madman
Super Moderator
ABSTRACT
A significant barrier to the usage of isotretinoin has been concerns regarding its adverse effect profile. The dose-dependent mucocutaneous side effects of isotretinoin are well recognized and easily managed, particularly if a lower dose is used. A possible association with depression has gained widespread media attention and is a source of concern for many patients and their carers, but data from prospective studies and recent meta-analyses have been reassuring. Furthermore, there has been much confusion amongst both patients and physicians regarding a possible association with inflammatory bowel disease, as well the ocular and rheumatological adverse effects of isotretinoin. We provide an update on the evidence surrounding the adverse effects of isotretinoin and discuss practical strategies to prevent and manage these adverse effects. We also discuss appropriate laboratory monitoring for patients taking isotretinoin.
FLARE OF ACNE
A flare of acne may occur in the first few weeks of isotretinoin therapy. Short term exposure of sebocytes to isotretinoin increases intracellular lipid content as well as the expression of sterol-regulatory element-binding protein (SREBP)-1 and the eicosanoid synthesizing enzyme 5-lipoxygenase (LOX). (2) Both SREBP-1 and 5-LOX are involved in sebum production, and their upregulation may contribute to the flare of acne seen in the first few weeks of therapy.
The presence of multiple macrocomedones appears to be an important risk factor for a flare of acne in the first few weeks of isotretinoin. (3)(4) Macrocomedones can be treated with diathermy or surgically, ideally prior to commencement of isotretinoin.
Commencing isotretinoin at a low dose should reduce the risk of a flare of acne in the first few weeks of treatment.
DEPRESSION
The association between isotretinoin and adverse psychological effects has been clarified over the last decade. Initial concerns regarding an association between isotretinoin and depression arose from case reports. In some of these patients, symptoms of depression settled after cessation of isotretinoin and recurred after rechallenge with isotretinoin. (6)(7)
Biological mechanisms for an association between isotretinoin and acne have been postulated. Retinoids are lipid-soluble and can cross the blood-brain barrier. It has been suggested that isotretinoin may lead to depressive symptoms by decreasing hippocampal neurogenesis, and/or by altering the expression of components of the serotonergic neurotransmitter system, thereby leading to impaired serotonin signaling. (8) Acne itself is associated with an increased risk of depression and suicidal ideation,(9)(10)(11) although not all studies have found this. (12
*In summary, the data from prospective studies and recent meta-analyses do not support an association between isotretinoin and depression. Nevertheless, the reports of cases of depression that resolve with de-challenge and recur with re-challenge, suggest that a small subset of patients may be susceptible to mood change from isotretinoin. This possibility should be conveyed to patients and their carers prior to commencing isotretinoin and the patient is advised to report any symptoms of mood disturbance occurring during therapy. There is an anecdotal observation that psychological symptoms occurring during isotretinoin treatment are seen more often in young adult patients exposed to cannabinoids and methamphetamines.
Given the potential for isotretinoin to improve psychological health and quality of life, isotretinoin should actively be considered in patients with a history of a mood disorder; shared follow-up with the patient’s family physician and/or mental health care professional, particularly in the first few months of therapy, is recommended.
INFLAMMATORY BOWEL DISEASE
*In summary, most epidemiological studies do not demonstrate an association between isotretinoin and inflammatory bowel disease and there is no clear evidence of a causal link. (41)
Patients with established inflammatory bowel disease who have clinically significant acne, should actively be considered for treatment with isotretinoin.
BENIGN INTRACRANIAL HYPERTENSION
An important reported adverse effect of isotretinoin is benign intracranial hypertension, which can lead to permanent visual impairment.
Benign intracranial hypertension should be considered in the case of a new headache or a headache that is different from the patient’s usual headache disorder,(47) especially when accompanied by other symptoms such as visual disturbances or tinnitus. Isotretinoin has been used safely in patients with a previous history of drug-induced benign intracranial hypertension,(48) but it would be sensible to use low dosages of isotretinoin (e.g. 10 mg/day) and to monitor the patient closely for symptoms and signs of raised intracranial pressure in liaison with the patient’s neurologist/ophthalmologist.
OCULAR EFFECTS
A number of dose-dependent ocular side effects have been attributed to isotretinoin.
