**Appendix I.**

**[Overview of Psychiatric Adverse Event Association with
Isotretinoin]{.underline}**

An understanding of causality in drug-associated adverse reactions is
important for maximizing safe and effective use. Causal linkage between
isotretinoin treatment and psychiatric events cannot be established from
the observations in post-marketing reports due to under-reporting, the
high background incidence of psychiatric illness in the population, and
the incomplete nature of spontaneous reports. However, the observations
available in the spontaneous reports and in the published literature
provide signals for consideration in determining what measures should be
taken in response to the reported events.

According to the sponsor, the number of domestic and foreign reports of
*serious* adverse events in the post-marketing adverse event database
for Accutane® as of April 30, 2000 was 5,665. Of the 28 organ system
categories, the one with the largest percentage of *serious* reports is
psychiatric (18.8%). The most recent Periodic Adverse Drug Event Report
for Accutane® includes, for a *12-month period*, over 750 *new*
psychiatric adverse event reports (foreign and domestic), including 200
coded as serious, 9 suicide attempts and 6 completed suicides.

The true number of cases is, of course, unknown since under-reporting of
adverse events is significant. Under-reporting is exacerbated when the
event has a high background rate and the drug has been marketed for many
years. For events such as depression, reporting is probably further
hampered by failure to recognize the diagnosis in many affected
patients. On the other hand, spontaneous reports are entered into
databases even if they contain no data suggesting a contribution of the
drug to the reported adverse event.

The FDA performed an analysis of suicides and *hospitalized* cases of
depression, suicidal ideation, and suicide attempts in U.S. patients on
isotretinoin. The analysis included reports that had been entered into
the FDA Adverse Event Reporting System (AERS) database from marketing to
May 2000[^1].

There were 24 persons reported who committed suicide during, and 13
persons who committed suicide after, isotretinoin use. There were 85
persons reported who were hospitalized for depression, suicidal
ideation, and/or suicide attempt during or shortly after isotretinoin
use, and 25 persons reported hospitalized for these conditions after
stopping isotretinoin. In total, there were 147 cases reported of
suicide and hospitalized depression. Among these, 38% had a previous
psychiatric history, 33% had none, and information was unknown for 29%.

Of the 37 individuals who committed suicide, 84% were male (31 of 37).
The median age was 17 years. The median time from starting use of
isotretinoin to suicide was about three months. Of the individuals who
were hospitalized for depression, suicidal ideation and uncompleted
suicide attempts, 56% were female. The median time from beginning use of
isotretinoin to hospitalization was about one month, and some
experienced persistent depression after isotretinoin was stopped. One
person with unspecified previous history developed a psychotic
depression and had a positive dechallenge with isotretinoin
discontinuation, followed by a positive rechallenge when isotretinoin
was restarted.

The number of *reported* suicide cases in the isotretinoin database for
U.S. patients was about one-ninth the number of suicides predicted based
on the 1998 U.S. age-specific suicide rate in 15-19 year olds. Because
the extent of under-reporting is unknown and the usage data is an
estimate it is not possible to say whether the total number of suicides
in U.S. Accutane users exceeds the predicted number.

Reports that best inform adverse event assessment have substantive
content and few or no confounders. Especially useful are such reports
that document resolution of symptoms when the suspect drug is stopped,
and recurrence when it is resumed (positive dechallenge and
rechallenge). According to a consultant's report submitted by the
sponsor, a majority of 344 mood disorder cases with substantive content
had off-set of psychiatric symptoms within 30 days of stopping
isotretinoin (foreign cases were included in this analysis). Most of
those cases resolved within 15 days. Of the 25 cases that had *both*
on-set and off-set within 15 days, 23 had resolution reported within 7
days. Of those 23 cases, off-set was reported to occur within 4 days for
17 cases

This finding is consistent with the agency's analysis of 28 cases of
depression, mood disorder, and self-injurious behavior with positive
dechallenge *and* positive rechallenge. The median time to onset of
symptoms was 36 days with a median recovery period of 7 days.
Improvement or resolution of symptoms occurred after discontinuation of
Accutane®, Accutane treatment course completion, or dose reduction. Some
patients required psychiatric intervention or antidepressant
medications. Upon rechallenge, the median time to recurrence was 9 days
with a median recovery period of 8 days.

