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Accutane Package Insert, Sanford Guide, & article

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1st post is the from Sanford Guide & article

next 2 are the Package Insert

from The Sanford Guide to Antimicrobial Therapy

systemic isotretinoin (accutane) reserved for pts w/ severe widespread nodular cystic lesion that fail oral antibiotic rx 4-5 months course of .1 to 1 mg/kg day after primary and alternatives have failed,

tretinoin, erythro, bp, oral antibiotics, adapalene, azelaic acid, tazarotene, clinda, doxy, minocycline, tetracycline, TMP/SMXc

article

Accutane's Historical Timeline

1971:

Roche created Roaccutane, marketed as Accutane in the USA.

1982:

FDA approves Accutane as a drug designed to treat severe cystic acne.

June 1985

Roche amends Accutane's package insert under 'Adverse Reactions' to state:

"The following CNS reactions have been reported and may bear no relationship to therapy - seizures, emotional instability including depression, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy and paresthesias."

1986:

After only 4 years on the market accutane's packaging information is updated to include a warning stating that depression had been recorded as a side effect by some users.

1988:

Non profit public interest “Public Citizen†commences petition for a ban on the sale of Accutane.

Godfrey Oakley, director of the Division of Birth Defects and Developmental Disabilities at the Centers for Disease Control, wrote that "40 infants born alive after first trimester exposure to Accutane have died ... because of the developmental errors that Accutane caused." Oakley argued that "we simply need to remove the drug from the market."

1990:

14 years before his recent Senate testimony, FDA scientist David Graham wrote; Accutane "cannot safely be given to women of childbearing age or potential" because the drug causes birth defects and results in abortions among women unwilling to give birth to children with deformities. There is no alternative to immediate withdrawal of Accutane from the market. To delay only compounds the body count."

1990

In a 1990 memo, FDA concluded that as a result of Accutane's risks of birth defects, "The magnitude of injury and death has been great and permanent, with 11,000 to 13,000 Accutane-related abortions and 900 to 1,100 Accutane-related birth defects."

1994:

An FDA memo of a telephone conference with Roche showed the firm had reviewed reports of suicide and depression related to Accutane and had "concurred that there does appear to be a problem."

1997:

In France Roche is forced to list suicide on the list of potential side effects. A Roche doctor recommends that users are monitored for signs of depression and taken off their treatment if necessary.

August 1997

FDA issues a warning letter to Roche for failing to submit serious adverse event reports in a timely manner. Roche claims its computer systems are responsible for delays of up to eight years in complying with the law.

Feb. 1998:

In the USA the FDA dictates that packaging must include a warning that that users have experienced depression, psychosis, and "rarely, suicidal ideation, suicide attempts and suicide.

March 1998:

Health regulators in Britain and Ireland request warnings regarding the link between of psychiatric disorders Accutane.

December 1999:

Roche issues "Psychiatric Disorder Issue Work-Up" a paper for the FDA where they insist that of the 168 cases of suicide linked to the product that no direct link can be proven.

May 2000:

Roche update Accutane’s warning label to include possible side effects involving depression, rare suicidal thoughts, suicide attempts and suicide.

September 2000:

The FDA dermatology committee rules that Accutane patients were linked to 147 suicides and hospitalizations for depression from 1982 to May 2000 in the US and decides that additional research is necessary to determine the drug’s link to birth defects.

June 20, 2002:

Another change to the label warns of "depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.

Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, told a House subcommittee in 2002 that the agency had received reports of 3,104 adverse psychiatric events involving Accutane. She said the FDA at the time knew of 173 suicide reports associated with Accutane.

Nov. 18, 2004:

FDA scientist David Graham (who previously has described Accutane as "a 20-year regulatory failure by the FDA") tells a Senate committee the drug should be studied for possible withdrawal.

Nov. 23 2004:

FDA announces registry of prescribers, patients and pharmacies for Accutane, requires women test negative for pregnancy before getting prescription.

Aug 15 2005:

The FDA introduce the I PLEDGE program , women who wish to take accutane have to agree to use two forms of contraceptive and have pregnancy test while using the drug.

Overview Labelling iPLEDGE

Blog | Info |

ZENMED® vs. Accutane®

Considering Taking Accutane? Compare ZENMED first and discover why the natural solution is the smarter solution

www.ZENMED.com

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1

ACCUTANE

(isotretinoin capsules)

Rx only

CAUSES BIRTH

DEFECTS

DO NOT GET

PREGNANT

CONTRAINDICATIONS AND WARNINGS

Accutane must not be used by female patients who are or may become

pregnant. There is an extremely high risk that severe birth defects will result

if pregnancy occurs while taking Accutane 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 Accutane 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.

2

If pregnancy does occur during treatment of a female patient who is taking

Accutane, Accutane must be discontinued immediately and she should be

referred to an Obstetrician-Gynecologist experienced in reproductive toxicity

for further evaluation and counseling.

Special Prescribing Requirements

Because of Accutane’s teratogenicity and to minimize fetal exposure,

Accutane is approved for marketing only under a special restricted

distribution program approved by the Food and Drug Administration. This

program is called iPLEDGE . Accutane must only be prescribed by prescribers

who are registered and activated with the iPLEDGE program. Accutane must

only be dispensed by a pharmacy registered and activated with iPLEDGE, and

must only be dispensed to patients who are registered and meet all the

requirements of iPLEDGE (see PRECAUTIONS).

Table 1 Monthly Required iPLEDGE Interactions

Female Patients of

Childbearing Potential

Male Patients, And Female

Patients Not of Childbearing

Potential

PRESCRIBER

Confirms patient counseling X X

Enters the 2 contraception methods

chosen by the patient

X

Enters pregnancy test results X

PATIENT

Answers educational questions before

every prescription

X

Enters 2 forms of contraception X

PHARMACIST

Calls system to get an authorization X X

DESCRIPTION

Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg soft

gelatin capsules for oral administration. Each capsule contains beeswax, butylated

hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated

vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens

(methyl and propyl), with the following dye systems: 10 mg — iron oxide (red)

and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and

titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow No. 10, and

titanium dioxide.

Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid

and retinol (vitamin A). It is a yellow to orange crystalline powder with a

molecular weight of 300.44. The structural formula is:

3

CLINICAL PHARMACOLOGY

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of

0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits

sebaceous gland function and keratinization. The exact mechanism of action of

isotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a

reduction in sebum secretion. The decrease in sebum secretion is temporary and is

related to the dose and duration of treatment with Accutane, and reflects a

reduction in sebaceous gland size and an inhibition of sebaceous gland

differentiation.1

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when

given with a high-fat meal. In a crossover study, 74 healthy adult subjects

received a single 80 mg oral dose (2 x 40 mg capsules) of Accutane under fasted

and fed conditions. Both peak plasma concentration (Cmax) and the total exposure

(AUC) of isotretinoin were more than doubled following a standardized high-fat

meal when compared with Accutane given under fasted conditions (see Table 2).

The observed elimination half-life was unchanged. This lack of change in half-life

suggests that food increases the bioavailability of isotretinoin without altering its

disposition. The time to peak concentration (Tmax) was also increased with food

and may be related to a longer absorption phase. Therefore, Accutane capsules

should always be taken with food (see DOSAGE AND ADMINISTRATION).

