Standardized laboratory monitoring with

use of isotretinoin in acne

Timothy J. Hansen, MD,a SaraMarian Lucking, MD,c Jeffrey J. Miller, MD, MBA,a
Joslyn S. Kirby, MD, MPH,a Diane M. Thiboutot, MD,a and Andrea L. Zaenglein, MDa,b
Hershey, Pennsylvania

Background: Laboratory monitoring for adverse effects to isotretinoin occurs with variability.
Standardization of laboratory monitoring practices represents an opportunity to improve quality of care.

Objective: We sought to develop an evidence-based approach to laboratory monitoring of patients

receiving isotretinoin therapy for acne.

Methods: We reviewed laboratory data from 515 patients with acne undergoing 574 courses of isotretinoin
from March 2003 to July 2011. Frequency, timing, and severity of abnormalities were determined.

Results: Clinically insignificant leukopenia or thrombocytopenia occurred in 1.4% and 0.9% of patients,
respectively. Elevated liver transaminases were detected infrequently and not significantly increased
compared with baseline detection rates (1.9% vs 1.6% at baseline). Significant elevations occurred with
triglyceride (19.3%) and cholesterol (22.8%) levels. The most severe abnormalities were grade 2
(moderate). 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.

Limitations: This was a single-center experience examining variable isotretinoin laboratory monitoring
practices.

Conclusions: In healthy patients with normal baseline lipid panel and liver function test results, repeated
studies should be performed after 2 months of isotretinoin therapy. If findings are normal, no further testing
may be required. Routine complete blood cell count monitoring is not recommended. ( J Am Acad
Dermatol 2016;75:323-8.)

Key words: acne; hypercholesterolemia; hypertriglyceridemia; isotretinoin; laboratory monitoring;

leukopenia; thrombocytopenia; transaminitis.

T he US Food and Drug Administration (FDA)

approved isotretinoin for the treatment of
severe cystic acne in 1982.1 Most recent
labeling recommends monitoring lipid levels and
Abbreviations used:
ALT:
CBC:
FDA:
alanine aminotransferase
complete blood cell count
Food and Drug Administration
liver function at weekly or biweekly intervals until
the response to isotretinoin has been established,
which is defined as ‘‘usually [occurring] within escalation for their patients, with many studies
4 weeks.’’2 Prescribers of isotretinoin use varied reporting a monthly interval of monitoring rather
protocols for laboratory monitoring and dose than weekly or biweekly, throughout the course of

From the Departments of Dermatologya and Pediatrics,b Pennsyl-
vania State/Hershey Medical Center, and Pennsylvania State
College of Medicine.c
Funding sources: None.
Disclosure: Dr Zaenglein is a consultant and researcher for
Ranbaxy. Drs Hansen, Lucking, Miller, Kirby, and Thiboutot
have no conflicts of interest to declare.
Presented at the American Academy of Dermatology Residents and
Fellows Symposium, March 3, 2013, Miami, Florida.
Accepted for publication March 21, 2016.
Reprint requests: Andrea L. Zaenglein, MD, Penn State Department
of Dermatology, HU14, 500 University Drive, Hershey, PA 17033.
E-mail: azaenglein@hmc.psu.edu.
Published online May 14, 2016.
0190-9622/$36.00
Ó 2016 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2016.03.019

