Oral isotretinoin therapy for acne vulgaris - UpToDate 29/11/24, 10:28

Oral isotretinoin therapy for acne vulgaris

author: Cindy Owen, MD
section editors: Robert P Dellavalle, MD, PhD, MSPH, Moise L Levy, MD, Jeffrey P Callen, MD, FACP, MAAD, MACR
deputy editor: Abena O Ofori, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2024.

This topic last updated: May 13, 2024.

INTRODUCTION

Oral isotretinoin (13-cis retinoic acid) is a retinoid most often used for the treatment of
acne vulgaris, particularly severe or recalcitrant disease. Isotretinoin is teratogenic and
associated with a number of other adverse effects that can limit its use. Thus, it must be
used with caution and should only be prescribed by clinicians who are completely
familiar with the medication.

The clinical use of oral isotretinoin for acne vulgaris will be reviewed here. Discussions of
the clinical manifestations, diagnosis, and approach to treatment for acne vulgaris as
well as detailed drug information on isotretinoin are provided separately.

● (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".)

● (See "Acne vulgaris: Overview of management".)

● (See "Acne vulgaris: Management of moderate to severe acne in adolescents and

adults".)

● (See "Postadolescent acne in women".)

● (See "Acne in infants, young children, and preadolescents".)

● (See "Management of acne scars".)

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● (See "Isotretinoin: Drug information".)

● (See "Isotretinoin: Pediatric drug information".)

MECHANISM OF ACTION

Oral isotretinoin counteracts the pathogenic factors that contribute to the development
of acne vulgaris [1,2]. Therapy leads to shrinkage of sebaceous glands and a marked
attenuation of sebum secretion. The decrease in sebum results in the inhibition of the
sebum-dependent bacterium Cutibacterium (formerly Propionibacterium) acnes, which is
a key promoter of inflammation in acne vulgaris. Direct anti-inflammatory effects of oral
isotretinoin may occur through normalization of the toll-like receptor 2-mediated innate
immune response to C. acnes [3]. Oral isotretinoin also inhibits comedogenesis by
fostering keratinocyte differentiation and by normalizing desquamation. (See
"Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on
'Pathogenesis'.)

ADVERSE EFFECTS

Isotretinoin is a teratogenic drug that is associated with a broad range of

mucocutaneous and extracutaneous adverse effects. Side effects of isotretinoin are
usually manageable, permitting continuation of therapy. In a 2018 systematic review of
11 randomized trials, severe adverse events requiring withdrawal from trials occurred in
only 12 of 372 patients taking isotretinoin (3 percent). The severe adverse events
included Stevens-Johnson syndrome, cheilitis, xerosis, acne flare, photophobia, elevated
liver enzymes, decreased appetite, headaches, and depressed mood [4].

The management of common side effects is reviewed below. (See 'Management of

complications' below.)

Mucocutaneous — The common mucocutaneous side effects of isotretinoin, including

cheilitis, dry skin and mucous membranes, epistaxis, desquamation, photosensitivity,
and pruritus, are predictable and dose dependent. In the systematic review,
dermatologic side effects represented nearly 65 percent of all reported side effects, with
cheilitis and xerosis as the most frequent [4].

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Isotretinoin is also associated with risk for ocular abnormalities (eg, dryness, irritation,
conjunctivitis) related to dysfunction of meibomian glands within the conjunctiva [4-6].
Cutaneous staphylococcal infections may also occur [7]. Paronychia, pyogenic
granulomas, temporary diffuse alopecia, and nail brittleness occasionally appear [8].

Transient worsening of acne may occur in the beginning of isotretinoin therapy. Rarely,
isotretinoin induces acne fulminans, a severe manifestation [9,10]. (See 'Severe acne'
below.)

Teratogenicity — Isotretinoin causes severe, life-threatening, congenital malformations

and spontaneous abortions [11]. Embryopathy associated with exposure in the first
trimester of pregnancy includes craniofacial, cardiac, thymic, and central nervous system
malformations [12]. Fetal abnormalities have not been attributed to the use of
isotretinoin in men [2]. (See "Congenital anomalies: Causes", section on 'Drug
exposure'.)

Among pregnant women exposed to isotretinoin, the risk of spontaneous abortion is

approximately 20 percent; among pregnancies that progress, approximately 20 to 30
percent of neonates have evidence of embryopathy [13]. Although data are limited,
children who appear physically normal may still have a higher rate of intellectual
disability and impaired neuropsychologic function [13].