These observations from spontaneous reports are also consistent with
published cases. For example, Scheinman *et al* (1*)* reported
depression in 7 of 700 patients with cystic acne, psoriasis, cutaneous
disorders of keratinization, or basal cell carcinoma on isotretinoin
therapy. The symptoms of depression resolved within 1 week of stopping
therapy. One patient was rechallenged and symptoms recurred. Two of the
seven patients had had previous Accutane® treatment without episodes of
depression.

Hazen *et al* (2) reported that 6 of 110 patients with acne or
keratinizing disorders experienced depressive symptoms while being
treated with isotretinoin. One of these patients had a previous history
of depression. Five patients continued on the drug despite the symptoms,
which rapidly resolved upon discontinuation of the isotretinoin.

Offset after suspect drug discontinuation *in response to* the
occurrence of depression may be biased by "power of suggestion".
However, positive dechallenges are observed in the spontaneous reports
after isotretinoin is stopped upon completion of the acne treatment
course, as opposed to discontinuation in response to the psychiatric
event. It has been hypothesized that resolution of clinical *depression*
at completion of Accutane® therapy reflects improved appearance, but
data supporting this hypothesis are not conclusive. (3, 4)

The AERS database also includes reports documenting negative
dechallenge. Analysis of the 85 cases hospitalized for depression,
suicidal ideation or suicide attempts showed that 18% had persistent
problems after isotretinoin discontinuation.

Another type of evidence helpful in causality assessment is the
occurrence of the event with administration of pharmacologically
distinct substances that bind to the same physiologic receptors.
Symptoms similar to those seen in Accutane® reports (depression, mood
swings, insomnia, fatigue, headache, aggressive behavior, irritability,
and/or uncontrollable crying) have been documented in association with
high-dose vitamin A, and with etretinate, a systemic retinoid used in
severe psoriasis. In 1972, Restak (5) described the development of a
severe neuropsychiatric reaction to chronic high dose vitamin A in an 18
year-old acne patient who had no antecedent psychiatric illness. In this
case, severe depression preceded the development of pseudotumor cerebri.
Resolution of both effects occurred rapidly upon discontinuation of the
vitamin A (pseudotumor cerebri is also a well-documented adverse effect
of the synthetic retinoids). Another report describes depression in a 54
year old with no prior psychiatric history who had ingested twelve times
the recommended daily allowance of vitamin A for 2 years. Full recovery
occurred within 2 months of stopping the vitamin supplement (6).

Pharmacologic plausibility is also supported when there is evidence of a
dose response. There are two published cases (7, 8) that suggest
etretinate-associated psychiatric events *might be* dose dependent.
There are a number of Accutane® cases that also suggest a dose effect.
However, a dose threshold *cannot* be ascertained from spontaneous
reports or published cases because of incomplete information and/or bias
introduced when dosage is decreased *in response to* depression.

Biologic plausibility is another type of information that can inform
adverse event assessment. This does not require knowledge of a mechanism
of action for the putative association, but rather an examination of
whether the association is biologically "feasible", given the available
science.

The effects of isotretinoin on fetal brain development have been
extensively

studied, but little is known about functional effects of isotretinoin on
the adult

brain. There is, however, substantial information about retinoic acid
and the

adult central nervous system. It is known that retinoids, including
isotretinoin (8),

enter the central nervous system, and that retinoid receptors are
present in adult

brain. Data linking retinoids with regulation of neuronal pathways
thought to be

involved in mood and thought are also emerging. For example, retinoid
receptor

mutant mice have impaired dopamine signaling (9). Retinoic acid may also
be

involved in regulation of a brain signal transducer called MARCKS
(myristolated

alanine-rich C kinase substrate). Specifically, it has been reported
that retinoic

acid down-regulates expression of MARCKS in a dose-dependent manner in

immortalized hippocampal cells, and there is accumulating evidence that

MARCKS is a primary target of long-term lithium treatment (10). The
clinical

importance, if any, of these examples is unknown, but they serve to

illustrate that retinoid effects on neuropsychiatric function are not
biologically

implausible.

