US - August,
2005 (See
FDA website)
UNDER PSYCHIATRIC DISORDERS the current label warnings
states:
"Accutane may cause depression, psychosis and, rarely,
suicidal ideation, suicide attempts, suicide, and aggressive
and/or violent behaviors. No mechanism of action has been established
for these events. Prescribers should read the brochure, Recognizing
Psychiatric Disorders in Adolescents and Young Adults: A Guide
for Prescribers of Isotretinoin. Prescribers should be alert
to the warning signs of psychiatric disorders to guide patients
to receive the help they need. Therefore, prior to initation
of Accutane therapy, patients and family members should be asked
about any history of psychiatric disorder, and at each visit
during therapy patients should be assessed for symptoms of depression,
mood disturbance, psychosis, or aggression to determine if further
evaluation may be necessary. Signs and symptoms of depression,
as described in the brochure (Recognising Psychiatric Disorders
in Adolescents and Young Adults) include sad mood, hopelessness,
feelings of guilt, worthlessness or helplessness, loss of pleasure
or interests in activities, fatigue, difficulty in concentrating,
change in sleep pattern, change in weight or appetite, suicidal
thoughts or attempts, restlessness, irritability, acting on
dangerous impluses, and peristent physical symptoms unresponsive
to treatment. Patients should stop Accutane and the patient
or a family member should promplty contact their prescriber
if the patient develops depression, mood disturbance, psychosis,
or aggression, without waiting until the next visit. Discontinuation
of Accutane therapy may be insufficent; further evaluation may
be necessary. While such monitoring may be helpful, it may not
detect all patients at risk. Patients may report mental health
problems or family history of psychiatric disorders. These reports
should be discussed with the patient and/or the patient's family.
A referral to a mental health professional may be necessary.
The physican should consider whether Accutane therapy is appropiate
in this setting; for some patients the risks may outweigh the
benefits of Accutane therapy.
EU Warnings
-Roaccutane was registered in all EU Member States, except
Sweden, from 1983. The EMEA (European Agency for the Evalation of
Medicinal Products) was established in 1995 which provided
a centralised and mutual recognition procedure for authorising medicinal
products. However as Roaccutane was not approved by the EU central
authorisation system it remained the responsibility of national authorties
to take more restrictive measures if necessary. However, it could
be referred to the EMEA for an opinoin at the request of a competent
authority if there was evidence of new and unexpected risks.
- On 29 May 2002, France requested a referral of Roaccutane due to
the fact that Roaccutane did not have the same summary of product
characteristics across Member States due to divergent national decisions.
An amended summary of product characteristics was approved in October
1993. (EMEA
website)
Ireland:- (See
IPHA website) July
2004
UNDER PSYCHIATRIC DISORDERS the summary
of product characteristics (SPC) states:
"Depression, depression aggravated, anxiety, aggressive
tendencies, mood alterations, psychotic symptoms, and very
rarely, suicidal ideation, suicide attempts and suicide have
been reported in patients treated with isotretinoin (see section
4.8). Particular care needs to be taken in patients with a
history of depression and all patients should be monitored
for signs of depression and referred for appropriate treatment
if necessary. However, discontinuation of isotretinoin may
be insufficient to alleviate symptoms and therefore further
psychiatric or psychological evaluation may be necessary."
The Patient Information Leaflet (PIL)
states:
- "Rare cases of depression, worsening depression, anxiety,
mood changes, psychotic symptoms and very rarely suicidal
thoughts, suicide attempts and suicide have been observed.
If you have any kind of mental problems, or, if you observe
signs of depression while taking Roaccutane such as feeling
very sad for no reason, crying spells, difficulty concentrating
or you become withdrawn from your friends or family, please
inform your doctor. Your doctor may refer you for appropiate
treatment if necessary. Discontinuation of your Roaccutane
therapy may not be sufficent to alleviate symptoms and you
may require further psychiatric or psychological evaluation.
- There have been reports of patients on Roaccutane becoming
violent or aggressive.
UK:- (See
EMC website)
- Similar warnings to Ireland, above
History of Label Warnings for Roaccutane / Accutane
1971
Hoffman La-Roche (Roche) develops Accutane,
but chooses not to pursue marketing because of its risk of birth
defects.