Clinical studies have shown that there is no difference in the pharmacokinetics of

isotretinoin between patients with nodular acne and healthy subjects with normal

skin.

4

Table 2 Pharmacokinetic Parameters of Isotretinoin Mean

(%CV), N=74

Accutane

2 x 40 mg

Capsules

AUC0-∞

(ngâ‹…hr/mL)

Cmax

(ng/mL)

Tmax

(hr)

t1/2

(hr)

Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%)

Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%)

*Eating a standardized high-fat meal

Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been

identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and

4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are

geometric isomers and show reversible interconversion. The administration of one

isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to

4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of Accutane to 74 healthy adult subjects,

concurrent administration of food increased the extent of formation of all

metabolites in plasma when compared to the extent of formation under fasted

conditions.

All of these metabolites possess retinoid activity that is in some in vitro models

more than that of the parent isotretinoin. However, the clinical significance of

these models is unknown. After multiple oral dose administration of isotretinoin

to adult cystic acne patients (≥18 years), the exposure of patients to 4-oxoisotretinoin

at steady-state under fasted and fed conditions was approximately 3.4

times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin

metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are

further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid

suspension, 14C-activity in blood declined with a half-life of 90 hours. The

metabolites of isotretinoin and any conjugates are ultimately excreted in the feces

and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg

oral dose of Accutane to 74 healthy adult subjects under fed conditions, the

mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were

21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple

5

doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43

in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotretinoin were evaluated after single and multiple

doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years)

who received Accutane for the treatment of severe recalcitrant nodular acne. In

both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxotretinoin

were also observed. The dose-normalized pharmacokinetic parameters

for isotretinoin following single and multiple doses are summarized in Table 3 for

pediatric patients. There were no statistically significant differences in the

pharmacokinetics of isotretinoin between pediatric and adult patients.

Table 3 Pharmacokinetic Parameters of Isotretinoin Following

Single and Multiple Dose Administration in Pediatric

Patients, 12 to 15 Years of Age

Mean (± SD), N=38*

Parameter Isotretinoin

(Single Dose)

Isotretinoin

(Steady-State)

Cmax (ng/mL) 573.25 (278.79) 731.98 (361.86)

AUC(0-12) (ngâ‹…hr/mL) 3033.37 (1394.17) 5082.00 (2184.23)

AUC(0-24) (ng⋅hr/mL) 6003.81 (2885.67) –

Tmax (hr)† 6.00 (1.00-24.60) 4.00 (0-12.00)

Cssmin (ng/mL) – 352.32 (184.44)

T1/2 (hr) – 15.69 (5.12)

CL/F (L/hr) – 17.96 (6.27)

*The single and multiple dose data in this table were obtained following a

non-standardized meal that is not comparable to the high-fat meal that was used in the

study in Table 2.

†Median (range)

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of

isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours,

respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for

pediatric patients.

INDICATIONS AND USAGE

Severe Recalcitrant Nodular Acne

Accutane is indicated for the treatment of severe recalcitrant nodular acne.

Nodules are inflammatory lesions with a diameter of 5 mm or greater. The

nodules may become suppurative or hemorrhagic. “Severe,†by definition,2 means

“many†as opposed to “few or several†nodules. Because of significant adverse

effects associated with its use, Accutane should be reserved for patients with

6

severe nodular acne who are unresponsive to conventional therapy, including

systemic antibiotics. In addition, Accutane is indicated only for those female

patients who are not pregnant, because Accutane can cause severe birth defects

(see Boxed CONTRAINDICATIONS AND WARNINGS).A single course of therapy for 15 to 20 weeks has been shown to result in

complete and prolonged remission of disease in many patients.1,3,4 If a second

course of therapy is needed, it should not be initiated until at least 8 weeks after

completion of the first course, because experience has shown that patients may

continue to improve while off Accutane. The optimal interval before retreatment

has not been defined for patients who have not completed skeletal growth (see

WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature

Epiphyseal Closure).

CONTRAINDICATIONS

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND

WARNINGS.

Allergic Reactions

Accutane is contraindicated in patients who are hypersensitive to this medication

or to any of its components. Accutane should not be given to patients who are

sensitive to parabens, which are used as preservatives in the gelatin capsule (see

PRECAUTIONS: Hypersensitivity).

WARNINGS

Psychiatric Disorders

Accutane may cause depression, psychosis and, rarely, suicidal ideation,

suicide attempts, suicide, and aggressive and/or violent behaviors. No

mechanism of action has been established for these events (see ADVERSE

REACTIONS: Psychiatric). Prescribers should read the brochure,

Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide

for Prescribers of Isotretinoin. Prescribers should be alert to the warning

signs of psychiatric disorders to guide patients to receive the help they need.

Therefore, prior to initiation of Accutane therapy, patients and family

members should be asked about any history of psychiatric disorder, and at

each visit during therapy patients should be assessed for symptoms of

depression, mood disturbance, psychosis, or aggression to determine if

further evaluation may be necessary. Signs and symptoms of depression, as

described in the brochure (“Recognizing Psychiatric Disorders in

Adolescents and Young Adultsâ€), include sad mood, hopelessness, feelings of

guilt, worthlessness or helplessness, loss of pleasure or interest in activities,

fatigue, difficulty concentrating, change in sleep pattern, change in weight or

appetite, suicidal thoughts or attempts, restlessness, irritability, acting on

dangerous impulses, and persistent physical symptoms unresponsive to

treatment. Patients should stop Accutane and the patient or a family member

7

should promptly contact their prescriber if the patient develops depression,

mood disturbance, psychosis, or aggression, without waiting until the next

visit. Discontinuation of Accutane therapy may be insufficient; further

evaluation may be necessary. While such monitoring may be helpful, it may

not detect all patients at risk. Patients may report mental health problems or

family history of psychiatric disorders. These reports should be discussed

with the patient and/or the patient’s family. A referral to a mental health

professional may be necessary. The physician should consider whether

Accutane therapy is appropriate in this setting; for some patients the risks

may outweigh the benefits of Accutane therapy.

Pseudotumor Cerebri

Accutane use has been associated with a number of cases of pseudotumor

cerebri (benign intracranial hypertension), some of which involved

concomitant use of tetracyclines. Concomitant treatment with tetracyclines

should therefore be avoided. Early signs and symptoms of pseudotumor

cerebri include papilledema, headache, nausea and vomiting, and visual

disturbances. Patients with these symptoms should be screened for

papilledema and, if present, they should be told to discontinue Accutane

immediately and be referred to a neurologist for further diagnosis and care

(see ADVERSE REACTIONS: Neurological).

