Expedientes Secretos X de la Isotretinoina !!!

  Bibliographical references sources:

                         DERMNET  NEW ZEALAND  isotretinoin side effects, and photos !!!    

                          DERMAGIC/EXPRESS The isotretinoin, the good the bad and the ugly !!! (96 references)

 All that you will read has bibliographical support !!!!

more than 100 references in total !!!

Data-Medicos 
Dermagic/Express No. 4-(5) X file) 
15 Diciembre 2.002 / 15 December  2.002 

 
EDITORIAL ESPAÑOL        
================                 

Hola amigos de la red, DERMAGIC EXPRESS con una nueva edicion, en esta ocasión el tema sobre LA ISOTRETINOINA, popular droga para el tratamiento del acne, en el mercado desde 1.982.

En el año de 1.999 para el primer aniversario del DERMAGIC se publico el TEMA, la ISOTRETINOINA, LO BUENO, LO MALO Y LO FEO, la cual gusto mucho en la RED. 

De hecho el LABORATORIO ROCHE me invito a una conferencia sobre EL ACCUTANE-ROACCUTANE (ISOTRETINOINA) que se llevo a efecto en el HOTEL PIPO de Maracay a traves de su VISITADOR medico.

Hoy TRES AÑOS DESPUÉS (diciembre 2.002) por mi propia cuenta voy a realizar UNA ACTUALIZACION sobre los efectos adversos de ESTA POPULAR DROGA, para ALERTAR A los JOVENES de nuestro pais y el mundo, quienes padecen de ACNE, sobre los efectos adversos que esta pastilla produce en sus cuerpos, especialmente a las del sexo FEMENINO, DONDE LA FDA RECIENTEMENTE APROBO UNA RESOLUCIÓN QUE PARA PODER TOMAR LA MEDICINA, DEBEN ESTAR UTILIZANDO 2 (DOS), REPITO 2 (DOS) METODOS DE ANTICONCEPCIÓN al mismo tiempo para evitar un embarazo, pues de producirce, el NIÑO VENDRA CON MALFORMACIONES !! 

MAS AUN, TODA PACIENTE DEL SEXO FEMENINO EN EDAD FERTIL, QUE VAYA A TOMAR ROACCUTANE SOLO SE LE SUMINISTRARA TRATAMIENTO POR UN MES (30 DIAS) Y CADA MES DEBERA PRACTICARSE UN TEST DE EMBARAZO PARA VER SI SE CONTINUA CON EL TRATAMIENTO. Este es un nuevo PROGRAMA denominado SMART que hace unos meses se puso en practica en ESTADOS UNIDOS DE NORTEAMERICA para evitar MALFORMACIONES CONGENITAS !!! 

Invito tambien a los medicos DEL UNIVERSO A INFORMAR ADECUADAMENTE A LOS PACIENTES DE LOS EFECTOS ADVERSOS que la droga produce, para que estos en base a su PROPIO CRITERIO DECIDAN TOMAR O NO LA MEDICINA, Y LAS HEMBRAS FIRMAR, REPITO FIRMAR EL COMPROMISO ESCRITO QUE EL MEDICO DEBE PRESENTARLES ANTES DE INICIAR EL TRATAMIENTO CON ISOTRETINOIN, bajo un formato que EL MISMO LABORATORIO DISTRIBUYE A LOS MEDICOS. 

PRINCIPALES EFECTOS ADVERSOS DE LA ISOTRETINOINA, 
(según estudios y casos reportados) 
====================================== 
1.) Xerosis cutis, resequedad de la Piel. 
2.) Eritema (enrojeciemiento) 
3.) Artralgia (dolores articulares) 
4.) Resequedad de labios. 
5.) Resequedad de mucosa nasal 
6.) Dolores musculares, daño muscular y aumento de enzima CPK 
7.) Penfigo (piel) 
8.) Pseudotumor cerebral 
9.) Empeoramiento del ACNE. 
10.) Sangramiento nasal 
11.) Granuloma piogenico(Piel) 
12.) Hiperandrogenismo en la mujer 
13.) Acne FULMINANTE. 
14.) Eritema Nodoso (Piel) 
15.) TERATOGENESIS en la mujer embarazada: malformaciones fetales: OIDO, CEREBRO, CORAZON, RETARDO MENTAL, ANORMALIDADES CRANEO-FACIALES. 
16.) Osificacion de ligamentos 
17.) Alteraciones oseas: TRASTORNOS EN LA OSTEOGENESIS, hiperostosis, PERDIDA DE LA DENSIDAD OSEA. 
18.) Vasculitis (piel) 
19.) Alteraciones oculares: resequedad de conjuntiva, vision borrosa, dificultad para la vision nocturna. ALGUNAS NO IRREVERSIBLES LUEGO DE CONCLUIDO EL TRATAMIENTO. 
20.) Alteraciones en el cabello: cabello rizado, perdida del cabello 
21.) Aumento de enzimas hepaticas y lipidos sanguineos. 
22.) Induccion a la DEPRESION Y SUICIDIO: cambios de humor y conducta. 
23.) Cambios a nivel sanguineo: FIBRINOLISIS. 
24.) Miliaria cristalina (piel) 
25.) Alteraciones de las uñas: Distrofia mediana canaliforme, paroniquia. 
26.) Alteraciones RENALES: Uretritis, empeoramiento de funcion renal. 
27.) Ineficacia del tratamiento.
28.) Enfermedad pulmonar: neumonia eosinofilica
29.) Alteracion en el metabolismo esteroideo en la mujer con acne
30.) No puede donar SANGRE durante el tratamiento y hasta un mes despues de terminado el mismo. Donar sangre durante tratamiento con isotretinoina a una mujer embarazada puede resultar peligroso para el bebe.
31.) Reacción alérgica: Prurito y habones, inflamacion de la cara o manos, hinchazón u hormigueo en la boca o garganta, pesadez en el pecho, problemas respiratorios. 
32.) Problemas auditivos o campaneo en los oidos. 
33.) Diarrea, náusea, o dolor del estómago. 
34.) Dolor de cabeza, vértigo, náusea, vomitos. 
35.) piel amarilla u ojos. 
36.) CONVULSIONES.

MUY PROBABLEMENTE EXISTAN OTROS MAS...

Pacientes con historia de DIABETES, TRASTORNOS PSICOLOGICOS, ENFERMEDAD CARDIACA, TRIGLICERIDOS Y COLESTEROL ELEVADOS, ASMA, OSTEOPOROSIS, ANOREXIA NERVIOSA Y ENFERMEDAD HEPATICA no deberan tomar isotretinoin o tomarlo a dosis monitoreadas por el medico. 

EL ISOTRETINOIN ES UNA DROGA de uso DELICADO, pero que ha mostrado SUS BENEFICIOS EN EL ACNE SEVERO, pero que TIENE MUCHOS EFECTOS ADVERSOS SOBRE TODO EN LA MUJER SI SALE EMBARAZADA, y los JOVENES ANTES DE COMPLETAR EL DESARROLLO ESQUELETICO DEBEN SABER QUE ESTA DROGA PUEDE PRODUCIR ALTERACIONES EN LOS HUESOS. !!! 

SI USTED TOMA ISOTRETINOIN Y OBSERVA ALGUN EFECTO INDESEADO, CONSULTE A SU MEDICO INMEDIATAMENTE !!! Y NO SE AUTOMEDIQUE !!! 

en las referencias los hechos....

Saludos a todos y FELIZ NAVIDAD 2003

Dr. Jose Lapenta R.

ENGLISH EDITORIAL
================== 
Hello friends of the net, DERMAGIC EXPRESS with a new edition, in this occasion the topic on THE ISOTRETINOIN, popular drug for the treatment of the acne in the market since 1.982. 

In the year of 1.999 for the first anniversary of the DERMAGIC publishes the TOPIC, the ISOTRETINOIN, THE GOOD, THE BAD AND THE UGLY, which I like a lot in the NET. 

In fact the Roche LABORATORY invites myself to a conference on THE ACCUTANE-ROACCUTANE (ISOTRETINOIN) that takes to effect in the HOTEL PIPO of Maracay through its medical VISITOR.

Today THREE YEARS LATER (December 2.002) for my own bill I will carry out An UPDATE on the adverse effects of THIS POPULAR DRUG, to ALERT TO the YOUNG PEOPLE of our country and the world who suffer of ACNE, the adverse effects that this pill takes place in its bodies, especially to those of the FEMININE sex, WHERE THE FDA RECENTLY APPROVED A RESOLUTION THAT to BE ABLE to TAKE THE MEDICINE, they should BE USING 2 (TWO),I REPEAT 2 (TWO) METHODS OF CONTRACEPTION at the same time to avoid a pregnancy, because if it takes place, the baby will COME WITH MALFORMATIONS!! 

EVEN, ALL PATIENT OF THE FEMININE SEX IN FERTILE AGE THAT ROACCUTANE will TAKE, ONLY was GIVEN TREATMENT BY one MONTH (30 DAYS) AND EVERY MONTH A TEST OF PREGNANCY will BE PRACTICED to SEE IF THE TREATMENT WILL be CONTINUED. This is a new denominated SMART PROGRAM that some months ago put on in practices in EEUU to avoid CONGENITAL MALFORMATIONS!!! 

I also invite the doctors OF THE UNIVERSE to INFORM APPROPRIATELY TO THE PATIENTS OF THE ADVERSE EFFECTS that the drug takes place, so that them based on its OWN APPROACH DECIDE to TAKE OR NOT THE MEDICINE, AND THE FEMALES to SIGN, I REPEAT to SIGN THE WRITTEN COMMITMENT THAT THE DOCTOR should PRESENT THEM BEFORE OF BEGINNING THE TREATMENT WITH ISOTRETINOIN, under a format that THE SAME LABORATORY DISTRIBUTES to THE DOCTORS. 

