육지형 전임의(서울의료원 산부인과)

1. Safety Guideline
of Isotretinoin
I
서울의료원 산부인과
육 지 형

2. Isotretinoin
• 13-cis-retinoic acid ( Roaccutane®)
• Approved by Food and Drug Administration for the treatment
of severe nodulo-cystic acne since 1982

3. 2010-10-08

5. Indications of Isotretinoin
 Inhibitis sebaceous gland function and keratinization
 exact action mechanism is unknown
– Reduction in sebum secretion
– Reduction in sebaceous gland size
– Inhibition of sebaceous gland differentiation
 For the treatment of Severe Cystic Acne Vulgaris
(severe, recalcitrant nodular acne)
 Treatment of lesser degrees of acne resistant to other treatments
 Effective for hidradenitis suppurativa, severe acne rosacea, harlequin
ichthyosis, xeroderma pigmentosum, generalized lichen planus, cutaneous
lupus erythematosus

6. Pharmacokinetics of oral isotretinoin
 High level of lipophilicity
 Primarily (99.9%) bound to plasma proteins, mostly albumin
 Three metabolites
 4-oxo-isotretinoin, retinoic acid, 4-oxo-retinoic acid
 Also oxidizes, irreversibly, to 4-oxo-isotretinoin
 The metabolites of isotretinoin :excreted through both urine and feces
 Elimination half-life 21 hours ± 8.2 hours
 The elimination half-life of the longest-lived isotretinoin metabolite
 up to 50 hour
( most of the drugs and its biotransformation products would be gone within 10 day
of the last dose)
Isotretinoin
2x40mg capsules

7. The most important information we should know about isotretinoin
 Isotretinoin can cause birth defects.
 Isotretinoin may cause serious mental health problems.
1. Birth defects (deformed babies), loss of a baby before birth (miscarriage),
death of the baby, and early (premature) births.
Female patients who are pregnant or who plan to become pregnant must not
take isotretinoin.
Female patients must not get pregnant:
• For 1 month before starting isotretinoin
• While taking isotretinoin
• For 1 month after stopping isotretinoin
2. Serious mental health problems. Isotretinoin may cause:
• Depression
• Psychosis
• Suicide

8. Isotretinoin use also has been associated with
 Pseudotumor cerebri
 may occur more often in patients also taking tetracycline
 Serious skin reactions (eg. SJS, TEN)
 Acute pancreatitis
 Elevation of serum triglyceride
 Hearing impairment
 Hepatotoxicity
 Inflammatory bowel disease
 Hyperostosis
 Premature epiphyseal closure
 Vision impairment- corneal opacities, decreased night vision

9. Embryonic Exposure to isotretinoin
 Inhibition of migration of cranial neural crest cells during early embryonic
development
 The most concerning side effects are teratogenicity and an increase in the
rate of spontaneous abortion and premature delivery
 External abnormalities
 Skull abnormality; ear abnormalities (anotia, micropinna, small or
absent external auditory canals); eye abnormalities (microphthalmia);
facial dysmorphia; cleft palate
 Internal abnormalities
 CNS abnormalities (cerebral abnormalities, cerebellar malformation,
hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular
abnormalities; thymus gland abnormality; parathyroid hormone
deficiency

10. •Low set deformed or absent ear
•Wide-set eyes

11. The iPLEDGE program is a computer-based risk management program designed to
further the public health goal to eliminate fetal exposure to isotretinoin through a
special restricted distribution program approved by the FDA.
The program strives to ensure that:
• No female patient starts isotretinoin therapy if pregnant
• No female patient on isotretinoin therapy becomes pregnant

12. Overview of History of Isotretinoin (Accutane) Risk Management Approaches
1988~2001
2002~2006
March, 2006~

13. In 1988, Risk Management System;Pregnancy Prevention Program
SM
established for Women on Accutane®
(isotretinoin)
by Hoffman-La Roche, Inc., Accutane’s manufacturer
1988~2001
“Avoid Pregnancy” icon
Patient consent form
Required pregnancy test prior to start of treatment
Required selection of two forms of birth control

14. 1988 PPP; Label Change
Pregnancy test required 7 days before starting Accutane
Two reliable forms of birth control
Begin therapy on 2nd or 3rd day of next menses
One month prescription only
Monthly pregnancy testing
Monthly contraceptive counseling
1988~2001

15. PPP; Accutane-Exposed Pregnancies
 Pregnancy rate for women taking Accutane
 3 pregnancies per 1000  Pregnancy rate 0.3%
*Roche Accutane Drug Safety Database (1991-1998)
 Pregnancy occurred during therapy  64%
 11% reported they believed they would be able to maintain abstinence
 34% reported failure to use contraception on the perceived day of conception
 33% occurred while using one form of contraception
 51% reported contraception failure
 61% occurred while using one form of contraception
1988~2001