Pancreatitis

Acute pancreatitis has been reported in patients with either elevated or normal

serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has

been reported. Accutane should be stopped if hypertriglyceridemia cannot be

controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipids

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in

patients treated with Accutane. Marked elevations of serum triglycerides were

reported in approximately 25% of patients receiving Accutane in clinical trials. In

addition, approximately 15% developed a decrease in high-density lipoproteins

and about 7% showed an increase in cholesterol levels. In clinical trials, the

effects on triglycerides, HDL, and cholesterol were reversible upon cessation of

Accutane therapy. Some patients have been able to reverse triglyceride elevation

by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose

while continuing Accutane.5

Blood lipid determinations should be performed before Accutane is given and

then at intervals until the lipid response to Accutane is established, which usually

occurs within 4 weeks. Especially careful consideration must be given to

risk/benefit for patients who may be at high risk during Accutane therapy

(patients with diabetes, obesity, increased alcohol intake, lipid metabolism

disorder or familial history of lipid metabolism disorder). If Accutane therapy is

8

instituted, more frequent checks of serum values for lipids and/or blood sugar are

recommended (see PRECAUTIONS: Laboratory Tests).The cardiovascular consequences of hypertriglyceridemia associated with

Accutane are unknown. Animal Studies: In rats given 8 or 32 mg/kg/day of

isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day

after normalization for total body surface area) for 18 months or longer, the

incidences of focal calcification, fibrosis and inflammation of the myocardium,

calcification of coronary, pulmonary and mesenteric arteries, and metastatic

calcification of the gastric mucosa were greater than in control rats of similar age.

Focal endocardial and myocardial calcifications associated with calcification of

the coronary arteries were observed in two dogs after approximately 6 to 7

months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to

60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after

normalization for total body surface area).

Hearing Impairment

Impaired hearing has been reported in patients taking Accutane; in some cases,

the hearing impairment has been reported to persist after therapy has been

discontinued. Mechanism(s) and causality for this event have not been

established. Patients who experience tinnitus or hearing impairment should

discontinue Accutane treatment and be referred for specialized care for further

evaluation (see ADVERSE REACTIONS: Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to Accutane

therapy has been reported. Additionally, mild to moderate elevations of liver

enzymes have been observed in approximately 15% of individuals treated during

clinical trials, some of which normalized with dosage reduction or continued

administration of the drug. If normalization does not readily occur or if hepatitis is

suspected during treatment with Accutane, the drug should be discontinued and

the etiology further investigated.

Inflammatory Bowel Disease

Accutane has been associated with inflammatory bowel disease (including

regional ileitis) in patients without a prior history of intestinal disorders. In some

instances, symptoms have been reported to persist after Accutane treatment has

been stopped. Patients experiencing abdominal pain, rectal bleeding or severe

diarrhea should discontinue Accutane immediately (see ADVERSE

REACTIONS: Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of Accutane on the developing musculoskeletal system

are unknown. There is some evidence that long-term, high-dose, or multiple

9

courses of therapy with isotretinoin have more of an effect than a single course of

therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a

single course of therapy with Accutane for severe recalcitrant nodular acne, bone

density measurements at several skeletal sites were not significantly decreased

(lumbar spine change >-4% and total hip change >-5%) or were increased in the

majority of patients. One patient had a decrease in lumbar spine bone mineral

density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in

lumbar spine bone mineral density >4%, and all the other patients (92%) did not

have significant decreases or had increases (adjusted for body mass index). Nine

patients (4.5%) had a decrease in total hip bone mineral density >5% based on

unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone

mineral density >5%, and all the other patients (89%) did not have significant

decreases or had increases (adjusted for body mass index). Follow-up studies

performed in 8 of the patients with decreased bone mineral density for up to 11

months thereafter demonstrated increasing bone density in 5 patients at the

lumbar spine, while the other 3 patients had lumbar spine bone density

measurements below baseline values. Total hip bone mineral densities remained

below baseline (range –1.6% to –7.6%) in 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13-18 years, who

started a second course of Accutane 4 months after the first course, two patients

showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see

PRECAUTIONS: Pediatric Use).

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed

healing of bone fractures have been seen in the Accutane population. While

causality to Accutane has not been established, an effect cannot be ruled out.Longer term effects have not been studied. It is important that Accutane be given

at the recommended doses for no longer than the recommended duration.

Hyperostosis

A high prevalence of skeletal hyperostosis was noted in clinical trials for

disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally,

skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of

disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of

ligaments and tendons have also been observed by x-ray in prospective studies of

nodular acne patients treated with a single course of therapy at recommended

doses. The skeletal effects of multiple Accutane treatment courses for acne are

unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe

recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of

treatment with approximately 1 mg/kg/day of Accutane given in two divided

doses. Hyperostosis may require a longer time frame to appear. The clinical

course and significance remain unknown.

10

Premature Epiphyseal Closure

There are spontaneous reports of premature epiphyseal closure in acne patients

receiving recommended doses of Accutane. The effect of multiple courses of

Accutane on epiphyseal closure is unknown.

Vision Impairment

Visual problems should be carefully monitored. All Accutane patients

experiencing visual difficulties should discontinue Accutane treatment and have

an ophthalmological examination (see ADVERSE REACTIONS: Special

Senses).

Corneal Opacities

Corneal opacities have occurred in patients receiving Accutane for acne and more

frequently when higher drug dosages were used in patients with disorders of

keratinization. The corneal opacities that have been observed in clinical trial

patients treated with Accutane have either completely resolved or were resolving

at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE

REACTIONS: Special Senses).

Decreased Night Vision

Decreased night vision has been reported during Accutane therapy and in some

instances the event has persisted after therapy was discontinued. Because the

onset in some patients was sudden, patients should be advised of this potential

problem and warned to be cautious when driving or operating any vehicle at

night.

PRECAUTIONS

Accutane must only be prescribed by prescribers who are registered and activated

with the iPLEDGE program. Accutane must only be dispensed by a pharmacy

registered and activated with iPLEDGE, and must only be dispensed to patients

who are registered and meet all the requirements of iPLEDGE. Registered and

activated pharmacies must receive Accutane only from wholesalers registered

with iPLEDGE.

iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are

described below:

Wholesalers:

For the purpose of the iPLEDGE program, the term wholesaler refers to

wholesaler, distributor, and/or chain pharmacy distributor. To distribute Accutane,

wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE

requirements for wholesale distribution of isotretinoin products. Wholesalers must

register with iPLEDGE by signing and returning the iPLEDGE wholesaler

agreement that affirms they will comply with all iPLEDGE requirements for

distribution of isotretinoin. These include:

11

• Registering prior to distributing isotretinoin and re-registering annually

thereafter

• Distributing only FDA approved isotretinoin product

• Only shipping isotretinoin to

− wholesalers registered in the iPLEDGE program with prior written

consent from the manufacturer or

− pharmacies licensed in the US and registered and activated in the

iPLEDGE program

• Notifying the isotretinoin manufacturer (or delegate) of any non-registered

and/or non-activated pharmacy or unregistered wholesaler that attempts to

order isotretinoin

• Complying with inspection of wholesaler records for verification of

compliance with the iPLEDGE program by the isotretinoin manufacturer (or

delegate)

• Returning to the manufacturer (or delegate) any undistributed product if

registration is revoked by the manufacturer or if the wholesaler chooses to not

re-register annually

• Providing product flow data to manufacturer (or delegate) as detailed in the

wholesalers agreement

Prescribers:

To prescribe isotretinoin, the prescriber must be registered and activated with the

pregnancy risk management program iPLEDGE. Prescribers can register by

signing and returning the completed registration form. Prescribers can only

activate their registration by affirming that they meet requirements and will

comply with all iPLEDGE requirements by attesting to the following points:

• I know how to diagnose and treat the various presentations of acne.

• 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 her to an expert for such counseling, reimbursed by

the manufacturer.

