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Adverse Reactions

What is the most frequently reported adverse event for Accutane/Roaccutane

According to Dr. Wysowski of the FDA in her publication in 2005 the most frequently reported adverse event for Accutane/Roaccutane was depression.

Ranking of Accutane/Roaccutane compared to other drugs for adverse reports of depression and suicide

Comment
"Compared wtih all drugs in the AERS database to June 2000, isotretinoin (Accutane) ranked number 4 and 5 in number of reports of depression and serious depression, respectively, and 10th in number of reports of suicide attempt. (Most drugs with top ranks have known psychoactive properties and psychiatric indications; in fact, isotretinoin was the only drug with a nonpsychiatric indication in the top 10 ranked drugs for suicide attempt)." Wysowski (FDA), 2001 - J Am Acad Dermatol.
Depression (ranking number 1) and headache (ranking number 4) were amoung the most frequently reported adverse events for the suspect drug isotretinoin (Accutane/Roaccutane). Wysowski (FDA), 2005 (Arch Dermatol)
There are more than 500,000 different prescription medications sold via pharmacists in the U.S. and other countries. The FDA indicate that Accutane/Roaccutane is number 4 on the FDA top ten list of medications attracting serious adverse reaction reports and is number 5 on the FDA top ten list of medications attracting severe psychiatric adverse reaction reports (Source:News articles, April 2002):
An analysis of adverse reactions on the FDA database was conducted for the year ending 2001. Accutane was ranked second for all drugs for depression and ninth for all drugs for suicide. The other drugs were mainly drugs used in the treatment of psychiatric disorders, anxiety and alcohol. FDA database analysis
Isotretinoin ranks among the top 10 drugs in the FDA's data base in terms of the number of reports of depression and suicide attempts among its users. Wysowski (FDA), 2001 (NEJM)
. Dr. Marilyn Pitts, FDA: The top 10 adverse events for Accutane include depression, ranked number 6. By contrast, we looked at tetracycline, which is another agent used for less severe acne. We have 8 cases of depression and 2 deaths, and we looked at Claritin in the AERS database where we have 10 cases of depression and 2 deaths. FDA Hearings, 2000
We did look at the rank order for depression of all drugs in the spontaneous reporting system and the Adverse Event Reporting database. For depression, Accutane ranks number 4. For serious depression, it ranks number 5, and for suicide attempt, it ranked number 10 of all drugs. Dr Wysowski (FDA Hearing 2000)

Comparsion of adverse events reported for Accutane/Roaccutane to other acne medications

Dr. Middelkoop reviewed and compared adverse drug reaction (ADR) events obtained directly from Roche, World Health Organisation and National Health Authorties (France, UK, Ireland, FDA) for Accutane/Roaccutane to five of the most commonly prescribed antiacne treatments. The study, published in 1999, found that there were 1830 reports of psychiatric events attributable to the six medications, of which Accutane/Roaccutane was implicated in 60%. Second was minocycline which was implicated in 14%. Suicide and suicide ideation were reported in association with the use of Accutane/Roaccutane in 47 and 56 cases, respectively, with none being reported for other medications. The study found that Accutane/Roaccutane was 900 times more likely to cause depression than the 5 other acne medicines reviewed. Click here for study

Dr O' Donnell published paper 'Overview of Existing Research and Information Linking Isotretinoin (Accutane), Depression, Psychosis, and Suicide' which discussed adverse drug reaction reports (page 152).

Dr Pitts, FDA (FDA Heaing, 2000). There were 8 cases of depression and 2 cases of suicide on the database for all of the tetracyclines (acne antibiotics), tetracycline, oxytetracycline, minocycline, and doxytetracycline.

Why is it necessary to report adverse reaction reports


The reports are evaluated by clinical reviewers in Health Authorties to detect safety signals and to monitor drug safety. They form the basis for further epidemiological studies when appropriate.
As a result, Health Authorties may take regulatory actions to improve product safety and protect the public health, such as updating a product’s labeling information or re-evaluating an approval decision.
Click here for more information on how to file an adverse report
and the World Health Organisation (WHO) for definitions of adverse reactions (WHO Website). Dr. O' Connell, Medical Reviewer at the FDA stated in her report, which reviewed submissions from Roche in 1998 regarding psychiatric adverse events, that the investigation was "based on the seriousness of accumulating reports and on the pattern of robust positive de-challenge and re-challenge cases."


What percentage of adverse reactions are reported

A problem with spontaneous reporting is that less than 10% of serious, and only 2-4% of non-serious adverse reactions are reported. [Source -See Report on Adverse Drug Reactions by the Irish National Medicines Information Center, 2000 (http://www.ukmi.nhs.uk/NewMaterial/html/docs/08070201.pdf)]. The report also states that ADR's are hte leading cause of death in the US.

Dechallenge/Rechallenge

Positive dechallenge occurs when the adverse reaction disappears once the drug is stopped. Positive rechallenge occurs when the adverse reaction re-emerges once the drug is restrarted.