Psychiatric effects — The relationship between isotretinoin therapy and depression

and suicide is uncertain. Reviews, including a systematic review and meta-analysis, have
concluded that data on suicidal behavior and depression during treatment with
isotretinoin are inadequate to establish a causal relationship [14-18]. Given the
uncertainty, patients should be advised of a possible link and should be followed closely
for the development of depression or suicidal ideation. (See "Suicidal ideation and
behavior in adults" and "Suicidal ideation and behavior in children and adolescents:
Prevention and treatment".)

Some authors have proposed that psychologic distress over severe acne, rather than
isotretinoin, could be a contributing factor to occurrences of suicide or depression in
patients treated with the drug [19-21]. In a population-based cohort study, risk for major
depressive disorder was higher among patients with acne than in the general
population without acne [20]. The risk was unchanged after excluding patients who
received isotretinoin. (See "Pediatric unipolar depression: Epidemiology, clinical features,

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assessment, and diagnosis".)

A large, global, retrospective cohort study provides additional support for relative safety
of isotretinoin therapy in regard to some psychiatric outcomes [22]. The study used
electronic health record data to compare psychiatric outcomes from patients with acne
treated with isotretinoin (n = 75,708) and outcomes from patients with acne treated with
oral antibiotics who also had no documentation of isotretinoin therapy (n = 75,708).
Although there was an increase in risk for suicidal ideation among patients treated with
isotretinoin (hazard ratio [HR] 1.41, 95% CI 1.32-1.50), there was no increase in suicidal
attempts (HR 0.97, 95% CI 0.85-1.11) or major depressive disorder (HR 0.97, 95% CI 0.92-
1.03). Risk for depression, post-traumatic stress disorder, anxiety, bipolar disorder,
schizophrenia, and adjustment disorder were lower in patients treated with isotretinoin.

Inflammatory bowel disease — Although observational studies have found conflicting

results on the relationship between isotretinoin therapy and inflammatory bowel
disease (IBD), analysis of the available data suggests that isotretinoin therapy is not a
risk factor for IBD. A 2012 meta-analysis of three case-control studies and two additional
unpublished studies did not find a statistically significant relationship between
isotretinoin therapy and IBD (relative risk for IBD 0.94, 95% CI 0.65-1.36) [23]. Several
subsequent, large, cohort studies also suggest that isotretinoin therapy for acne does
not increase risk for IBD:

● A 12-year cohort study of 46,922 patients treated with isotretinoin, 184,824

patients treated with topical acne medication, and 1,526,946 untreated controls (all
between the ages of 12 and 29) did not find a significant association between
isotretinoin use and IBD on primary analysis (rate ratio 1.14, 95% CI 0.92-1.41) [24].
Although an association between isotretinoin and IBD was detected in a subgroup
of patients aged 12 to 19 years (rate ratio 1.39, 95% CI 1.03-1.87), a similar
association was detected between the use of topical acne medications and
ulcerative colitis (rate ratio 1.19, 95% CI 1.00-1.42), suggesting an association
between acne and IBD independent of treatment.

● A retrospective cohort study that used electronic health record data to compare
risk for IBD and irritable bowel syndrome in patients with acne treated with
isotretinoin (n = 77,005) with risk for these diseases in patients with acne treated
with oral antibiotics but not isotretinoin (n = 77,005) found similar lifetime risk for

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both Crohn disease (HR 1.05, 95% CI 0.89-1.24) and ulcerative colitis (HR 1.13, 95%
CI 0.95-1.34) between the two groups [25]. An increase in risk for ulcerative colitis
in the first six months after starting isotretinoin (HR 1.93, 95% CI 1.29-2.88)
resolved after this period and was associated with a low absolute risk difference (5
additional cases per 100,000 patients starting isotretinoin, 95% CI 2.5-7.7). Risk for
irritable bowel syndrome was lower for patients in the isotretinoin therapy group
than for patients in the oral antibiotics group.

● A retrospective cohort study performed with electronic health record data did not
find an association between oral isotretinoin therapy and risk for incident IBD
within one year [26]. The study compared the risk of incident IBD in four groups:
patients without acne (n = 353,381), patients with acne that was not treated with
systemic medication (n = 351,570), patients with acne treated with oral tetracycline
antibiotics (n = 144,986), and patients with acne treated with isotretinoin (n =
11,199). The risk of incident IBD within one year in patients treated with
isotretinoin did not differ from the risk in patients who did not receive systemic
therapy for their acne (odds ratio [OR] 1.29, 95% CI 0.64-2.59) or from patients who
were treated with oral antibiotics (OR 1.13, 95% CI 0.57-2.21). There was an
association between acne and risk for incident IBD (OR 1.42, 95% CI 1.23-1.65), but
the absolute risk remained small (0.04 percent, 95% CI 0.02-0.05 percent).