• I will comply with the iPLEDGE program requirements described in the

booklets entitled The iPLEDGE Program Guide to Best Practices for

Isotretinoin and The iPLEDGE Program Prescriber Contraception

Counseling Guide.

• Before beginning treatment of female patients of childbearing potential with

isotretinoin and on a monthly basis, the patient will be counseled to avoid

pregnancy by using two forms of contraception simultaneously and

12

continuously one month before, during, and one month after isotretinoin

therapy, unless the patient commits to continuous abstinence.

• I will not prescribe isotretinoin to any female patient of childbearing potential

until verifying she has 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 1 month later.

• I will report any pregnancy case that I become aware of while the female

patient is on isotretinoin or 1 month after the last dose to the pregnancy

registry.

To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the

internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

1) Register each patient in the iPLEDGE program.

2) Confirm monthly that each patient has received counseling and education.

3) For female patients of childbearing potential:

• Enter patient’s two chosen forms of contraception each month.

• Enter monthly result from CLIA-certified laboratory conducted pregnancy

test.

Isotretinoin must only be prescribed to female patients who are known not to be

pregnant as confirmed by a negative CLIA-certified laboratory conducted

pregnancy test.

Isotretinoin must only be dispensed by a pharmacy registered and activated with

the pregnancy risk management program iPLEDGE and only when the registered

patient meets all the requirements of the iPLEDGE program. Meeting the

requirements for a female patient of childbearing potential signifies that she:

• Has been counseled and has signed a Patient Information/Informed

Consent About Birth Defects (for female patients who can get pregnant)

form that contains warnings about the risk of potential birth defects if the

fetus is exposed to isotretinoin. The patient must sign the informed

consent form before starting treatment and patient counseling must also be

done at that time and on a monthly basis thereafter.

• Has 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 CLIAcertified

laboratory. The interval between the 2 tests should be at least 19

days.

13

− For patients with regular menstrual cycles, the second pregnancy test

should be done during the first 5 days of the menstrual period and

within 7 days of the office visit, 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 within 7 days following the office visit,

immediately preceding the beginning of isotretinoin therapy and after

the patient has used 2 forms of contraception for 1 month.

• Has had a negative result from a urine or serum pregnancy test in a CLIAcertified

laboratory before receiving each subsequent course of

isotretinoin. A pregnancy test must be repeated every month, in a CLIAcertified

laboratory, prior to the female patient receiving each prescription.

• Has selected and has committed to use 2 forms of effective contraception

simultaneously, at least 1 of which must be a primary form, unless the

patient commits to continuous abstinence from heterosexual contact, or the

patient has undergone a hysterectomy or bilateral oophorectomy, or has

been medically confirmed to be post-menopausal. Patients must use 2

forms of effective contraception for at least 1 month prior to initiation of

isotretinoin therapy, during isotretinoin therapy, and for 1 month after

discontinuing isotretinoin therapy. Counseling about contraception and

behaviors associated with an increased risk of pregnancy must be repeated

on a monthly basis.

If the patient has unprotected heterosexual intercourse at any time 1 month

before, during, or 1 month after therapy, she must:

1. Stop taking Accutane immediately, if on therapy

2. Have a pregnancy test at least 19 days after the last act of

unprotected heterosexual intercourse

3. Start using 2 forms of effective contraception simultaneously again

for 1 month before resuming Accutane therapy

4. Have a second pregnancy test after using 2 forms of effective

contraception for 1 month as described above depending on

whether she has regular menses or not.

Effective forms of contraception include both primary and secondary

forms of contraception:

14

Primary forms

• tubal sterilization

• partner’s vasectomy

• intrauterine device

• hormonal (combination

oral contraceptives,

transdermal patch,

injectables,

implantables, or vaginal

ring)

Secondary forms

Barrier forms (always used with

spermicide):

• male latex condom

• diaphragm

• cervical cap

Others:

• vaginal sponge (contains

spermicide)

Any birth control method can fail. There have been reports of pregnancy

from female patients who have used oral contraceptives, as well as

transdermal patch/injectable/implantable/vaginal ring hormonal birth

control products; these pregnancies occurred while these patients were

taking Accutane. These reports are more frequent for female patients who

use only a single method of contraception. Therefore, it is critically

important that female patients of childbearing potential use 2 effective

forms of contraception simultaneously. Patients must receive written

warnings about the rates of possible contraception failure (included in

patient education kits).

Using two forms of contraception simultaneously substantially reduces the

chances that a female will become pregnant over the risk of pregnancy

with either form alone. A drug interaction that decreases effectiveness of

hormonal contraceptives has not been entirely ruled out for Accutane (see

PRECAUTIONS: Drug Interactions). Although hormonal

contraceptives are highly effective, prescribers are advised to consult the

package insert of any medication administered concomitantly with

hormonal contraceptives, since some medications may decrease the

effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the

herbal supplement St. John’s Wort because a possible interaction has been

suggested with hormonal contraceptives based on reports of breakthrough

bleeding on oral contraceptives shortly after starting St. John’s Wort.

Pregnancies have been reported by users of combined hormonal

contraceptives who also used some form of St. John’s Wort.

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. Any suspected fetal exposure during or 1

month after isotretinoin therapy must be reported immediately to the FDA

via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE

15

pregnancy registry at 1-866-495-0654 or via the internet

(www.ipledgeprogram.com).

All Patients

Isotretinoin is contraindicated in female patients who are pregnant. 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 the prescription within 7 days of the office visit

• Must not donate blood while on isotretinoin and for 1 month after treatment

has ended

• Must not share isotretinoin with anyone, even someone who has similar

symptoms

Female Patients of Childbearing Potential

Isotretinoin is contraindicated in female patients who are pregnant. 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, and understand behaviors associated with an

increased risk of pregnancy

• 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 program via the internet

(www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting

16

isotretinoin, on a monthly basis during therapy, and 1 month after the last dose

to answer questions on the program requirements and to enter the patient’s

two chosen forms of contraception

• Must have been informed of the purpose and importance of providing

information to the iPLEDGE program should she become pregnant while

taking isotretinoin or within 1 month of the last dose

Pharmacists:

To dispense isotretinoin, pharmacies must be registered and activated with the

pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and

returning the completed registration form. After registration, the Responsible Site

Pharmacist can only activate the pharmacy registration by affirming that they

meet requirements and will comply with all iPLEDGE requirements by attesting

to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.

• I will train all pharmacists, who participate in the filling and dispensing of

isotretinoin prescriptions, on the iPLEDGE program requirements.

• I will comply and seek to ensure all pharmacists who participate in the filling

and dispensing of isotretinoin prescriptions comply with the iPLEDGE

program requirements described in the booklet entitled The iPLEDGE

Program Pharmacist Guide for Isotretinoin.

• I will obtain Accutane product only from iPLEDGE registered wholesalers.

• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any

manner to or from another pharmacy.

• I will return to the manufacturer (or delegate) any unused product if

registration is revoked by the manufacturer or if the pharmacy chooses to not

reactivate annually.

• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1) be trained by the Responsible Site Pharmacist concerning the iPLEDGE

program requirements.