MAIN ADVERSE EFFECTS OF THE ISOTRETINOIN: 
(according to studies and reported cases)
==================================== 

1.) Xerosis Cutis, Dryness of the Skin. 
2.) Facial Erythema. 
3.) Arthralgia. 
4.) Dryness of lips. 
5.) Dryness of mucous nasal. 
6.) Muscular pain, I damage muscular and enzyme increase CPK. 
7.) Pemphigus. (skin)
8.) Cerebral Pseudotumor 
9.) Worsening of the ACNE. (skin) 
10.) Nasal bleeding. 
11.) Pyogenic Granuloma. 
12.) Hyperandrogenism in the woman 
13.) acne FULMINANS. 
14. ) Erythema Nodosum (Skin) 
15.) TERATOGENESIS in the pregnant woman: fetal malformations: HEARD, BRAIN, HEART, MENTAL RETARD, CRANIO-FACIAL ABNORMALITIES. 
16.) Ossification of ligaments 
17.) Bone alterations: DYSFUNCTIONS IN THE OSTEOGENESIS, hyperostosis, LOST OF THE BONE DENSITY. 
18.) Vasculitis (skin-blood vessels) 
19.) ocular alterations: Dryness of conjunctive, blurred vision, difficulty for the night vision. SOME NOT IRREVERSIBLE THEN OF CONCLUDED THE TREATMENT. 
20.) Alterations in the hair: curly hair, loss hair
21.) Increase of hepatic enzymes and sanguine lipids. 
22.) induction to the DEPRESSION AND SUICIDE: changes of mood and behavior. 
23.) Changes at sanguine level: FIBRINOLYSIS. 
24.) Miliaria crystallina (skin) 
25.) Alterations of the fingernails: Median canaliform dystrophy, paronychia
26.) RENAL alterations: Urethritis, renal impairment. 
27.) Inefficacy of the treatment.
28.) LUNG disease: Eosinophilic pneumonia.
29.) Alteration in steroid metabolism in women with acne. 
30.) Do not donate blood while taking this medicine or for 1 month after your last dose. Blood donated while taking isotretinoin may be given to a pregnant woman and be harmful to her baby.
31.) Allergic reaction: Itching or hives, swelling in face or hands, swelling or tingling in the mouth or throat, tightness in chest, trouble breathing 
32.) Hearing problems or ringing in the ears 
33.) diarrhea, nausea, or stomach pain 
34.) headache, dizziness, nausea, vomiting 
35.) Yellow skin or eyes 
36.) SEIZURES.
 

VERY PROBABLY EXIST MORE...
 

Patient with history of DIABETES, PSYCHOLOGICAL DYSFUNCTIONS, CARDIAC ILLNESS, ELEVATED LEVELS OF TRIGLYCERIDES AND CHOLESTEROL, ASTHMA, OSTEOPOROSIS, ANOREXIA NERVOSA AND LIVER DISEASE, they won't take isotretinoin or to take it in doses monitoring by the doctor who prescribe the drug. 

THE ISOTRETINOIN is A DRUG of DELICATE use, but that it has shown ITS BENEFITS IN THE SEVERE ACNE, but that HAS MANY ADVERSE EFFECTS mainly IN THE WOMAN IF become PREGNANT, and the YOUNG PEOPLE BEFORE OF COMPLETING THE TOTAL SKELETAL DEVELOPMENT they should KNOW THAT THIS DRUG can PRODUCE ALTERATIONS IN THE BONES. !!! 

IF you TAKE ISOTRETINOIN AND OBSERVES SOME ADVERSE EFFECT, CONSULT TO YOUR DOCTOR IMMEDIATELY!!! AND NOT TAKE DRUGS BY YOUR OWN DECISION !!! 

in the reference,,,, the facts...

Greetings to all and Happy Christmas 2.003

Dr Jose Lapenta R.

==========================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
==========================================================
1.) An analysis of reports of depression and suicide in patients treated with isotretinoin.
2.) Acne, hyperandrogenism and oral isotretinoin resistance. 23 cases. Therapeutic implications] 
3.)Predictive factors for failure of isotretinoin treatment in acne patients: results from a cohort of 237 patients. 
4.)[Aggravation of acne by isotretinoin. 6 cases, predictive factors] 
5.) Acne fulminans and erythema nodosum during isotretinoin therapy responding to dapsone. 
6.) [Muscular damage during isotretinoin treatment] 
7.) [Lung disease induced by isotretinoin] 
8.) Vestibular dysfunction in a child with embryonic exposure to accutane. 
9.) Extraspinal enthesopathy caused by isotretinoin therapy. 
10.) Retinoid-induced ossification of the posterior longitudinal ligament. 
11.) Isotretinoin-induced vasculitis imitating polyarteritis nodosa, with perinuclear antineutrophil cytoplasmic antibody in titers correlated with clinical symptoms. 
12.) Depression and suicide in patients treated with isotretinoin.
13.) Isotretinoin treatment alters steroid metabolism in women with acne.
14.) ISOTRETINOIN (eye-so-TRET-i-noin): 
15.) New Measures to Manage Risks Associated With Accutane
16.) What is the most important information I should know about isotretinoin?
17.) Accutane's Safety Labeling Revised for Psychiatric Disorders, Other Warnings
18.) Accutane®-Exposed PregnanciesCalifornia, 1999
19.) July 2002 AADA letter to the FDA regarding Isotretinoin 
20.) Isotretinoin pregnancy prevention program undergoes significant changes 
21.) US introduces new system for prescribing Accutane 
22.) Mass mailing warns of Accutane's psychiatric risks
==========================================================
==========================================================
1.) An analysis of reports of depression and suicide in patients treated with isotretinoin.
==========================================================
J Am Acad Dermatol 2001 Oct;45(4):515-9 

Wysowski DK, Pitts M, Beitz J.

Division of Drug Risk Evaluation I, Office of Post-Marketing Drug Risk Assessment, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857, USA. [email protected]

BACKGROUND: The Food and Drug Administration (FDA) has received reports of depression and suicide in patients treated with isotretinoin. OBJECTIVE: Our purpose was to provide the number and describe the cases of depression and suicide reported to the FDA in US patients treated with isotretinoin and to consider the nature of a possible association between isotretinoin and depression. METHODS: An analysis was made of reports of depression, suicidal ideation, suicide attempt, and suicide in US isotretinoin users voluntarily submitted to the manufacturer and the FDA from 1982 to May 2000 and entered in the FDA's Adverse Event Reporting System database. RESULTS: From marketing of isotretinoin in 1982 to May 2000, the FDA received reports of 37 US patients treated with isotretinoin who committed suicide; 110 who were hospitalized for depression, suicidal ideation, or suicide attempt; and 284 with nonhospitalized depression, for a total of 431 patients. Factors suggesting a possible association between isotretinoin and depression include a temporal association between use of the drug and depression, positive dechallenges (often with psychiatric treatment), positive rechallenges, and possible biologic plausibility. Compared with all drugs in the FDA's Adverse Event Reporting System database to June 2000, isotretinoin ranked within the top 10 for number of reports of depression and suicide attempt. CONCLUSION: The FDA has received reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin. Additional studies are needed to determine whether isotretinoin causes depression and to identify susceptible persons. In the meantime, physicians are advised to inform patients prescribed isotretinoin (and parents, if appropriate) of the possibility of development or worsening of depression. They should advise patients (and parents) to immediately report mood swings and symptoms suggestive of depression such as sadness, crying, loss of appetite, unusual fatigue, withdrawal, and inability to concentrate so that patients can be promptly evaluated for appropriate treatment, including consideration of drug discontinuation and referral for psychiatric care.

============================================================ 
2.) Acne, hyperandrogenism and oral isotretinoin resistance. 23 cases. 
Therapeutic implications] 
============================================================ 
Author 
Lehucher-Ceyrac D; Chaspoux C; Weber MJ; Morel P; Vexiau P 
Address 
Service Dermatologie, H^opital Saint-Louis, Paris. 
Source 
Ann Dermatol Venereol, 124(10):692-5 1997 
Abstract 
BACKGROUND: We earlier demonstrated that oral isotretinoin can be 
associated with hyperandrogenism in women with acne. The aim of this study 
was to evaluate the causal relationships of the different etiologies in 
case of unsuccessful treatment. PATIENTS AND METHODS: The study group 
included 120 patients with late-onset acne resistant to different treatment 
and signs of hyperandrogenism. A complete hormone work-up was obtained in 
all patients. There was a group of 23 patients who failed to respond to 
isotretinoin and 97 patients in the control group. Unsuccessful treatment 
was defined as persistance of grade 2 lesions after a mean cumulative dose 
of 166 mg/kg isotretinoin. RESULTS: In the non-responders to isotretinoin, 
hyperandrogenism was observed in 22 out of 23 cases: pituitary (n = 2), 
adrenal (n = 5), ovarian (n = 13), peripheral (n = 2). In the control 
group, hyperandrogenism was found in 89 out of 97 patients: pituitary (n = 
6), adrenal (n = 45), ovarian (n = 33), peripheral (n = 5). The 
distribution of two etiologies, ovary and adrenal, demonstrated a 
significant difference between isotretinoin non-responders and controls, 
the former having a higher frequency of ovarian hyperandrogenism. 
DISCUSSION: These findings confirm that untreated hyperandrogenism, 
particularly ovarian hyperandrogenism, is a source of unsuccessful 
treatment with oral isotretinoin. 