More studies are necessary to confirm whether isotretinoin therapy is a risk factor for
IBD. Until additional information is available, during discussions of the potential adverse
effects of isotretinoin with patients, it is reasonable to mention that although an
increased risk for IBD has been reported, a relationship between these disorders has not
been proven.

Hyperlipidemia — Isotretinoin has been associated with a number of other side effects
[4]. Hypertriglyceridemia is common, occurring in up to 45 percent of patients taking
isotretinoin, and total cholesterol and low-density lipoprotein elevations occur in
approximately 30 percent [27]. The development of hyperlipidemia during isotretinoin
therapy may be associated with increased risk for future development of hyperlipidemia
and metabolic syndrome [28]. (See 'Laboratory abnormalities' below.)

Other side effects — Other less common side effects include myalgias (particularly in
patients who engage in vigorous physical activity), visual changes (decreased night

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vision, corneal opacities), hepatotoxicity, bone marrow suppression, idiopathic

intracranial hypertension (pseudotumor cerebri), and bone changes (hyperostosis and,
rarely, premature epiphyseal closure) [29-34]. (See "Idiopathic intracranial hypertension
(pseudotumor cerebri): Epidemiology and pathogenesis", section on 'Medications'.)

For additional information on isotretinoin side effects, refer to the drug information
monograph included within UpToDate. (See "Isotretinoin: Drug information".)

CONTRAINDICATIONS AND PRECAUTIONS

Contraindications — Isotretinoin should not be given to pregnant individuals or

individuals who may become pregnant during or within one month after therapy.
Effective measures to prevent pregnancy are indicated for all individuals who could
become pregnant. Also, individuals with a history of hypersensitivity to isotretinoin or
any of its components should not receive isotretinoin. Isotretinoin capsules contain
soybean oil and should be used with caution in patients with severe soy allergy.

Drug interactions — Simultaneous treatment with medications that share the side
effect of idiopathic intracranial hypertension with isotretinoin, such as tetracyclines,
should be avoided. In addition, vitamin A supplementation may increase the adverse
effects of isotretinoin and should be avoided. A list of additional drug interactions is
provided separately. (See "Isotretinoin: Drug information".)

Specific interactions of isotretinoin with other medications may be determined using the
drug interactions program included in UpToDate. This program can also be accessed
from the UpToDate online search page or through the individual drug information topics
(also referred to as monographs) in the section on Drug interactions.

Children — The effectiveness and safety of isotretinoin has not been established in
children under 12 years of age.

Cutaneous procedures — Delaying cutaneous procedures until at least six months after
the completion of oral isotretinoin therapy has been historically practiced due to
concern for increased risk for abnormal scarring and delayed wound healing. However,
the available data suggest that this may not be necessary for some procedures.

Based upon a systematic review of the literature, a multispecialty panel of experts found

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insufficient evidence to recommend delaying manual dermabrasion, superficial chemical

peels, cutaneous surgery, laser hair removal, and fractional ablative and nonablative
laser procedures for patients with current or recent isotretinoin use [35]. The panel
recommended avoidance of mechanical dermabrasion and fully ablative laser
procedures in patients with recent isotretinoin use based upon limited evidence
suggesting increased risk for scarring. A task force from the American Society for
Dermatologic Surgery (ASDS) reached similar conclusions, with the exception of
specifying that while focal or superficial manual dermabrasion does not appear to be
associated with increased risk for scarring or delayed wound healing, full-face manual
dermabrasion is not recommended within six months after isotretinoin therapy [36].

Although prospective, controlled trials are necessary to confirm the level of risk
associated with cutaneous procedures in this population, the findings of the systematic
review and ASDS task force aid in counseling patients who may benefit from earlier
performance of procedures.

Alcohol use — Although alcohol consumption is not contraindicated during isotretinoin

therapy, we generally counsel patients to avoid excessive alcohol consumption. Similar
to isotretinoin, alcohol consumption may contribute to hypertriglyceridemia and hepatic
transaminase elevations. Moreover, excessive alcohol consumption may contribute to
impaired judgment and substandard use of pregnancy prevention methods and has
negative effects on overall health. (See "Overview of the risks and benefits of alcohol
consumption".)

INITIATION OF THERAPY

The initiation of isotretinoin therapy involves careful patient counseling and a

pretreatment clinical and laboratory assessment. The goal is to support successful
treatment and minimize risk for serious adverse effects. (See 'Patient counseling' below
and 'Baseline clinical and laboratory evaluation' below and 'Dosing and administration'
below and 'Use of other acne medications' below.)