2) obtain authorization from the iPLEDGE program via the internet

(www.ipledgeprogram.com) or telephone (1-866-495-0654) for every

isotretinoin prescription. Authorization signifies that the patient has met all

program requirements and is qualified to receive isotretinoin.

3) write the Risk Management Authorization (RMA) number on the prescription.

Accutane must only be dispensed:

• in no more than a 30-day supply

17

• with an Accutane Medication Guide

• after authorization from the iPLEDGE program

• prior to the “do not dispense to patient after†date provided by the iPLEDGE

system (within 7 days of the office visit)

• with a new prescription for refills and another authorization from the

iPLEDGE program (No automatic refills are allowed)

An Accutane Medication Guide must be given to the patient each time Accutane

is dispensed, as required by law. This Accutane Medication Guide is an important

part of the risk management program for the patients.

Accutane must not be prescribed, dispensed or otherwise obtained through the

internet or any other means outside of the iPLEDGE program. Only FDAapproved

Accutane products must be distributed, prescribed, dispensed, and used.

Patients must fill Accutane prescriptions only at US licensed pharmacies.

A description of the iPLEDGE program educational materials available with

iPLEDGE is provided below. The main goal of these educational materials is to

explain the iPLEDGE program requirements and to reinforce the educational

messages.

1) The iPLEDGE Program Guide to Best Practices for Isotretinoin includes:

isotretinoin teratogenic potential, information on pregnancy testing, and the

method to complete a qualified isotretinoin prescription.

2) The iPLEDGE Program Prescriber Contraception Counseling Guide

includes: specific information about effective contraception, the limitations of

contraceptive methods, behaviors associated with an increased risk of

contraceptive failure and pregnancy and the methods to evaluate pregnancy

risk.

3) The iPLEDGE Program Pharmacist Guide for Isotretinoin includes:

isotretinoin teratogenic potential and the method to obtain authorization to

dispense an isotretinoin prescription.

4) The iPLEDGE program is a systematic approach to comprehensive patient

education about their responsibilities and includes education for contraception

compliance and reinforcement of educational messages. The iPLEDGE

program includes information on the risks and benefits of isotretinoin which is

linked to the Medication Guide dispensed by pharmacists with each

isotretinoin prescription.

5) Female patients not of childbearing potential and male patients, and female

patients of childbearing potential are provided with separate booklets. Each

booklet contains information on isotretinoin therapy including precautions and

warnings, a Patient Information/Informed Consent (for all patients) form, and

a toll-free line which provides isotretinoin information in 2 languages.

18

6) The booklet for female patients not of childbearing potential and male

patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and

Female Patients Who Cannot Get Pregnant, also includes information about

male reproduction and a warning not to share isotretinoin with others or to

donate blood during isotretinoin therapy and for 1 month following

discontinuation of isotretinoin.

7) The booklet for female patients of childbearing potential, The iPLEDGE

Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant,

includes a referral program that offers female patients free contraception

counseling, reimbursed by the manufacturer, by a reproductive specialist; and

a second Patient Information/Informed Consent About Birth Defects (for

female patients who can get pregnant) form concerning birth defects.

8) The booklet, The iPLEDGE Program Birth Control Workbook includes

information on the types of contraceptive methods, the selection and use of

appropriate, effective contraception, the rates of possible contraceptive failure

and a toll-free contraception counseling line.

9) In addition, there is a patient educational DVD with the following videos —

“Be Prepared, Be Protected†and “Be Aware: The Risk of Pregnancy While

on Isotretinoin†(see Information for Patients).

General

Although an effect of Accutane on bone loss is not established, physicians should

use caution when prescribing Accutane to patients with a genetic predisposition

for age-related osteoporosis, a history of childhood osteoporosis conditions,

osteomalacia, or other disorders of bone metabolism. This would include patients

diagnosed with anorexia nervosa and those who are on chronic drug therapy that

causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D

metabolism, such as systemic corticosteroids and any anticonvulsant.

Patients may be at increased risk when participating in sports with repetitive

impact where the risks of spondylolisthesis with and without pars fractures and

hip growth plate injuries in early and late adolescence are known. There are

spontaneous reports of fractures and/or delayed healing in patients while on

therapy with Accutane or following cessation of therapy with Accutane while

involved in these activities. While causality to Accutane has not been established,

an effect must not be ruled out.

Information for Patients

See PRECAUTIONS and Boxed CONTRAINDICATIONS AND

WARNINGS.

• Patients must be instructed to read the Medication Guide supplied as required

by law when Accutane is dispensed. The complete text of the Medication

Guide is reprinted at the end of this document. For additional information,

patients must also be instructed to read the iPLEDGE program patient

19

educational materials. All patients must sign the Patient Information/Informed

Consent (for all patients) form.

• Female patients of childbearing potential must be instructed that they must not

be pregnant when Accutane therapy is initiated, and that they should use 2

forms of effective contraception simultaneously for 1 month before starting

Accutane, while taking Accutane, and for 1 month after Accutane has been

stopped, unless they commit to continuous abstinence from heterosexual

intercourse. They should also sign a second Patient Information/Informed

Consent About Birth Defects (for female patients who can get pregnant) form

prior to beginning Accutane therapy. They should be given an opportunity to

view the patient DVD provided by the manufacturer to the prescriber. The

DVD includes information about contraception, the most common reasons

that contraception fails, and the importance of using 2 forms of effective

contraception when taking teratogenic drugs and comprehensive information

about types of potential birth defects which could occur if a female patient

who is pregnant takes Accutane at any time during pregnancy. Female patients

should be seen by their prescribers monthly and have a urine or serum

pregnancy test, in a CLIA-certified laboratory, performed each month during

treatment to confirm negative pregnancy status before another Accutane

prescription is written (see Boxed CONTRAINDICATIONS AND

WARNINGS and PRECAUTIONS).

• Accutane is found in the semen of male patients taking Accutane, 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.

• Prescribers should be alert to the warning signs of psychiatric disorders to

guide patients to receive the help they need. Therefore, prior to initiation of

Accutane treatment, patients and family members should be asked about any

history of psychiatric disorder, and at each visit during treatment patients

should be assessed for symptoms of depression, mood disturbance, psychosis,

or aggression to determine if further evaluation may be necessary. Signs and

symptoms of depression include sad mood, hopelessness, feelings of guilt,

worthlessness or helplessness, loss of pleasure or interest in activities,

fatigue, difficulty concentrating, change in sleep pattern, change in weight

or appetite, suicidal thoughts or attempts, restlessness, irritability, acting

on dangerous impulses, and persistent physical symptoms unresponsive

to treatment. Patients should stop Accutane and the patient or a family

member should promptly contact their prescriber if the patient develops

depression, mood disturbance, psychosis, or aggression, without waiting until

the next visit. Discontinuation of Accutane treatment may be insufficient;

further evaluation may be necessary. While such monitoring may be helpful,

20

it may not detect all patients at risk. Patients may report mental health

problems or family history of psychiatric disorders. These reports should be

discussed with the patient and/or the patient’s family. A referral to a mental

health professional may be necessary. The physician should consider whether

Accutane therapy is appropriate in this setting; for some patients the risks may

outweigh the benefits of Accutane therapy.

