitretin Is A Retinoid, An Aromatic Analog Of VitaminA. The Mechanism Of Action Is Unknown; However, Evidence Exists For A Wide Range Of Actions At Various Cellular And Subcellular Levels. These Include: Regulation Of RNA/DNA Synthesis, Modulation Of Factors Which Influence Epidermal Proliferation, Modification Of Glycoprotein Synthesis And Modulation Of The Immune Response. Whatever The Exact Mechanism Of Action, The Most Prominent Effect Of Acitretin Is A Modulation Of Cellular Differentiation In The Epidermis, Which Re-establishes A More Normal Pattern Of Cell Growth.
Use Of Acitretin In Psoriatic Patients Results In Improvement Manifested By A Decrease In Scale, Erythema And Thickness Of Lesions, And Decreased Inflammation In The Epidermis And Dermis.
Oral Absorption Of Acitretin Was Optimal When Given With Food. Following Administration Of A Single Oral Dose Of 50mg Acitretin To Healthy Volunteers, Maximum Plasma Acitretin Concentrations Ranged From 196to 728ng/mL (mean 416ng/mL) And Were Achieved In 2to 5hours (mean 2.7hours). Following Multiple Doses, Acitretin Plasma Concentrations Reached Steady-state Conditions Within 2weeks. In Psoriatic Patients Who Received Acitretin (10to 50mg/day) For 8weeks, Mean Steady-state Trough Concentrations Of Acitretin Ranged Between 6and 25ng/mL In A Dose-dependent Manner. In Patients Administered Multiple Oral Doses Of Acitretin For Up To 9months, The Range Of Elimination Half-life (t 1/2) Values Observed Was 33to 92hours For Acitretin (harmonic Mean=48hours) And 28to 123hours For Cis-acitretin (harmonic Mean=64hours).
In A Multiple-dose Study In Healthy Young And Elderly Subjects, Increased Acitretin Plasma Concentrations Were Seen In Elderly Subjects. The Range Of Terminal Elimination Half-lives Observed For Acitretin Were 37to 96hours (harmonic Mean=54hours) In Elderly And 39to 70hours (harmonic Mean=53hours) In Young Subjects.
Following Oral Absorption, Acitretin Undergoes Metabolism And Interconversion By Simple Isomerization To Its 13-cis Form. Both Acitretin And Its 13-cis Isomer Are Eliminated From The Body Primarily By Metabolism To Chain-shortened Breakdown Products And Conjugates. Acitretin Is More Than 98% Bound To Plasma Proteins, Primarily Albumin.
Measurable Levels Of Etretinate, Of Which Acitretin Is The Active Metabolite, Have Been Detected In Plasma Samples Of Patients Administered Acitretin. The Use Of Alcohol May Have Been A Factor Contributing To The Presence Of Etretinate In These Patients. In A 2-way Crossover Study In Healthy Volunteers, All 10subjects Formed Etretinate Following The Ingestion Of A Single 100mg Oral Dose Of Acitretin In The Presence Of Alcohol (1.4g/kg Ethanol Over Approximately 3hours). Peak Concentrations Of Etretinate Measured In These Subjects Ranged From 22ng/mL To 105ng/mL (mean: 55ng/mL). When Acitretin Was Administered In The Absence Of Ethanol In This Study, Etretinate Was Not Measurable. However, The Formation Of Etretinate From Acitretin In The Absence Of Ethanol Cannot Be Excluded. Etretinate Has A Long Elimination Phase. When Etretinate Has Been Used As Primary Therapy, Etretinate Has Been Found In The Blood Of Some Patients Up To 2.9years After Discontinuation Of Treatment. Of 240evaluated Psoriatic Patients Who Received Treatment With Acitretin (5to 60mg/day) With No Restrictions On Alcohol Use, 7.5% Were Found To Have Measurable Concentrations Of Etretinate (range: 5to 62ng/mL) And A Further 27% Had A Trace Of Etretinate In The Plasma Which Was Not Measurable.
Contraindications
Pregnancy: Acitretin is contraindicated in pregnancy. Retinoids are known to cause severe birth defects in a very high percentage of infants exposed to them in utero (see Warnings; Pregnancy, Pregnancy Testing, Contraception).