Patient counseling — In addition to a discussion of the risks and benefits of treatment,

patients who will begin isotretinoin therapy should be thoroughly informed of the
monitoring and pregnancy prevention measures that are required for isotretinoin
therapy. Some countries have implemented mandatory risk management programs

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designed to prevent fetal exposure to isotretinoin, though positive effects of such

programs on reducing fetal exposure are unproven [37].

In the United States, prescribing and receipt of isotretinoin requires participation in the
iPLEDGE program. The iPLEDGE program provides detailed guidelines for pregnancy
prevention counseling, pregnancy screening, and contraceptive use during treatment.
(See 'iPLEDGE program' below.)

In general, prescribing clinicians should be able to discuss contraceptive options and

appropriate use with patients of childbearing potential. Alternatively, these patients
should be referred to a provider who can provide this service. All patients who are at risk
for pregnancy during treatment should begin highly effective contraceptive measures
one month prior to, during, and for one month after completion of isotretinoin therapy.
In addition, patients should avoid sharing isotretinoin pills with others and should avoid
blood donation during therapy and for one month after completion of therapy.

A discussion of the ocular side effects of isotretinoin may be particularly important for
patients in occupations with strict guidelines for vision, such as airline pilots. In the
United States, the Federal Aviation Administration has policies regarding isotretinoin
therapy.

iPLEDGE program — In 2006, the US Food and Drug Administration (FDA) established a
computer-based Risk Evaluation and Mitigation Strategy (REMS) risk management
program with the goal of eliminating fetal exposure to isotretinoin (iPLEDGE).
Prescribers, pharmacies dispensing isotretinoin, wholesalers distributing isotretinoin,
and all patients receiving isotretinoin are required to comply with the registry
requirements.

Access to the iPLEDGE program is available online. The iPLEDGE program requires the
following [38]:

● All patients who can get pregnant must select and commit to the use of two forms
of birth control for at least one month prior to starting isotretinoin therapy, during
therapy, and for one month after therapy. The forms of contraception that meet
these requirements are specified by the iPLEDGE program.

● All patients who can get pregnant must have two negative urine or blood

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pregnancy tests (with a sensitivity of at least 25 milli-international units/mL) before

receiving the initial prescription. The second pregnancy test must be conducted in
a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. For
each month of therapy and one month after completing therapy, patients must
return to their clinicians for evaluation, counseling, education, and a pregnancy
test conducted by a CLIA-certified laboratory.

● For patients who can get pregnant, prescribing clinicians must, on a monthly basis,
document in the iPLEDGE system the results of the pregnancy test as well as report
the two forms of birth control being used by the patient. The clinician must also
confirm that the patient has received counseling and education. For all other
patients, prescribers must document that the patient was counseled on the
iPLEDGE program requirements, which include knowledge of the fetal injury that
may result from the use of isotretinoin by individuals of childbearing potential.

● As part of this system, clinicians must certify expertise in the diagnosis and
treatment of acne and knowledge of the risk and severity of fetal injury with
isotretinoin.

Baseline clinical and laboratory evaluation — The pretreatment clinical and

laboratory evaluation serves to identify patients who are not candidates for isotretinoin
therapy (eg, pregnant individuals) and patients who may require closer monitoring
during therapy. Examples of patients for whom additional counseling or monitoring may
be helpful include patients with [2]:

● Prior contraceptive failure

● History of uncontrolled depression or suicidal ideation
● Hyperlipidemia or family history of early-onset hyperlipidemia
● Personal or family history of inflammatory bowel disease
● Eye or vision problems (particularly dry eyes and contact lens use)
● Heavy alcohol use
● Extreme physical activity

Current medications should be reviewed to identify potential drug interactions. In

particular, treatment with other drugs that may cause pseudotumor cerebri, such as
tetracyclines, should be avoided. (See 'Drug interactions' above.)

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Baseline laboratory testing is indicated to identify pregnant patients and patients with
liver or lipid abnormalities. In the past, obtaining full liver function, lipid, and complete
blood count panels in addition to a urine or serum pregnancy test for individuals who
could become pregnant was common. However, the need for this extent of testing in
healthy patients has been questioned [39]. (See 'Laboratory monitoring' below.)