• Patients must be informed that some patients, while taking Accutane or soon

after stopping Accutane, 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 Accutane 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 Accutane becoming aggressive or

violent. No one knows if Accutane caused these behaviors or if they would

have happened even if the person did not take Accutane. Some people have

had other signs of depression while taking Accutane.

• Patients must be informed that they must not share Accutane with anyone else

because of the risk of birth defects and other serious adverse events.

• Patients must be informed not to donate blood during therapy and for 1 month

following discontinuation of the drug because the blood might be given to a

pregnant female patient whose fetus must not be exposed to Accutane.

• Patients should be reminded to take Accutane with a meal (see DOSAGE

AND ADMINISTRATION). To decrease the risk of esophageal irritation,

patients should swallow the capsules with a full glass of liquid.

• Patients should be informed that transient exacerbation (flare) of acne has

been seen, generally during the initial period of therapy.

• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser)

should be avoided during Accutane therapy and for at least 6 months

thereafter due to the possibility of scarring (see ADVERSE REACTIONS:

Skin and Appendages).

• Patients should be advised to avoid prolonged exposure to UV rays or

sunlight.

• Patients should be informed that they may experience decreased tolerance to

contact lenses during and after therapy.

• Patients should be informed that approximately 16% of patients treated with

Accutane in a clinical trial developed musculoskeletal symptoms (including

21

arthralgia) during treatment. In general, these symptoms were mild to

moderate, but occasionally required discontinuation of the drug. Transient

pain in the chest has been reported less frequently. In the clinical trial, these

symptoms generally cleared rapidly after discontinuation of Accutane, but in

some cases persisted (see ADVERSE REACTIONS: Musculoskeletal).

There have been rare postmarketing reports of rhabdomyolysis, some

associated with strenuous physical activity (see Laboratory Tests: CPK).

• Pediatric patients and their caregivers should be informed that approximately

29% (104/358) of pediatric patients treated with Accutane developed back

pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a

higher frequency in female patients than male patients. Arthralgias were

experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in

7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system

should be done in patients who present with these symptoms during or after a

course of Accutane. Consideration should be given to discontinuation of

Accutane if any significant abnormality is found.

• Neutropenia and rare cases of agranulocytosis have been reported. Accutane

should be discontinued if clinically significant decreases in white cell counts

occur.

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous

allergic reactions and serious cases of allergic vasculitis, often with purpura

(bruises and red patches) of the extremities and extracutaneous involvement

(including renal) have been reported. Severe allergic reaction necessitates

discontinuation of therapy and appropriate medical management.

Drug Interactions

• Vitamin A: Because of the relationship of Accutane to vitamin A, patients

should be advised against taking vitamin supplements containing vitamin A to

avoid additive racyclines: Concomitant treatment with Accutane and tetracyclines should

be avoidtoxic effects.

• Teted because Accutane use has been associated with a number of cases

of pseudotumor cerebri (benign intracranial hypertension), some of which

involved concomitant use of tetracyclines.

• Micro-dosed Progesterone Preparations: Micro-dosed progesterone

preparations (“minipills†that do not contain an estrogen) may be an

inadequate method of contraception during Accutane therapy. Although other

hormonal contraceptives are highly effective, there have been reports of

pregnancy from female patients who have used combined oral contraceptives,

as well as transdermal patch/injectable/implantable/vaginal ring hormonal

birth control products. These reports are more frequent for female patients

who use only a single method of contraception. It is not known if hormonal

contraceptives differ in their effectiveness when used with Accutane.

22

Therefore, it is critically important for female patients of childbearing

potential to select and commit to use 2 forms of effective contraception

simultaneously, at least 1 of which must be a primary form (see

PRECAUTIONS).

• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female

patients with severe recalcitrant nodular acne receiving OrthoNovum 7/7/7

Tablets as an oral contraceptive agent, Accutane at the recommended dose of

1 mg/kg/day, did not induce clinically relevant changes in the

pharmacokinetics of ethinyl estradiol and norethindrone and in the serum

levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing

hormone (LH). Prescribers are advised to consult the package insert of

medication administered concomitantly with hormonal contraceptives, since

some medications may decrease the effectiveness of these birth control

products.

• St. John’s Wort: Accutane use is associated with depression in some

patients (see WARNINGS: Psychiatric Disorders and ADVERSE

REACTIONS: Psychiatric). Patients should be prospectively cautioned not

to self-medicate with the herbal supplement St. John’s Wort because a

possible interaction has been suggested with hormonal contraceptives based

on reports of breakthrough bleeding on oral contraceptives shortly after

starting St. John's Wort. Pregnancies have been reported by users of combined

hormonal contraceptives who also used some form of St. John's Wort.

• Phenytoin: Accutane has not been shown to alter the pharmacokinetics of

phenytoin in a study in seven healthy volunteers. These results are consistent

with the in vitro finding that neither isotretinoin nor its metabolites induce or

inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is

known to cause osteomalacia. No formal clinical studies have been conducted

to assess if there is an interactive effect on bone loss between phenytoin and

Accutane. Therefore, caution should be exercised when using these drugs

together.

• Systemic Corticosteroids: Systemic corticosteroids are known to cause

osteoporosis. No formal clinical studies have been conducted to assess if there

is an interactive effect on bone loss between systemic corticosteroids and

Accutane. Therefore, caution should be exercised when using these drugs

together.

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 Accutane prescription. The first test (a screening test) is

obtained by the prescriber when the decision is made to pursue qualification

of the patient for Accutane. The second pregnancy test (a confirmation test)

23

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 and within 7 days

following the office visit, immediately preceding the beginning of Accutane

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 within 7 days following the office visit, immediately preceding the

beginning of Accutane therapy and after the patient has used 2 forms of

contraception for 1 month.

− Each month of therapy, patients must have a negative result from a urine or

serum pregnancy test. A pregnancy test must be repeated each month, in a

CLIA-certified laboratory, prior to the female patient receiving each

prescription.

• Lipids: Pretreatment and follow-up blood lipids should be obtained under

fasting conditions. After consumption of alcohol, at least 36 hours should

elapse before these determinations are made. It is recommended that these

tests be performed at weekly or biweekly intervals until the lipid response to

Accutane is established. The incidence of hypertriglyceridemia is 1 patient in

4 on Accutane therapy (see WARNINGS: Lipids).

• Liver Function Tests: Since elevations of liver enzymes have been observed

during clinical trials, and hepatitis has been reported, pretreatment and followup

liver function tests should be performed at weekly or biweekly intervals

until the response to Accutane has been established (see WARNINGS:

Hepatotoxicity).

• Glucose: Some patients receiving Accutane have experienced problems in the

control of their blood sugar. In addition, new cases of diabetes have been

diagnosed during Accutane therapy, although no causal relationship has been

established.

• CPK: Some patients undergoing vigorous physical activity while on Accutane

therapy have experienced elevated CPK levels; however, the clinical

significance is unknown. There have been rare postmarketing reports of

rhabdomyolysis, some associated with strenuous physical activity. In a

clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant

nodular acne, transient elevations in CPK were observed in 12% of patients,

including those undergoing strenuous physical activity in association with

reported musculoskeletal adverse events such as back pain, arthralgia, limb

injury, or muscle sprain. In these patients, approximately half of the CPK

elevations returned to normal within 2 weeks and half returned to normal

within 4 weeks. No cases of rhabdomyolysis were reported in this trial.