323
324 Hansen et al J AM ACAD DERMATOL
AUGUST 2016

treatment.3-5 Case reports indicating possible throm- with normal baseline values who developed abnor-
bocytopenia and leukopenia have prompted malities during therapy. Descriptive statistics were
providers to also monitor complete blood cell counts tabulated. The data were summarized by propor-
(CBC).6,7 There is little consensus and no standard- tions and percentages or mean, 95% confidence
ized comprehensive clinical practice guidelines intervals, and SD. Both P values less than .05 and
regarding appropriate frequency and interval of 95% confidence intervals that did not overlap with 1
laboratory testing. Development of a standardized were considered statistically significant. Laboratory
approach to laboratory values were further evalu-
monitoring of isotretinoin ated using paired compari-
CAPSULE SUMMARY
would benefit patients, sons (McNemar test) for
providers, and the health sys- d The optimal timing of laboratory tests for statistical significance. No
tem by eliminating unneces- patients on isotretinoin treatment for power or sample size calcu-
sary testing and reducing acne is uncertain. lations were performed
overall cost, while ensuring because the sample is a con-
safe administration of the
d In this series, although abnormalities in venience sample of a defined
medication. The aim of this serum lipids in patients receiving population. Analyses were
study was to develop an isotretinoin were not infrequent, they performed with software
evidence-based approach were mild to moderate, and were (SAS, Version 9.3, SAS
for laboratory monitoring of generally noted around the second Institute, Cary, NC).
isotretinoin therapy for acne. month of treatment.
d For healthy patients on isotretinoin, we RESULTS
METHODS recommend that a lipid panel and liver The iPLEDGE database
The study cohort consisted function test be performed at baseline revealed 1008 patients
of patients treated from May and at month 2, when peak dosing is registered to our institution;
2003 through July 2011 at the achieved. Further testing should be 515 patients receiving 574
Department of Dermatology, considered if a significant abnormal courses of isotretinoin were
Pennsylvania State/Hershey value is noted. identified to have recorded
Medical Center. This study dosage and laboratory data
was approved by our institu- (Table II).
tional review board. Patients were eligible if they Fig 1 illustrates the percentage of patients with
received at least 1 course of isotretinoin. Patients were detected abnormalities for each laboratory test at any
excluded if isotretinoin was used for a condition other time during treatment. Common Terminology
than acne vulgaris. Patients were identified using the Criteria for Adverse Events v3.0 grades are noted in
iPLEDGE database followed by chart review. Patient Table III. No values above grade 2 were detected.
demographic data, cumulative isotretinoin dose, num- Leukopenia was detected during 14 (2.4%) patient
ber of courses, and characteristics of laboratory testing courses. The lowest white blood cell count value was
during treatment were recorded. Laboratory results for 2200/L, found at baseline and resolved to normal
the following tests were recorded: serum triglyceride range despite continued therapy. Thrombocytopenia
level, total cholesterol, alanine aminotransferase was detected during 9 (1.6%) patient courses and
(ALT), white blood cell count, and platelet count. proved clinically insignificant.
Abnormalities were graded according to the National ALT elevations were found during 19 (3.3%)
Cancer Institute Common Terminology Criteria for courses of isotretinoin. The most severe transaminitis
Adverse Events v3.0 grading system8 (Table I). occurred 2 months into treatment in a male patient
Because white blood cell count and platelet abnor- who had just began a new vitamin supplement, with
malities do not fall into this grading system, values ALT values peaking at 264 U/dL. The vitamin
above or below the reference ranges were considered supplement was discontinued, dose of isotretinoin
abnormal. Aspartate aminotransferase levels were not was halved, and ALT values normalized within a
included, as the standard liver profile at our institution month. A possible spurious grade-2 transaminitis
includes ALT only, as this transaminase shows better was detected in a male patient after 1 month of
organ specificity. therapy, with 4-fold elevation of ALT. Repeated
The rate of laboratory abnormalities was calcu- measurement showed normal values with no dosage
lated as the proportion of patient courses with alteration.
abnormalities at baseline and at any time during Lipid abnormalities occurred most frequently;
therapy. The interval to detection of laboratory hypercholesterolemia occurred in 148 (25.8%)
abnormalities was calculated in months for patients courses and hypertriglyceridemia occurred in 129
J AM ACAD DERMATOL Hansen et al 325
VOLUME 75, NUMBER 2

Table I. Grading system used to evaluate laboratory abnormalities (based on the National Cancer Institute
Common Terminology Criteria for Adverse Events v3.0)
Triglycerides, mg/dL Cholesterol, mg/dL ALT, IU/L WBC, 3103/mL Platelets, 3103/mL
Normal \200 \200 \69 4-12.5 150-350
Grade 1 200-500 200-300 69-173 3-4 75-150
Grade 2 500-1000 300-400 173-346 2-3 50-75
Grade 3 1000-2000 400-500 346-1381 1-2 25-50
Grade 4 [2000 [500 [1381 \1 \25

ALT, Alanine aminotransferase; WBC, white blood cell count.