============================================================ 
3.)Predictive factors for failure of isotretinoin treatment in acne 
patients: results from a cohort of 237 patients. 
============================================================ 
Author 
Lehucher-Ceyrac D; de La Salmoni`ere P; Chastang C; Morel P 
Address 
Service de Dermatologie, H^opital Saint-Louis, Paris, France. 
Source 
Dermatology, 198(3):278-83 1999 
Abstract 
BACKGROUND: The efficacy of oral isotretinoin in acne has been established, 
though the role of the mean daily dose (MDD) is still unclear. OBJECTIVE: 
To determine the predictive factors of resistance to oral isotretinoin and 
the role of the MDD of isotretinoin on relapse of acne while taking into 
account patient characteristics and the total cumulative dose (TCD). 
METHODS: Two hundred and thirty-seven patients treated with oral 
isotretinoin for the first time were enrolled by a single dermatologist. 
Patients with closed comedonal acne and with hyperandrogenism received 
adequate therapy prior to isotretinoin. RESULTS: Closed comedonal acne was 
the only predictive factor of resistance to isotretinoin with an adjusted 
OR = 2.7 (95% CI: 1.0-7.3). The estimated rates of relapse at 1, 3 and 5 
years were 14, 40 and 48%, respectively. Age and grade of facial acne were 
the only predictive factors for relapse with adjusted relative risks of 0.6 
(95% CI: 0.4-0.8) for age >/= 20 and 1.5 (95% CI: 1.0-2.2) for grade > 3. 
CONCLUSION: MDD, TCD, closed comedonal acne and hyperandrogenism that have 
been adequately treated prior to isotretinoin treatment had no prognostic 
value for relapse. 

============================================================ 
4.) [Aggravation of acne by isotretinoin. 6 cases, predictive factors] 
============================================================ 
Author 
Lehucher Ceyrac D; Chaspoux C; Sulimovic L; Morel P; Lefrancq H 
Address 
Service Dermatologie, H^opital Saint-Louis, Paris. 
Source 
Ann Dermatol Venereol, 125(8):496-9 1998 Aug 
Abstract 
OBJECTIVE: Acne flare-ups are frequent in the early phase of isotretinoin 
treatment. Severity varies from one patient to another. Clinical factors 
favoring a potentially severe course were assessed on the basis of 6 cases. 
CASE REPORTS: Six male patients, mean age 16.5 years, with inflammatory 
acne with a major retentional component were studied. Isotretinoin 
administered at a daily dose 0.5 mg/kg led to explosive development of 
massive nodulocystic lesions or pyogenic granulomas within two months. The 
lesions healed at withdrawal of isotretinoin and administration of 
antibiotics and antiinflammatory drugs. There was important scar sequellae. 
DISCUSSION: Four concomitant factors were identified which contribute to 
the development of acne flare-ups: sex (male), young age, retentional form 
of acne and daily isotretinoin dose 0.5 mg/kg. 
Language 

============================================================ 
5.) Acne fulminans and erythema nodosum during isotretinoin therapy 
responding to dapsone. 
============================================================ 
Author 
Tan BB; Lear JT; Smith AG 
Address 
Department of Dermatology, Central Outpatients, Stoke-on-Trent, UK. 
Source 
Clin Exp Dermatol, 22(1):26-7 1997 Jan 
Abstract 
Acne vulgaris is very common, 85% of teenagers being affected at any one 
time. In most cases, the disease is mild and patients do not present to the 
dermatologist. Most are instead treated with over-the-counter products and 
conventional treatment such as peeling agents or topical and systemic 
antibiotics. Isotretinoin has revolutionized the treatment of severe acne 
unresponsive to oral antibiotics. Explosive and very severe acne such as 
pyoderma faciale, acne conglobata and acne fulminans are rare, the features 
that distinguish acne fulminans from the other conditions being systemic 
upset with fever, joint pain, malaise and leucocytosis, while there have 
been two reports of the condition associated with erythema nodosum. The 
recommended treatment for acne fulminans is a combination of oral steroids 
and systemic antibiotics, isotretinoin probably not being the treatment of 
choice. We now report a patient who developed acne fulminans and erythema 
nodosum within 3 weeks of starting isotretinoin and then responded to 
dapsone without oral steroids. 

============================================================ 
6.) [Muscular damage during isotretinoin treatment] 
============================================================ 
Author 
Heudes AM; Laroche L 
Address 
Unit´e d'Immuno-Dermatologie, Universit´e de Paris XIII, H^opital Avicenne, 
Bobigny. 
Source 
Ann Dermatol Venereol, 125(2):94-7 1998 Feb 
Abstract 
BACKGROUND: The effect of isotretinoin on muscle is considered to be 
uncommon and benign. We analyzed the files of all our patients given 
isotretinoin over a 5-year period and determined the incidence and gravity 
of its effect on muscles. MATERIALS AND METHODS: Sixty treatments with 
isotretinoin were studied. Myalgia and elevated CPK observed at the 
pretherapeutic consultation and each month or 2 months thereafter were 
recorded. RESULTS: Muscle symptoms were noted in 60 p. 100 of the cases: 
myalgia in 51 p. 100 and elevated CPK in 41 p. 100. In this group, male sex 
(H/F = 2.6) and sports activities (70 p. 100) were found more often. In 5 
patients, CPK level was 5 times the normal, defining rhabdomyolysis. One 
patient interrupted treatment because of persistently high CPK levels. 
DISCUSSION: Myalgia and elevated CPK signal skeletal muscle involvement. 
These signs were more frequent in our series than in reports in the 
literature, probably because we systematically looked for them. Besides use 
of isotretinoin, one case of viral infection and sports activities, no 
other explanatory cause could be found. Isotretinoin could have a 
potentializing effect on other myotoxicity inducers (drugs, infection, 
fever, muscular exertion...). The benign nature of the muscle effect 
appears to be validated although there were some patients who had 
persistent and/or severe signs. 

============================================================ 
7.) [Lung disease induced by isotretinoin] 
============================================================ 
TO: Pneumopathie induite par l'isotretinoine. 
AU: Oliviero-G; Constans-P; Caby-I; De-Rohan-Chabot-P; Lacherade-JC 
AD: Service de Pneumologie et Medecine Interne, CHG Longjumeau. 
SO: Rev-Mal-Respir. 1995; 12(6): 631-3 
ISSN: 0761-8425 
PY: 1995 
LA: FRENCH; NON-ENGLISH 
CP: FRANCE 
AB: A young man without any past history of note had taken isotretinoin for 
disfiguring acne before the summer season. He presented with a severe 
bilateral pneumonia, associated with dyspnoea two months after the start of 
treatment. On the pulmonary radiography there was a bilateral ground glass 
appearance which was worse on the right. The elevated level of eosinophils 
(54% in 564,000 cells/ml) in the alveolar lavage lead to a diagnosis of 
allergic pneumonia. The rapidly favourable outcome following the cessation 
of the medication and with the addition of corticosteroids seemed to us a 
supplementary argument in favour of a diagnosis of eosinophilic pneumonia, 
due to isotretinoin which seemed the primary initiating factor. 

============================================================ 
8.) Vestibular dysfunction in a child with embryonic exposure to accutane. 
============================================================ 
AU: Westerman-ST; Gilbert-LM; Schondel-L 
AD: Hahnemann Medical College, Philadelphia, Pennsylvania, USA. 
SO: Am-J-Otol. 1994 May; 15(3): 400-3 
ISSN: 0192-9763 
PY: 1994 
LA: ENGLISH 
CP: UNITED-STATES 
AB: Children with a history of embryonic exposure to Accutane 
(isotretinoin) are at great risk for major physical malformations, brain 
malformations, and decreased intelligence. A case is presented of a 4-year 
7-month-old black male with a history of embryonic exposure to Accutane who 
was born with embryopathy that includes bilateral major ear deformities. 
The child has a significant bilateral conductive hearing loss, and, in 
addition, a left sided sensorineural loss. Vestibular function testing 
revealed evidence of peripheral and central vestibular dysfunction. A 
course of diphenhydramine hydrochloride and Donnatal (phenobarbital, 
hyoscyamine sulfate, atropine sulfate, and scopolamine hydrobromide) 
significantly alleviated the symptoms of vestibular dysfunction. Otologic 
management of these children should include clinical documentation of the 
external deformities, evaluation of cochlear function, and early auditory 
habilitation. Vestibular function should also be evaluated in all children 
with a history of embryonic exposure to isotretinoin. 

============================================================ 
9.) Extraspinal enthesopathy caused by isotretinoin therapy. 
============================================================ 
J Manipulative Physiol Ther 1999 Jul-Aug;22(6):417-20 

Brandt JR, Mick TJ 
Department of Radiology, Northwestern College of Chiropractic, Bloomington, 
MN 55431-1599, USA. 

OBJECTIVE: To discuss a case of diffuse peripheral enthesopathy in a 
patient previously treated with long-term isotretinoin (Accutane) for 
severe acne. CLINICAL FEATURES: A 47-year old man with 1 month history of 
moderate neck and right upper extremity pain, with hypoesthesia of the 
right second and third fingers. Palpable bony prominences around multiple 
superficial joints were noted on physical examination, raising the initial 
question of osteochondromatosis. Multiple active acne pustules were noted. 
A limited skeletal survey demonstrated diffuse peripheral enthesophyte 
formation and hyperostoses, resembling those of diffuse idiopathic skeletal 
hyperostosis, but without accompanying spinal changes. A history of 
long-term Accutane therapy was then elicited. INTERVENTION AND OUTCOME: The 
enthesopathy was believed to represent an asymptomatic, longstanding, 
iatrogenically induced abnormality. No specific therapy or follow-up was 
indicated. The patient had discontinued use of Accutane years ago. Cervical 
symptoms improved with four sessions of cervical traction and nonsteroidal 
anti-inflammatory medications, but upper extremity symptoms were 
refractory. CONCLUSION: Accutane-induced enthesopathy should be considered 
in individuals with correlating radiologic and clinical features and 
history of retinoic acid therapy for acne. This should be a diagnosis by 
exclusion, after eliminating other potential causes of peripheral 
enthesopathy, particularly diffuse idiopathic skeletal hyperostosis, 
seronegative spondylarthropathy, and fluorosis. 