Females must not become pregnant while taking acitretin and effective contraception must be practised for an undetermined period of time of at least 2years following discontinuation of acitretin. Thereafter, the patient and physician should assess the risks and desirability of discontinuing effective contraception, based on the most current information available. Measurable levels of etretinate, the prodrug of acitretin, have been detected in plasma samples of patients administered acitretin. The use of alcohol appears to be a factor contributing to the interconversion of acitretin back to etretinate. Ethanol must not be ingested during treatment with acitretin as clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and alcohol. Ethanol should be avoided for 2months after cessation of therapy. The length of time necessary to wait after termination of acitretin treatment to ensure that no etretinate will be detectable in the blood has not been determined. Etretinate has a long elimination phase. When etretinate has been used as primary therapy, etretinate has been found in the blood of some patients up to 2.9years after discontinuation of treatment.
Acitretin is contraindicated in females of childbearing potential unless all of the following conditions apply:
1.The patient has severe psoriasis or other severe disorders of keratinization.
2.The patient is reliable in understanding and carrying out instructions.
3.The patient is able to comply with mandatory contraceptive measures.
4.The patient has received, and acknowledged understanding of, a careful oral and printed explanation of the hazards of fetal exposure to acitretin and the risk of possible contraception failure. This explanation may include showing a line drawing to the patient of an infant with the characteristic external deformities resulting from retinoid exposure during pregnancy.
5.The patient has had a serum or urine pregnancy test with a sensitivity of at least 50mIU/mL with a negative result, performed in a licensed laboratory, within 2weeks prior to initiating therapy. The patient has had 2or 3days of the next normal menstrual period before acitretin therapy is initiated.
(Regarding items 2to 5, see Warnings; Pregnancy, Pregnancy Testing, Contraception.)
Acitretin is also contraindicated in patients with severely impaired hepatic or renal function, intractable hyperlipidemia, hypervitaminosisA or hypersensitivity to vitaminA or its metabolites.
Pregnancy: Acitretin is contraindicated in pregnancy. Retinoids are known to cause severe birth defects in a very high percentage of infants exposed to them in utero (see Warnings; Pregnancy, Pregnancy Testing, Contraception).
Females must not become pregnant while taking acitretin and effective contraception must be practised for an undetermined period of time of at least 2years following discontinuation of acitretin. Thereafter, the patient and physician should assess the risks and desirability of discontinuing effective contraception, based on the most current information available. Measurable levels of etretinate, the prodrug of acitretin, have been detected in plasma samples of patients administered acitretin. The use of alcohol appears to be a factor contributing to the interconversion of acitretin back to etretinate. Ethanol must not be ingested during treatment with acitretin as clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and alcohol. Ethanol should be avoided for 2months after cessation of therapy. The length of time necessary to wait after termination of acitretin treatment to ensure that no etretinate will be detectable in the blood has not been determined. Etretinate has a long elimination phase. When etretinate has been used as primary therapy, etretinate has been found in the blood of some patients up to 2.9years after discontinuation of treatment.
Acitretin is contraindicated in females of childbearing potential unless all of the following conditions apply:
1.The patient has severe psoriasis or other severe disorders of keratinization.
2.The patient is reliable in understanding and carrying out instructions.
3.The patient is able to comply with mandatory contraceptive measures.
4.The patient has received, and acknowledged understanding of, a careful oral and printed explanation of the hazards of fetal exposure to acitretin and the risk of possible contraception failure. This explanation may include showing a line drawing to the patient of an infant with the characteristic external deformities resulting from retinoid exposure during pregnancy.
5.The patient has had a serum or urine pregnancy test with a sensitivity of at least 50mIU/mL with a negative result, performed in a licensed laboratory, within 2weeks prior to initiating therapy. The patient has had 2or 3days of the next normal menstrual period before acitretin therapy is initiated.
(Regarding items 2to 5, see Warnings; Pregnancy, Pregnancy Testing, Contraception.)
Acitretin is also contraindicated in patients with severely impaired hepatic or renal function, intractable hyperlipidemia, hypervitaminosisA or hypersensitivity to vitaminA or its metabolites.
Safety Information / Warning
Pregnancy, Pregnancy Testing and Contraception: The use of systemic retinoids in humans has been associated with congenital abnormalities. There is an extremely high risk that major human fetal abnormalities will occur if pregnancy occurs during treatment with acitretin. Potentially any exposed fetus can be affected. Major fetal abnormalities associated with retinoid administration during pregnancy have been reported; including meningomyelocoele, meningoencephalocoele, multiple synostosis, facial dysmorphia, anophthalmia, syndactyly, absences of terminal phalanges, malformations of hip, ankle and forearm, low set ears, high palate, decreased cranial volume and alterations of the skull and cervical vertebrae on x-ray.