Table II. Demographics and number of isotretinoin
courses
Male 313
Female 202
Mean age, y (range) 19.0 (10.7-48.6)
Courses of isotretinoin 574
First 515
Second 58
Third 1
Mean total dose, mg (range) 8230 (800-20,400)
(22.5%) courses. Baseline abnormalities were
frequent; baseline hypercholesterolemia comprised
40% and baseline hypertriglyceridemia comprised
31% of their respective abnormalities. The maximum
cholesterol level in any patient was 325 mg/dL
(grade 2), with an average maximum value (for
courses with detected abnormalities) of 226 mg/dL.
Triglyceride elevations reached as high as 972 mg/dL
(grade 3), specifically in a 46-year-old male patient
with concurrent acne and hidradenitis suppurativa
after 9 months of therapy. A grade-2 triglyceride level
was observed in 1 patient at baseline and 7 patients
over the course of treatment. Six (85.7%) of these
patients had grade-1 elevations at baseline. The
remaining patient had a normal baseline triglyceride
value that increased to grade-2 levels when his dose
was increased from 40 to 120 mg per day. Of
those with hypertriglyceridemia, the average
maximum triglyceride value per patient course was
301 mg/dL (range 200-972 mg/dL). Importantly of
note, fasting prior to testing was not required by all
providers. No patients with mild to moderate
elevations discontinued isotretinoin therapy.
The time from treatment initiation to detection of
laboratory abnormalities was calculated: 9.5% of
abnormalities were detected at 30 days (95%
confidence interval, 5.8%-14.4%) and 67.7%
were detected by 60 days (95% confidence interval,
60.7%-74.1%). Specifically, the mean time to
detection of abnormalities for each test was:
leukopenia at 69.7 days, thrombocytopenia at
45.4 days, ALT elevation at 61.9 days, hypercholes-
terolemia at 50.2 days, and hypertriglyceridemia at
56.3 days.
DISCUSSION
Since the introduction of isotretinoin treatment for
acne in the 1980s, a variety of laboratory monitoring
intervals have been used in clinical practice. A recent
meta-analysis of available data from 1960 through
2013 has definitively concluded that routine monthly
laboratory monitoring of patients on isotretinoin is
unnecessary.9
Routine monitoring of a CBC is unwarranted,10 as
abnormal values tend to resolve or remain stable
despite continued therapy.9 Postinfectious and
benign ethnic neutropenia are common causes in
otherwise healthy adolescents. Reports of severe
leukopenia6,11-13 or thrombocytopenia7,14-16 occur-
ring in patients on isotretinoin are very rare and
likely idiosyncratic reactions, not substantiated by
multiple large studies reviewing incidence of
laboratory abnormalities.5,9,10,17
Regarding liver abnormalities, hepatitis presumed
to be secondary to isotretinoin therapy has been
reported.18 Mild to moderate ALT levels can be
detected in up to 8.9% of asymptomatic individuals.
Fatty liver, as a result of obesity, and alcohol intake
can cause elevated levels. It is notable that several
decades of isotretinoin use has not produced reports
of irreversible hepatic sequelae.19 Nonsteroidal
anti-inflammatory agents and antibiotics account
for the majority of drug-induced liver injuries and
routine laboratory monitoring is rarely recommen-
ded with their use.
Lipid abnormalities are by far the most common
laboratory abnormality seen with isotretinoin
therapy. Mild to moderate triglyceride elevations
were seen in 23.5% of patients in this study. Many
of our providers do not require patients taking
isotretinoin to fast before laboratory testing, so
normal postprandial elevations in triglyceride levels
likely account for many of these mild elevations.
Drug-induced pancreatitis caused by isotretinoin is
326 Hansen et al J AM ACAD DERMATOL
AUGUST 2016

Fig 1. Percentage of evaluated courses with detected abnormalities for each laboratory
measure: white blood cell count (WBC ), platelet count (Plt), alanine aminotransferase (ALT ),
triglycerides (TG), and cholesterol (Chol ). *P value \.0001. NS, Not significant.

Table III. Grading of detected abnormalities according to the National Cancer Institute Common Terminology
Criteria for Adverse Events v3.0 guidelines
CTCAE WBC, 3103/mL Platelets, 3103/mL ALT, IU/L Total cholesterol, mg/dL Triglycerides, mg/dL
Grade 1 $3 and \4 $75 and \150 $69 and \173 $200 and \300 $200 and \500
n = 10 (1.9%) n = 10 (1.9%) n = 17 (3.3%) n = 147 (28.5%) n = 121 (23.5%)
Grade 2 $2 and \3 $50 and \75 $173 and \346 $300 and \400 $500 and \1000
n = 3 (0.6%) n=0 n = 2 (0.4%) n = 1 (0.2%) n = 8 (1.6%)

ALT, Alanine aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events v3.0; WBC, white blood cell count.