[[Conclusion]{.underline}]{.smallcaps}

None of these elements of evidence, or their totality, allows a
determination as to whether isotretinoin *causes* psychiatric morbidity.
Warnings about serious adverse events associated with drugs are not
dependent on proof of causality, and the manufacturer of Accutane® has
incorporated a warning into the labeling based on the inconclusive
evidence. The question before the agency is whether the current labeling
is an adequate risk management strategy given the available information.

[Options for Risk-Management]{.underline}

The options for risk management in this situation must be considered in
the context of the substantial benefits of the drug and the population
in which it is used. Specifically, Accutane® is uniquely and highly
effective for the most severe form of acne, which if not adequately
treated causes significant and often permanent disfigurement. In many
cases a single 16-20 week treatment course is *curative*.

At the same time, the population for whom Accutane® is prescribed is
overwhelmingly young and healthy. Accutane® has been associated with
many adverse events affecting nearly every organ system, and is a potent
teratogen. Some of these adverse events are serious/life-threatening and
the current labeling includes a Black Box Warning, 11 additional
Warnings, and 18 Precautions.

Two options for risk management are:

1)  Maintain the current labeled Warning

2)  Implement elements of risk management in addition to those
    accomplished by the sponsor and the Agency to date

[[Risk-Management Elements for Consideration]{.underline}:]{.smallcaps}

1.  [Education/Intervention]{.underline}

-   Professional continuing education programs for prescribers/health
    care providers

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-   Informed Consent

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-   Directed assessment during treatment

2.  [Labeling Change]{.underline}

-   Constrained by absence of data (risk factors, dose, etc)

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-   Interim labeling: active monitoring, description of symptoms, advice
    about drug discontinuation...

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-   Patient Information Brochure -- *Optional* use; the current Brochure
    is under revision

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-   Medication Guide for Patients -- *Required* distribution of
    easy-to-understand information

3.  [Formal Studies]{.underline}

• Prospective controlled trial designed to determine causality or lack

thereof

-   Large open cohort studies aimed at better characterizing psychiatric
    events and generating hypotheses for controlled trials

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-   An adequately powered, well-designed retrospective epidemiologic

cohort study

-   Basic science research to improve knowledge base about the effects
    of isotretinoin on the central nervous system

-   Other

[References]{.smallcaps}

1 Scheinman PL et al. Acute Depression from Isotretinoin. JAAD 1990;
22:1112-1114.

2 Hazen PG et al. Depression-a side effect of 13-cis-retinoic acid
therapy. JAAD1983; 9:278-279.

3 Rubinow DR et al. Reduced anxiety and depression in cystic acne
patients after successful treatment with oral isotretinoin. JAAD 1987;
17:25-32

4 Niemeier V et al. Coping with acne vulgaris. Dermatol 1998;
196:108-115

5 Restak RM. Pseudotumor cerebri, psychosis, and hypervitaminosis A. J.
Nervous and Mental Dis. 1972; 155: 72-75.

6 McCance-Katz EF and LH Price. Depression associated with Vitamin A
intoxication. Psychosomatics 1992; 33:117.

7 Martinez JM et al. Effecto secundario inusual por etretimato. Medicino
Clinica. 1987;13:577.

8 Le Doze F et al. Pharmacokinetics of all-trans retinoic acid, 13-cis
retinoic acid, and fenretinide in plasma and brain of rat. Drug Metab
Dispos 2000; 28:205-8.

9 Krezel W et al. Impaired locomotion and dopamine signaling in retinoid
receptor mutant mice. Science 1998; 279:205-8.

10 Watson DG et al. Phorbol ester and retinoic acid induced regulation
of the protein kinase C substrate MARCKS in immortalized hippocampal
cells. J Neurochem 1994; 63:1666-74.

[^1]: Note that not all cases reported to the agency as of May 2000 had
    been entered into the database at the time of this analysis. Foreign
    cases were not analyzed even though they are included in the
    database.