Most Recent Update:

MARCH 2023

The iPLEDGE REMS

Prescriber Guide

The resource to help your patients prepare, plan

treatments, and prevent pregnancies during the
course of isotretinoin treatment

1
 INDICATION

Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne in non-
pregnant patients 12 years of age and older with multiple inflammatory nodules with a
diameter of 5mm or greater. The nodules may become suppurative or
hemorrhagic. “Severe,” by definition,1 means “many” as opposed to “few or
several” nodules. Because of significant adverse effects associated with its use,
isotretinoin should be reserved for patients with severe nodular acne who are
unresponsive to conventional therapy, including systemic antibiotics. In addition,
isotretinoin is indicated only for those patients who are not pregnant, because isotretinoin
can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).

CONTRAINDICATIONS AND WARNINGS

Isotretinoin must not be used by patients who are or may become pregnant. There is
an extremely high risk of life-threatening birth defects will result if pregnancy occurs
while taking isotretinoin in any amount, even for short periods of time. Potentially
any fetus exposed during pregnancy can be affected. There are no accurate means of
determining whether an exposed fetus has been affected.
Birth defects which have been documented following isotretinoin exposure include
abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular
system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with
or without other abnormalities have been reported. There is an increased risk of
spontaneous abortion, and premature births have been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities
(including anotia, micropinna, small or absent external auditory canals); eye
abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented
internal abnormalities include: CNS abnormalities (including cerebral abnormalities,
cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit);
cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone
deficiency. In some cases death has occurred with certain of the abnormalities
previously noted.
If pregnancy does occur during treatment of a patient who is taking isotretinoin,
isotretinoin must be discontinued immediately, and the patient should be referred to an
Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation
and counseling.

SPECIAL PRESCRIBING REQUIREMENTS

Because of isotretinoin’s teratogenicity and to minimize fetal exposure, isotretinoin is
approved for marketing only under a special restricted distribution program approved
by the Food and Drug Administration. This REMS is called iPLEDGE®. Isotretinoin must
only be prescribed by prescribers enrolled and activated in the iPLEDGE REMS.
Isotretinoin must only be dispensed by pharmacies enrolled and activated in the iPLEDGE
REMS, and must only be dispensed to patients enrolled and meet all the requirements of
the iPLEDGE REMS (see PRECAUTIONS).

Reference: 1. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J
Am Acad Dermatol 24:495-500, 1991.

2
TABLE OF CONTENTS

About isotretinoin ....................................................................................... 6

The iPLEDGE REMS ................................................................................. 8

Key information for prescribers ................................................................. 9

Activating prescriber enrollment……………………....................................... 10

iPLEDGE REMS prescribing checklists ..................................................... 11

Determine reproductive potential of patients who can become pregnant…...12

Referral for contraception counseling…………………………………………….13

Requirements for patients who can become pregnant……………………..14

iPLEDGE REMS Birth Control Information Sheet……………………………15

The importance of the patient prescription window ………………………..17

In the event of pregnancy ......................................................................... 18

Program materials .................................................................................... 19

Delegates and office staff .......................................................................... 21

3
 About Isotretinoin
Isotretinoin is used to treat severe recalcitrant nodular acne. Isotretinoin belongs to a class of
drugs known as retinoids, commonly understood to include all natural and synthetic
analogues of vitamin A. Treatment with isotretinoin should not be undertaken before
conventional treatment has been tried first, including the use of systemic antibiotic therapy,
and the patient has been fully counseled about the warnings and precautions in the isotretinoin
package insert.

Isotretinoin is teratogenic and must not be used when pregnant. Patients should not become
pregnant while taking isotretinoin or for 1 month after treatment is discontinued. A patient
who becomes pregnant during treatment should stop taking isotretinoin and immediately
contact the prescriber.

Pregnancy After Isotretinoin Treatment

The terminal elimination half-life of isotretinoin varies but is generally within 10 to 20
hours. The elimination half-life of 1 of the isotretinoin metabolites, 4-oxoisotretinoin, is
approximately 25 hours. Since plasma elimination is host dependent, prescribers should warn
patients not to become pregnant for 1 month post treatment. Women who become pregnant
during this month should be counseled as to the outcome data. In 1989, Dai et al reported
the results of an epidemiologic study of pregnancies that occurred in women who conceived
after discontinuing isotretinoin.2 They studied women from 5 days to more than 60 days
between the last dose of isotretinoin and conception. The incidence of birth defects in former
isotretinoin patients was not significantly different from the rate in the general population.
Isotretinoin is found in the semen of male patients taking isotretinoin, but the amount
delivered to a female partner would be about 1 million times lower than an oral dose of 40
mg. While the no-effect limit for isotretinoin-induced embryopathy is unknown, 20 years of
postmarketing reports include 4 with isolated defects compatible with features of retinoid-
exposed fetuses; however, 2 of these reports were incomplete, and 2 had other possible
explanations for the defects observed.

CAUSES
BIRTH DEFECTS

DO NOT GET
PREGNANT

Reference: 2. Dai WS, Hsu M-A, ltri LM. Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol.
1989;125:362-355.