June 1982
The Food and Drug Administration (FDA)
approves Accutane for the treatment of severe cystic acne which
is unresponsive to other treatments. Shortly after marketing, FDA
and Roche receive reports of Accutane-related birth defects.
September 1983
Public Citizen, a consumer advocacy
group, petitions FDA for warning labels on Accutane's risk of birth
defects and other side effects.
March and October 1984
FDA requires stronger warnings
and physician mailings on Accutane's risk of birth defects.
June 1985 ** DEPRESSION ADDED TO THE
LABEL WARNING**
Roche amends Accutane's package insert
under 'Adverse Reactions' to state:
"The following CNS reactions have been reported and may bear
no relationship to therapy - seizures, emotional instability including
depression, dizziness, nervousness, drowsiness, malaise, weakness,
insomnia, lethargy and paresthesias."
August 1986
Roche amends Accutane's package
insert to state:
"Depression has been reported in some patients on Accutane
therapy. In some of these patients, this has subsided with discontinuation
and recurred with reinstitution of therapy."
May 1988
FDA requires stronger warnings and
physician mailings on Accutane's risk of birth defects. FDA also
requires additional studies, including follow-up patient surveys.
Disregarding an advisory committee recommendation, FDA does not
restrict prescribing of Accutane to board-certified dermatologists.
Industry contends that FDA lacks the statutory authority to require
all such conditions on Accutane's distribution.
1990
In a 1990 memo, FDA concluded that as a result of Accutane's risks
of birth defects, "The magnitude of injury and death has been
great and permanent, with 11,000 to 13,000 Accutane-related abortions
and 900 to 1,100 Accutane-related birth defects."
1996
An FDA physician noted two cases of
suicide in a listing of recent adverse events associated with Accutane.
FDA began a re-evaluation of the drug's potential link to suicide.
Because suicide is the most serious consequence of depression, the
FDA reviewing division enlisted the help of specialists in the FDA
epidemiology division to try to determine whether the cases could
possibly be related to Accutane use. The division undertook a systematic
analysis of the published literature, previously reported cases
entered into databases, and incoming safety reports. Some of the
reports, however, included important details that did suggest the
possible involvement of Accutane. Some reports described a consistent
pattern of symptoms in patients with no previous history of such
symptoms and no other identifiable reason for their occurrence.
Other cases were described in which the symptoms began during the
Accutane treatment and then resolved soon after the medicine was
stopped. In a subset of these cases, Accutane was then restarted
and the same symptoms returned. While these findings do not prove
that Accutane causes psychiatric illness, they are suggestive of
a possible link. [Source, JONCA
BULL, M.D - DEPUTY OFFICE DIRECTOR, FDA- Statement Congress Hearing
2000]
FDA initiates a MedGuide program to provide patients with drug information
leaflets (also known as "patient package inserts" or PPIs).
In the past, FDA had established PPIs through independent regulations
or through voluntary manufacturer agreement. Where public health
warranted, MedGuide would have permitted FDA to develop PPIs without
manufacturer consent.
In response to industry objections, Congress enacts an appropriations
rider limiting the MedGuide program. Congress permits FDA to develop
MedGuides for 40 drugs with serious side-effects, including Accutane.
Roche unsuccessfully seeks in Federal court in New Jersey to suppress public availability of extensive Accutane documents, including adverse event reports, marketing plans and clinical data, relating to Accutane's risk of birth defects.
According to a 1996 press account of FDA
documents, "More than 90 percent of females treated with Accutane
did not have severe cystic acne."
May 1997
Dr Kathyrn O Connell, Medical Reviewer at the FDA, issues memo
to Dr Jonathon Wilkin stating that depression should be added to
the boxed warning for Accutane. The database contained 51 patientss
on Accutane therapy who had committed/attempted suicide. Only 11
had documented previous psychiatric illness. Dr. O' Connell stated
that "..the overall impression from these sources is that Accutane
may precipitate serious psychiatric disturbance and suicide".