Female patients of childbearing potential must not be given acitretin until pregnancy is excluded. A serum or urine pregnancy test with a sensitivity of at least 50mIU/mL must be performed within 2weeks prior to starting acitretin treatment. Acitretin treatment should start on the second or third day of the next normal menstrual period following this negative pregnancy test.
Effective contraception must be used for at least 1month before starting acitretin treatment, during treatment and for an undetermined period of time of at least 2years duration after discontinuation of treatment (see Contraindications). Thereafter, the patient and physician should assess the risks and desirability of discontinuing effective contraception, based on the most current information available. It is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method.
Pregnancy occurring during treatment with acitretin and for an undetermined period of time of at least 2years duration after its discontinuation carries the risk of fetal malformation (see Warnings above). Females must be fully counselled on the serious risks to the fetus should they become pregnant whilst undergoing acitretin treatment or after discontinuation of acitretin treatment. If pregnancy does occur during this time the physician and patient should discuss the desirability of continuing the pregnancy.
It is strongly recommended that all female patients of childbearing potential treated with acitretin have monthly pregnancy tests during treatment and at regular intervals for an undetermined period of time of at least 2years duration after the discontinuation of treatment. These pregnancy tests will: a)Serve primarily to reinforce to the patient the necessity of avoiding pregnancy. b)In the event of accidental pregnancy, provide the physician and patient an immediate opportunity to discuss the serious risk to the fetus from this exposure to acitretin and the desirability of continuing the pregnancy in view of the potential teratogenic effect of acitretin (see Warnings above).
Women of childbearing potential who have switched from etretinate therapy to acitretin must continue to follow the contraceptive recommendations for etretinate when on acitretin therapy.
Lactation: Clinical data indicate that acitretin is excreted in human milk. Therefore, nursing mothers should not receive acitretin because of the potential for serious adverse reactions in nursing infants. Women should not breast-feed for an undetermined period of time of at least 2years following discontinuation of acitretin.
Hyperostosis: In clinical trials with acitretin, patients were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column following 6months of treatment. Of 262patients treated with acitretin, 7% had pre-existing abnormalities of the spine which showed new changes or progression of pre-existing findings. Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, and narrowing and destruction of cervical disc space. These existing abnormalities may be in some part attributable to the underlying psoriasis and/or the patient's age. During the 6-month period of observation, no bone changes were seen in patients who had normal pretreatment x-rays. Other retinoids including etretinate, of which acitretin is the active metabolite, have been associated with the development of extraosseous calcification and/or hyperostosis. Calcification of the ligaments of the spine, tendon insertions of the arms and legs, and intraosseous membranes of the arms and legs, have been reported. Hyperostotic changes of the vertebrae, forearms, hips, acetabula, legs and calcanei have also been reported. It is not clear whether the extraosseous calcification and/or hyperostosis are progressive. Pre-treatment radiographs of the cervical, thoracic and lumbar spine may be useful when monitoring patients on long-term acitretin therapy. Early recognition of musculoskeletal symptoms associated with acitretin therapy may be important. There is some evidence that scintigraphic changes appear before radiographic findings. Scintigraphic changes may disappear after discontinuation of acitretin treatment; however, radiographic changes may persist. Bone scintigraphy may be important in monitoring patients on acitretin therapy since scintigraphic changes seem to precede radiographic changes.
In adults receiving long-term treatment with acitretin, appropriate examinations should be periodically performed in view of possible ossification abnormalities. If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis. In 1 patient, spinal hyperostosis and calcification of spinal ligaments, resulting in compression of the spinal chord, appeared after several years' therapy with Tegison.
Hepatotoxicity: Hepatic function should be checked before starting treatment with acitretin every 1 to 2 weeks for the first 2 months after commencement and then every 3 months during treatment. If abnormal results are obtained, weekly checks should be instituted. If hepatic function fails to return to normal or deteriorates further, acitretin must be withdrawn. In such cases it is advisable to continue monitoring hepatic function for at least 3 months. Elevations of AST, ALT or LDH have occurred in 20to 28% of patients treated with acitretin. One of the 329patients treated in clinical trials had clinical jaundice with elevated serum bilirubin and transaminases considered possibly related to acitretin treatment. Liver function test results in this patient returned to normal after acitretin was discontinued.
If hepatotoxicity is suspected during treatment with acitretin, the drug should be discontinued and the etiology further investigated.
