Press coverage Around the World
Roaccutane /Accutane Label History

Current Label warnings for Roaccutane / Accutane

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

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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

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History of Label Warnings for Roaccutane / Accutane

US Historical Warning

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

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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.

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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.

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UK Historical Label Warnings

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 .

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Other Countries

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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