Wysowksi, 2001 (J Am Acad Dermatol). Dr Wysowski selects positive rechallenge reports - see page 3 of the publication - Click here

FDA Hearings, 2000. Dr. Marilyn Pitts, FDA: In conclusion, dechallenge-rechallenge cases provide strong evidence to support a link between a drug and an observed adverse event. We have presented 41 cases of positive dechallenge-rechallenge which provide further evidence to support a relationship between Accutane and depressive symptoms.

FDA Hearings, 2000. Dr.Wysowski, FDA: In evaluating spontaneous adverse events, positive dechallenge/rechallenge cases provide the best evidence to support a relationship between a drug and an observed event.

**In 1998, OPDRA analyzed spontaneous adverse drug event reports of positive dechallenge/rechallenge cases of depression, mania, psychosis, and suicide attempt. The 1998 case series supported the Accutane labeling change, which included a warning concerning psychiatric disorders. The warning stated that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts, and suicide. There were 20 cases in this report. 19 were U.S. cases. There were 14 cases of depression, 5 cases of psychosis, and 1 case of a mood disorder.

**In support of this meeting, OPDRA analyzed dechallenge/rechallenge cases of Accutane-associated depression, mood changes, and suicide attempts. Spontaneous adverse event reports were reviewed for positive dechallenge/rechallenge cases. We found 41 cases. 20 cases were from the previously reviewed 1998 case series and 21 new dechallenge/rechallenge cases focusing on depression and suicide attempt were found. There were again 21 cases in this case series. 17 of the 21 cases were from the U.S. There were 14 cases of depression, 3 cases of depression with suicidal ideation, and 4 cases of mood changes. There were 16 females and 5 males. The median age was 23 years. 5 patients reported a psychiatric history, and 1 patient required hospitalization.

Current Number of Psychiatric Adverse Reaction Reports on FDA Database (May 2005)

**According to FDA alert in May 2005, the following data is available:

-*From isotretinoin’s initial marketing in 1982 through August 2004, 4,992 spontaneous reports of psychiatric disturbances associated with using isotretinoin in patients in the United States have been submitted to the FDA.

*The number of reported suicides among isotretinoin users in the United States was 190 through January 2005. Between 1982 and 2002, there were 165 reported suicides, which were fewer than the 220 predicted based on U.S. vital statistics data. However, because the degree of under-reporting of suicides is unknown, the fact that the reported number is lower than the predicted number cannot be interpreted as evidence against a causal association.

Reports indicate that an increasing proportion of Roaccutane/Accutane (Isotretinoin) are used for mild and moderate acne

Roaccutane/Accutane is licensed for the treatment of severe forms of acne (such as cystic and conglobate acne or acne at risk of permanent scarring) resistant to adequate causes of standard therapy with systemic antibacterials and topical therapy.

Dr Wysowski reported that in the last 8 years there was a 2.5 fold (250%) increase in the number of dispensed prescriptions for isotretinoin in the United States. Data also revealed an increasing proportion of isotetinoin use for mild and moderate acne [link to Wysowski 2002]

Roche Report on Number of Psychiatric Events recorded for age group 13-17 between 01 Nov 01 and 31 May 04

Roche provided to the MHRA (UK licensing authority) a review of all suspected adverse reports for Roaccutane in children (<18 years) for the period 1st Nov 2001 to 31st May 2004 (Period of 2 years and 7 months).

The document entitled "Review of Adverse Events reported for Roaccutane for children and adolescents aged under 18 years of age" provides all serious and non serious events from both clinical trials and spontaneous suspected adverse reaction reporting where the patient age was stated to be <18 years. Reports between 01/11/2001 and 31/05/2004 were retrieved.

For the age group 13-17, psychiatric events were the most frequently reported serious adverse event. The following serious events were recorded: 27 cases of completed suicide (4.2%) 36 cases of suicidal attempt (6%) 28 cases of suicidal ideation (4.4%) 119 cases of depression (19%) 5 cases of psychotic disorder 6 cases of obsessive compulsive disorder For <13 year olds, there were 25 serious reports which included one report of suicidal ideation and one report of suicide attempt.

Report on Number of Suicides recorded for children under 18 years of age between 1989 and June 2003.

According to recent report - "In 2004, The Alliance for Human Research Protection asked Keith Altman, Adverse Drug Reaction Statistics Analyst, to analyze FDA's Medwatch database for drug-linked suicides by children under 18 years of age.
Altman found that between 1989 and June 2003, there were 216 reported drug-linked suicides in under 18 year olds. Of these, 72 suicides were linked to Accutane.

The next highest number of suicides - 55--involved Prozac." Source, http://www.ahrp.org/infomail/04/12/07.php

How many cases of suicide, suicide attempt and suicide ideation were reported to Roche before the label warning change to include 'suicide' as a possible side effect in 1998

Roche revealed a total of 170 cases of suicide, suicide attempt or suicide ideation were reported as associated with the drug as of December 1997. Roche also stated that they had 40,000 adverse drug reactions on their database.

Adverse drug reaction reports are available from the following websites

A full list of adverse drug reaction reports recorded by the FDA for is available on a seperate web site: http://www.house.gov/stupak/accutane.htm.

The FDA adverse event reporting system database can be obtained from http://www.fda.gov/cder/aers/extract.htm

How to File an Adverse Drug Reaction (ADR):-

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