Ten of 652patients treated in clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment. There have been 4reports of hepatitis-related deaths worldwide; 2of these patients had received etretinate for a month or less before presenting with hepatic symptoms.
Pregnancy, Pregnancy Testing and Contraception: The use of systemic retinoids in humans has been associated with congenital abnormalities. There is an extremely high risk that major human fetal abnormalities will occur if pregnancy occurs during treatment with acitretin. Potentially any exposed fetus can be affected. Major fetal abnormalities associated with retinoid administration during pregnancy have been reported; including meningomyelocoele, meningoencephalocoele, multiple synostosis, facial dysmorphia, anophthalmia, syndactyly, absences of terminal phalanges, malformations of hip, ankle and forearm, low set ears, high palate, decreased cranial volume and alterations of the skull and cervical vertebrae on x-ray.
Female patients of childbearing potential must not be given acitretin until pregnancy is excluded. A serum or urine pregnancy test with a sensitivity of at least 50mIU/mL must be performed within 2weeks prior to starting acitretin treatment. Acitretin treatment should start on the second or third day of the next normal menstrual period following this negative pregnancy test.
Effective contraception must be used for at least 1month before starting acitretin treatment, during treatment and for an undetermined period of time of at least 2years duration after discontinuation of treatment (see Contraindications). Thereafter, the patient and physician should assess the risks and desirability of discontinuing effective contraception, based on the most current information available. It is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method.
Pregnancy occurring during treatment with acitretin and for an undetermined period of time of at least 2years duration after its discontinuation carries the risk of fetal malformation (see Warnings above). Females must be fully counselled on the serious risks to the fetus should they become pregnant whilst undergoing acitretin treatment or after discontinuation of acitretin treatment. If pregnancy does occur during this time the physician and patient should discuss the desirability of continuing the pregnancy.
It is strongly recommended that all female patients of childbearing potential treated with acitretin have monthly pregnancy tests during treatment and at regular intervals for an undetermined period of time of at least 2years duration after the discontinuation of treatment. These pregnancy tests will: a)Serve primarily to reinforce to the patient the necessity of avoiding pregnancy. b)In the event of accidental pregnancy, provide the physician and patient an immediate opportunity to discuss the serious risk to the fetus from this exposure to acitretin and the desirability of continuing the pregnancy in view of the potential teratogenic effect of acitretin (see Warnings above).
Women of childbearing potential who have switched from etretinate therapy to acitretin must continue to follow the contraceptive recommendations for etretinate when on acitretin therapy.
Lactation: Clinical data indicate that acitretin is excreted in human milk. Therefore, nursing mothers should not receive acitretin because of the potential for serious adverse reactions in nursing infants. Women should not breast-feed for an undetermined period of time of at least 2years following discontinuation of acitretin.
Hyperostosis: In clinical trials with acitretin, patients were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column following 6months of treatment. Of 262patients treated with acitretin, 7% had pre-existing abnormalities of the spine which showed new changes or progression of pre-existing findings. Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, and narrowing and destruction of cervical disc space. These existing abnormalities may be in some part attributable to the underlying psoriasis and/or the patient's age. During the 6-month period of observation, no bone changes were seen in patients who had normal pretreatment x-rays. Other retinoids including etretinate, of which acitretin is the active metabolite, have been associated with the development of extraosseous calcification and/or hyperostosis. Calcification of the ligaments of the spine, tendon insertions of the arms and legs, and intraosseous membranes of the arms and legs, have been reported. Hyperostotic changes of the vertebrae, forearms, hips, acetabula, legs and calcanei have also been reported. It is not clear whether the extraosseous calcification and/or hyperostosis are progressive. Pre-treatment radiographs of the cervical, thoracic and lumbar spine may be useful when monitoring patients on long-term acitretin therapy. Early recognition of musculoskeletal symptoms associated with acitretin therapy may be important. There is some evidence that scintigraphic changes appear before radiographic findings. Scintigraphic changes may disappear after discontinuation of acitretin treatment; however, radiographic changes may persist. Bone scintigraphy may be important in monitoring patients on acitretin therapy since scintigraphic changes seem to precede radiographic changes.
In adults receiving long-term treatment with acitretin, appropriate examinations should be periodically performed in view of possible ossification abnormalities. If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis. In 1 patient, spinal hyperostosis and calcification of spinal ligaments, resulting in compression of the spinal chord, appeared after several years' therapy with Tegison.