4
Birth Defects
There is an extremely high risk that a deformed infant will result if pregnancy occurs
while patients who can become pregnant are taking isotretinoin in any amount, even for
short periods of time. Potentially, any fetus exposed during pregnancy can be affected. Not
every fetus exposed to isotretinoin has resulted in a deformed child. However, there are
no accurate means of determining which fetus has been affected and which fetus has not
been affected.
When isotretinoin is taken during pregnancy, it has been associated with fetal malformations,
and there is an increased risk for spontaneous abortions and premature birth. The following
human fetal abnormalities have been documented.

External Abnormalities
Skull abnormality; ear abnormalities (including
anotia, micropinna, small or absent external
auditory canals); eye abnormalities (including
microphthalmia); facial dysmorphia; cleft palate.
Internal Abnormalities
Line drawing represents the possible abnormalities of the low-set,
CNS abnormalities including cerebral deformed, or absent ears; wide-set eyes; depressed bridge of
nose; enlarged head; and small chin.
abnormalities, cerebellar malformation,
hydrocephalus, microcephaly, cranial nerve deficit;
cardiovascular abnormalities; thymus gland
abnormalities; parathyroid hormone deficiencies.
In some cases, death has occurred with certain of
the abnormalities noted.

Line drawing represents the possible abnormalities of

the brain, heart, and thymus gland that may occur.

5
 The iPLEDGE® REMS
Because of isotretinoin’s teratogenicity and to minimize fetal exposure, isotretinoin is
approved for marketing only under a special restricted distribution program approved
by the Food and Drug Administration. This REMS is called the iPLEDGE REMS.
The iPLEDGE REMS is a computer-based risk management system that uses verifiable,
traceable links between prescriber, patient, pharmacy, and wholesaler to control prescribing,
using, dispensing, and distribution of isotretinoin.
The iPLEDGE REMS is a, shared (includes multiple manufacturers) Risk Evaluation and
Mitigation Strategy (REMS) with requirements for prescribers, pharmacies, patients, and
wholesalers. The iPLEDGE REMS also includes a pregnancy registry for patients who get
pregnant.
The goal of the iPLEDGE REMS is to:
• prevent pregnancies in patients taking isotretinoin
and to
• prevent pregnant patients from taking isotretinoin
Isotretinoin must only be prescribed by prescribers enrolled and activated in the
iPLEDGE REMS. Isotretinoin must only be dispensed by pharmacies enrolled and
activated in the iPLEDGE REMS and must only be dispensed to patients enrolled and
meet all the requirements of the iPLEDGE REMS.

Traceable links of the iPLEDGE REMS

CAUSES
BIRTH DEFECTS

DO NOT GET
PREGNANT

6
 Key Information For Prescribers
The key areas prescribers must understand and follow include:
• The Non-Compliance Action Policy (NCAP)
• The iPLEDGE® REMS educational materials for prescribers and patients
• Activation in the iPLEDGE REMS automated system
• Prescriber steps required “Before,” “During,” and “After” treatment with isotretinoin
• Specific program criteria and procedures for patients who can become pregnant
• Education for all patients about isotretinoin and the iPLEDGE REMS requirements
• Patient enrollment
• The initial and monthly procedures for prescribing isotretinoin and information on the
requirements for pharmacists
• Information on what to do in the event of a pregnancy
• Prescriber delegates and office staff designees

Non-Compliance Action Policy (NCAP)

The Non-Compliance Action Policy was implemented to monitor compliance with the
iPLEDGE REMS requirements, address deviations, and institute appropriate
corrective actions. The NCAP sets forth the principles by which Non-Compliance by
iPLEDGE REMS stakeholders will be evaluated. The NCAP can be
found on the iPLEDGE REMS website at [Link]/#Main/Resources.

Activating Prescriber Enrollment 7

You must activate your iPLEDGE® enrollment in the iPLEDGE REMS website before you can
prescribe isotretinoin. You must re-activate annually.
 The iPLEDGE REMS website will report the expiration date of your activation. To retrieve this
information:
• On the website, log in and choose “My Program Status” on the left navigation
• In the phone system, log in and select the option to hear “Program Status”

You should review the iPLEDGE REMS Prescriber Guide to understand the program requirements.
Activation requires you to attest to the following statements in the iPLEDGE REMS website:
• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance
of unplanned pregnancy.
• I have the expertise to provide the patient with detailed pregnancy prevention
counseling, or I will refer the patient to an expert for such counseling, reimbursed by
the manufacturer.
• I will comply with the iPLEDGE Program requirements described in the booklet entitled
iPLEDGE REMS Prescriber Guide .
• Before beginning treatment of patients who can become pregnant with isotretinoin, and
on a monthly basis, the patient will be counseled to avoid pregnancy by using 2 forms of
contraception simultaneously and continuously for at least one month prior to initiation of
isotretinoin treatment, during isotretinoin treatment and for one month after
discontinuing isotretinoin treatment, unless the patient commits to continuous abstinence,
not having any sexual contact with a partner that could result in pregnancy.
• I will not prescribe isotretinoin to any patient who can become pregnant until verifying
a negative screening pregnancy test and monthly negative CLIA-certified (Clinical
Laboratory Improvement Amendment) pregnancy tests. Patients should have a
pregnancy test at the completion of the entire course of isotretinoin and another
pregnancy test one month later.
• I will report any pregnancy case that I become aware of while the patient who can become
pregnant is on isotretinoin or one month after the last dose to the pregnancy registry.