============================================================ 
10.) Retinoid-induced ossification of the posterior longitudinal ligament. 
============================================================ 
Skeletal Radiol 1985;14(3):191-3 

Pennes DR, Martel W, Ellis CN 
Vitamin A and its synthetic congeners are known to produce a variety of 
skeletal abnormalities in patients on prolonged treatment with these 
medications. Two patients are described who developed posterior 
longitudinal ligament ossification following treatment with the synthetic 
retinoid 13-cis-retinoic acid. In both cases, this finding became apparent 
after other retinoid-induced skeletal abnormalities were observed and was 
less marked than the ossification of the anterior longitudinal ligament. 
Although spinal cord compression did not occur in our patients, patients on 
long-term retinoid therapy should be carefully observed for this 
complication. 

============================================================ 
11.) Isotretinoin-induced vasculitis imitating polyarteritis nodosa, with perinuclear antineutrophil cytoplasmic antibody in titers correlated with clinical symptoms. 
============================================================ 
Chochrad D; Langhendries JP; Stolear JC; Godin J 
Internal Medicine Department, Tournai Medical and Surgical Institute, 
Belgium. 
Rev Rhum Engl Ed (FRANCE) Feb 1997 64 (2) p129-31 ISSN: 0035-2659 
Language: ENGLISH 
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9708 
Subfile: INDEX MEDICUS 
The adverse effects of retinoids on bones and joints are being 
increasingly documented. A case is reported in which isotretinoin was 
considered responsible for polyarteritis-like vasculitis. Perinuclear 
antineutrophil cytoplasmic antibodies were present in titers that 
correlated with clinical and laboratory test abnormalities. 

==============================================================
12.) Depression and suicide in patients treated with isotretinoin.
==============================================================
N Engl J Med 2001 Feb 8;344(6):460 

Wysowski DK, Pitts M, Beitz J.

Publication Types: 
Letter 
==============================================================
==============================================================
13.) Isotretinoin treatment alters steroid metabolism in women with acne.
==============================================================
Br J Dermatol 1991 Apr;124(4):361-4 

Rademaker M, Wallace M, Cunliffe W, Simpson NB.

Department of Dermatology, Glasgow Royal Infirmary, U.K.

The effect of isotretinoin (Roaccutane) on serum steroids and urinary steroid metabolites was investigated in seven female patients receiving the drug for treatment of severe acne over a 16-week period. Serum concentrations of dehydroepiandrosterone sulphate (DHAS), androstenedione (A2), and free androgen index (FAI) were not significantly altered. There was a significant fall in testosterone during treatment and a significant reduction in the 24 h urinary excretion of androsterone, tetrahydrocortisone (THE) and tetrahydrocortisol (THF) from week 8 onwards and for aetiocholanolone and allo-THF from week 12 (P less than 0.05). Although pretreatment levels of urinary steroid metabolites were not abnormal, the ratios of the 5 alpha/5 beta metabolites (androsterone:aetiocholanolone and allo-THF:THF) were at the upper limit of the reference range and were lowered after treatment, suggesting that 5 alpha-reductase activity is sensitive to isotretinoin.

==========================================================
14.) ISOTRETINOIN (eye-so-TRET-i-noin): 
==========================================================
Source: www.medformation.com

Treats severe acne and other skin conditions. This medicine is related to vitamin A. 

BRAND NAME(S): Accutane®

WHEN YOU SHOULD NOT USE THIS MEDICINE: 
You should not use this medicine if you have had an allergic reaction to isotretinoin, or if you are pregnant or plan to become pregnant during your treatment.

HOW TO USE AND STORE THIS MEDICINE 
Capsules: 

Your doctor will tell you how much of this medicine to take and how often. Do not take more medicine or take it more often than your doctor tells you to. 
It is best to take this medicine with food or milk. Swallow the capsules whole. Do not break, crush, or chew them. 
This medicine comes with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions. Your doctor may ask you to sign some forms to show that you understand this information. 
Store the medicine at room temperature, away from heat and direct light. 
Keep all medicine away from children and never share your medicine with anyone. 
If you miss a dose:

If you miss a dose or forget to take your medicine, take it as soon as you can. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. 
Do not use extra medicine to make up for a missed dose. 

DRUGS AND FOODS TO AVOID: 

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.

Make sure your doctor knows if you are using tetracycline antibiotics or any vitamin A supplements. 
Do not drink alcohol while you are using this medicine. Avoid skin treatments or wax hair removal while you are using this medicine and for at least 6 months after your last dose. 

WARNINGS:

Using this medicine while you are pregnant can harm your unborn baby. Use two forms of birth control for 1 month before starting this medicine and for 1 month after your last dose. If you think you have become pregnant while using the medicine, tell your doctor right away. 
Make sure your doctor knows if you are breastfeeding, or if you have diabetes, heart disease, alcoholism, allergies, asthma, liver disease, a history of mental illness, or other medical problems. 
At first, your skin problems may get worse for a short time before starting to improve. Your acne may continue to improve even after you stop taking this medicine. 
Do not donate blood while taking this medicine or for 1 month after your last dose. 
This medicine may make your skin more sensitive to sunlight. Use a sunscreen when you are outdoors. Avoid sunlamps and tanning beds. 
This medicine may cause you to have trouble seeing in dim light or darkness. Be careful when driving a car or using machinery. 
Your doctor will need to check your progress at regular visits while you are using this medicine. Be sure to keep all appointments. 
SIDE EFFECTS 
Call your doctor right away if you have any of these side effects:

Allergic reaction: Itching or hives, swelling in face or hands, swelling or tingling in the mouth or throat, tightness in chest, trouble breathing 
Depressed mood, irritability, unusual behavior, thoughts of hurting yourself 
Hearing problems or ringing in the ears 
Severe diarrhea, nausea, or stomach pain 
Severe headache, blurred vision, dizziness, nausea, vomiting 
Yellow skin or eyes 
If you have problems with these less serious side effects, talk with your doctor.

Dry, cracked lips, mouth, or nose, or dry eyes 
Dry, itching, or peeling skin 
Muscle or joint pain or aching 
Trouble wearing contact lenses 

IF YOU HAVE OTHER SIDE EFFECTS THAT YOU THINK ARE CAUSED BY THIS MEDICINE, TELL YOUR DOCTOR.

==============================================================
14.) Mass mailing warns of Accutane's psychiatric risks
==============================================================
Source: www.usatoday.com

06/19/2001 - Updated 03:23 PM ET 

By Rita Rubin, USA TODAY

Under pressure from the Food and Drug Administration, the maker of the popular acne medication Accutane is sending information about the drug's link to mental problems to every dermatologist, family physician, psychiatrist and pharmacist in the country.

Hoffmann-La Roche this week began mailing copies of a plain-English "medication guide" and a patient consent form detailing the link, spokeswoman Melissa Ziriakus said Thursday. Both documents are posted on the FDA's Web site.

The FDA requires medication guides for products it believes pose serious risks that can be reduced by informing patients. Only a handful of other drugs, including Mifeprex, or RU486, the so-called abortion pill, have such guides. Pharmacists are to dispense the Accutane medication guide with the pills.

Accutane, sold since 1982 for the treatment of severe acne, was Roche's second-best-selling U.S. drug in 1999; sales totaled nearly $500 million. Rocephin, an antibiotic, was first.

Accutane's package insert has noted links to depression since 1986 and to suicide since May. As of early December, the FDA had received reports of 66 suicides and 1,373 cases of psychiatric problems among users.

But patients often don't read the fine print. In recent months, parents of many Accutane users who attempted or committed suicide have come forward to say their doctors never told them the drug might cause mental problems. They include Rep. Bart Stupak, D-Mich., whose son, 17, killed himself in May. If the consent form and guide are distributed as required, Stupak says, "I think you'll never find a situation like my wife and I experienced."

Besides the link to mental problems, the medication guide details the well-documented risk of birth defects in babies of mothers who took Accutane while pregnant.

The new consent form, devoted mainly to psychiatric problems, is to be completed by the patient or a parent or guardian and signed by the prescriber. In addition, a consent form outlining the risk of birth defects will continue to be given to female patients. Without completed consent forms, Accutane prescribers could be liable if a patient develops problems.

Accutane's maker still does not believe it can cause mental problems, Ziriakus says.

==============================================================
15.) New Measures to Manage Risks Associated With Accutane
==============================================================
Source: JAMA Vol. 285 No. 9,
March 7, 2001


Bernard A. Schwetz, DVM, PhD
Acting Principal Deputy Commissioner
Food and Drug Administration

The FDA and Hoffmann-La Roche Inc, Nutley, NJ, have developed a new informed consent form and a medication guide to strengthen protection for patients who use isotretinoin (Accutane) to treat severe recalcitrant nodular acne.

The informed consent form is available from the manufacturer and is to be completed by the patient or the patient's parent or guardian and signed by the health care practitioner. It includes the patient's agreement to fully inform the prescriber about any history of mental depression and to see the practitioner monthly while taking Accutane to renew the prescription and check treatment progress and possible signs of adverse effects.

The medication guideto be dispensed with each filled prescriptionsummarizes important information from the professional labeling. It emphasizes the possible association of Accutane with psychiatric problems and suicideat least 66 Accutane users have committed suicideand the well-established risk of Accutane-induced birth defects.