Hepatotoxicity: Hepatic function should be checked before starting treatment with acitretin every 1 to 2 weeks for the first 2 months after commencement and then every 3 months during treatment. If abnormal results are obtained, weekly checks should be instituted. If hepatic function fails to return to normal or deteriorates further, acitretin must be withdrawn. In such cases it is advisable to continue monitoring hepatic function for at least 3 months. Elevations of AST, ALT or LDH have occurred in 20to 28% of patients treated with acitretin. One of the 329patients treated in clinical trials had clinical jaundice with elevated serum bilirubin and transaminases considered possibly related to acitretin treatment. Liver function test results in this patient returned to normal after acitretin was discontinued.
If hepatotoxicity is suspected during treatment with acitretin, the drug should be discontinued and the etiology further investigated.
Ten of 652patients treated in clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment. There have been 4reports of hepatitis-related deaths worldwide; 2of these patients had received etretinate for a month or less before presenting with hepatic symptoms.
Precautions
General: Patients should be advised that a transient worsening of their psoriasis may occur during the initial acitretin treatment period.
Benign Intracranial Hypertension (Pseudotumor Cerebri): Acitretin and other retinoids have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Early symptoms and signs of benign intracranial hypertension include headache, nausea and vomiting and visual disturbances. Patients with these symptoms should be examined for papilledema and if present, they should discontinue acitretin immediately and be referred for neurological diagnosis and care.
As tetracyclines can also cause an increase in intracranial pressure, their combination with acitretin should be avoided.
Ophthalmic Effects: Drug-related ophthalmic effects (dry eyes, irritation of eyes, brow and lash loss, blepharitis and/or crusting of lids, photophobia, redness, recurrent styes, pannus and subepithelial corneal lesions) were noted during treatment with acitretin in 29% of 252patients who were followed with ophthalmic examinations. Patients should be advised that they may experience decreased tolerance to contact lenses during the initial treatment period.
Overall in clinical studies, decreased night vision was reported by 2patients and blurring of vision by 3patients.
The following additional ophthalmic effects have occurred in patients taking etretinate, of which acitretin is the active metabolite: decreased visual acuity, minimal posterior subcapsular cataract, iritis, blot retinal hemorrhage and scotoma.
Any patient receiving acitretin therapy, experiencing visual difficulties should discontinue this drug and undergo ophthalmic evaluation.
Lipids: Blood lipid determinations should be performed before acitretin is administered and again at intervals of 1or 2weeks until the lipid response to the drug is established, which is usually within 4to 8weeks. Approximately 65% of patients receiving acitretin during clinical trials experienced an elevation in serum triglycerides. Approximately 30% developed a decrease in high density lipoproteins (HDL). Approximately 9% experienced elevated serum cholesterol levels. These effects of acitretin were reversible upon cessation of therapy.
Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake or a familial history of these conditions.
Hypertriglyceridemia and lowered HDL may increase a patient's cardiovascular risk status. In addition, elevation of serum triglycerides to greater than 800mg/dL has been associated with acute pancreatitis. Therefore, every attempt should be made to control significant elevations of triglycerides or HDL decreases by reduction of weight or restriction of dietary fat and alcohol intake while continuing acitretin therapy.
If, despite these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of acitretin should be considered. An associated risk of atherogenesis cannot be ruled out if these conditions persist.
VitaminA: Acitretin is a derivative of vitaminA. To avoid the risk of additive toxic effects, patients should be advised against taking other systemic retinoids or vitamin supplements containing vitaminA.
Methotrexate: Due to an increased hepatitis risk, the combined use of acitretin and methotrexate should be avoided.
Children: Safety and efficacy of acitretin in children have not been established. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostosis and premature epiphyseal closure have been reported with other systemic retinoids, including etretinate of which acitretin is the active metabolite. Due to the uncertain effect of long-term acitretin therapy on growth and skeletal development, acitretin should only be used in pediatric patients with the most severe forms of keratinization disorders for which there are no effective alternative therapies. Pretreatment x-rays for bone age including x-rays of the knees are advised. Bone scans (scintigraphs) and/or x-rays should be considered at yearly intervals when monitoring children on long-term therapy. In addition pain or limitation of movement should be evaluated by appropriate radiological examination.
Blood Donation: It is recommended that blood donation for transfusion purposes be deferred during therapy with acitretin and for an undetermined period of time of at least 2years duration after discontinuation of treatment. Theoretically, blood from such donors could present a small risk to the fetus if transfused to a pregnant mother during the first trimester of pregnancy (see Contraindications).
Drug Interactions : Concomitant administration of vitaminA and other systemic retinoids must be avoided due to the risk of possible additive toxic effects.