- Supporting Documentation- Memo
from Dr. O’Connell to Dr. Wilkin about suggested addition of depression
to box warning
FDA
Memorandum dated 23 February 1998
August 1997
FDA issues a warning letter to Roche
for failing to submit serious adverse event reports in a timely
manner. Roche claims its computer systems are responsible for delays
of up to eight years in complying with the law.
February 1998
A 1998 FDA memo concludes that Roche
"had not acted in good faith to truly and accurately answer
questions relating to Accutane use in women and pregnancy exposure."
The memo recommends "active consideration of removal of Accutane
from the market." The memo also
concludes that: "Given all the pieces of evidence available,
it is difficult to avoid the conclusion that Accutane can adversely
affect the adult human brain in clinically significant ways and
that Accutane use is associated with severe psychiatric disease
in some patients." In response
to calls to withdraw Accutane, Roche proposes more intensive patient
education on the drug's risks of birth defects, including patient
materials and informed consent forms.
- Supporting Documentation- FDA Memo
February 25, 1998
FDA requires Roche to add the following
new bold-face warning to Accutane's physician package insert. FDA
is still unaware of the new French warning.
"WARNINGS - Psychiatric Disorders: Accutane may cause depression,
psychosis and, rarely, suicidal ideation, suicide attempts and suicide.
Discontinuation of Accutane therapy may be insufficient; further
evaluation may be necessary. No mechanism of action has been established
for these events. "ADVERSE REACTIONS
- In the postmarketing period, a number of patients treated with
Accutane have reported depression, psychosis and rarely, suicidal,
ideation, suicide attempts and suicide. Of the patients reporting
depression, some reported that the depression subsided with discontinuation
of therapy and recurred with reinstitution of therapy." In
its press release, Roche claims there is no proof of causation and
that "teenagers are at particular risk for depression."
- Supporting Documentation- FDA
Talk Paper dated 25 February 1998
March 1998
The U.K. and Ireland require warnings
of Accutane's risk of psychiatric disorders which are similar to
those in the U.S.
March 5, 1998
Just two weeks after Roche is compelled
to strengthen warnings of Accutane's risks of "depression,
psychosis and, rarely, suicidal ideation, suicide attempts and suicide,"
the FDA is forced to issue a warning letter requiring Roche to cease
"false and misleading" advertisements which promote Accutane
as an "effective treatment of severe acne... [that] minimizes
negative psychosocial effects such as depression and poor self-image."
FDA adds, "This claim is particularly troublesome in light of information recently presented in a Dear Doctor letter that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts and suicide."
FDA charges Roche to "prominently disclose information about the psychiatric disorders described in the warnings section of the revised labeling" in Accutane advertisements.
July 1998
FDA becomes aware that French authorities
had already required the addition of an Accutane "suicide attempt"
warning in 1997, of the 1992-94 French study associating Accutane
with depression, and of Roche's failure to disclose this information
to the agency.
December 21, 1999
Roche prepares a "Psychiatric Disorder Issue Work-Up"
for FDA, concluding:
"Psychotic Disorders: There are a very small number (3) of
reported cases that imply causality between a described psychotic
disorder and Accutane administration... Suicidal Behavior: There
are no reports amongst the 168 reviewed that would imply causality
between suicidal behavior and Accutane."
May 1, 2000
Roche changes the warnings on the package
label to include:
"...DEPRESSION, AND RARELY SUICIDAL THOUGHTS, SUICIDE ATTEMPTS
AND SUICIDE..."
This is the first time that the actual packaging contains the full
psychiatric warnings.
September 18-19, 2000
FDA's Dermatologic and Ophthalmic Drug
Advisory Committee holds a meeting on Accutane's risks of birth
defects and psychiatric disorders. FDA concludes that from 1982
to May, 2000, Accutane is associated with 147 suicides and hospitalizations
for depression.
The Advisory Committee determines that further research is needed
to establish Accutane's risks of birth defects and of depression,
suicide and other psychiatric disorders – but fails to specifically
recommend that FDA require such studies. FDA suggests that such
research should be conducted, but does not commit to requiring them.