The guide warns that the drug, which is contraindicated for use by pregnant women, poses "an extremely high risk" that the infant of a woman taking Accutane "will be deformed or will die" and that sexually active women of childbearing potential "must use two separate effective forms of birth control at the same time" 1 month before, while, and 1 month after taking the drug. Additional measures to strengthen the existing program to prevent patients from becoming pregnant while taking Accutane are in development.

============================================================== 
16.) What is the most important information I should know about isotretinoin?
==============================================================
Source:http: //content.health.msn.com/

o Isotretinoin is a medication taken to treat severe nodular acne that has not been helped by other treatments, including antibiotics. However, isotretinoin can cause serious side effects. Before starting treatment with isotretinoin, discuss with your doctor how bad the acne is, the possible benefits of isotretinoin, and the possible side effects. Your doctor will ask you to read and sign a form indicating that you understand the serious risks associated with isotretinoin therapy.
o Do not take isotretinoin if you are pregnant or if you could become pregnant during treatment or for one month after you stop taking isotretinoin. Isotretinoin is in the FDA pregnancy category X. This means that isotretinoin is known to cause severe birth defects in an unborn baby. It can also cause miscarriage, premature birth, or death of the baby. You must take a pregnancy test and have negative results when you and your doctor decide that isotretinoin may be beneficial for your condition. You must have a second pregnancy test with negative results during the first 5 days of the menstrual period right before you start taking isotretinoin. Two reliable forms of birth control must be used at the same time (unless abstinence is the chosen method of birth control or if you have undergone a hysterectomy) for one month before starting treatment with isotretinoin, during treatment with isotretinoin, and for at least 1 month following the end of treatment. You will also be asked to take a pregnancy test on a monthly basis. Your doctor will discuss with you and provide for you a video and written information regarding choices for birth control, possible causes for birth control failure, and the importance of using birth control while taking isotretinoin. If you become pregnant, stop using birth control, or miss your menstrual period, immediately stop taking isotretinoin and notify your doctor. 
o Some patients have experienced depression (including feelings of sadness, irritability, unusual tiredness, trouble concentrating, and loss of appetite) and suicidal thoughts and / or behavior during, and soon after stopping, treatment with isotretinoin. Notify your doctor immediately if you begin to experience signs of depression or if you begin to have thoughts about taking your own life during or shortly following treatment with isotretinoin.
o Do not take vitamin supplements containing vitamin A during treatment with isotretinoin. This could cause increased side effects.
o Do not donate blood while taking isotretinoin and for at least 1 month following the end of treatment. Blood donated while taking isotretinoin may be given to a pregnant woman and be harmful to her baby.
o Do not use wax hair removal systems or have any skin resurfacing procedures (such as dermabrasion or laser treatment) performed while taking isotretinoin and for six months following treatment due to the possibility of scarring.
o Avoid exposure to sunlight or UV rays while taking isotretinoin. Isotretinoin may increase the sensitivity of the skin to sunlight and a severe sunburn could result.
o Use caution when driving a vehicle at night. Isotretinoin can cause decreased night vision. The onset of decreased night vision may be sudden.
o Take all of the isotretinoin that has been prescribed for you even if your symptoms start to improve. The acne may seem to get worse at the start of therapy, but should then begin to improve. For the best results, finish all of the medication that has been prescribed. You may require more than one course of therapy with isotretinoin.
Back to Top What is isotretinoin?
o Isotretinoin is a form of vitamin A. It decreases the amount of sebum (oil) that is released by the sebaceous (oil) glands, and it increases that rate at which the skin renews itself.
o Isotretinoin is used to treat severe nodular acne that has not responded to other treatments, including antibiotics.
o Isotretinoin may also be used for purposes other than those listed in this medication guide.
Back to Top What should I discuss with my healthcare provider before taking isotretinoin?
o Before taking isotretinoin, tell your doctor if you have
· a personal or family history of mental problems including depression, suicidal behavior, or psychosis (loss of contact with reality, hearing voices, or seeing things that are not there);
· diabetes;
· asthma;
· heart disease;
· osteoporosis (bone loss) or weak bones;
· anorexia nervosa;
· high cholesterol or triglyceride levels (types of fat) in the blood; or
· liver disease.
o You may not be able to take isotretinoin, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.
o Do not take isotretinoin if you are pregnant or if you could become pregnant during treatment or for one month after you stop taking isotretinoin. Isotretinoin is in the FDA pregnancy category X. This means that isotretinoin is known to cause severe birth defects in an unborn baby. It can also cause miscarriage, premature birth, or death of the baby. You must take a pregnancy test and have negative results when you and your doctor decide that isotretinoin may be beneficial for your condition. You must have a second pregnancy test with negative results during the first 5 days of the menstrual period right before you start taking isotretinoin. Two reliable forms of birth control must be used at the same time (unless abstinence is the chosen method of birth control or if you have undergone a hysterectomy) for one month before starting treatment with isotretinoin, during treatment with isotretinoin, and for at least 1 month following the end of treatment. You will also be asked to take a pregnancy test on a monthly basis. Your doctor will discuss with you and provide for you a video and written information regarding choices for birth control, possible causes for birth control failure, and the importance of using birth control while taking isotretinoin. If you become pregnant, stop using birth control, or miss your menstrual period, immediately stop taking isotretinoin and notify your doctor. 
o It is not known whether isotretinoin passes into breast milk. Do not take isotretinoin without first talking to your doctor if you are breast-feeding a baby.
Back to Top How should I take isotretinoin?
o Take isotretinoin exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.
o Isotretinoin is a medication taken to treat severe nodular acne that has not been helped by other treatments, including antibiotics. However, isotretinoin can cause serious side effects. Before starting treatment with isotretinoin, discuss with your doctor how bad the acne is, the possible benefits of isotretinoin and the possible side effects. Your doctor will ask you to read and sign a form indicating that you understand the serious risks associated with isotretinoin therapy.
o You will get no more than a 30-day supply of isotretinoin at a time. Your prescription should have a special yellow self-adhesive sticker attached to it. If your prescription does not have this yellow sticker, call your doctor. The pharmacy should not fill the prescription without this sticker. 
o Take each dose of isotretinoin with a full glass of water. This will help prevent the medication inside the capsule from irritating the lining of the esophagus. For the same reason, do not chew or suck on the capsule.
o Take isotretinoin twice a day with food or milk to get the best results from this medication, unless otherwise directed by your doctor.
o Take all of the isotretinoin that has been prescribed for you even if your symptoms start to improve. The acne may seem to get worse at the start of therapy, but should then begin to improve. For the best results, finish all of the medication that has been prescribed. You may require more than one course of therapy with isotretinoin.
o Your doctor may perform blood tests during treatment with isotretinoin to monitor side effects from this medication.
o Due to the serious side effects that may occur with the use of this medication, do not share it with anyone else.
o Store isotretinoin at room temperature away from moisture and heat.
Back to Top What happens if I miss a dose?
o Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and only take the next regularly scheduled dose. Do not take a double dose of this medication.
Back to Top What happens if I overdose?
o Seek emergency medical attention.
o Symptoms of an isotretinoin overdose include vomiting, abdominal pain, flushing of the face, inflammation of the lips, headache, dizziness, and clumsiness.
Back to Top What should I avoid while taking isotretinoin?
o Do not take vitamin supplements containing vitamin A during treatment with isotretinoin. This could cause increased side effects.
o Do not donate blood while taking isotretinoin and for at least 1 month following the end of treatment. Blood donated while taking isotretinoin may be given to a pregnant woman and be harmful to her baby.
o Do not use wax hair removal systems or have any skin resurfacing procedures (such as dermabrasion or laser treatment) performed while taking isotretinoin and for six months following treatment due to the possibility of scarring.
o Avoid exposure to sunlight or UV rays while taking isotretinoin. Isotretinoin may increase the sensitivity of the skin to sunlight and a severe sunburn could result.
o Use caution when driving a vehicle at night. Isotretinoin can cause decreased night vision. The onset of decreased night vision may be sudden.
Back to Top What are the possible side effects of isotretinoin?
o Stop taking isotretinoin and seek emergency medical attention or contact your doctor immediately if you experience any of the following serious side effects:
· an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);
· changes in vision, blurred vision, or decreased vision (especially at night);
· painful or constant dryness of the eyes;
· depression including feelings of sadness, crying spells, irritability, changes in sleep patterns, unusual tiredness, trouble concentrating, loss of appetite, and / or suicidal thoughts or other mental problems;
· stomach, chest, or bowel pain;
· rectal bleeding, or severe or bloody diarrhea;
· difficulty or pain when swallowing;
· new or worsening heartburn;
· yellowing of the skin or eyes or persistently dark urine;
· severe headache or dizziness;
· seizures;
· nausea and vomiting;
· joint or muscle pain or bone problems;
· hearing problems or hearing loss;
· trouble breathing;
· fainting;
· increased thirst or urination;
· slurred speech or problems moving;
· leg swelling;
· increased levels of cholesterol or triglyceride (types of fat) in your blood (detected by blood tests).
o Other, less serious side effects are more likely to occur. Continue to take isotretinoin and talk to your doctor if you experience
· inflammation, dryness, or cracking of the lips;
· dry skin, dry mouth, dry or bleeding nose, dryness of the eyes and / or difficulty wearing contact lenses;
· itching; or
· increased sensitivity of the skin to the sun.
o Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
Back to Top What other drugs will affect isotretinoin?
o Do not take any of the following medicines while taking isotretinoin:
· vitamin supplements containing vitamin A; or
· a tetracycline antibiotic such as tetracycline (Sumycin, Achromycin, Panmycin, Robitet, others), minocycline (Minocin, Dynacin, Vectrin), doxycycline (Doryx, Monodox, Vibramycin, Vibra-Tabs), demeclocycline (Declomycin), or troleandomycin (TAO).
o Taking any of the drugs listed above during treatment with isotretinoin may be dangerous.
o Before taking isotretinoin, tell your doctor if you are taking carbamazepine (Tegretol, Carbatrol, Epitol). You may require a dosage adjustment or special monitoring during treatment.
o Do not use other acne medications unless otherwise directed by your doctor. They may interfere with the treatment or increase irritation of the skin.
o Do not take birth control pills that do not contain estrogen ("minipills") during treatment with isotretinoin. They may not work while taking isotretinoin.
o Drugs other than those listed here may also interact with isotretinoin. Talk to your doctor or pharmacist before taking any prescription or over-the-counter medicines, including herbal products.
Back to Top Where can I get more information?
o Your pharmacist has additional information about isotretinoin written for health professionals that you may read.