16. Required two pregnancy tests prior to start of treatment
Pharmacists required to give medication guide with prescription
Required use of qualification stickers by registered prescribers
Because of the FDA’s concerns that the PPP was not sufficiently
effective in reducing fetal exposure to isotretinoin, Hoffman-La Roche
instituted SMART (System to Manage Accutane-Related Teratogenicity)
in April 2002.
• Education and consent process about the teratogenic risk of Accutane
• Screening pregnancy test (urine or serum)
• Contraceptive counseling about using two accepted forms of birth control
one month before, during, and one month after therapy
• Follow-up/confirmatory negative pregnancy test no more than seven days
prior to initiating treatment and for every subsequent month for which
therapy was sought
2002~2006

17. Generic Programs
• Amnesteem® Mylan Pharmaceuticals Inc.
: SPIRIT
(the System to Prevent Isotretinoin- Related Issues of Teratogenicity)
Nov 2002
• Sotret® Ranbaxy Laoratories, Inc.
: IMPART
(the Isotretinoin Medication Programme Alerting you to the Risks of Teratogenicity)
Dec 2002
• Claravis® Teva Pharmaceuticals USA.
: ALERT
(the Adverse Event Learning and Education Regarding Teratogenicity)
April 2003
The patent for Accutane expired in 2002, and since then three generic brands —
Amnesteem, Sotret, and Claravis — have been approved in the U.S. Each of
these brands initiated their own risk management program, modeled after the
SMART program
2002~2006

18. iPLEDGE
Required monthly pregnancy tests
Required registration in database by patients, prescribers, pharmacists, and wholesalers
Qualifying questions for patient
Monthly identification of contraceptive methods by patients and doctors
• Physicians and pharmacies must be registered members of the iPLEDGE program
to prescribe and dispense isotretinoin.
• All patients receiving an isotretinoin prescription must be registered in the
system, visit their provider monthly, and fill their prescription within 7 days of the
office visit.
(1) further reduction in fetal exposure to isotretinoin
(2) the creation of a comprehensive system to monitor the prescribing, dispensing, and
distribution of isotretinoin and to capture critical information about patients regardless
of which brand of isotretinoin is prescribed.
* Became mandatory in March 2006
March, 2006~

19. • Additional requirements for patients of childbearing potential included:
• The requirement to use two forms of contraception while on isotretinoin therapy;
these methods must be disclosed to the prescribing provider, who enters them into
the iPLEDGE system.
• Patients must successfully complete a monthly assessment of their understanding of
the risks of pregnancy before filling a prescription for isotretinoin.
• Patients of childbearing potential are required to have a negative pregnancy
test no more than 7 days before filling a 30-day prescription for isotretinoin.
• In addition, iPLEDGE includes a pregnancy registry for women who get
pregnant while on isotretinoin therapy.
March, 2006~

20. The iPLEDGE program is a computer-based risk management system that uses
verifiable, trackable links between prescriber, patient, pharmacy, and wholesaler
to control prescribing, using, dispensing, and distribution of isotretinoin
iPLEDGE
March, 2006~

21. March, 2006~

22. March, 2006~

23. Effective forms of Contraception
Primary forms Secondary forms
Tubal sterilization Barrier forms( always used with spermicide)
• Diaphragm
• Cervical cap
Partner’s vasectomy Barrier forms( used with or without spermicide)
•Male latex condom
Intrauterine device Others
Vaginal sponge (contains spermicide)Hormonal (combination oral
contraceptives, transdermal patch,
injectables, or vaginal ring)
March, 2006~

24. Laboratory Tests
• Pregnancy Test:
-Female patients of childbearing potential must have had two negative urine or serum
pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial
isotretinoin prescription.
The first test (a screening test) is obtained by the prescriber when the decision is made to
pursue qualification of the patient for isotretinoin.
The second pregnancy test (a confirmation test) must be done in a CLIA-certified
laboratory.
 The interval between the two tests must be at least 19 days.
- For patients with regular menstrual cycles, the second pregnancy test must be done
during the first 5 days of the menstrual period immediately preceding the beginning of
isotretinoin therapy and after the patient has used 2 forms of contraception for 1
month.
- For patients with amenorrhea, irregular cycles, or using a contraceptive method that
precludes withdrawal bleeding, the second pregnancy test must be done immediately
preceding the beginning of isotretinoin therapy and after the patient has used 2 forms
of contraception for 1 month.
- A pregnancy test must be repeated each month, in a CLIA-certified laboratory.
March, 2006~