*NOTE: Each prescriber’s office location that conducts pregnancy tests must be
CLIA certified.

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iPLEDGE® REMS Checklist
Patients Who Can Become Pregnant

BEFORE TREATMENT DURING TREATMENT (at each monthly visit)

PLANNING
☐ Verify patient who can become pregnant qualification criteria ☐ Counsel patient on contraception adherence.
(see page 10). ☐ Order a pregnancy test using a CLIA-certified laboratory.
☐ Plan for office visits, counseling, pregnancy testing. ☐ Confirm patient counseling of program requirements in the
☐ Educate about isotretinoin and the contraception requirements of iPLEDGE REMS website.
the iPLEDGE REMS. ☐ Enter pregnancy test results and the patient’s 2 forms of
☐ Screen with serum or urine pregnancy test, which may be contraception in the iPLEDGE REMS website within the 7-day
performed in the prescriber’s office: must be negative for the patient to prescription window (allowable timeframe), counting the date of
enter the iPLEDGE REMS website. specimen collection for the pregnancy test as DAY 1. Your patient will
☐ Enroll patient in the iPLEDGE REMS website, ensure the patient not be able to answer the comprehension questions and then obtain
the prescription until you have completed this task.
can access their Patient ID number and
☐ Provide a prescription for no more than a 30-day supply.
educational materials.
☐ Obtain the Patient informed consent using the Enrollment Form for
Patients Who Can Become Pregnant
COUNSEL ON CONTRACEPTION AFTER TREATMENT
☐ Counsel patient in the office or refer to healthcare professional with
AFTER THE LAST DOSE
expertise in contraception. Please see the “Referral for Contraception
Counseling” section for information on referring for contraception ☐ Order a pregnancy test using a CLIA-certified laboratory after the
counseling. last dose.
☐ Counsel patient on the mandatory use of 2 effective ☐ Enter pregnancy test results and the patient’s 2 forms of
forms of contraception simultaneously for at least 1 month before contraception in the iPLEDGE REMS website.
starting treatment. There is a 30-day mandatory waiting period during • If you do not enter the results of the pregnancy test at the conclusion of
treatment, the patient will be classified as Lost to Follow-Up, and both
which the patient must be using both chosen forms of birth control
you and the patient may be contacted for additional information.
before being eligible to begin treatment with isotretinoin. ☐ Counsel patient on contraception adherence for 30 more days.
☐ Obtain the patient’s informed consent using the ☐ Counsel patient not to give blood for at least 1 month after the
Patient Enrollment Form for Patients Who Can Become Pregnant last dose.
☐ Inform patient about confidential iPLEDGE REMS ☐ Counsel the patient not to use leftover medication
Pregnancy Registry ☐ Counsel the patient to properly dispose of unused medication to avoid
unintended exposed pregnancies
PRESCRIBE
☐ Order a pregnancy test using a CLIA-certified laboratory (at least30 ONE MONTH AFTER THE LAST DOSE
days after registration): ☐ Order a pregnancy test using a CLIA-certified laboratory.
• During the first 5 days of the menstrual cycle, OR ☐ Enter pregnancy test results and the patient’s 2 forms of
• For patients with amenorrhea, irregular cycles, or using a contraception in the iPLEDGE REMS website.
contraceptive form that precludes withdrawal bleeding, the second • If you do not enter the results of the pregnancy test at the conclusion
pregnancy test must be done immediately preceding the beginning of of treatment, the patient will be classified as Lost to Follow-Up, and
isotretinoin treatment and after the patient has used 2 forms of both you and the patient may be contacted for additional information.
contraception for 1 month.
☐ Confirm patient counseling of program requirements in the ☐ Counsel the patient not to use leftover medication
iPLEDGE REMS website. ☐ Counsel the patient to properly dispose of unused medication to avoid
unintended exposed pregnancies refer to the section ‘In The Event of
☐ Enter pregnancy test results and the patient’s 2 forms of
Pregnancy’ below for information about reporting pregnancies to the
contraception in the iPLEDGE REMS website within the 7-day confidential iPLEDGE REMS Pregnancy Registry.
prescription window (allowable timeframe), counting the date of
specimen collection for the pregnancy test as DAY 1. Your patient
will not be able to answer the comprehension questions and then
obtain the prescription until you have completed this task.
☐ Provide a prescription for no more than a 30-day supply
.

9
 Determine Reproductive Potential of Patients Who Can
Become Pregnant
Qualification Criteria
Before enrolling your patient in the iPLEDGE REMS, you must determine if this is a patient who can
become pregnant. In the iPLEDGE REMS, the definition of a patient who can become pregnant is:
• A patient who has not had a hysterectomy and/or bilateral oophorectomy
• The patient is not post-menopausal
• A patient who has not yet started menstruating
• A patient who has had a tubal sterilization
• A transgender male with viable female reproductive organs
iPLEDGE REMS Definition of Patient Categories
Patients Who Can Become Pregnant Patients Who Can NOT Become Pregnant
• Cisgender females (born a • Cisgender male (born a male, aka cis-male)
female with a uterus and at • Cisgender females and transgender males that have
least one ovary, aka cis- undergone a hysterectomy( surgical removal of the
female) uterus)
• Transgender males( born • Cisgender females and transgender males that have
female with a uterus and at undergone a bilateral oophorectomy ( surgical removal
least one ovary, transitioned to of both ovaries)
a male, aka trans- male)
• Cisgender females and transgender males who are
post-menopausal according to the iPLEDGE Program
definition*
• Transgender female (born male and transitioned to
female)
*Menopause can be assumed to have occurred in a woman when there is either:1) Appropriate medical documentation of prior complete bilateral oophorectomy
(i.e., surgical removal of the ovaries, resulting in “surgical menopause” and occurring at the age at which the procedure was performed), OR 2) Permanent
cessation of previously occurring menses as a result of ovarian failure with documentation of hormonal deficiency by a certified healthcare provider (i.e.,
“spontaneous menopause,” which occurs in the United States at a mean age of 51.5 years).