The concomitant administration of methotrexate and etretinate has been associated with hepatitis, a similar increased hepatitis risk may be expected with the combined use of acitretin and methotrexate.
Preliminary studies indicated that acitretin does not influence the endogenous progesterone plasma concentrations induced by oral contraceptives. The effect of microdosed progesterone preparations may be diminished by interaction with acitretin. Therefore, microdosed progesterone preparations or “minipills” should not be used.
Concomitant administration of phenprocoumon and acitretin does not alter the hypothrombinemic effect of phenprocoumon or the plasma disposition of acitretin.
The pharmacokinetics of acitretin and digoxin are not altered by concomitant multiple dose regimens of these 2drugs.
Concomitant administration of cimetidine did not alter the oral bioavailability of acitretin or the isomerization to its 13-cis form. Single oral doses of acitretin did not affect the steady state plasma concentration or renal clearance of cimetidine.
Limited data which could not be duplicated, indicated that acitretin treatment either increased insulin sensitivity directly or interacted with glyburide to do so. Careful supervision of diabetic patients under treatment with acitretin is recommended.
General: Patients should be advised that a transient worsening of their psoriasis may occur during the initial acitretin treatment period.
Benign Intracranial Hypertension (Pseudotumor Cerebri): Acitretin and other retinoids have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Early symptoms and signs of benign intracranial hypertension include headache, nausea and vomiting and visual disturbances. Patients with these symptoms should be examined for papilledema and if present, they should discontinue acitretin immediately and be referred for neurological diagnosis and care.
As tetracyclines can also cause an increase in intracranial pressure, their combination with acitretin should be avoided.
Ophthalmic Effects: Drug-related ophthalmic effects (dry eyes, irritation of eyes, brow and lash loss, blepharitis and/or crusting of lids, photophobia, redness, recurrent styes, pannus and subepithelial corneal lesions) were noted during treatment with acitretin in 29% of 252patients who were followed with ophthalmic examinations. Patients should be advised that they may experience decreased tolerance to contact lenses during the initial treatment period.
Overall in clinical studies, decreased night vision was reported by 2patients and blurring of vision by 3patients.
The following additional ophthalmic effects have occurred in patients taking etretinate, of which acitretin is the active metabolite: decreased visual acuity, minimal posterior subcapsular cataract, iritis, blot retinal hemorrhage and scotoma.
Any patient receiving acitretin therapy, experiencing visual difficulties should discontinue this drug and undergo ophthalmic evaluation.
Lipids: Blood lipid determinations should be performed before acitretin is administered and again at intervals of 1or 2weeks until the lipid response to the drug is established, which is usually within 4to 8weeks. Approximately 65% of patients receiving acitretin during clinical trials experienced an elevation in serum triglycerides. Approximately 30% developed a decrease in high density lipoproteins (HDL). Approximately 9% experienced elevated serum cholesterol levels. These effects of acitretin were reversible upon cessation of therapy.
Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake or a familial history of these conditions.
Hypertriglyceridemia and lowered HDL may increase a patient's cardiovascular risk status. In addition, elevation of serum triglycerides to greater than 800mg/dL has been associated with acute pancreatitis. Therefore, every attempt should be made to control significant elevations of triglycerides or HDL decreases by reduction of weight or restriction of dietary fat and alcohol intake while continuing acitretin therapy.
If, despite these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of acitretin should be considered. An associated risk of atherogenesis cannot be ruled out if these conditions persist.
VitaminA: Acitretin is a derivative of vitaminA. To avoid the risk of additive toxic effects, patients should be advised against taking other systemic retinoids or vitamin supplements containing vitaminA.
Methotrexate: Due to an increased hepatitis risk, the combined use of acitretin and methotrexate should be avoided.
Children: Safety and efficacy of acitretin in children have not been established. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostosis and premature epiphyseal closure have been reported with other systemic retinoids, including etretinate of which acitretin is the active metabolite. Due to the uncertain effect of long-term acitretin therapy on growth and skeletal development, acitretin should only be used in pediatric patients with the most severe forms of keratinization disorders for which there are no effective alternative therapies. Pretreatment x-rays for bone age including x-rays of the knees are advised. Bone scans (scintigraphs) and/or x-rays should be considered at yearly intervals when monitoring children on long-term therapy. In addition pain or limitation of movement should be evaluated by appropriate radiological examination.