25. All Patients: To receive isotretinoin all patients must meet all of the
following conditions:
 Must be registered with the iPLEDGE program by the prescriber
 Must understand that severe birth defects can occur with the use of isotretinoin by
female patients
 Must be reliable in understanding and carrying out instructions
 Must sign a Patient Information/Informed Consent (for all patients) form that contains
warnings about the potential risks associated with isotretinoin
 Must fill and pick up the prescription within 7 days of the date of specimen collection for
the pregnancy test for female patients
 Must fill and pick up the prescription within 30 days of the office visit for male patients
and females patients not of child bearing potential
 Must not donate blood while on isotretinoin and for one month after treatment has ended
 Must not share isotretinoin with anyone, even someone who has similar symptoms
March, 2006~

26. Female Patients of Childbearing Potential: In addition to the
requirements for all patients described above, female patients of childbearing
potential must meet the following conditions:
 Must NOT be pregnant or breast-feeding
 Must comply with the required pregnancy testing at a CLIA-certified laboratory
 Must be capable of complying with the mandatory contraceptive measures required for
isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse
 Must understand that it is her responsibility to avoid pregnancy one month before,
during and one month after isotretinoin therapy
 Must have signed an additional Patient Information/Informed Consent About Birth
Defects (for female patients who can get pregnant) form, before starting isotretinoin,
that contains warnings about the risk of potential birth defects if the fetus is exposed
to isotretinoin
 Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or
telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during
therapy and one month after the last dose to answer questions on the program
requirements and to enter the patient’s two chosen forms of contraception
March, 2006~

27. PATIENT INFORMATION/INFORMED CONSENT (for all patients):
To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.
Read each item below and initial in the space provided if you understand each item and agree to follow
your doctor’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take isotretinoin if there is anything that you do not
understand about all the information you have received about using isotretinoin.
1. I, ____________________________________________________________,
(Patient’s Name)
understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up
by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender
lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My doctor has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These
have been explained to me. These side effects include serious birth defects in babies of pregnant
patients.
[Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients
who can get pregnant)].
Initials: ______
March, 2006~

28. 4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have
become depressed or developed other serious mental problems.
Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses,
anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in
weight or appetite, school or work performance going down, or trouble concentrating. Some patients
taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives
(suicidal thoughts). Some people tried to end their own lives. And some people have ended their own
lives. There were reports that some of these people did not appear depressed.
There have been reports of patients on isotretinoin becoming aggressive or violent.
No one knows if isotretinoin caused these behaviors or if they would have happened even if the person
did not take isotretinoin.
Some people have had other signs of depression while taking isotretinoin (see #7 below).
Initials: ______
5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression
(see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for
any of these problems. Being psychotic means having a loss of contact with reality, such as hearing
voices or seeing things that are not there.
Initials: ______
6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in
my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other se
rious mental problems.
Initials: ______
March, 2006~

29. 7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any
of the following signs and symptoms of depression or psychosis happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
• Start acting on dangerous impulses
• Start seeing or hearing things that are not real
Initials: ______
8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for
isotretinoin, to check my progress, and to check for signs of side effects.
Initials: ______
9. Isotretinoin will be prescribed just for me — I will not share isotretinoin with other people because it
may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking isotretinoin or for 1 month after I stop taking isotretinoin. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
isotretinoin and may be born with serious birth defects.
Initials: ______
March, 2006~

30. 11. I have read The iPLEDGE Program Patient Introductory Brochure, and other materials my provider
gave me containing important safety information about isotretinoin. I understand all the information I
received.
Initials: ______
12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the
iPLEDGE program to have my prescription filled each month. I understand that I can stop taking
isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin.
Initials: ______
I now allow my doctor _______________________________________ to begin my treatment with isotretinoin.
Patient Name (print) ________________________________________________
Patient Address ____________________________________________________
Telephone (_________._________.___________)
I have:
• fully explained to the patient, _______________________________________,
the nature and purpose of isotretinoin treatment, including its benefits and risks
• given the patient the appropriate educational materials, The iPLEDGE Program Patient Introductory
Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin
• answered those questions to the best of my ability
Doctor Signature: __________________________________________________
Date: ____________
PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT’S MEDICAL RECORD.
PLEASE PROVIDE A COPY TO THE PATIENT. March, 2006~

31. PATIENT INFORMATION/INFORMED CONSENT ABOUT BIRTH DEFECTS
(for female patients who can get pregnant)
To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by
her doctor.
Read each item below and initial in the space provided to show that you understand each item and
agree to follow your doctor’s instructions. Do not sign this consent and do not take isotretinoin if
there is anything that you do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before
signing the consent.
_________________________________________________________________________________
(Patient’s Name)
1. I understand that there is a very high chance that my unborn baby could have severe birth defects
if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and
even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin.
Initial: ______
2. I understand that I must not get pregnant one month before, during the entire time of my
treatment and for one month after the end of my treatment with isotretinoin.
Initial: ______
3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective
forms of birth control (contraception) at the same time. The only exceptions are if I have had surgery
to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my
doctor has medically confirmed that I am post-menopausal.
Initial: ______
March, 2006~