Hormonal deficiency should be properly documented in the case of suspected spontaneous menopause
as follows:
1. If age >54 years and with the absence of normal menses: Serum FSH (Follicle Stimulating
Hormone) level elevated to within the post-menopausal range based on the laboratory
reference range where the hormonal assay is performed;
2. If age <54 years and with the absence of normal menses: Negative serum or urine
-HCG with concurrently elevated serum FSH (Follicle Stimulating Hormone) level in the post-
menopausal range, depressed estradiol (E2) level in the post-menopausal range, and absent
serum progesterone level, based on the laboratory reference ranges where the hormonal assays
are performed.

10
Referral For Contraception Counseling
2
Contraception counseling is an important part of the patient choosing 2 contraceptive forms. The
counseling should be done by the prescriber or a healthcare professional with expertise in
 pregnancy prevention. If the prescriber is not comfortable with providing this counseling, they are
encouraged to take advantage of the opportunity to refer patients to a qualified counselor.
Before beginning treatment, if you and the patient choose referral to a healthcare professional with
expertise in pregnancy prevention, the makers of isotretinoin will reimburse 1 visit for contraception
counseling. To facilitate the referral, complete the referral form, which should be taken to the
contraception counselor by the patient or sent in advance. The form instructs the counselor to fill in the
appropriate information and return it to the prescriber with the patient’s contraception choices to enter
into the iPLEDGE REMS website. The second page of the form has information for the counselor on the
reimbursement process. The contraception counselor should access the Contraception Counseling Guide
to review the contraception requirements and the effective forms of contraception of the iPLEDGE
REMS.

Referring to a Gynecologist
You may want to specifically refer a patient to a gynecologist for an exam prior to starting oral contraceptive
agents or a hormonal transdermal patch, insertion of an IUD or hormonal vaginal ring, fitting a diaphragm
or a cervical cap, or for a more detailed explanation of contraception options
You may wish to ask for gynecologic consultation if:
• The patient’s history is suggestive of polycystic ovary syndrome (Stein-Leventhal syndrome). In
addition to acne, there are conditions such as excessive facial hair growth, obesity, amenorrhea (no
menstrual period) or irregular, heavy bleeding or anovulation.
• The patient has irregular menses, possibly related to pregnancy; an eating disorder; or endometriosis.
• There are indications of sexual abuse found during the physical examination or counseling session.
• There is a history or symptoms of sexually transmitted infection (STI).

11
 Requirements for Patients Who Can Become Pregnant
The requirements include the patient taking pregnancy tests and using 2 forms of birth control
consistently for at least 1 month prior to initiation of isotretinoin treatment, during isotretinoin
treatment, and for 1 month after discontinuing isotretinoin treatment. To receive monthly
prescriptions, a patient who can become pregnant must also answer questions in the
iPLEDGE® REMS website about the program requirements and pregnancy prevention.
Answering these questions can only take place after the prescriber has confirmed
counseling and entered the pregnancy test result and the patient’s 2 forms of
contraception (or committing to abstinence, not having any sexual contact with a
partner that could result in pregnancy) into the system. In addition to answering the
questions, the patient must also enter the 2 forms of birth control that the patient is using (or
indicate that the patient is relying on abstinence).

The pregnancy test can be obtained prior to, at the time of, or after the office visit. However,
the 7-day prescription window (allowable timeframe) will begin on the date that the
specimen collection was performed.
MORE EFFECTIVE

MORE EFFECTIVE
About The Patient Comprehension Questions
Prior to being able to obtain a prescription, patients who can become pregnant must
answer questions about the iPLEDGE REMS and pregnancy prevention.
• These questions must be answered after you have confirmed counseling, entered
pregnancy test results and 2 contraceptive forms (or commitment to abstinence)
into the iPLEDGE REMS website, but before the 7-day prescription window
(allowable timeframe) for their prescription expires.
• Patients answer these questions via the website or phone system. (Access
information is provided in the patient guide.) The patient may use their patient
guide to help with the answers.
• The system provides questions in several specific categories and correct answers
for those questions, with references to the appropriate patient education material.
• A replacement question in the same category is provided for an incorrectly
answered question.
• If a patient misses a replacement question, the iPLEDGE REMS website will
direct them to review the materials and try again at a later time. Patients may also
contact you so that program education and counseling can be reinforced. The
patient should also review educational materials and then answer the questions
again.

