Presentation to the FDA Tuesday 19 th September 2000 Accutane and Psychiatric Illness Liam Grant, Chairman, Roacccutane Action Group, Dublin, Ireland

Roaccutane Action Group Set up in 1997 Members include individuals who suffered severe side effects with Accutane and their families. We are in contact with similar groups from UK, USA France, Norway and other countries. Objectives:1. To provide support to Accutane victims 2. To carry out a review of scientific reports on Accutane and collect Adverse Drug Reaction reports from National Agencies worldwide 3. To fund and coordinate a series of scientific studies on Accutane in order to determine the mechanism by which Accutane causes so many severe physical and psychiatric side effects We have consulted medical and scientific experts including Psychiatrists, General Practitioners, Biochemists, Pharmacologists and Medical Statisticans.

Accutane and Side effects Many general side effects have been reported for Accutane such as; dryness of the skin and mucous membranes, photophobia, muscle and joint pain, insomnia, lethargy Central Nervous System side effects include pseudotumor cerebri, visual disturbances, hearing deficincies, headache, nausea, malaise and drowsiness, Amnesia, hallucinations Psychiatric disorders include behavioural disorders, seizures, psychosis, schidzophrenia, depression, suicide ideation, suicide attempt and suicide Accutane is also a teratogen

Accutane, Vitamin A & Psychiatric Disorders Accutane is an analog of Vitamin A. Hypervitaminosis A which results from ingestion of large amounts of Vitamin A is known to cause psychiatric illness (‘Pseudotumor Cerebri/ Psychosis/Hypervitaminosis A. Journal of Nervous and Mental Disease 155, 72-75, 1972). Considering the close relationship between Accutane and Vitamin A it is not surprising that Accutane treatment results in psychiatric side effects. Therefore the manufacturers of Accutane, Roche/ Hoffman La Roche, would have been able to predict with reasonable certainty, the main side effects caused by Accutane including psychiatric side effects and teratogenicity In fact, the current package insert for Accutane in the USA states: ‘Many of the side effects and adverse reactions seen or expected in patients receiving Accutane are similar to those described in patients taking high doses of Vitamin A’

Scientific Literature Reports on Accutane and Psychiatric Disorders There are a substantial number of published studies linking Accutane and psychiatric disorders as far back as 1983, less than one year after its release onto the market. 1. Hazan, P.G. et al, Depression a side effect of 13-cis-retinoic therapy. The American Academy of Dermatology 9, , The authors report that 5.5% of patients experienced depressive symptoms while on Accutane,. In the case of one 21 yr. Old man symptoms of depression and forgetfulness were severe enough to cause withdrawl of the drug.

2. Bigby, M. et al. Adverse Reactions to Isotretinoin. The Journal of the American Academy of Dermatology 18, , This report showed that by 1988 there were 104 adverse drug reaction reports in the USA from the period of october 1982 to June This represented the highest number of adverse reaction reports received by any agency for any prescription drug. It also states that 22% of Adverse drug reactions for Accutane relate to central nervous system disorders such as headache, depression, dizziness, personality disorder and pseudotumor cerebri.

3. Bravard, P. et al, Isotretinoin and depression: care is needed. Nouv. Dermatol 12, 215, 1993 This study resulted in a national inquiry in France between 1993 and 1994 and the results were presented at the third forum of the National and Provincial Journals of Dermatology in Montpellier, France March th The study was funded by Roche and the results were never published.

Study on link between various Acne medications and Psychiatric illness Acne has been proposed to be a cause of depression. Dr. T.V. Middelkoop (Research Scientist) investigated the link between 6 acne medications; Accutane, Minocycline, Doxycycline, Tetracycline, Dianette, Oxytetracycline and psychiatric disorders in particular suicide, suicide attempt and suicide ideation. Data on the number of prescriptions and Adverse Drug Reactions were obtained from Medicines Control Agencies and Health Boards in various countries Roaccutane (Isotretinoin) and the Risk of Suicide: Case Report and a Review of the Literature and Pharmacovigilance Reports, Middelkoop, T, Journal of Pharmacy Practice Vol X11, , 1999

Table 1 Worldwide psychiatric ADR reports Number of people prescribed Accutane worldwide - 6 million Number of people prescribed the other 5 Acne meds million MedicationTOTAL SUICIDE ATTEMPT SUICIDE IDEATION Roaccutane Minocycline Doxycycline Tetracycline Dianette Oxytetracycline 0 000

Table 2 UK ADR data (source MCA) Data for Roaccutane cut-off date July 1999 Earliest Reaction date February Medication No. of Prescriptions Total SUICIDE ATTEMPT SUICIDE IDEATION Roaccutane 12, Minocycline 8,802, Tetracycline 147,237, Oxytetracycline 31,301, Doxycycline 13,650, Dianette 1,214,

Conclusion of Study Accutane is 900 times more likely to cause depression than the 5 other acne medicines

Number of Accutane Adverse Drug Reactions Worldwide May Roche issued a letter to the Irish Medicines Board which disclosed that there were 40, 000 Adverse Drug Reactions (ADRs) on the Roche database in respect of Accutane A review of all ADR data recorded since that time by all leading national health authorities suggest that the number of ADRs presently held on the Roche database in respect of Accutane is in excess of 55,000 Studies show that only 1 in 10 serious ADRs are ever reported Publication by Bigby et al (1988) showed that 22% of Accutane ADRs relate to psychiatric disorders.