Back to Top Brand Names:
o Accutane 
Back to Top Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. The information in this leaflet is not intended to cover all 

==============================================================
17.) Accutane's Safety Labeling Revised for Psychiatric Disorders, Other Warnings
==============================================================
Source:www.medscape.com

Medscape Staff Report

Nov. 1, 2002 — Roche Laboratories and the U.S. Food and Drug Administration (FDA) have extensively revised the safety labeling for isotretinoin (Accutane). The acne drug's labeling has changed regarding warnings for psychiatric disorders, warnings for pediatric patients, and a new table to clarify when pregnancy tests and Accutane Qualification stickers are needed.

In a letter to Accutane prescibers, Roche details the additions to the labeling. Under the heading Warnings: Psychiatric, "aggressive and/or violent behaviors have been added to the list of events that Accutane may cause."

For pediatric patients with a family history of age-related osteoporosis or a personal history of bone metabolism disorders, prescribers are warned to be cautious when prescribing Accutane. In addition, pediatric patients who receive Accutane and participate in repetitive-impact sports may be at risk of fracture, spondylolisthesis with and without pars fractures, and hip growth plate injuries. The new labeling also notes that "29% of pediatric patients treated with Accutane in the studies developed back pain and 22% experienced arthralgias."

Systemic corticosteroids and phenytoin both have been added under the Drug Interactions section of Precautions and prescribers for pediatric patients are advised to use caution with these drug combinations. In addition, Roche recommends that patients receive Accutane at the recommended dose and no longer than the recommended duration.

Under Contraindications and Warnings, a new table was added that identifies the need for pregnancy tests and accutane qualification stickers for different patient populations: men, women of child-bearing age, and women of non-child-bearing age.

For more information, healthcare professionals may contact Roche at 1-800-526-6367. The full text of the revised label is available in PDF format on the FDA Web site at http://www.fda.gov/medwatch/SAFETY/2002/accutane_PI_6-02.pdf.

Reviewed by Gary D. Vogin, MD
==============================================================
18.) Accutane®-Exposed PregnanciesCalifornia, 1999
============================================================== 
Source: archives of dermatology / Vol. 136 No. 5, May 2000


ACCUTANE®* (ROCHE Laboratories, Nutley, New Jersey), known by the generic name "isotretinoin," is a prescription oral medication approved by the Food and Drug Administration (FDA) to treat severe, recalcitrant nodular acne.1 It is also a known human teratogen that can cause multiple major malformations. Embryopathy associated with the mother's exposure to isotretinoin during the first trimester of pregnancy includes craniofacial, cardiac, thymic, and central nervous system malformations.2, 3 In response to FDA recommendations,4 the manufacturer began a pregnancy-prevention program (PPP) in 1988 that included educational materials for physicians and patients and offered women reimbursement for contraceptive counseling by a physician. The PPP coordinators asked reproductive-aged women being treated with isotretinoin to enroll voluntarily in the Boston University Accutane Survey (BUAS).5 The total number of reproductive-aged women taking isotretinoin in the United States is unknown; however, 454,273 women enrolled in the BUAS from 1989 to October 1999. BUAS has estimated that 38%-40% of reproductive-aged women taking isotretinoin chose to enroll in the survey (BUAS, unpublished data, 1999). Although isotretinoin is contraindicated in pregnancy and has a package label warning users to avoid pregnancy while taking it, exposed pregnancies occur.5-7 Approximately 900 pregnancies occurred among BUAS enrollees during 1989-1998 (BUAS, unpublished data, 1999). Roche Laboratories began direct-to-consumer print advertisements in 1996, added television and radio advertisements to selected cities in 1997, and expanded the campaign to the entire United States in 1998.

During March 1999, CDC interviewed women who had had recent isotretinoin-exposed pregnancies. The objective of the study was to draw attention to the continued occurrence of isotretinoin-exposed pregnancies 11 years after the inception of the PPP and to learn more about why these exposed pregnancies happened. California was selected as the study site because of its large population and the availability of referrals from the California Teratogen Information Service and Clinical Research Center (CTIS). This report summarizes the results of the study, which suggest that some isotretinoin-exposed pregnancies can be prevented. The case reports describe the experiences of three study respondents.



Summary of Interviews



Eligible women resided in California, used isotretinoin while pregnant, had their last menstrual period after January 1, 1997, and reported their pregnancy to the BUAS or to the CTIS. Twenty-three women met these criteria; 14 consented to be interviewed. The nine eligible women who did not respond or declined to participate were enrolled in the BUAS. Two of the 14 respondents had pregnancies reported to both the BUAS and the CTIS. Nine respondents were interviewed in person and five by telephone. The interview included questions on indications for and use of isotretinoin, contraceptive history, pregnancy history, procedures used in the initial prescription of isotretinoin, and recall of advertisements for prescription acne medication.

The 14 respondents were aged 15-39 years at the time of the exposed pregnancy (median age: 25.5 years); 10 (71%) were aged 21-39 years. Eight (57%) reported having at least one instance of sexual intercourse without using contraception at the time of the exposed pregnancy; 13 (93%) did not use two forms of contraception as recommended in the PPP procedures. Ten had pregnancy tests before starting isotretinoin; however, three whose pregnancy test results were negative were pregnant when they began taking isotretinoin. Two respondents reported that their exposed pregnancies occurred while using leftover isotretinoin from earlier prescriptions, and one received and filled the isotretinoin prescription in Mexico.

Seven (50%) respondents reported viewing an advertisement for prescription acne treatment before taking isotretinoin. Four of the seven reported that the advertisement contributed to their decision to seek acne treatment and to ask their physician about isotretinoin. Four live-born infants with no major malformations resulted from these 14 pregnancies. One live-born infant had major malformations. The other pregnancy outcomes were four spontaneous abortions and five induced abortions. No information was available on the presence of malformations in the aborted fetuses.

Although all 14 respondents knew that isotretinoin should not be used during pregnancy, none reported seeing all components of the PPP, and four had not seen any component other than the information available on the isotretinoin packet. None of the women reported being referred for contraceptive counseling or being told that they would not have to pay for the counseling.




Case Reports



Case 1

After taking isotretinoin for 1 month, a 25-year-old woman was notified by her dermatologist that her pregnancy test was positive, despite negative results on a pregnancy test before beginning isotretinoin. She had been using two forms of contraception but did not wait for menstruation before starting isotretinoin therapy as recommended by the PPP. Her infant was born with multiple anomalies including complex congenital heart disease consisting of double outlet right ventricle with dextrocardia and aortic atresia, hydrocephalus, and facial dysmorphism. After extensive medical treatment and cardiac surgery, the infant died at age 9 weeks.

Case 2

A 35-year-old woman who had been taking isotretinoin for approximately 6 months tested positive on a home pregnancy test. She was 12 weeks pregnant when she discontinued isotretinoin use. Since 1989, she had had three isotretinoin-exposed pregnancies; only the third pregnancy resulted in a live birth. The first course of isotretinoin was prescribed by a dermatologist; she obtained the other prescriptions from a friend who was a health-care worker. The outcome of the third exposed pregnancy was a full-term infant with no apparent malformations.

Case 3

A 35-year-old woman who was using an intrauterine device tested positive on a home pregnancy test. She had been taking isotretinoin for approximately 3 years before this pregnancy and had taken two doses of isotretinoin since her last menstrual period. She did not have acne. She took isotretinoin for approximately 1 week each month before menstruation to prevent oily skin. She was a health-care provider and received the prescription from a colleague who did not ask about or recommend contraception. She elected to terminate the pregnancy because of the exposure.

Reported by:

CD Chambers, MPH, KL Jones, MD, Dept of Pediatrics, Div of Dysmorphology and Teratology, Univ of California, San Diego, La Jolla; EJ Lammer, MD, Children's Hospital, Oakland, California. CM Van Bennekom, MPH, AA Mitchell, MD, Slone Epidemiology Unit, Boston Univ, Boston, Massachusetts. Birth Defects and Pediatric Genetics Br, Div of Birth Defects, Child Development, and Disability and Health (proposed), National Center for Environmental Health, CDC.