exceedingly rare. The few reported cases in the
literature illustrate that pancreatitis is not likely
caused by hypertriglyceridemia because elevations
were mild to moderate.16,20 Reports of acute pancre-
atitis secondary to severely elevated triglycerides
were primarily in women.16,21-23 The onset of
pancreatitis was highly variable from 15 days to
6 months after initiation of isotretinoin. Acute
pancreatitis was detected with the onset of acute
abdominal pain, not by routine laboratory testing.
Therefore, monthly screening for pancreatitis risk
detection, in our opinion, is not warranted.
However, patients with significantly abnormal
triglyceride levels trending upward should be
regularly monitored, and dose adjustments made
before pancreatitis occurs.
One area unexplored by larger studies is the
timing of when irregularities are detected during
treatment. Our findings suggest that most laboratory
abnormalities develop after the first month of
therapy. Only 9.5% of abnormalities were detected
at 30 days from baseline testing. This is explained by
dose escalation practices, wherein patients receive
0.5 mg/kg for the first month then are increased to
1.0 mg/kg. In the current study, 64% of patients
received an increased dose during the second month
of treatment. Given that clinically significant morbid-
ities very rarely occur as a result of isotretinoin-
associated hyperlipidemia or transaminitis, prescribers
may defer follow-up testing after baseline until the
maximum daily dose is achieved, unless individual
circumstances dictate otherwise, such as abnormal
baseline study results, strong family history of early
lipid abnormalities, development of abdominal
pain, or changes in medications or addition of
supplements.17
In this era of increasing medical costs, it is useful
to consider cost savings of eliminating a CBC from
isotretinoin laboratory monitoring. Our institution
charges $45 for a CBC ($73 if a differential is
J AM ACAD DERMATOL
VOLUME 75, NUMBER 2
included). Assuming a minimum of baseline mea-
surement plus 1 additional test while on therapy,
removing the CBC from standard isotretinoin
monitoring would save $90 per patient. Using FDA
data, 196,384 patients were enrolled in iPLEDGE
from March 2010 to February 2011. If we extrapolate
the savings, that would be more than $17 million per
year by eliminating the CBC alone.
Furthermore, decreasing monitoring frequency
from monthly testing to 1 baseline and 1 follow-up
measurement during therapy would add significant
additional cost savings. At our institution, the cost of
a lipid panel is $141 and a liver function panel is $82.
If performed monthly, the cost for a 20-week course
would be $1115; performed at baseline and
2 months, the cost would be $446. The total savings
per patient would be $669. Extrapolating the savings
to the 196,384 iPLEDGE patients per year, the overall
savings would be $131,380,896 per year. Indirect
costs of testing should also be considered, including
patient discomfort with frequent blood draws,
additional workup of spurious abnormalities, and
additional time away from work or school to obtain
testing.
For our department to decrease variability and
improve outcome reporting in isotretinoin labora-
tory monitoring, we implemented the following
standardized protocol:
1. Documentation of family and personal history of
lipid, liver, or blood count abnormalities.
2. Elimination of CBC monitoring, unless known
abnormality or risk factor is identified.
3. Baseline liver function and lipid panel.
4. If baseline study results are normal, repeated
liver function and lipid panel in 2 months (after
peak dose attained). If repeated study findings in
2 months are normal, then no more laboratory
monitoring is required.
5. If baseline study findings, or study findings at
month 2, are abnormal, or if there is a known lipid
abnormality, then more frequent monitoring is
required. If new medications or supplements are
added during isotretinoin therapy, repeated
laboratory testing should be considered.
6. All female patients of childbearing potential
receive monthly urine pregnancy tests according
to iPLEDGE guidelines.
Limitations
This was a single-center study and the results
may not be generalizable to other populations.
The historical laboratory data was extracted from
our clinical experience, not a controlled trial.
Hansen et al 327
Additional studies would be needed to assess
accurately the true cost-effectiveness of management
with reduced monitoring compared with more
frequent monitoring.
Conclusion
Given the low prevalence of clinically significant
liver and lipid abnormalities, practitioners should
examine their laboratory monitoring practices and
consider adjustments to improve the patient
experience and reduce the per capita cost of health
care, while maintaining patient safety. Another
important principle is reducing variability in our
health care delivery, which, in the case of frequency
of isotretinoin laboratory monitoring, aims to
balance patient care and reduction of unnecessary
testing.
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