12
iPLEDGE® Program Approved Forms of Contraception

Choose 1 Primary + 1 Secondary Birth Control Form

 Primary Form How
of Birth Control How to Use it Well it Benefits Risks
† †
(Choose One)* Works

Hormonal Implant Placed under theskin of >99%1 • Nothing to do or remember • Irregular periods
thearm by a clinician. • Light or no periods
‡
• May decrease acne
Works for 3 years.1
• No increased risk of clots
Hormonal IUD Placed in theuterus by the >99%1 • Light or no periods • Irregular periods
clinician. Self-check • No increased risk of clots
monthly.
Works for 3-5 years.1,2,3
Non-Hormonal IUD Placed in theuterus by the >99%1 • No hormones • May cause heavier
clinician. Self-check • Periods remain regular periods and
• Effective immediately
monthly. cramping
• No increased risk of clots
Works for 10 years.4
Tubal Sterilization A surgical procedure to >99%5 • It is a virtually • If you want to have a
close the tubes permanent form of child later, it is very
between the uterus and birth control difficult to re-open the
MORE EFFECTIVE

the ovaries. • Nothing to do or remember tubes

Male Vasectomy A surgical procedure >99%5 • It is a virtually • If you want to have a
that closes off the permanent form of child later, it is very
tubes that carry a birth control difficult to re-open the
partner’s sperm. • Nothing to do or remember tubes
Hormonal Shot Given every 3 months >97%1 • Light or no periods • Irregular periods
by a clinician. • No increased risk of clots • May cause weight gain

Vaginal Ring You place it in the 92%1 • Lighter periods • Blood clots
vagina. Replace per • May decrease acne
prescriber’s
instructions.
Hormonal Patch You place it on the 92%1 • Lighter periods • Blood clots
skin. Replace • May decrease acne
weekly.
Birth Control Pill Swallow at the same 92%1 • Lighter periods • Blood clots
(Combination Type) time daily. • May decrease acne

Secondary Form of
How to Use Benefits Risks
Birth Control (Choose One)
it
Male Latex Condoms (with Partner must be willing to use each • Protects from STIs • Allergic reactions
or without spermicide) and every time you have sex. and HIV/AIDS

Cervical Cap, Diaphragm Place in the vagina before you • You are in control of its use • Allergic reactions
(must be used with have sex.
spermicide). Vaginal Sponge
*Consult your doctor if you are considering choosing 2 primary forms of birth control rather than a primary and secondary form.
†
Benefits and Risks are not inclusive. Please review Full Prescribing Information for the products listed.
All pictograms from FDA website [Link]/downloads/forconsumers/byaudience/forwomen/freepublications/[Link]. Accessed January 20, 2016.
1
‡

References 1. Werner CA, Papic MJ, Ferris LK, Schwartz EB. Promoting safe use of isotretinoin by increasing contraceptive knowledge. JAMA Dermatol. 2015;151(4):389-393. 2. Skyla® Prescribing Information, Bayer
HealthCare Pharmaceuticals Inc., February 2018. 3. Liletta® Prescribing Information, Actavis Pharma, Inc., August 2017. 4. PARAGARD® Prescribing Information, Cooper Surgical Inc., January 2018.
5. Trussell, J. Contraception failure in the United States. Contraception. 2011;83:397-404. Available at [Link] Accessed September 9, 2014. 3
 Abstinence
For this program, all patients who can become pregnant must fully commit to
pregnancy prevention. Isotretinoin is not recommended for any patient who
can become pregnant who cannot or will not follow the contraceptive
requirements of the iPLEDGE® REMS.
Abstinence may be appropriate when it is a lifestyle choice, such as religious practice,
and not just a social circumstance, such as not having a current partner. If, after
counseling, a sexually active patient chooses abstinence, the patient must understand
that the patient has committed to not having any sexual contact (penis-vaginal) with
a partner that could result in pregnancy for 1 month before starting taking isotretinoin,
while on isotretinoin and for 1 month after stopping isotretinoin.

A patient who switches contraception choices during treatment from

abstinence to two forms of iPLEDGE approved contraception is required to
wait for 30 days while consistently using 2 forms of birth control before
continuing treatment. The patient will be required to have a negative
pregnancy test, which starts the 30-day wait period. When the 30-day wait
period is over, the patient will need to have negative pregnancy test,
complete the comprehension questions and be confirmed by the prescriber
before continuing treatment.

One of the most common reasons for pregnancy is engaging in sexual

contact (penis-vaginal) with a partner that could result in pregnancy
when planning to be abstinent.
Unacceptable Forms of Contraception Include:
• Progesterone-only “mini-pills”
• Female condoms
• Natural family planning (rhythm method or fertility awareness)
• Breastfeeding
• Withdrawal
• Cervical shield*
Contraception Counseling
The prescriber must ensure that each individual patient receives adequate counseling
about all pregnancy prevention options (including abstinence) and that the patient
knows how to select and use 2 separate iPLEDGE REMS–effective forms of
contraception that will give the patient the lowest failure rate.
The patient must understand the critical responsibility assumed in electing to
undertake treatment with isotretinoin and that any form of birth control, apart
from complete abstinence, can fail.
*A cervical shield should not be confused with a cervical cap, which is an effective secondary form of contraception.