CDC Editorial Note:

These cases identified challenges to preventing isotretinoin-exposed pregnancies; 13 of the 14 respondents did not use two forms of effective contraception, and eight had used no contraception when the exposed pregnancy occurred. The study also illustrated problems with acquiring a prescription outside a clinical setting, using leftover medication, purchasing the medication outside the United States, failing to perform pregnancy testing before therapy, and failing to wait 3 days after menstruation before beginning treatment.5, 7

Although the 14 respondents did not represent all women taking isotretinoin or all women with isotretinoin-exposed pregnancies, they were similar to others enrolled in the BUAS (e.g., the average age of the respondents was similar to the women enrolled in the BUAS [median: 26 years])5; however, respondents included more women aged >30 years than in previous studies of isotretinoin-exposed pregnancies.6, 7 Seventy-one percent had some type of pregnancy test before starting isotretinoin, which is similar to the 60% reported for all women enrolled in the BUAS.5 The highest percentage of pregnancies in the BUAS occurred among women using oral contraceptives5; nevertheless, more than half the 14 respondents reported at least one instance of sexual intercourse when contraception was not used, indicating that failure to use contraception may be as important as contraceptive failure.

The warning label on isotretinoin packaging states that it should not be used by women of childbearing potential unless the patient meets such conditions as having "severe, disfiguring nodular acne that is recalcitrant to standard therapies".1 At least half of the 14 respondents reported that they did not meet this definition. Recent reports suggest that some dermatologists view isotretinoin as an effective method for treating conditions other than cystic acne.8, 9 More widespread use of isotretinoin may result in more isotretinoin-exposed pregnancies.

The findings in this study are subject to at least two limitations. First, these cases were a convenience sample of 14 women from California, and they may not represent all isotretinoin-exposed pregnancies. Second, the findings cannot be generalized to evaluate the overall effectiveness of the PPP or other prevention programs.

Despite the increased demand that may be generated by Accutane advertising,10 physicians should limit use of the drug in women of childbearing potential to those who meet the criteria on the package insert. When isotretinoin treatment is necessary, physicians should provide precautions, contraindications, and all PPP elements; care should be taken by women and their physicians to ensure that contraceptive recommendations are understood and followed. In addition, women of childbearing potential should not use isotretinoin unless they are under the care of a physician familiar with isotretinoin use.

MMWR. 2000;49:28-31.

*Use of trade names and commercial sources is for identification only and does not imply endorsement by CDC or the U.S. Department of Health and Human Services.



REFERENCES


1. Medical Economics Company. Physicians' desk reference. 53rd edition. Montvale, New Jersey: Medical Economics Company, 1999. 

2. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313:837-41. MEDLINE 

3. CDC. Birth defects caused by isotretinoinNew Jersey. MMWR. 1988;37:171-2,177. 

4. Dermatologic Drugs Advisory Committee. Open public hearings on NDA 18-662 Accutane (isotretinoin capsules) [Transcript]. Rockville, Maryland: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, 1988. 

5. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med. 1995;333:101-6. MEDLINE 

6. Pastuszak A, Koren G, Rieder MJ. Use of the retinoid pregnancy prevention program in Canada: patterns of contraception use in women treated with isotretinoin and etretinate. Reprod Toxicol. 1994;8:63-8. MEDLINE 

7. Atanackovic G, Koren G. Fetal exposure to oral isotretinoin: failure to comply with the pregnancy prevention program. CMAJ. 1999;160:1719-20. MEDLINE 

8. Cunliffe WJ, van de Kerkhof PCM, Caputo R, et al. Roaccutane treatment guidelines: results of an international survey. Dermatology. 1997;194:351-7. MEDLINE 

9. Newton JN. How cost-effective is oral isotretinoin? Dermatology. 1997;195:S10-S14. 

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19.) Current Trends Birth Defects Caused by Isotretinoin -- New Jersey 
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March 25, 1988 / 37(11);171-2,177 
Source: www.cdc.gov/

Between June 1983 and January 1987, four infants with isotretinoin embryopathy were born in New Jersey. Isotretinoin embryopathy consists of severe birth defects associated with first-trimester exposure to the synthetic retinoid isotretinoin (AccutaneTM*, Roche Laboratories, A Division of Hoffmann-La Roche, Inc.), which is used to treat severe, recalcitrant cystic acne. Two of the cases were reported to the New Jersey Birth Defects Registry. A third case was described in the pediatric literature (1). The fourth was identified through a teratologist currently investigating cases of isotretinoin embryopathy in the United States (Massachusetts General Hospital, unpublished data). These cases are similar to a larger number of cases that have been reported to the Food and Drug Administration (FDA) from all areas of the United States. 

Case 1: In June 1983, a 1,260 g female infant of 30 weeks gestation was born to a 22-year-old woman with no previous pregnancies. The woman had taken isotretinoin for 8 days when she was 4 to 6 weeks pregnant. Isotretinoin treatment had been stopped when the woman learned that she was pregnant. At birth, the infant had microcephaly, bilateral microphthalmia, and bilateral rudimentary pinnae. She died on the 28th day of life. Postmortem examination revealed lissencephaly, rudimentary pinnae, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and interrupted aortic arch (1). 

Case 2: In June 1985, a full-term male infant weighing 2,760 g was born to a 22-year-old woman who had taken isotretinoin during the first weeks of gestation. She had been counseled about the risk of drug-induced birth defects and had elected to carry the pregnancy to term. The infant had micrognathia, facial dysmorphism, missing ear lobes, Dandy-Walker malformation, and hearing and visual impairment. He now has severe mental retardation and developmental delay and requires institutional care. 

Case 3: In September 1986, a male infant of 27 weeks gestation was born to a woman who had taken isotretinoin during the second month of gestation. The infant had dysplastic external ears and hydrocephalus, which was treated with a ventriculo- peritoneal shunt. This abnormality is thought to be secondary to an intraventricular hemorrhage during the early neonatal period. 

Case 4: In January 1987, a full-term male infant weighing 3,558 g was born with dysplastic ears and hearing loss. His mother had been treated with isotretinoin during the first trimester of pregnancy. Reported by: M Knapp, MSN, RN, Special Child Health Svcs and New Jersey Birth Defects Registry; New Jersey State Dept of Health. Birth Defects and Genetic Diseases Br, Div of Birth Defects and Developmental Disabilities, Center for Environmental Health and Injury Control, CDC. 

Editorial Note: 

Isotretinoin was recognized as an animal teratogen before it was first marketed in September 1982. It was, therefore, classified by FDA as Category X, contraindicated for use during pregnancy. A statement to that effect was included in the package insert. 

In June 1983, human teratogenicity was reported to FDA and to the public (2). Subsequent reports have documented a strong association between a characteristic group of birth defects and exposure to isotretinoin during the first weeks of gestation (3,4). These defects include external ear malformations, cleft palate, micrognathia, conotruncal heart defects, ventricular septal defects, aortic-arch malformations, and certain brain malformations (3). In one prospective follow-up study, eight of 36 pregnancies that were exposed to isotretinoin resulted in spontaneous abortions during the first trimester; four resulted in live-born infants with at least one major malformation; one, in a malformed stillborn infant; and 23, in infants without major malformations (3). This study found a relative risk of 25.6 (95% confidence interval, 11.4 to 57.5) for the defects associated with isotretinoin embryopathy. 

Human birth defects also have been observed after prenatal exposure to etretinate (TegisonTM**, Roche Laboratories, A Division of Hoffmann-La Roche, Inc.), a drug approved in October 1986 for treatment of severe, recalcitrant psoriasis (2). Etretinate also carries Category X labeling. Measurable serum concentrations of this drug have been documented more than 2 years after cessation of therapy (5), and the risk of teratogenicity may extend for an indefinite period of time after therapy (6). 

Isotretinoin embryopathy is a preventable syndrome, and the number of infants born with these problems can be reduced by following the guidelines developed cooperatively by FDA and the manufacturer, Hoffmann-La Roche, Inc. This information is distributed in the form of package inserts and patient information leaflets. Current information for prescribing AccutaneTM and TegisonTM has been published in the 1988 Physicians' Desk Reference (7). A summary of these guidelines follows: 

Isotretinoin and etretinate should not be used by women who are pregnant or who may become pregnant while taking the drug. 

Pregnancy should be ruled out before treatment begins. This precaution may best be accomplished by obtaining a negative pregnancy test no more than 2 weeks prior to the beginning of therapy and starting therapy on the second or third day of the patient's next normal menstrual period. 

An effective form of contraception should be used for at least 1 month before therapy begins. 

Women who have received isotretinoin should continue using an effective form of contraception for 1 month after discontinuing treatment. 

The period of time during which pregnancy must be avoided after treatment is discontinued has not been determined for women who have received etretinate. 

Female patients should be counseled on the risk of major birth defects associated with first-trimester exposure to isotretinoin or etretinate. Should a pregnancy occur during treatment (or after treatment, in the case of etretinate), the woman should consult her physician about the management of her pregnancy. In addition, patients should be counseled not to share these prescription drugs with friends or family members. 

The approach suggested by these guidelines cannot be expected to prevent all fetal exposures. It can be anticipated that infants will be born with defects caused by first-trimester exposures to the synthetic retinoids isotretinoin and etretinate as long as these drugs are available for use. 


References 

de la Cruz E, Sun S, Vangvanichyakorn K, Desposito F. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 1984;74:428-30. 

Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986; 33:355-64. 

Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41. 

Rosa FW. Teratogenicity of isotretinoin (Letter). Lancet 1983;2:513. 

Food and Drug Administration. Etretinate approved. FDA Drug Bull 1986;16:16-7. 

Roche Laboratories. Tegison brand of etretinate/Roche capsules (Package Insert). Nutley, New Jersey: Hoffmann-La Roche, Roche Laboratories, 1986. 

Medical Economics Company. Physicians' desk reference. 42nd ed. Oradell, New Jersey: Medical Economics Company, 1988:1705,1746. *Use of trade names is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services or the Public Health Service. **Use of trade names is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services or the Public Health Service. 