Our typical pretreatment tests include:

● Alanine aminotransferase (ALT) and triglyceride levels within one month prior to
the start of therapy

● Urine or serum pregnancy test in individuals of childbearing potential (note that

two tests are required prior to the start of therapy for the iPLEDGE program) (see
'iPLEDGE program' above)

Dosing and administration — Absorption of isotretinoin is improved when taken with

food (especially high-fat meals); thus, administration during meals is recommended. A
formulation of isotretinoin that uses lipid encapsulation technology to enclose
isotretinoin demonstrates increased bioavailability in the fasting state [40]. This
formulation is dosed twice daily and can be given without regard to meals.

Severe acne — Severe acne is considered acne with many inflammatory nodules or
other severe features (eg, extensive involvement of one or more body regions with
comedonal or papulopustular acne) ( picture 1A-F). The treatment goal for these
patients is a cumulative dose of 120 to 150 mg/kg of isotretinoin to decrease the risk of
acne recurrence [33]. Most patients achieve this goal within 20 to 24 weeks.

Treatment is usually initiated at a dose of 0.5 mg/kg per day for the first month of
therapy to minimize risk for isotretinoin-induced acne flares and is subsequently
increased to 1 mg/kg per day. The total daily dose of isotretinoin is typically divided in
two doses taken with food; alternatively, isotretinoin can be taken once daily to increase
adherence to therapy.

Isotretinoin-induced acne flaring or acne fulminans may occur at the start of isotretinoin
therapy in patients with severe inflammatory acne (eg, acne conglobata, acne fulminans)
or deep comedonal acne. Starting doses lower than 0.5 mg/kg per day are suggested for
this population. In addition, systemic glucocorticoids may be given prior to the start of

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isotretinoin or concurrently for the first two to four weeks. (See "Acne vulgaris:
Management of moderate to severe acne in adolescents and adults", section on 'Acne
conglobata' and "Acne vulgaris: Management of moderate to severe acne in adolescents
and adults", section on 'Acne fulminans'.)

There is some evidence that high cumulative doses (eg, ≥220 mg/kg) of isotretinoin may
reduce the risk of relapse in patients with severe acne vulgaris [41,42]. Additional studies
are needed to confirm this finding as well as the safety of high-dose isotretinoin therapy.

Moderate acne — Moderate acne appropriate for isotretinoin therapy may be

considered less extensive acne that is treatment resistant, relapses rapidly after
cessation of oral antibiotic therapy, scars, or induces significant psychosocial distress (
picture 2) [33]. Patients with moderate acne are usually treated with a regimen
identical to that used for severe acne, achieving a cumulative dose of 120 to 150 mg/kg
over the course of 20 to 24 weeks.

However, a lower-dose regimen (at 0.25 to 0.4 mg/kg per day for the duration of
therapy) may be an alternative [33,43,44]. The advantage of this lower dose is reduced
risk for drug side effects [33].

A 24-week single-blind randomized trial in which 60 patients with moderate acne were
treated with one of three regimens of isotretinoin, 0.5 to 0.7 mg/kg per day (higher-dose
regimen), 0.25 to 0.4 mg/kg per day (lower-dose regimen), or 0.5 to 0.7 mg/kg daily for
one week every four weeks (intermittent regimen), supports efficacy of lower-dose
therapy [44]. All three treatment courses resulted in clinically significant improvement
and marked reductions in mean acne lesion counts. The lower-dose and higher-dose
regimens were similarly effective and had equivalent rates of relapse after one year;
however, more adverse effects were reported in the higher-dose group during
treatment. A lesser degree of improvement and a lower duration of effect were detected
in the patients who received intermittent therapy.

Use of other acne medications — Other acne medications are typically discontinued at
the start of isotretinoin therapy. Isotretinoin causes temporary xerosis, cutaneous
atrophy, and skin fragility, and topical acne medications may be poorly tolerated [2].
Isotretinoin should not be given with tetracyclines due to the risk of idiopathic
intracranial hypertension (pseudotumor cerebri) associated with both of these drugs.

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DURING THERAPY

Follow-up visits are typically held on a monthly basis to assess response and side effects,
address patient questions, and fulfill the counseling and monitoring requirements of the
iPLEDGE program.

Clinical assessment — Patient assessment should include a patient history and skin
examination to assess for response and adverse effects. We typically ask the patient
about the following:

● Perceived worsening/improvement of acne

● Dryness of skin or mucous membranes
● Nosebleeds
● Vision changes
● Headaches
● Abdominal pain
● Joint, muscle, or bone pain
● Bowel symptoms
● Mood changes, symptoms of depression, or suicidality

We examine involved skin as well as any other areas of concern for the patient. In our
experience, signs of improvement in acne often become evident after the first one to
two months of therapy, with progressive improvement over subsequent months.