Blood Donation: It is recommended that blood donation for transfusion purposes be deferred during therapy with acitretin and for an undetermined period of time of at least 2years duration after discontinuation of treatment. Theoretically, blood from such donors could present a small risk to the fetus if transfused to a pregnant mother during the first trimester of pregnancy (see Contraindications).
Drug Interactions : Concomitant administration of vitaminA and other systemic retinoids must be avoided due to the risk of possible additive toxic effects.
The concomitant administration of methotrexate and etretinate has been associated with hepatitis, a similar increased hepatitis risk may be expected with the combined use of acitretin and methotrexate.
Preliminary studies indicated that acitretin does not influence the endogenous progesterone plasma concentrations induced by oral contraceptives. The effect of microdosed progesterone preparations may be diminished by interaction with acitretin. Therefore, microdosed progesterone preparations or “minipills” should not be used.
Concomitant administration of phenprocoumon and acitretin does not alter the hypothrombinemic effect of phenprocoumon or the plasma disposition of acitretin.
The pharmacokinetics of acitretin and digoxin are not altered by concomitant multiple dose regimens of these 2drugs.
Concomitant administration of cimetidine did not alter the oral bioavailability of acitretin or the isomerization to its 13-cis form. Single oral doses of acitretin did not affect the steady state plasma concentration or renal clearance of cimetidine.
Limited data which could not be duplicated, indicated that acitretin treatment either increased insulin sensitivity directly or interacted with glyburide to do so. Careful supervision of diabetic patients under treatment with acitretin is recommended.
Side Effects / Adverse Effects
Adverse Effects: HypervitaminosisA produces a wide spectrum of signs and symptoms primarily of the mucocutaneous, musculoskeletal, hepatic and central nervous systems. Nearly all of the clinical adverse events reported to date with acitretin administration resemble those of the hypervitaminosisA syndrome. TablesI andII list, grouped by frequency, the adverse reactions reported during clinical trials in which patients were treated with acitretin for psoriasis.
a Some may bear no relationship to therapy.
b Based on review of eye examination forms by consulting ophthalmologist (n=252).
c Incidence of 7% based on review of films by consulting radiologist (n=262).
d Vasculitis has not been documented with acitretin but has been seen with other retinoids.
e Increased incidence of vulvovaginitis due to C. albicans has been noted during treatment with Soriatane.
f Events observed and reported rarely.
Other reported laboratory abnormalities include: increased creatinine phosphokinase (37%), increased (21%) or decreased (7%) fasting blood sugar and increased (7%) or decreased (3%) iron.
Adverse Effects: HypervitaminosisA produces a wide spectrum of signs and symptoms primarily of the mucocutaneous, musculoskeletal, hepatic and central nervous systems. Nearly all of the clinical adverse events reported to date with acitretin administration resemble those of the hypervitaminosisA syndrome. TablesI andII list, grouped by frequency, the adverse reactions reported during clinical trials in which patients were treated with acitretin for psoriasis.
a Some may bear no relationship to therapy.
b Based on review of eye examination forms by consulting ophthalmologist (n=252).
c Incidence of 7% based on review of films by consulting radiologist (n=262).
d Vasculitis has not been documented with acitretin but has been seen with other retinoids.
e Increased incidence of vulvovaginitis due to C. albicans has been noted during treatment with Soriatane.
f Events observed and reported rarely.
Other reported laboratory abnormalities include: increased creatinine phosphokinase (37%), increased (21%) or decreased (7%) fasting blood sugar and increased (7%) or decreased (3%) iron.
Overdose
Symptoms and Treatment: To date, there has been no experience with acute overdose of acitretin. In the event of acute overdosage, evacuation of the stomach should be considered during the first few hours after this overdose. Signs and symptoms of overdosage with acitretin would probably be similar to acute vitaminA toxicity, i.e., severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Elevated intracranial pressure has been reported with both acute and chronic vitaminA overdoses as well as in patients treated with therapeutic doses of acitretin. Patients with a acitretin overdose should be monitored closely for signs of increased intracranial pressure. If overdosage occurs in patients already receiving therapeutic doses of acitretin, the drug must be discontinued immediately.
All female patients of childbearing potential who have taken an overdose of acitretin must: 1.Have a pregnancy test at the time of the overdose. 2.Use an effective form of contraception for an undetermined period of time of at least 2years duration after the overdose.
If the pregnancy test is positive, the patient should be fully counselled on the serious risk to the fetus from this exposure to acitretin and the physician and patient should discuss the desirability of continuing the pregnancy (see Contraindications and Warnings).