14
The Importance of the Patient Prescription Window
All patients have a specific period of time in which they can obtain their prescription.
This is called the “prescription window”, and its start and end dates depend on
the type of patient, as follows:

Patients Who Can Become Pregnant Patients Who Cannot Become Pregnant
The prescription window is 7 days and starts on The prescription window is 30 days and starts on
the date that the urine or blood sample is taken for the date the prescriber enters as the date of the
a pregnancy test. This date is counted as DAY 1. office visit. This date is counted as DAY 1.
To determine the end date of their 7-day To determine the end date of their 30-day
prescription window, these patients should add prescription window, these patients should add
6 days to the date of the blood or urine sample 29 days to the date of their office visit.
is taken.
After 11:59 p.m. Eastern Time on the last day of the prescription window, the prescription can no
longer be obtained, and the patient must start the process over to get a new prescription window.*
*One notable exception is that patients who can become pregnant who do not obtain their first month of treatment prescription in their first 7-day prescription
window must wait at least 19 days from their most recent pregnancy test until getting their new pregnancy test. This is based on the requirement that the most
recent pregnancy test prior to beginning treatment must be conducted in the first 5 days of the menstrual cycle.

There are different program requirements for patients who cannot become pregnant and for patients who can become pregnant. .

NOTE: The iPLEDGE REMS Sponsors monitor and investigates Patient classification, and
you may be required to provide documentation to support your Patient classification
request*. Intentional falsification of Patient classification type that is determined to be an
attempt to violate program requirements is defined as non-compliance in the Non-
Compliance Action Policy. This may result in Permanent Deactivation from the iPLEDGE
REMS and a permanent loss of isotretinoin prescribing privilege.

Clinical documentation may be requested by the iPLEDGE REMS to support the classification of a
patient who cannot become pregnant.

*Examples of clinical documentation include the following: physician’s name, address, and date of
hysterectomy, documentation including the following: physician’s name, address, and date of bilateral
oophorectomy, documentation (certified laboratory tests documenting hormonal deficiency) including
physician’s name, address, confirming permanent cessation of previously occurring menses as a result
of ovarian failure).

15
 In the Event of Pregnancy
Counseling a Pregnant Patient
If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued
immediately. The patient should be referred to an obstetrician/gynecologist experienced in
reproductive toxicity for further evaluation and counseling.

Reporting Pregnancy
The iPLEDGE® REMS Pregnancy Registry
The iPLEDGE REMS Pregnancy Registry collects data on pregnancies that occur in patients who
become pregnant while taking isotretinoin or within 1 month of their last dose. Data from the
registry are reported to the FDA and are used to assess the effectiveness of the iPLEDGE REMS.
The data are also used to evaluate further ways to reduce fetal exposure. Information gathered in the
iPLEDGE REMS Pregnancy Registry will be used for statistical purposes only and will be held in
the strictest confidence.
You must report to the iPLEDGE REMS Pregnancy Registry any pregnancy case that you become
aware of while the patient is on isotretinoin or 1 month after the last dose. Report a pregnancy by
calling 1-866-495-0654. Select the option to “Report a Pregnancy.” All pregnancies should also be
reported to the FDA via the MedWatch number: 1-800-FDA-1088.
In Patients Taking Isotretinoin
1. Positive pregnancy test results should be entered in the iPLEDGE REMS website. A Safety
Surveillance Associate will call you.
2. You should call the iPLEDGE REMS Contact Center if you do not have a pregnancy test result
but think that the patient is pregnant.
After a healthcare provider or designee enters a positive pregnancy test or pregnant diagnosis
into the iPLEDGE REMS website, the office will be contacted by a Pregnancy Registry
representative. The prescriber or designee is strongly encouraged to provide all requested
pregnancy- related details for the initial report and updates throughout the pregnancy and up to
one year following birth, as applicable. Your contribution to this collaborative program will
enable the Sponsors of the iPLEDGE REMS to make continuous evaluations and improvements
and may help prevent pregnancies in the future.

In Partners of Patients Being Treated With Isotretinoin*

If the prescriber becomes aware of a pregnancy in the partner of a patient taking isotretinoin, the
prescriber should report this pregnancy to the iPLEDGE REMS Pregnancy Registry. The
information will be forwarded to the manufacturer of the specific isotretinoin product for follow-
up.

*The information in this section refers to partners of cis-male or transgender females who retain male reproductive organs.

Isotretinoin Products
To get information about specific brands of isotretinoin, the contact information for individual
manufacturers can be obtained by calling 1-866-495-0654 or via [Link].

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Program Materials
The iPLEDGE® REMS materials can be accessed, downloaded or ordered from the iPLEDGE

REMS website.

Prescriber Materials Patient Materials

iPLEDGE REMS Prescriber Guide iPLEDGE REMS Factsheet

Recognizing Psychiatric Disorders in Adolescents And iPLEDGE REMS Guide for Patients Who Can
Young Adults Get Pregnant

Contraception Counseling Guide Patient Enrollment Form for Patients who can

get Pregnant

Non-Compliance Action Policy Patient Enrollment Form for Patients who

cannot get Pregnant

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 Determine the Reproductive Potential of Patients
You must determine if your patient can become pregnant before enrollment in the iPLEDGE® REMS.
In the iPLEDGE REMS, the definition of a patient who cannot become pregnant is:
• A patient who has had a hysterectomy and/or bilateral oophorectomy
• A patient who is post-menopausal
• A patient who was born with male reproductive organs

iPLEDGE® REMS Checklist

Patients Who Cannot Become Pregnant

BEFORE TREATMENT
PLANNING
☐ Plan for monthly office visits.
☐ Educate patients about isotretinoin.
☐ Enroll patients in the program
☐ Obtain the Patient’s informed consent on the Patient Enrollment Form for Patients who cannot get
pregnant

PRESCRIBE
☐ Confirm patient counseling of program requirements in the iPLEDGE REMS system within the
30-day prescription window, counting the patient’s office visit as DAY 1. The patient will not be
able to obtain their prescription until you have completed this task.
☐ Provide a prescription for no more than a 30-day supply.