*In summary, night vision impairment may occur in patients being treated with isotretinoin. Subclinical impairments in electrophysiological examination findings in the absence of any patient-reported changes in night vision may not be infrequent. The decline in night vision appears to be in most cases reversible upon cessation of isotretinoin, although subclinical abnormalities in electrophysiological tests may last longer than initially thought. Isotretinoin is thought to cause night vision impairment by inhibiting ocular retinol dehydrogenases, leading to a reduction in the formation of the visual chromophore 11-cis-retinal.(56) Therefore, the use of lower dosages of isotretinoin (10-20 mg/day) may reduce the likelihood of clinical or subclinical abnormalities in night vision, although data to confirm this is lacking
It is important to counsel prospective pilots (and long-distance truck drivers) appropriately, and if isotretinoin is to be used, the dosage kept low, after discussion with their aviation medical specialist.
HYPEROSTOSES
*In summary, the data regarding an association between isotretinoin and DISH has been conflicting. The most methodologically robust study, a randomized controlled trial, shows a possible association, although the participants were not acne patients and were significantly older. However, several studies demonstrate that isotretinoin-associated hyperostotic changes do not appear to correlate with additional symptoms of pain or stiffness.
PREMATURE EPIPHYSEAL CLOSURE
Another issue that has been a source of concern has been the possible association between isotretinoin and premature epiphyseal closure.
The biologic mechanism of a retinoid effect on epiphyses may involve specific retinoid receptors. Animal studies have shown that guinea pigs treated with all-trans-retinoic acid and a retinoic acid receptor (RAR) selective agonist developed dose-dependent closure of the proximal tibial epiphyseal plate. (71) It would therefore be sensible to use lower dosages of isotretinoin in pre-pubertal children (e.g. 0.1 mg/kg/day), even though the risk is undetermined.
MUSCULAR EFFECTS
Myalgia is a common dose-dependent adverse effect of isotretinoin. In general symptoms of myalgia and muscle tenderness are mild, and quickly reversible on discontinuation of therapy. (72)
Elevations of creatine kinase (CK) levels may occur in patients on isotretinoin and are frequently asymptomatic.
In patients who develop myalgia or increased CK levels while on isotretinoin, the dose of isotretinoin may be reduced or the drug temporarily discontinued until these findings resolve. (75) These patients should be encouraged to reduce strenuous physical activity or contact sports while on isotretinoin, and to avoid any medications that may also lead to myopathy. CK levels, electrolytes, and urinalysis (including testing for myoglobinuria) should be performed in patients presenting with severe muscle pain or weakness or change in the color of urine. There is no evidence to support regular monitoring of CK (or recommending reduced exercise) in physically active patients who are asymptomatic.
TERATOGENICITY
Isotretinoin is a known teratogen. The precise molecular basis of retinoid embryopathy remains unknown, but it has recently been hypothesized that isotretinoin exaggerates neural crest cell apoptosis via upregulation of the pro-apoptotic transcription factor p53. (76) Retinoic acid embryopathy produces malformations particularly affecting craniofacial, cardiac, thymic, and central nervous system structures. (77) In one study of 94 prospectively ascertained pregnancies exposed to isotretinoin which ended in birth, 28% resulted in congenital malformation. (78) Several other prospectively reported cases of exposure to isotretinoin appeared to have had normal outcomes at birth, but were later found to have impairment of the central nervous system, hearing, or vision (i.e. neurodevelopmental delay). (79) Exposure to isotretinoin during pregnancy also appears to increase the risk of spontaneous abortion. (80)
In an effort to reduce the number of pregnancies in patients on isotretinoin therapy, the iPLEDGE program, a computerized risk management program, was launched in the USA in 2006. The iPLEDGE program requires the registration of all wholesalers distributing isotretinoin, all healthcare professionals prescribing isotretinoin, all pharmacies dispensing isotretinoin and all patients prescribed isotretinoin. (81) Amongst the requirements of the program are two negative pregnancy tests prior to the commencement of isotretinoin and monthly negative pregnancy tests prior to issuing each monthly prescription. Most other countries have not adopted such a stringent pregnancy prevention program, but simply recommend that the possibility of pregnancy be excluded prior to the commencement of isotretinoin and that patients are advised to avoid falling pregnant during the treatment and for 1 month after completion of the treatment,(82) using two reliable methods of contraception. There is little evidence that stringent pregnancy prevention programs such as iPLEDGE is more effective, but they do significantly reduce access to isotretinoin, particularly amongst socio-economically disadvantaged patients. (83)
Should a patient become pregnant on isotretinoin, isotretinoin should be immediately discontinued, and advice sought from a perinatal specialist. There is currently no evidence that very low doses of isotretinoin (e.g. 5 mg/day) are safe in pregnancy, although up to 10,000 IU vitamin A daily does appear to be safe. (84)
MALE AND FEMALE FERTILITY
Despite some initial concerns, male fertility is not adversely affected by isotretinoin. (85)
LABORATORY MONITORING
Isotretinoin medicine data sheets recommend baseline investigations (complete blood count, renal and liver function), repeated regularly during treatment, in addition to appropriate pregnancy screening.