32. 4. I understand that hormonal birth control products are among the most effective forms of birth
control. Combination birth control pills and other hormonal products include skin patches, shots,
underthe-skin implants, vaginal rings and intrauterine devices (IUDs).
Any form of birth control can fail.
That is why I must use two different birth control methods at the same time starting one month
before, during, and for one month after stopping therapy every time I have sexual intercourse, even
if one of the methods I choose is hormonal birth control.
Initial: ______
5. I understand that the following are effective forms of birth control:
A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm
I understand that at least one of my two forms of birth control must be a primary method.
Initial: ______
6. I will talk with my doctor about any medicines including herbal products I plan to take during my
isotretinoin treatment because hormonal birth control methods may not work if I am taking certain
medicines or herbal products.
Initial: ______
7. I may receive a free birth control counseling session from a doctor or other family planning expert.
My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation.
Initial: ______
8. I must begin using the birth control methods I have chosen as described above at least one month
before I start taking isotretinoin.
Initial: ______
March, 2006~

33. 9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two
negative pregnancy test results. The first pregnancy test should be done when my doctor decides to
prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my
menstrual period right before starting isotretinoin therapy treatment or as instructed by my doctor.
I will then have one pregnancy test; in a lab.
• every month during treatment
• at the end of treatment
• and 1 month after stopping treatment
I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from
two pregnancy tests, and the second test has been done in a lab.
Initial: ______
10. I have read and understand the materials my doctor has given to me, including The iPLEDGE
Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control
Workbook and The iPLEDGE Program Patient Introductory Brochure.
My doctor gave me and asked me to watch the DVD containing a video about birth control and a
video about birth defects and isotretinoin.
I was told about a private counseling line that I may call for more information about birth control. I have
received information on emergency birth control.
Initial: ______
11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected
menstrual period, stop using birth control or have sexual intercourse without using my two birth control
methods at any time.
Initial: ______
March, 2006~

34. 12. My doctor gave me information about the purpose and importance of providing information to the
iPLEDGE program should I become pregnant while taking isotretinoin or within one month of the
last dose. I understand that if I become pregnant, information about my pregnancy, my health, and
my baby’s health may be shared with the makers of isotretinoin, authorized parties who maintain
the iPLEDGE program for the makers of isotretinoin and government health regulatory authorities.
Initial: ______
13. I understand that being qualified to receive isotretinoin in the iPLEDGE program means that I:
• have had two negative urine or blood pregnancy tests before receiving the first isotretinoin
prescription. The second test must be done in a lab. I must have a negative result from a urine
or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin
prescription.
• have chosen and agreed to use two forms of effective birth control at the same time. At least
one method must be a primary form of birth control, unless I have chosen never to have sexual
contact with a male (abstinence), or I have undergone a hysterectomy. I must use two
forms of birth control for at least one month before I start isotretinoin therapy, during therapy
and for one month after stopping therapy. I must receive counseling, repeated on a monthly
basis, about birth control and behaviors associated with an increased risk of pregnancy.
• have signed a Patient Information/Informed Consent About Birth Defects (for female patients
who can get pregnant) that contains warnings about the chance of possible birth defects if I
am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have interacted with the iPLEDGE program before starting isotretinoin and on a monthly basis
to answer questions on the program requirements and to enter my two chosen forms of birth
control.
Initial: ______
March, 2006~

35. My doctor has answered all my questions about isotretinoin and I understand that it is my
responsibility not to get pregnant one month before, during isotretinoin treatment, or for one
month after I stop taking isotretinoin.
Initial: ______
I now authorize my doctor ___________________________________to begin my treatment with
isotretinoin.
Patient Signature: _________________________________________________ Date: ____________
Parent/Guardian Signature (if under age 18): ____________________________ Date: ____________
Please print: Patient Name and Address _________________________________________________
__________________________________________ Telephone _____________________________
I have fully explained to the patient, __________________________________, the nature and purpose
of the treatment described above and the risks to female patients of childbearing potential.
I have asked the patient if she has any questions regarding her treatment with isotretinoin and have
answered those questions to the best of my ability.
Doctor Signature: _______________________________________________ Date: ______________
PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT’S MEDICAL RECORD.
PLEASE PROVIDE A COPY TO THE PATIENT.
March, 2006~