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19.) July 2002 AADA letter to the FDA regarding Isotretinoin 
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July 16, 2002 
Source:www.aadassociation.org/

Jonathan Wilkin, M.D.
Director, Dermatologic and Dental Drug Products Division
U.S. Food and Drug Administration
N214 COR
9201 Corporate Boulevard
Rockville, Maryland 20850

Dear Dr. Wilkin:

On behalf of the American Academy of Dermatology Association, I am writing to continue the positive and useful dialogue established between the Food and Drug Administration and the AADA during the development and launch of the System to Manage Accutane Related Teratogenicity (SMART). 

Dermatologists are taking the SMART program seriously. According to Roche, 9,500 dermatologists are enrolled in the program. Indeed, more than 92 percent of Accutane prescribers have enrolled in this risk management program, and the majority of these prescribers are dermatologists. As experience with the SMART program grows, some of our members have asked valuable questions and made useful suggestions about components of the program. I would like to share these comments with you, in the hope that the FDA and AADA might collaborate on modifications to SMART that adhere to its purpose and goals.

What follows is a summary of comments and questions received so far:

Can the requirement for pregnancy testing be disassociated from a female patient’s menstrual cycle? Using a woman’s period as the gauge for when to administer the second, confirmatory pregnancy test is of no value if a woman does not have a period. Such cases include, but are not limited to, women on Depo Provera, women who use oral contraceptives to inhibit their menstrual cycle, or women who are post-menopausal. Keying pregnancy testing to the menstrual cycle is also of limited value for female patients whose periods are abnormally absent or suppressed because of amenorrhea. Indeed, the menstrual cycle can be a faulty counter-indicator of female patients’ pregnancy status. 

Of most importance is confirming that a female patient is not pregnant, not whether she has a period. Accordingly, it would be more useful for risk management purposes to conduct pregnancy testing for female patients 11 days after sexual intercourse, as is now required for patients who have an irregular period. If the patient is not sexually active, is a lesbian, has been surgically sterilized, or has not had sexual intercourse for a while, it then would be appropriate to simply conduct the confirmatory test 11 days after the first test. The sensitivity and reliability of the tests required by the SMART program make this approach a reasonable one. Of course, if a woman is having sexual intercourse, then the current guidelines would apply.

Clarification is needed on the administration of pregnancy tests. Specifically, do both the initial and the confirmatory tests need to be conducted in a physician’s office? 

Can the monthly pregnancy testing and birth control counseling requirements, and refill limits, be adjusted to accommodate women unable to visit their dermatologist on a monthly basis? Some women simply cannot visit their dermatologist on a monthly basis because they are attending college, are traveling executives, or the demands of their profession keep them away from home and/or their physician for long periods of time (e.g., military personnel). For these women, the mandatory monthly testing, counseling, and refill requirements – as presently written – may prevent them for starting Accutane therapy or else disrupt an ongoing course of treatment.

With respect to generic versions of Accutane, will the FDA subject generic isotretinoin products to the same regulatory scheme as that which now applies to Accutane? Will generic manufacturers be required to develop their own SMART-like programs? Will all materials from one isotretinoin risk management program be interchangeable with the materials from SMART-like program? How will prescribers know if a patient receives a generic or brand name isotretinoin product? 

A pressing administrative concern that impacts compliance with the SMART program are delays with managed care preauthorization for isotretinoin (when required) and how such delays impact the timing of initial and confirmatory pregnancy tests for female patients. Are the FDA and Roche reaching out to health plans to educate them on the new risk management program for isotretinoin, and the importance of handling preauthorizations in a timely manner? 
The AADA is committed to the safe and responsible use of Accutane for the treatment of severe acne, and is committed to the success of the SMART program. The FDA has been responsive to our concern that the risk management program not limit the ability of qualified patients, in consultation with their physicians, to receive this medication. We hope that this input is received in the spirit of collaboration, so that we may discuss the possibility of modifications to the SMART program when such changes are warranted.

We would like to schedule a meeting with you and the other members of the FDA’s SMART team to discuss the issues discussed above. Laura Saul Edwards of our Washington Office (202/8432-3555 or [email protected]) will be contacting you to arrange this meeting. 

Thank you for considering our views, and I look forward to meeting with you soon.

Sincerely,

Fred F. Castrow II, MD, President

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20.) Isotretinoin pregnancy prevention program undergoes significant changes 
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source:www.medicalsexuality.org/

Significant changes to a pregnancy prevention program involving isotretinoin (Accutane®, Hoffman-LaRoche) have been approved by the FDA. Isotretinoin was conclusively linked to birth defects and fetal death 13 years ago, when the program was initiated. Recent reports have shown that women taking the drug are still getting pregnant despite the potentially dangerous side effects. The recently approved program, System to Manage Accutane Related Teratogenicity (SMART), requires women on the drug to sign a consent form showing that they are aware of the potential risks and to take monthly pregnancy tests to show that they are not pregnant. 

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21.) US introduces new system for prescribing Accutane 
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Date: January 24, 2002 Time: 2:30 pm
source: www.cma.ca/cmaj/

A new and intensive pregnancy-prevention program aimed at women taking isotretinoin (Accutane) in the US likely isn't needed in Canada, Health Canada says. 
SMART, a system to manage Accutane-related teratogenicity, was launched in the US last November to manage "significant potential risks" — these include birth defects and fetal deaths — associated with the acne medication. The US Food and Drug Administration (FDA) has also issued its most stringent "black box" warning about the drug. 

Isotretinoin, manufactured by Roche Laboratories, is used to treat acne that is painful, permanently disfiguring and doesn't respond to other treatments. Since it was approved in the US in 1982, Roche has received nearly 2000 reports of pregnant women exposed to the drug; 70% of these occurred after Roche launched its own patient and physician education initiative, the Pregnancy Prevention Program, in 1988. 

The SMART program is meant to increase the number of safeguards with a new patient information/consent form and educational materials for physicians. Prescribers must also attach special yellow stickers to prescriptions to indicate to the pharmacist that the patient is "qualified" for the medication (i.e., has had negative pregnancy tests, education and counseling about pregnancy prevention). 

Furthermore, prescriptions are given for one month only; the patient must have a negative pregnancy test before each new prescription. In Canada, the Pregnancy Prevention Program is still used, but Health Canada says the incidence of pregnancy among Canadian women taking isotretinoin is much lower. "It's not an issue in Canada to the same extent," says spokesperson Ryan Baker. He wasn't sure why. 

Since the drug was approved in Canada in 1983, there have been 216 isotretinoin-related adverse drug reports (ADRs), but only 6 involve pregnancy. According to the ADRs, these resulted in the birth of 1 abnormal baby, 2 abortions and 1 still-birth. 

Despite these relatively low rates, Health Canada will still evaluate SMART to see if it's "applicable," Baker said. The Pregnancy Prevention Program requires female patients to use 2 reliable forms of contraception for 1 month before beginning isotretinoin therapy (unless abstinence is the chosen method). Two negative pregnancy tests must also be obtained prior to starting therapy, a monthly assessment is required and a negative pregnancy test must be obtained before prescriptions are renewed. Patients must also sign an informed consent form. 

The FDA estimates that 40% of women taking isotretinoin are sexually active. Birth defects include hydrocephaly, microcephaly, heart defects, facial deformities such as cleft lip and missing ears, and mental retardation. The FDA reports that 25% to 35% of exposed babies will suffer a malformation after exposure, and that doesn't account for other defects, such as learning disabilities, that aren't detectable at birth. 

Isotretinoin has also been linked to suicide ideation. According to Canadian ADRs posted since 1983, there have been 2 incidents of suspected isotretinoin-related suicide, 6 suicide attempts, 30 reports of depression, 10 reports of patients with suicidal tendencies and 3 reports of psychosis. 

Despite the risks, the drug remains very popular because of its effectiveness against acne, with Canadians spending nearly $40 million on it in 2000. 

— Barbara Sibbald, eCMAJ 

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22.) Mass mailing warns of Accutane's psychiatric risks
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source: www.usatoday.com/

By Rita Rubin, USA TODAY

Under pressure from the Food and Drug Administration, the maker of the popular acne medication Accutane is sending information about the drug's link to mental problems to every dermatologist, family physician, psychiatrist and pharmacist in the country.

Hoffmann-La Roche this week began mailing copies of a plain-English "medication guide" and a patient consent form detailing the link, spokeswoman Melissa Ziriakus said Thursday. Both documents are posted on the FDA's Web site.

The FDA requires medication guides for products it believes pose serious risks that can be reduced by informing patients. Only a handful of other drugs, including Mifeprex, or RU486, the so-called abortion pill, have such guides. Pharmacists are to dispense the Accutane medication guide with the pills.

Accutane, sold since 1982 for the treatment of severe acne, was Roche's second-best-selling U.S. drug in 1999; sales totaled nearly $500 million. Rocephin, an antibiotic, was first.

Accutane's package insert has noted links to depression since 1986 and to suicide since May. As of early December, the FDA had received reports of 66 suicides and 1,373 cases of psychiatric problems among users.

But patients often don't read the fine print. In recent months, parents of many Accutane users who attempted or committed suicide have come forward to say their doctors never told them the drug might cause mental problems. They include Rep. Bart Stupak, D-Mich., whose son, 17, killed himself in May. If the consent form and guide are distributed as required, Stupak says, "I think you'll never find a situation like my wife and I experienced."

Besides the link to mental problems, the medication guide details the well-documented risk of birth defects in babies of mothers who took Accutane while pregnant.

The new consent form, devoted mainly to psychiatric problems, is to be completed by the patient or a parent or guardian and signed by the prescriber. In addition, a consent form outlining the risk of birth defects will continue to be given to female patients. Without completed consent forms, Accutane prescribers could be liable if a patient develops problems.

Accutane's maker still does not believe it can cause mental problems, Ziriakus says.

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