24

Carcinogenesis, Mutagenesis and Impairment of Fertility

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or

32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day,

respectively, after normalization for total body surface area) for greater than 18

months, there was a dose-related increased incidence of pheochromocytoma

relative to controls. The incidence of adrenal medullary hyperplasia was also

increased at the higher dosage in both sexes. The relatively high level of

spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it

an equivocal model for study of this tumor; therefore, the relevance of this tumor

to the human population is uncertain.

The Ames test was conducted with isotretinoin in two laboratories. The results of

the tests in one laboratory were negative while in the second laboratory a weakly

positive response (less than 1.6 x background) was noted in S. typhimurium

TA100 when the assay was conducted with metabolic activation. No doseresponse

effect was seen and all other strains were negative. Additionally, other

tests designed to assess genotoxicity (Chinese hamster cell assay, mouse

micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with

human-derived lymphocytes, and unscheduled DNA synthesis assay) were all

negative.

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation

or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32

mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1.0

mg/kg/day, respectively, after normalization for total body surface area).

In dogs, testicular atrophy was noted after treatment with oral isotretinoin for

approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the

recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for

total body surface area). In general, there was microscopic evidence for

appreciable depression of spermatogenesis but some sperm were observed in all

testes examined and in no instance were completely atrophic tubules seen. In

studies of 66 men, 30 of whom were patients with nodular acne under treatment

with oral isotretinoin, no significant changes were noted in the count or motility

of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years)

receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects

were seen on ejaculate volume, sperm count, total sperm motility, morphology or

seminal plasma fructose.

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND

WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the

potential for adverse effects, nursing mothers should not receive Accutane.

25

Pediatric Use

The use of Accutane in pediatric patients less than 12 years of age has not been

studied. The use of Accutane for the treatment of severe recalcitrant nodular acne

in pediatric patients ages 12 to 17 years should be given careful consideration,

especially for those patients where a known metabolic or structural bone disease

exists (see PRECAUTIONS: General). Use of Accutane in this age group for

severe recalcitrant nodular acne is supported by evidence from a clinical study

comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (≥18

years). Results from this study demonstrated that Accutane, at a dose of 1

mg/kg/day given in two divided doses, was equally effective in treating severe

recalcitrant nodular acne in both pediatric and adult patients.

In studies with Accutane, adverse reactions reported in pediatric patients were

similar to those described in adults except for the increased incidence of back pain

and arthralgia (both of which were sometimes severe) and myalgia in pediatric

patients (see ADVERSE REACTIONS).

In an open-label clinical trial (N=217) of a single course of therapy with Accutane

for severe recalcitrant nodular acne, bone density measurements at several

skeletal sites were not significantly decreased (lumbar spine change >-4% and

total hip change >-5%) or were increased in the majority of patients. One patient

had a decrease in lumbar spine bone mineral density >4% based on unadjusted

data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density

>4%, and all the other patients (92%) did not have significant decreases or had

increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in

total hip bone mineral density >5% based on unadjusted data. Twenty-one

(10.6%) patients had decreases in total hip bone mineral density >5%, and all the

other patients (89%) did not have significant decreases or had increases (adjusted

for body mass index). Follow-up studies performed in 8 of the patients with

decreased bone mineral density for up to 11 months thereafter demonstrated

increasing bone density in 5 patients at the lumbar spine, while the other 3

patients had lumbar spine bone density measurements below baseline values.

Total hip bone mineral densities remained below baseline (range −1.6% to

−7.6%) in 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13 to 18 years, who

started a second course of Accutane 4 months after the first course, two patients

showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see

WARNINGS: Skeletal: Bone Mineral Density).

Geriatric Use

Clinical studies of isotretinoin did not include sufficient numbers of subjects aged

65 years and over to determine whether they respond differently from younger

subjects. Although reported clinical experience has not identified differences in

responses between elderly and younger patients, effects of aging might be

expected to increase some risks associated with isotretinoin therapy (see

WARNINGS and PRECAUTIONS).

26

ADVERSE REACTIONS

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational

studies of Accutane, and the postmarketing experience. The relationship of some

of these events to Accutane therapy is unknown. Many of the side effects and

adverse reactions seen in patients receiving Accutane are similar to those

described in patients taking very high doses of vitamin A (dryness of the skin and

mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse

reactions reported in clinical trials were reversible when therapy was

discontinued; however, some persisted after cessation of therapy (see

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WARNINGS and ADVERSE REACTIONS).

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity (see

PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight

loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels

(see PRECAUTIONS: Laboratory Tests)

Gastrointestinal

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease),

hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS:

Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal

ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms

Hematologic

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia,

thrombocytopenia, neutropenia, rare reports of agranulocytosis (see

PRECAUTIONS: Information for Patients). See PRECAUTIONS:

Laboratory Tests for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature

epiphyseal closure, decreases in bone mineral density (see WARNINGS:

Skeletal), musculoskeletal symptoms (sometimes severe) including back pain,

myalgia, and arthralgia (see PRECAUTIONS: Information for Patients),

27

transient pain in the chest (see PRECAUTIONS: Information for Patients),

arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare

reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).

Neurological

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness,

drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias,

seizures, stroke, syncope, weakness

Psychiatric

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression,

violent behaviors (see WARNINGS: Psychiatric Disorders), emotional

instability

Of the patients reporting depression, some reported that the depression subsided

with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

abnormal menses

Respiratory

bronchospasms (with or without a history of asthma), respiratory infection, voice

alteration

Skin and Appendages

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry

lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 flushing,

fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and

hypopigmentation, infections (including disseminated herpes simplex), nail

dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing

reactions, pruritus, pyogenic granuloma, rash (including facial erythema,

seborrhea, and eczema), sunburn susceptibility increased, sweating, urticaria,

vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS:

Hypersensitivity), abnormal wound healing (delayed healing or exuberant

granulation tissue with crusting; see PRECAUTIONS: Information for

Patients)

Special Senses

Hearing

hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision

corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision

which may persist (see WARNINGS: Decreased Night Vision), cataracts, color

28

vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic

neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific

urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological

parameters)

Laboratory

Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum

high-density lipoprotein (HDL) levels, elevations of serum cholesterol during

treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see

WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS:

Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts

(including severe neutropenia and rare reports of agranulocytosis; see

PRECAUTIONS: Information for Patients), elevated sedimentation rates,

elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

OVERDOSAGE

The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600

times the recommended clinical dose of 1.0 mg/kg/day after normalization of the

rat dose for total body surface area and >300 times the recommended clinical dose

of 1.0 mg/kg/day after normalization of the mouse dose for total body surface

area) and is approximately 1960 mg/kg in rabbits (653 times the recommended

clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In

humans, overdosage has been associated with vomiting, facial flushing, cheilosis,

abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve

without apparent residual effects.

Accutane causes serious birth defects at any dosage (see Boxed

CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing

potential who present with isotretinoin overdose must be evaluated for pregnancy.