Roche claims, "The number of suicides observed in the U.S. in the Accutane-exposed cohort is much less than would have been predicted... There is plainly no excess of observed suicidies in the Accutane-exposed population (32) compared to what would be predicted in the age-matched general population."
January 22, 2001
Medication Guide introduced for Accutane
- Supporting Documentation - See
FDA MedWatch Safety Website
February, 2002
Introduction of Brochure entitled "Recognizing Psychiatric
Disorders in Adolescents and Young Adults" was introduced.
The brochure lists behavioral warning signs for depression and suicide
in children and adolescents, and cautions that a link between Accutane
and depression should be considered even if other stresses exist
in a patient's life
November, 2002
Aggression and Violent behaviors added to label warnings. The
label warning now states "Accutane may cause depression, psychosis
and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive
and/or violent behaviors" According to MedWatch, an FDA-administered
safety information program, the warnings were the result of "post-marketing
safety reports."
- Supporting Documentation - See
FDA MedWatch Safety Website
August, 2005
FDA CHANGES LABEL WARNINGS UNDER PSYCHIATRIC DISORDERS "Accutane
may cause depression, psychosis and, rarely, suicidal ideation,
suicide attempts, suicide, and aggressive and/or violent behaviors.
No mechanism of action has been established for these events. Prescribers
should read the brochure, Recognizing Psychiatric Disorders in Adolescents
and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers
should be alert to the warning signs of psychiatric disorders to
guide patients to receive the help they need. Therefore, prior to
initation of Accutane therapy, patients and family members should
be asked about any history of psychiatric disorder, and at each
visit during therapy patients should be assessed for symptoms of
depression, mood disturbance, psychosis, or aggression to determine
if further evaluation may be necessary. Signs and symptoms of depression,
as described in the brochure (Recognising Psychiatric Disorders
in Adolescents and Young Adults) include sad mood, hopelessness,
feelings of guilt, worthlessness or helplessness, loss of pleasure
or interests in activities, fatigue, difficulty in concentrating,
change in sleep pattern, change in weight or appetite, suicidal
thoughts or attempts, restlessness, irritability, acting on dangerous
impluses, and peristent physical symptoms unresponsive to treatment.
Patients should stop Accutane and the patient or a family member
should promplty contact their prescriber if the patient develops
depression, mood disturbance, psychosis, or aggression, without
waiting until the next visit. Discontinuation of Accutane therapy
may be insufficent; further evaluation may be necessary. While such
monitoring may be helpful, it may not detect all patients at risk.
Patients may report mental health problems or family history of
psychiatric disorders. These reports should be discussed with the
patient and/or the patient's family. A referral to a mental health
professional may be necessary. The physican should consider whether
Accutane therapy is appropiate in this setting; for some patients
the risks may outweigh the benefits of Accutane therapy.
- Supporting Documentation -
See
FDA MedWatch Safety Website
French Historical Label Warnings
1991 ** DEPRESSION ADDED TO LABEL WARNING
In 1991 the Vidal in France was altered to include "In rare,
neuropsychological problems have been recorded (behavioural difficulties,
depression and convulsions)". A detailed
study took place in France, from 1992 to 1994, on the association
of depression with Roaccutane. The results of this inquiry were
presented at the 3rd Forum of the National and Provincial Journal
of Dermatology at Mont Pellier on the 14th -17th March 1996 and,
as far as can be determined, were never published.
March 1997 ** SUICIDE ATTEMPT ADDED
TO LABEL WARNING
On the 3rd March 1997, the date the French product license for Roaccutane
was altered, a note was added to the Rubric which includes 'suicide
attempt' along with pre-existing warnings of behavioural difficulties,
depressive syndrome and convulsions. The new warning on the information
leaflet thus reads:-
"In rare occasions, neuropsychological problems have been recorded - behavioural difficulties, depression, convulsions and suicide attempts".
Roche did not inform the FDA or other national Health Agencies of the increased label warning applied in France on the 3rd March 1997 featuring suicide as a possible side effect of their drug.