Laboratory monitoring — Laboratory monitoring during isotretinoin therapy generally

consists of assessments for pregnancy, liver dysfunction, and dyslipidemia. Baseline and
post-treatment testing are reviewed separately. (See 'Baseline clinical and laboratory
evaluation' above and 'Follow-up' below.)

Test selection and frequency — Historically, monthly checking of full liver function
and lipid panels during isotretinoin treatment was a routine and well-accepted practice.
However, in otherwise healthy, asymptomatic, young individuals without a personal or
family history of diabetes or dyslipidemia, there are data that suggest it may be safe to
perform less extensive and less frequent testing. (See 'Evidence' below.)

Monitoring of complete blood count panels is not necessary in the absence of a known
abnormality or risk factor for leukopenia. There are differing opinions on the need for

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monitoring creatine kinase levels. In general, obtaining a creatine kinase level is not
indicated in the absence of severe muscular pain [2].

Our approach to laboratory monitoring during isotretinoin therapy is as follows [45]

(see 'Baseline clinical and laboratory evaluation' above):

● Monthly pregnancy tests in individuals who can become pregnant. (See 'iPLEDGE
program' above.)

● If baseline alanine aminotransferase (ALT) and triglyceride levels were normal,

these tests should be repeated after the peak isotretinoin dose is reached (we
typically obtain these tests one month after starting the peak dose, which is usually
after completion of a total of two months of isotretinoin therapy).

● If the results of testing after reaching the peak dose are normal and the dose of
isotretinoin is not increased, then further monitoring is not required. If the results
of testing are abnormal or if the patient has a known lipid abnormality, then
periodic monitoring should be continued.

● Development of new symptoms (eg, abdominal pain), the initiation of new

medications or supplements, or an increase in the dose of isotretinoin may warrant
retesting.

Evidence — Examples of studies suggesting that a more limited approach to laboratory

testing in healthy patients is reasonable include:

● The findings of a systematic review and meta-analysis of studies reporting

laboratory values during isotretinoin therapy for acne support less frequent
testing; although isotretinoin was associated with statistically significant changes
in the mean values of some laboratory tests (white blood cell count, hepatic panel,
lipid panel), the changes did not meet criteria for high risk, and the proportion of
patients with laboratory abnormalities was low [46].

● In a retrospective study of 903 patients treated with isotretinoin for acne vulgaris,
no clinically significant hematologic abnormalities were detected during treatment
[47]. Although patients experiencing elevation of triglyceride levels (n = 197), ALT (n
= 113), and aspartate aminotransferase (AST; n = 102) were common, all but seven
cases of triglyceride, ALT, or AST elevation were successfully managed with

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observation or lowering of the isotretinoin dose, and all elevations resolved after
completion of isotretinoin.

● A Delphi consensus study that involved the administration of four rounds of

anonymous surveys on isotretinoin laboratory monitoring to a group of 22
international acne experts provides additional support [39]. Tests evaluated
included the components of liver function, basal metabolic, lipid, and complete
blood count panels, as well as creatine kinase and C-reactive protein levels.
Consensus was defined by agreement among ≥70 percent of participants.

Interventions that met consensus criteria included obtaining ALT and triglyceride
levels within one month prior to initiation of isotretinoin and after reaching peak
dose. There was consensus that the following were not necessary: obtaining ALT or
triglyceride levels monthly or after completion of isotretinoin therapy; obtaining
complete blood count or basal metabolic panels at any point during treatment; and
checking gamma-glutamyl transferase, bilirubin, albumin, total protein, low-density
lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or C-
reactive protein levels at any point during treatment. There was no consensus on
practices for checking AST, alkaline phosphatase, creatine kinase, and total
cholesterol levels.

Management of complications — Most of the adverse effects associated with

isotretinoin can be managed without discontinuing the drug.

Exacerbation of acne — Transient worsening of acne may occur during the first month
of treatment, particularly in patients with severe disease (see 'Severe acne' above).
Significant flares may require adjustments to therapeutic approach. For mild flares, no
adjustment in treatment is needed.

The approach to isotretinoin-induced acne fulminans is reviewed separately ( picture 3

and algorithm 1). (See "Acne vulgaris: Management of moderate to severe acne in
adolescents and adults", section on 'Acne fulminans'.)

Mucocutaneous — Dry skin and mucous membranes are common during treatment.
In particular, cheilitis can be significant and often requires the liberal use of topical
emollients, such as petroleum jelly or other lip moisturizers.