DURING TREATMENT
☐ Counsel patient on program adherence.
☐ Confirm patient counseling of program requirements in the iPLEDGE REMS website within
the 30-day prescription window, counting the patient’s office visit as DAY 1. The patient will
not be able to obtain their prescription until you have completed this task.
☐ Provide a prescription for no more than a 30-day supply.

AFTER TREATMENT
☐ Counsel patient not to give blood for at least 1 month after the last dose.
☐ Counsel the patient to not share any leftover isotretinoin with anyone.
☐ Counsel the patient not to use leftover medication
☐ Counsel the patient to properly dispose of unused medication to avoid
unintended exposed pregnancies

18 Delegates And Office Staff

The iPLEDGE REMS allows the prescriber to delegate patient management to other prescribers enrolled with the
 iPLEDGE REMS (these are known as delegates) and to designate office staff to assist with data entry (these are
known as designees).

Delegating to Another Prescriber

The prescriber can manage delegates by going to the prescriber home page at [Link].
The prescriber must first add the name and required information for delegates into the iPLEDGE REMS website.
This function also allows the prescriber to define time frames for delegation and add or delete delegates.

Office Designees
You may assign a member of your staff as your Office Staff Designee once the registration process has been
completed. An activated and designated Office Staff Designee may perform most patient activities for you in the
iPLEDGE REMS website. An activated designated Office Staff Designee may NOT confirm the serious
medical reason(s) exemption process in the iPLEDGE website on your behalf, as the confirmation requires
the digital signature of an enrolled prescriber.

The iPLEDGE REMS provides a unique username and password to identified office staff to allow them to perform
the following activities for the prescriber:
• Initiate Enrollment and maintain the patient’s information in the iPLEDGE REMS
• Enter patient pregnancy results
• Confirm patient counseling
• Discontinue patients
• Manage delegates
• Check patient’s program status
Only the prescriber may access the following functions:
• Prescriber Enrollment
• Prescriber Activation—initial and renewal
• Finalize Patient Enrollment or Re-enrollment by attesting that the patient category and patient
information is correct and providing electronic signature
• Serious Medical Reasons Exemption process
A prescriber may have 1 or more office staff designees. Designees may be associated with 1 or more prescribers.
• They need to register, and upon their initial activation, they can work with multiple prescribers who
assign them as designees. However, the designee must attest and activate annually.
• They may support all the enrolled prescribers in multiple physicians.
• They have rights for any patient delegated to an assigned prescriber.
Rights to perform the functions depend on the prescriber’s rights and program status.
• If a prescriber is not activated in the iPLEDGE REMS website, neither the prescriber nor the
designated office staff can enroll a patient.
Office Designees(Cont.)

Designees should not access the iPLEDGE REMS website using an ID other than their 19
own under any circumstances. Designated office staff may access the automated
system but must provide their own user ID and Date of Personal Significance as
identifiers.
 Please note: The enrolled and activated prescriber is responsible for all information entered
and activities performed in the iPLEDGE REMS website by the office staff designee.

To Designate Office Staff

The prescriber:
1. Logs in to the website, [Link]
2. Chooses “Manage Delegates/Designees” from the Prescriber home page
3. Chooses “Add New Designee” from the Manage Delegates and Designees page
4. Fills in the required information on the registration online form and submits
The office staff designee:
1. Signs and dates the completed form online.

A username and password will be emailed to the designee upon completion of the
registration process. The designee uses them:
• To log in to the automated system
• On the first log-in, to reset the password and choose a Date of Personal Significance
as a system identifier and to attest to the iPLEDGE REMS requirements
Managing Office Staff Designees
Managing Office Staff Designees Go to [Link] and log in by entering your username (DEA
number or program-generated username) and password. You will be presented with the Prescriber home page.
Select the “Manage Delegates/Designees” button. The Manage Delegates and Designees page will be presented.
Select the “Manage Designees” button to display the Manage Designees page. On the Manage Designees page,
enter the Office Staff Designee’s iPLEDGE username and select “Add.”
It is important to note the following:

• Your Office Staff Designee’s access to activities in the iPLEDGE REMS website is
dependent on your access to the system. Specifically, if you have not been activated
in the system or if your activation has expired, your Office Staff Designee will not be
able to perform activities in the iPLEDGE REMS website.

• Although several prescribers may utilize the same Office Staff Designee, the Office
Staff Designee only needs to register in the iPLEDGE REMS once.