La France
1991
Une étude détaillée a eu lieu en France, de 1992 à 1994, sur l'association
de la dépression avec Roaccutan. Les résultats de cette enquête
ont été présentés au 3ème forum du national et le journal provincial
de la dermatologie chez Mont Pellier sur le 14ème -17th mars 1996
et, dans la mesure où peut être déterminé, n'ont été jamais édités.
1997
Le 3 mars 1997, la date où le permis français de produit pour Roaccutane
a été modifié, une note a été ajoutée à la rubrique qui inclut la
' tentative de suicide ' avec des avertissements préexistants des
difficultés comportementales, syndrome et convulsions dépressifs.
Le nouvel avertissement sur le feuillet de l'information lit ainsi:
-
"Dans des occasions rares, des problèmes neuropsychological ont été enregistrés - les difficultés, la dépression, les convulsions et le suicide comportementaux essaye".
Roche n'a pas informé la FDA ou d'autres agences nationales de santé de l'avertissement accru d'étiquette appliqué en France le 3 mars 1997 comportant le suicide comme effet secondaire possible de leur drogue.
1998 * * ** SUICIDE ADDED
TO LABEL WARNING
- In March 1998, the UK Committee on Safety of Medicines introduced
increased warnings on the product information for Roaccutane viz:
- "Special Warnings and Precautions - Roaccutane may cause depression, psychotic symptoms and, rarely suicide attempts and suicide. Particular care needs to be taken with patients with a history of depression and all patients should be monitored for signs of depression and be referred for appropriate treatment if necessary. Undesirable Effects Depression, psychotic symptoms and rarely suicide attempts and suicide have been reported with Roaccutane. "
September 2004 ** AGGRESSION
ADDED TO LABEL WARNING **
The Expert Working Group of the Committee on Safety of Medicines
reviewed the issue of psychiatric adverse effects in association
with isotretinoin and the views were encorporated into the European
wide review assessment (see 17 October 2003). The warnings were
were further strengthened in September 2004 to include more explicit
descriptions of the symptoms and behaviours associated with psychiatric
disorders - The Patient Information Leaflet (PIL) now reads.. "Rare
cases of depression, worsening depression, anxiety, mood changes,
psychotic symptoms and very rarely suicidal thoughts, suicide attempts
and suicide have been observed. If you have any kind of mental problems,
or, if you observe signs of depression while taking Roaccutane such
as feeling very sad for no reason, crying spells, difficulty concentrating
or you become withdrawn from your friends or family, please inform
your doctor. Your doctor may refer you for appropiate treatment
if necessary. Discontinuation of your Roaccutane therapy may not
be sufficent to alleviate symptoms and you may require further psychiatric
or psychological evaluation.There have been reports of patients
on Roaccutane becoming violent or aggressive .
1998 - ** SUICIDE ATTEMPT
ADDED TO LABEL WARNING
In May 1998, the I. M.B. (Irish Medicines Board) introduced increased
warnings similar to the US. National Agencies in most countries have
insisted on the application of the increased label warning however,
pressure must now be exerted on Roche to immediately apply the new
label warnings of psychosis, suicide ideation, suicide attempt and
suicide on a global basis.
Canadian Label Warning - May 2000
Label Warning as of April 2000 on the Patient
Insert:- Special Symptons you Should Tell Your Doctor About:
If you feel or become depressed, have thoughts of suicide, are unable
to sleep and have mood swings while taking 'Accutane', tell your doctor
as soon as possible. These feelings, although they do not happen very
often, may occur when you are taking 'Accutane' or after you have
stopped taking 'Accutane'. It has not been established whether or
not these symptoms might be related to 'Accutane'. However, it is
important to tell your doctor as soon as possible, if you have feelings.
Accutane/Roaccutane Continues to be sold without inclusion of increased label warnings
We continue to receive reports from people in the U.S., France, U.K. and other countries that, at the time of this update (October 2000), Accutane/Roaccutane package inserts do not contain the increased label warnings featuring depression, psychiatric disorders and suicide as listed side effects. We appeal to people who have purchased the medication without the increased label warnings to provide us with full details including a copy of the label insert, date of purchase and name and address of the pharmacist from whom the product was purchased. We advise that formal written statement should be obtained from the pharmacist certifying the label warning insert featured when the product was purchased.
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