Symptoms and Treatment: To date, there has been no experience with acute overdose of acitretin. In the event of acute overdosage, evacuation of the stomach should be considered during the first few hours after this overdose. Signs and symptoms of overdosage with acitretin would probably be similar to acute vitaminA toxicity, i.e., severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Elevated intracranial pressure has been reported with both acute and chronic vitaminA overdoses as well as in patients treated with therapeutic doses of acitretin. Patients with a acitretin overdose should be monitored closely for signs of increased intracranial pressure. If overdosage occurs in patients already receiving therapeutic doses of acitretin, the drug must be discontinued immediately.
All female patients of childbearing potential who have taken an overdose of acitretin must: 1.Have a pregnancy test at the time of the overdose. 2.Use an effective form of contraception for an undetermined period of time of at least 2years duration after the overdose.
If the pregnancy test is positive, the patient should be fully counselled on the serious risk to the fetus from this exposure to acitretin and the physician and patient should discuss the desirability of continuing the pregnancy (see Contraindications and Warnings).
Recommended Dosage
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin. Individualization of dosage is required to achieve maximum therapeutic response while minimizing side effects.
Initial Therapy: Therapy should be initiated at 25mg/day, given as a single dose with the main meal. If by 4weeks the response is unsatisfactory, and in the absence of toxicity, the daily dose may be gradually increased to a maximum of 75mg/day. The dose may be reduced if necesssary to minimize side effects.
Maintenance Therapy: Psoriasis: Maintenance doses of 25 to 50mg/day may be given after initial response to treatment. The maintenance dose should be based on clinical efficacy and tolerability. It may be necessary in some cases to increase the dose to a maximum of 75mg/day.
In general, therapy should be terminated when lesions have resolved sufficiently. Relapses may be treated as outlined for initial therapy.
Other Keratinization Disorders: Maintenance doses of 10mg to a maximum of 50mg/day may be given for disorders of keratinization.
Information for the Patient: See Blue Section--Information for the Patient “Soriatane”.
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin. Individualization of dosage is required to achieve maximum therapeutic response while minimizing side effects.
Initial Therapy: Therapy should be initiated at 25mg/day, given as a single dose with the main meal. If by 4weeks the response is unsatisfactory, and in the absence of toxicity, the daily dose may be gradually increased to a maximum of 75mg/day. The dose may be reduced if necesssary to minimize side effects.
Maintenance Therapy: Psoriasis: Maintenance doses of 25 to 50mg/day may be given after initial response to treatment. The maintenance dose should be based on clinical efficacy and tolerability. It may be necessary in some cases to increase the dose to a maximum of 75mg/day.
In general, therapy should be terminated when lesions have resolved sufficiently. Relapses may be treated as outlined for initial therapy.
Other Keratinization Disorders: Maintenance doses of 10mg to a maximum of 50mg/day may be given for disorders of keratinization.
Information for the Patient: See Blue Section--Information for the Patient “Soriatane”.
Supplied / Packaging
10mg: Each brown and white, hard gelatin capsule (No.4), marked ROCHE ROCHE, contains: acitretin 10mg. Nonmedicinal ingredients: gelatin, maltodextrin, microcrystalline cellulose and sodium ascorbate; gelatin capsule shell: iron oxide (yellow, black and red) and titanium dioxide. Push-through blister packages of30.
25mg: Each brown and yellow, hard gelatin capsule (No.1), marked ROCHE ROCHE, contains: acitretin 25mg. Nonmedicinal ingredients: gelatin, maltodextrin, microcrystalline cellulose and sodium ascorbate; gelatin capsule shell: iron oxide (yellow, black and red) and titanium dioxide. Push-through blister packages of 30.
Store at 15 to 30°C. Protect from light.
10mg: Each brown and white, hard gelatin capsule (No.4), marked ROCHE ROCHE, contains: acitretin 10mg. Nonmedicinal ingredients: gelatin, maltodextrin, microcrystalline cellulose and sodium ascorbate; gelatin capsule shell: iron oxide (yellow, black and red) and titanium dioxide. Push-through blister packages of30.
25mg: Each brown and yellow, hard gelatin capsule (No.1), marked ROCHE ROCHE, contains: acitretin 25mg. Nonmedicinal ingredients: gelatin, maltodextrin, microcrystalline cellulose and sodium ascorbate; gelatin capsule shell: iron oxide (yellow, black and red) and titanium dioxide. Push-through blister packages of 30.
Store at 15 to 30°C. Protect from light.