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 Activating Designee Registration
iPLEDGE® REMS registration must be activated in the iPLEDGE REMS website before a
designee can interact with the iPLEDGE REMS.
The designee should review the iPLEDGE REMS Prescriber Guide to understand the program.
Activation requires the designee to acknowledge the following statements in the iPLEDGE
REMS website annually:
• Isotretinoin is teratogenic and must not be used by patients who are pregnant. The
goals of the iPLEDGE REMS are to prevent fetal exposure to isotretinoin and to
inform prescribers, pharmacists, and patients about isotretinoin’s serious risks and
safe-use conditions. With these program goals in mind, iPLEDGE data are routinely
analyzed to identify actions of Non-Compliance.
• Information entered into the iPLEDGE REMS website is considered part of the
patient’s medical record and can be used to investigate suspected Non-
Compliance. Verified Non-Compliance with regard to the iPLEDGE REMS
requirements can result in Permanent Deactivation from the iPLEDGE REMS.
• Prescribers are responsible for all iPLEDGE REMS activities performed by their
office staff designees. If an office staff designee is found to be non-compliant with
the iPLEDGE REMS, resulting actions, including possible Permanent Deactivation
from the iPLEDGE REMS, can include both the designee and
the prescriber.
• Verified Non-Compliance may be reported to the FDA.

Date of Personal Significance

The system requires setting your Date of Personal Significance. This is a date that you will be
able to easily remember. It will be used to verify your identity if needed by the iPLEDGE REMS
website or if a password is lost.
After initial activation, you must re-activate at least annually to remain active in the iPLEDGE
REMS. The iPLEDGE REMS website will display the “Activate” button on the Prescriber
home page when the activation for a prescriber is nearing expiration. However, a prescriber
can re-activate at any time using the “Prescriber Activation” button.

[Link] Phone
system: 1-866-495-0654

21
 This page was in the original design file and is intentionally blank or can be a “notes” page. It is needed to have the booklet
work and to have the Prescriber Flow Chart print front to back.

83

22
 Prescriber Flowchart

A flowchart to assist the prescriber with the

iPLEDGE® REMS requirements

Prescriber Flowchart 23
 ENROLLED AND ACTIVATED PRESCRIBER

Patients Who Can Become Pregnant Patients Who Cannot Become Pregnant
BEFORE TREATMENT

☐ Educate the patient about isotretinoin and contraception ☐ Educate the patient about isotretinoin
requirements of the iPLEDGE® REMS ☐ Enroll patient in the program
☐ Screen by obtaining a negative pregnancy test ☐ Obtain a signed Patient informed consent using the
☐ Enroll patient in the program Enrollment Form for Patients who cannot get Pregnant
☐ Obtain a signed Patient informed consent using the Enrollment ☐ Access* the website to confirm patient counseling of
Form for Patients who can get Pregnant program requirements
☐ Counsel patient, or refer to an expert, that the patient must use
☐ Provide a prescription for no more than a 30-day supply
2 effective forms of contraception simultaneously and correctly for
at least 1 month before starting treatment
☐ Order a pregnancy test using a CLIA-certified lab during the first
5 days of the menstrual cycle, at least 30 days after enrollment
(patients with amenorrhea/irregular cycle, please refer to the PI)
☐ Access* the website to confirm patient counseling of program and
contraception requirements, and to enter the pregnancy test result
and the patient’s forms of contraception
☐ Provide a prescription for no more than a 30-day supply

EACH MONTH DURING TREATMENT

☐ Counsel patient on program and contraception requirements

☐ Counsel patient on program requirements
☐ Order a pregnancy test using a CLIA-certified lab
☐ Access* the system to confirm patient counseling of
☐ Access* the system to confirm patient counseling of program and program requirements
contraception requirements and to enter pregnancy test result ☐ Provide a prescription for no more than a 30-day
and the patient’s forms of contraception supply
☐ Provide a prescription for no more than a 30-day supply

AFTER TREATMENT
☐ Order a pregnancy test using a CLIA-certified lab immediately ☐ Counsel the patient not to share any leftover isotretinoin
after the last dose with anyone
☐ Counsel the patient to continue to use 2 effective forms of ☐ Counsel the patient not to donate blood for 1 month after the
contraception simultaneously and correctly for at least 1 month last dose
after the last dose ☐ Counsel the patient not to use leftover medication
☐ Counsel the patient not to share any leftover isotretinoin ☐ Counsel the patient to properly dispose of unused
with anyone medication to avoid unintended exposed pregnancies
☐ Counsel the patient not to donate blood for 1 month after
last dose
☐ Order a pregnancy test 1 month after the last dose
☐ Access* the system to enter pregnancy test results after every *You can access the system via the website,
pregnancy test [Link], or the
☐ Counsel the patient not to use leftover medication and telephone, 1-866-495-0654
☐ Counsel the patient to properly dispose of unused
medication to avoid unintended exposed pregnancies

24
For iPLEDGE® REMS Information [Link]
1-866-495-0654

25
 [Link]
1-866-495-0654

WARNING
Isotretinoin must not be used by patients who are or may become
pregnant. There is an extremely high risk of life-threatening birth
defects will result if pregnancy occurs while taking isotretinoin in any
amount, even for a short period of time. Potentially any fetus exposed
during pregnancy can be affected. There are no accurate means of
determining whether an exposed fetus has been affected.
IMPORTANT NOTICE
Use only isotretinoin products approved by the US Food and Drug
Administration.
Obtain isotretinoin prescriptions only from pharmacies that are
licensed in the United States and are enrolled with and activated in
the iPLEDGE Program.

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