Leukopenia and thrombocytopenia may occur in patients taking isotretinoin.
Lipid abnormalities are the most common laboratory abnormalities seen in patients on isotretinoin. (95)
Lipid abnormalities are the most common laboratory abnormalities seen in patients on isotretinoin. (95)
Timing and frequency of monitoring
In a large meta-analysis, the changes in total cholesterol and triglycerides between 0 weeks and 8 weeks were similar to the changes in total cholesterol and triglycerides between 0 and 20 weeks, indicating no substantial late effect of therapy on these parameters. (91) In a retrospective review, the mean duration of treatment before abnormalities were detected was 56.3 days for hypertriglyceridemia, 61.9 days for alanine transaminitis, and 50.1 days for hypercholesterolemia. (92) On the basis of this, the authors of that review suggest that in healthy patients checking liver function tests and lipids two months after the peak dose (they used 0.5 to 1 mg/kg/day) is attained is sufficient with no further testing required if the results are normal. (92) Ongoing monitoring may be required for patients with known lipid abnormalities, those with risk factors for hyperlipidemia or liver abnormalities, including those who have commenced new medications or supplements, or patients with abdominal pain. Women of childbearing potential should have regular pregnancy tests while on isotretinoin.
OTHER ADVERSE REPORTS
With a medication that has been used in millions of patients over almost 40 years, it is not surprising that there have been many case reports of treatment-emergent adverse effects. Most of these have not been substantiated with larger cohort studies.
CONCLUSION
With almost 40 years of experience using isotretinoin in the management of acne vulgaris, our understanding of its mechanism of action, and the optimal way in which it should be prescribed continues to evolve. (99) Isotretinoin has been associated with numerous adverse effects, although the risk of many of these can be substantially reduced by using lower dosages. Recent meta-analyses examining the association between isotretinoin and depression and inflammatory bowel disease have been reassuring.
A significant barrier to the usage of isotretinoin has been concerns regarding its adverse effect profile. The dose-dependent mucocutaneous side effects of isotretinoin are well recognized and easily managed, particularly if a lower dose is used. A possible association with depression has gained widespread media attention and is a source of concern for many patients and their carers, but data from prospective studies and recent meta-analyses have been reassuring. Furthermore, there has been much confusion amongst both patients and physicians regarding a possible association with inflammatory bowel disease, as well the ocular and rheumatological adverse effects of isotretinoin. We provide an update on the evidence surrounding the adverse effects of isotretinoin and discuss practical strategies to prevent and manage these adverse effects. We also discuss appropriate laboratory monitoring for patients taking isotretinoin.
FLARE OF ACNE
A flare of acne may occur in the first few weeks of isotretinoin therapy. Short term exposure of sebocytes to isotretinoin increases intracellular lipid content as well as the expression of sterol-regulatory element-binding protein (SREBP)-1 and the eicosanoid synthesizing enzyme 5-lipoxygenase (LOX). (2) Both SREBP-1 and 5-LOX are involved in sebum production, and their upregulation may contribute to the flare of acne seen in the first few weeks of therapy.
The presence of multiple macrocomedones appears to be an important risk factor for a flare of acne in the first few weeks of isotretinoin. (3)(4) Macrocomedones can be treated with diathermy or surgically, ideally prior to commencement of isotretinoin.
Commencing isotretinoin at a low dose should reduce the risk of a flare of acne in the first few weeks of treatment.
DEPRESSION
The association between isotretinoin and adverse psychological effects has been clarified over the last decade. Initial concerns regarding an association between isotretinoin and depression arose from case reports. In some of these patients, symptoms of depression settled after cessation of isotretinoin and recurred after rechallenge with isotretinoin. (6)(7)
Biological mechanisms for an association between isotretinoin and acne have been postulated. Retinoids are lipid-soluble and can cross the blood-brain barrier. It has been suggested that isotretinoin may lead to depressive symptoms by decreasing hippocampal neurogenesis, and/or by altering the expression of components of the serotonergic neurotransmitter system, thereby leading to impaired serotonin signaling. (8) Acne itself is associated with an increased risk of depression and suicidal ideation,(9)(10)(11) although not all studies have found this. (12
*In summary, the data from prospective studies and recent meta-analyses do not support an association between isotretinoin and depression. Nevertheless, the reports of cases of depression that resolve with de-challenge and recur with re-challenge, suggest that a small subset of patients may be susceptible to mood change from isotretinoin. This possibility should be conveyed to patients and their carers prior to commencing isotretinoin and the patient is advised to report any symptoms of mood disturbance occurring during therapy. There is an anecdotal observation that psychological symptoms occurring during isotretinoin treatment are seen more often in young adult patients exposed to cannabinoids and methamphetamines.