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To minimize dry skin, patients are advised to wash with a gentle, nondetergent cleanser
followed by the application of emollients. A noncomedogenic emollient is recommended
for acne-prone skin areas. (See "Treatment of atopic dermatitis (eczema)", section on
'Emollients and moisturizers'.)

For patients with nasal crusting or dryness or with epistaxis, saline nasal spray and
application of petroleum jelly to the nostrils can be helpful. Artificial tears may help to
reduce symptoms of eye dryness. Patients who wear contact lenses may not be able to
tolerate them during treatment and may need to discontinue their use.

Sun-protective measures are indicated to minimize the effects of isotretinoin-induced

photosensitivity. Patients should use a facial moisturizer with a sun protection factor
(SPF) of at least 30 daily, and sun-protective clothing should be worn during sun
exposure. Sunscreen should be applied to exposed skin areas prior to sun exposure and
reapplied every two to three hours. (See "Selection of sunscreen and sun-protective
measures".)

Myalgias — Although checking of creatine kinase (CK) levels is not indicated in the
absence of severe muscle pain, CK levels are elevated in approximately 15 to 50 percent
of patients with isotretinoin-induced myalgias [2]. Mild to moderate pain usually can be
managed with anti-inflammatory drugs. Isotretinoin should be discontinued if pain
becomes severe or cannot be improved with anti-inflammatory drugs [2].

Laboratory abnormalities — Hypertriglyceridemia, hepatic transaminase elevations,

and CK elevations are common laboratory abnormalities during isotretinoin treatment:

● Hypertriglyceridemia – Minor or moderate elevations in triglyceride levels (300 to

500 mg/dL) do not necessitate alteration of the isotretinoin dose and can be
managed with lifestyle modification [48]. (See "Hypertriglyceridemia in adults:
Management", section on 'Moderate hypertriglyceridemia'.)

Triglyceride levels between 500 and 800 mg/dL require additional intervention,
such as reduction of the dose of isotretinoin and/or the addition of a lipid-lowering
agent [48]. (See "Hypertriglyceridemia in adults: Management", section on
'Treatment goals'.)

Severe hypertriglyceridemia (eg, above 800 mg/dL) may warrant cessation of

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isotretinoin therapy because of the risk of acute pancreatitis [48,49]. However,

pancreatitis secondary to isotretinoin is rare [50].

Although hypertriglyceridemia usually resolves with cessation of isotretinoin,

patients may need ongoing monitoring since one report suggests that they may be
at increased risk for future hyperlipidemia and metabolic syndrome [28]. In a cross-
sectional study, 102 patients in whom the serum triglyceride concentration
increased at least 89 mg/dL (1 mmol/L) during isotretinoin therapy (hyper-
responders) were compared with 100 patients in whom the serum triglyceride
concentration changed ≤9 mg/dL (0.1 mmol/L, nonresponders). Four years after
completion of isotretinoin therapy, hyper-responders were significantly more likely
to have hypertriglyceridemia (odds ratio [OR] 4.8, 95% CI 1.6-13.8),
hypercholesterolemia (OR 9.1, 95% CI 1.9-43), truncal obesity (OR 11.0, 95% CI 2.0-
59), and hyperinsulinemia (OR 3.0, 95% CI 1.6-5.7).

● Hepatic transaminase elevations – Mild, transient elevations in hepatic

transaminases occur early in the course of therapy in approximately 15 to 20
percent of patients; levels typically normalize within a few weeks [2].
Discontinuation of isotretinoin is recommended if hepatic transaminase levels
reach more than three times greater than normal values [2,51].

Pregnancy — Despite efforts to minimize risk for pregnancy during isotretinoin

therapy, such as mandatory participation in the iPLEDGE program in the United
States, pregnancies still occur [52]. If pregnancy occurs during treatment, isotretinoin
should be stopped immediately. The pregnant patient should be referred to an
obstetrician-gynecologist with experience in reproductive toxicity for management and
counseling [53]. In the United States, the iPLEDGE program requires reporting of
pregnancies that occur during therapy.

Other — The management of other extracutaneous adverse effects of isotretinoin (eg,

psychiatric effects, severe eye symptoms), may warrant consultation with appropriate
specialists to determine the best course of action for individual patients. Patients with
signs and symptoms suggestive of pseudotumor cerebri (eg, headache with new-onset
vision changes) require specialist evaluation and should discontinue use of isotretinoin.
(See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and
diagnosis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Prognosis

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and treatment".)

STOPPING THERAPY

In patients treated for severe acne, isotretinoin is usually discontinued after

achievement of the goal cumulative dose of 120 to 150 mg/kg and acne clearance. The
drug can be stopped abruptly; tapering is not necessary.