Norway In the late 1980s media reports highlighted the adverse effects of Accutane As a result of the nature and extent of side effects being reported the Norwegian authority commissioned a study in 1992 The study was financed by Roche and was conducted by Dermatologists from Sweden, UK and Germany. Two of the participating Dermatologists Prof. W.J. Cunliffe (Leeds University, UK) and Dr. A. Vahlquist (Linkoping, Sweden) have a long standing association with Roche. The above report made no reference to scientific publications linking Accutane to psychiatric disorders and did not disclose the number or nature of ADRs held on the Roche database for Accutane

Label Warnings France -3 rd March 1997 Label warnings featuring various behavioural and psychiatric disorders was introduced in France and the warning featured suicide as a possible side effect. When P. Bravard published his study in 1993, the label warning specifically featured depression. Roche did not inform the FDA or other national Health Agencies of the increased label warning appllied in France featuring suicide as a possible side effect Most countries applied the increased, explicit label warning for Accutane in February to May 1998 featuring various psychiatric disorders including ‘on rare occasions suicide, suicide attempt and suicide ideation’

Canadian Label Warning, May 2000 No reference to depression, psychiatric disorders or suicide. The Canadian label warning simply featured mood change as a possible side effect

FDA Warning re Misleading Advertising Folllowing the increased label warning Roche placed advertisements in the media indicating that Accutane could alleviate depression On 8 th March 1998 the FDA sent warning letters to Roche ordering them to withdraw this promotional material, stating they were ‘false and misleading and promote Accutane for an unapproved use’

Notice to Dermatologists following increased label warnings Following the increased label warning applied in the UK and Ireland in March/May 1998 Prof. W. Cunliffe and his colleague Dr. T. Chu produced an information leaflet stating that roaccutane caused depression in only a small number of patients and suggested that the acne itself is the cause of the depression. ‘Acne can occasionally cause depression. Clinical depresssion can cause suicide. A very small number of patients on Roaccutane develop clinical mood changes/psychotic symptomsand may develop clinical depression’ A recent correspondance from a prominent UK Dermatologist stated that; ‘In the few tragic cases where Roaccutane has caused depression and lead to suicide it is indeed difficult to justify the use of Roacutane’

Advertisements in Irish Medical Journals Following implementation of suicide warnings on Accutane packets Roche placed advertisements in Irish Medical Journals featuring letters from Dr. R. Bickers (Dermatologist, Colombia University, New York) and Dr. D. Jacobs (Professional Psychiatric Associates, Massachusetts) These letters stated that Roaccutane does not cause depression. Prior to the May 1998 strengthening of the Accutane label warning Roche employed Dr. Bickers and Dr. Jacobs to make presentations to the FDA on their behalf

Sale of Accutane on the Internet It came to our attention that Accutane was on sale on the Internet As far as we can determine the drug was not on sale on the Internet prior to the increased label warnings Order for Accutane To investigate the ease with which Accutane could be obtained on line we placed orders under in the names of boys and girls in their teens Within 10 days we were supplied with the drug from South Africa with a prescription from a Doctor with a South African address Despite the restrictions for prescription of Accutane such as blood tests or pregnancy tests it is possible to get Accutane without a medical consultation.

Dose response study of 13-cis-retinoic acid in acne vulgaris Jones, D.H., King, K., Miller, A.J. and Cunliffe, W.J. British Journal of Dermatology 108, , 1983 This study was performed prior to release of Accutane 76 subjects with moderate to severe acne were chosen for the study Three of the subjects were excluded from the study as a result of clinical side effects which were described as being ‘dose-related’ The side effects suffered by these three patients have not been disclosed

Further Studies Further studies need to be undertaken by Roche and/ or Dermatologists to elucidate the mechanism(s) by which Accutane interacts with the Central Nervous System and other systems in the body. This would give an insight into the cause (s) of the specific side effects. Roche have stated publicly for the past 17 years ‘we do not know the mechanism by which the drug works therefore there is no proof that Accutane causes depression or psychiatric disorders’

Recommendations In our view Accutane should only be used for severe recalcitrant cystic acne as a treatment of last resort. We believe that more than 80% of patients prescribed Accutane have mild or moderate acne which is in violation of the license. Prescribing Doctors should be required to certify that patient’s acne is within the license guidelines Patient should have all the appropriate tests (blood tests, pregnancy tests) prior to and during treatment and this needs to be strictly enforced. Sale of Accutane on the Internet should be prohibited Patients should be psychiatrically assessed (eg. using the Hamilton scale of depression) before and during Accutane treatment and in the event of an adverse response the patient should be immediately taken off the treatment Independent studied need to be carried out to establish exactly how it functions in the human body and to assess its safety Appropriate medical treatments must be devised to counteract the side effects suffered as a result of Accutane treatment