Given the potential for isotretinoin to improve psychological health and quality of life, isotretinoin should actively be considered in patients with a history of a mood disorder; shared follow-up with the patient’s family physician and/or mental health care professional, particularly in the first few months of therapy, is recommended.
INFLAMMATORY BOWEL DISEASE
*In summary, most epidemiological studies do not demonstrate an association between isotretinoin and inflammatory bowel disease and there is no clear evidence of a causal link. (41)
Patients with established inflammatory bowel disease who have clinically significant acne, should actively be considered for treatment with isotretinoin.
BENIGN INTRACRANIAL HYPERTENSION
An important reported adverse effect of isotretinoin is benign intracranial hypertension, which can lead to permanent visual impairment.
Benign intracranial hypertension should be considered in the case of a new headache or a headache that is different from the patient’s usual headache disorder,(47) especially when accompanied by other symptoms such as visual disturbances or tinnitus. Isotretinoin has been used safely in patients with a previous history of drug-induced benign intracranial hypertension,(48) but it would be sensible to use low dosages of isotretinoin (e.g. 10 mg/day) and to monitor the patient closely for symptoms and signs of raised intracranial pressure in liaison with the patient’s neurologist/ophthalmologist.
OCULAR EFFECTS
A number of dose-dependent ocular side effects have been attributed to isotretinoin.
*In summary, night vision impairment may occur in patients being treated with isotretinoin. Subclinical impairments in electrophysiological examination findings in the absence of any patient-reported changes in night vision may not be infrequent. The decline in night vision appears to be in most cases reversible upon cessation of isotretinoin, although subclinical abnormalities in electrophysiological tests may last longer than initially thought. Isotretinoin is thought to cause night vision impairment by inhibiting ocular retinol dehydrogenases, leading to a reduction in the formation of the visual chromophore 11-cis-retinal.(56) Therefore, the use of lower dosages of isotretinoin (10-20 mg/day) may reduce the likelihood of clinical or subclinical abnormalities in night vision, although data to confirm this is lacking
It is important to counsel prospective pilots (and long-distance truck drivers) appropriately, and if isotretinoin is to be used, the dosage kept low, after discussion with their aviation medical specialist.
HYPEROSTOSES
*In summary, the data regarding an association between isotretinoin and DISH has been conflicting. The most methodologically robust study, a randomized controlled trial, shows a possible association, although the participants were not acne patients and were significantly older. However, several studies demonstrate that isotretinoin-associated hyperostotic changes do not appear to correlate with additional symptoms of pain or stiffness.
PREMATURE EPIPHYSEAL CLOSURE
Another issue that has been a source of concern has been the possible association between isotretinoin and premature epiphyseal closure.
The biologic mechanism of a retinoid effect on epiphyses may involve specific retinoid receptors. Animal studies have shown that guinea pigs treated with all-trans-retinoic acid and a retinoic acid receptor (RAR) selective agonist developed dose-dependent closure of the proximal tibial epiphyseal plate. (71) It would therefore be sensible to use lower dosages of isotretinoin in pre-pubertal children (e.g. 0.1 mg/kg/day), even though the risk is undetermined.
MUSCULAR EFFECTS
Myalgia is a common dose-dependent adverse effect of isotretinoin. In general symptoms of myalgia and muscle tenderness are mild, and quickly reversible on discontinuation of therapy. (72)
Elevations of creatine kinase (CK) levels may occur in patients on isotretinoin and are frequently asymptomatic.
In patients who develop myalgia or increased CK levels while on isotretinoin, the dose of isotretinoin may be reduced or the drug temporarily discontinued until these findings resolve. (75) These patients should be encouraged to reduce strenuous physical activity or contact sports while on isotretinoin, and to avoid any medications that may also lead to myopathy. CK levels, electrolytes, and urinalysis (including testing for myoglobinuria) should be performed in patients presenting with severe muscle pain or weakness or change in the color of urine. There is no evidence to support regular monitoring of CK (or recommending reduced exercise) in physically active patients who are asymptomatic.