AFTER THERAPY

Outcomes — Oral isotretinoin is the only acne medication that can permanently alter
the natural course of the disorder. The majority of patients experience long-term
improvement in acne severity after one course of treatment [54]. In addition, continued
improvement may occur for several months after cessation of therapy; thus, at least five
months should elapse before considering retreatment with isotretinoin.

Response rates after a second course of isotretinoin are similar to those following the
initial course of treatment [51].

Reported relapse rates for patients treated with 120 to 150 mg/kg of isotretinoin range
between 20 and 60 percent [41]. In one study of 88 patients treated with isotretinoin for
severe or refractory acne and followed for up to 10 years, 82 percent of patients who
received cumulative doses less than 120 mg/kg relapsed (defined as deterioration in
acne sufficient to merit systemic antibiotic or isotretinoin therapy) compared with only
20 percent of patients given greater than 120 mg/kg [54]. Most relapses (78 percent)
occurred within the first 18 months after treatment. Patients with truncal acne relapsed
more frequently than patients with predominantly facial acne (40 versus 20 percent).

In addition to cumulative dose less than 120 to 150 mg/kg in patients with severe acne
and presence of truncal acne, additional risk factors for relapse include male sex, young
age at time of isotretinoin initiation (<16 years of age), postadolescent females with
acne, females with polycystic ovary syndrome, and females not receiving antiandrogen
therapy [55,56].

Patients who receive isotretinoin as young teenagers (under age 16) may also have an
increased risk for relapse [57].

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Follow-up — Individuals of childbearing potential require a final pregnancy test one

month after completion of isotretinoin. We counsel patients to return for re-evaluation
if acne recurs. Patients with scarring may benefit from referral to a clinician with
expertise in the treatment of acne scars. (See "Management of acne scars".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Acne
vulgaris".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to
6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)

● Basics topics (see "Patient education: Acne (The Basics)")

● Beyond the Basics topics (see "Patient education: Acne (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Mechanism of action – Isotretinoin is a treatment for acne vulgaris that is thought

to improve acne through reducing sebum production, inhibiting the growth of

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Cutibacterium (formerly Propionibacterium) acnes, inhibiting comedogenesis, and

altering the inflammatory response. (See 'Mechanism of action' above.)

● Adverse effects – Isotretinoin has multiple side effects, including teratogenicity,

mucocutaneous disorders, myalgias, visual changes, idiopathic intracranial
hypertension, hepatotoxicity, and hyperlipidemia. (See 'Adverse effects' above.)

Isotretinoin is teratogenic and should not be administered in pregnancy. In the

United States, all prescribing clinicians and patients are required to participate in
the iPLEDGE program, an online registry initiated by the US Food and Drug
Administration (FDA) in an attempt to minimize the risk of fetal exposure to
isotretinoin. (See 'Teratogenicity' above and 'Patient counseling' above and
'iPLEDGE program' above.)

● Dosing and administration:

• General approach – For the treatment of severe acne, isotretinoin is typically

started at a low dose (0.5 mg/kg per day) during the first month of therapy and
then increased to 1 mg/kg per day. A total dose of 120 to 150 mg/kg of
isotretinoin is given over the course of treatment. The duration of treatment is
often between 20 and 24 weeks or until acne is clear. (See 'Dosing and
administration' above.)

Other acne medications are typically discontinued during isotretinoin therapy.

In particular, the use of isotretinoin with tetracyclines should be avoided due to
the risk of idiopathic intracranial hypertension (pseudotumor cerebri). (See
'Drug interactions' above and 'Use of other acne medications' above.)

• Acne conglobata and acne fulminans – Patients with severe inflammatory

acne (eg, acne conglobata, acne fulminans) may require a lower initial dose
and/or concomitant treatment with systemic glucocorticoids starting before or
at the initiation of oral isotretinoin therapy. (See 'Severe acne' above and "Acne
vulgaris: Management of moderate to severe acne in adolescents and adults",
section on 'Acne conglobata' and "Acne vulgaris: Management of moderate to
severe acne in adolescents and adults", section on 'Acne fulminans'.)

● Outcomes – Most patients improve after isotretinoin therapy, although the

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majority of patients will continue to require the use of other acne therapies.
Continued improvement may occur for several months after isotretinoin therapy;
therefore, subsequent courses of isotretinoin should not be initiated until at least
five months after completion of the previous treatment period. (See 'Outcomes'
above.)

Use of UpToDate is subject to the Terms of Use.

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