TERATOGENICITY
Isotretinoin is a known teratogen. The precise molecular basis of retinoid embryopathy remains unknown, but it has recently been hypothesized that isotretinoin exaggerates neural crest cell apoptosis via upregulation of the pro-apoptotic transcription factor p53. (76) Retinoic acid embryopathy produces malformations particularly affecting craniofacial, cardiac, thymic, and central nervous system structures. (77) In one study of 94 prospectively ascertained pregnancies exposed to isotretinoin which ended in birth, 28% resulted in congenital malformation. (78) Several other prospectively reported cases of exposure to isotretinoin appeared to have had normal outcomes at birth, but were later found to have impairment of the central nervous system, hearing, or vision (i.e. neurodevelopmental delay). (79) Exposure to isotretinoin during pregnancy also appears to increase the risk of spontaneous abortion. (80)
In an effort to reduce the number of pregnancies in patients on isotretinoin therapy, the iPLEDGE program, a computerized risk management program, was launched in the USA in 2006. The iPLEDGE program requires the registration of all wholesalers distributing isotretinoin, all healthcare professionals prescribing isotretinoin, all pharmacies dispensing isotretinoin and all patients prescribed isotretinoin. (81) Amongst the requirements of the program are two negative pregnancy tests prior to the commencement of isotretinoin and monthly negative pregnancy tests prior to issuing each monthly prescription. Most other countries have not adopted such a stringent pregnancy prevention program, but simply recommend that the possibility of pregnancy be excluded prior to the commencement of isotretinoin and that patients are advised to avoid falling pregnant during the treatment and for 1 month after completion of the treatment,(82) using two reliable methods of contraception. There is little evidence that stringent pregnancy prevention programs such as iPLEDGE is more effective, but they do significantly reduce access to isotretinoin, particularly amongst socio-economically disadvantaged patients. (83)
Should a patient become pregnant on isotretinoin, isotretinoin should be immediately discontinued, and advice sought from a perinatal specialist. There is currently no evidence that very low doses of isotretinoin (e.g. 5 mg/day) are safe in pregnancy, although up to 10,000 IU vitamin A daily does appear to be safe. (84)
MALE AND FEMALE FERTILITY
Despite some initial concerns, male fertility is not adversely affected by isotretinoin. (85)
LABORATORY MONITORING
Isotretinoin medicine data sheets recommend baseline investigations (complete blood count, renal and liver function), repeated regularly during treatment, in addition to appropriate pregnancy screening.
Leukopenia and thrombocytopenia may occur in patients taking isotretinoin.
Lipid abnormalities are the most common laboratory abnormalities seen in patients on isotretinoin. (95)
Lipid abnormalities are the most common laboratory abnormalities seen in patients on isotretinoin. (95)
Timing and frequency of monitoring
In a large meta-analysis, the changes in total cholesterol and triglycerides between 0 weeks and 8 weeks were similar to the changes in total cholesterol and triglycerides between 0 and 20 weeks, indicating no substantial late effect of therapy on these parameters. (91) In a retrospective review, the mean duration of treatment before abnormalities were detected was 56.3 days for hypertriglyceridemia, 61.9 days for alanine transaminitis, and 50.1 days for hypercholesterolemia. (92) On the basis of this, the authors of that review suggest that in healthy patients checking liver function tests and lipids two months after the peak dose (they used 0.5 to 1 mg/kg/day) is attained is sufficient with no further testing required if the results are normal. (92) Ongoing monitoring may be required for patients with known lipid abnormalities, those with risk factors for hyperlipidemia or liver abnormalities, including those who have commenced new medications or supplements, or patients with abdominal pain. Women of childbearing potential should have regular pregnancy tests while on isotretinoin.
OTHER ADVERSE REPORTS
With a medication that has been used in millions of patients over almost 40 years, it is not surprising that there have been many case reports of treatment-emergent adverse effects. Most of these have not been substantiated with larger cohort studies.
CONCLUSION
With almost 40 years of experience using isotretinoin in the management of acne vulgaris, our understanding of its mechanism of action, and the optimal way in which it should be prescribed continues to evolve. (99) Isotretinoin has been associated with numerous adverse effects, although the risk of many of these can be substantially reduced by using lower dosages. Recent meta-analyses examining the association between isotretinoin and depression and inflammatory bowel disease have been reassuring.