Patients who are pregnant should receive counseling about the risks to the fetus,

as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Nonpregnant

patients must be warned to avoid pregnancy for at least one month and

receive contraceptive counseling as described in PRECAUTIONS. Educational

materials for such patients can be obtained by calling the manufacturer. Because

an overdose would be expected to result in higher levels of isotretinoin in semen

than found during a normal treatment course, male patients should use a condom,

29

or avoid reproductive sexual activity with a female patient who is or might

become pregnant, for 1 month after the overdose. All patients with isotretinoin

overdose should not donate blood for at least 1 month.DOSAGE AND ADMINISTRATION

Accutane should be administered with a meal (see PRECAUTIONS:

Information for Patients).

The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in

two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5,

and 1.0 mg/kg/day,8 it was found that all dosages provided initial clearing of

disease, but there was a greater need for retreatment with the lower dosages.

During treatment, the dose may be adjusted according to response of the disease

and/or the appearance of clinical side effects — some of which may be dose

related. Adult patients whose disease is very severe with scarring or is primarily

manifested on the trunk may require dose adjustments up to 2.0 mg/kg/day, as

tolerated. Failure to take Accutane with food will significantly decrease

absorption. Before upward dose adjustments are made, the patients should be

questioned about their compliance with food instructions.

The safety of once daily dosing with Accutane has not been established. Once

daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing

15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2

months or more off therapy, and if warranted by persistent or recurring severe

nodular acne, a second course of therapy may be initiated. The optimal interval

before retreatment has not been defined for patients who have not completed

skeletal growth. Long-term use of Accutane, even in low doses, has not been

studied, and is not recommended. It is important that Accutane be given at the

recommended doses for no longer than the recommended duration. The effect of

long-term use of Accutane on bone loss is unknown (see WARNINGS: Skeletal:

Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).

Contraceptive measures must be followed for any subsequent course of therapy

(see PRECAUTIONS).

30

Table 4 Accutane Dosing by Body Weight (Based on

Administration With Food)

Body Weight Total mg/day

kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg*

40 88 20 40 80

50 110 25 50 100

60 132 30 60 120

70 154 35 70 140

80 176 40 80 160

90 198 45 90 180

100 220 50 100 200

*See DOSAGE AND ADMINISTRATION: the recommended dosage range is

0.5 to 1.0 mg/kg/day.

INFORMATION FOR PHARMACISTS

Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or

telephone (1-866-495-0654) to obtain an authorization and the “do not dispense

to patient after†date. Accutane must only be dispensed in no more than a 30-day

supply.

REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW

AUTHORIZATION FROM THE iPLEDGE SYSTEM.

An Accutane Medication Guide must be given to the patient each time Accutane

is dispensed, as required by law. This Accutane Medication Guide is an important

part of the risk management program for the patient.

HOW SUPPLIED

Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10 ROCHE.

Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0155-

49).

Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE 20 ROCHE.

Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0169-

49).

Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE 40 ROCHE. Boxes

of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0156-49).

Storage

Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from

light.

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and

conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2.

31

Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus

conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.

3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with

13-cis-retinoic acid: evaluation of sebum production and the clinical response in a

multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D,

Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980. 5. Katz

RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral

isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980.

6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin

therapy is associated with early skeletal radiographic changes. J Am Acad

Dermatol 10:1024-1029, 1984. 7. Dicken CH, Connolly SM. Eruptive xanthomas

associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952,

1980. 8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne:

results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496,

1984.

OrthoNovum 7/7/7 is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.

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 1 month before, during the entire

time of my treatment, and for 1 month after the end of my treatment with

isotretinoin.

Initial: ______

32

3. I understand that I must avoid sexual intercourse completely, or I must use 2

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: ______

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, under-the-skin implants,

vaginal rings, and intrauterine devices (IUDs). Any form of birth control can

fail. That is why I must use 2 different birth control methods at the same time,

starting 1 month before, during, and for 1 month after stopping therapy every

time I have sexual intercourse, even if 1 of the methods I choose is hormonal

birth control.

Initial: ______

5. I understand that the following are effective forms of birth control:

Primary forms

• tying my tubes (tubal

sterilization)

• partner’s vasectomy

• intrauterine device

• hormonal (combination

birth control pills, skin

patches, shots, underthe-

skin implants, or

vaginal ring)

Secondary forms

Barrier forms (always used with

spermicide):

• male latex condom

• diaphragm

• cervical cap

Others:

• vaginal sponge (contains

spermicide)

A diaphragm, condom, and cervical cap must each be used with spermicide, a

special cream that kills sperm

I understand that at least 1 of my 2 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: ______

33

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 1 month before I start taking isotretinoin.

Initial: ______

9. I cannot get my first prescription for isotretinoin unless my doctor has told me

that I have 2 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 1 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 2 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 2 birth control methods at any time.

Initial: ______

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 1 month of the last dose. If I become

pregnant, I agree to be contacted by the iPLEDGE program and be asked

questions about my pregnancy. I also understand that if I become pregnant,

information about my pregnancy, my health, and my baby’s health may be

given to the maker 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 2 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 2 forms of effective birth control at the

same time. At least 1 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 2 forms of

birth control for at least 1 month before I start isotretinoin therapy, during

therapy, and for 1 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 been informed of and understand the purpose and importance of

providing information to the iPLEDGE program should I become pregnant

while taking isotretinoin or within 1 month of the last dose. I agree to be

contacted by the iPLEDGE program and be asked questions about my

pregnancy.

• 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: ______

35

My doctor has answered all my questions about isotretinoin and I

understand that it is my responsibility not to get pregnant 1 month before,

during isotretinoin treatment, or for 1 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.

36

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: ______

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

37

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 serious mental problems.

Initials: ______

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: ______

38

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: ______

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 Signature: ____________________________________ Date: ______

Parent/Guardian Signature (if under age 18): _______________ Date: ______

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: ______

39

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT’S

MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT.

MEDICATION GUIDE

ACCUTANE (ACK-U-TANE)

(isotretinoin capsules)

Read the Medication Guide that comes with Accutane before you start taking it

and each time you get a prescription. There may be new information. This

information does not take the place of talking with your doctor about your

medical condition or your treatment.

What is the most important information I should know about

Accutane?

• Accutane is used to treat a type of severe acne (nodular acne) that has not

been helped by other treatments, including antibiotics.

• Because Accutane can cause birth defects, Accutane is only for patients

who can understand and agree to carry out all of the instructions in the

iPLEDGE program.

• Accutane 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 Accutane. Female

patients must not get pregnant:

• for 1 month before starting Accutane

• while taking Accutane

• for 1 month after stopping Accutane.

If you get pregnant while taking Accutane, stop taking it right away and

call your doctor. Doctors and patients should report all cases of pregnancy

to:

• FDA MedWatch at 1-800-FDA-1088, and

• the iPLEDGE pregnancy registry at 1-866-495-0654

2. Serious mental health problems. Accutane may cause:

• depression

• psychosis (seeing or hearing things that are not real)

• suicide. Some patients taking Accutane 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.

40

Stop Accutane and call your doctor right away if you or a family member

notices that you have any of the following signs and symptoms of

depression or psychosis:

• start to feel sad or have crying spells

• lose interest in activities you 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 your appetite or body weight

• have trouble concentrating

• withdraw from your friends or family

• feel like you have no energy

• have feelings of worthlessness or guilt

• start having thoughts about hurting yourself or taking your own life

(suicidal thoughts)

• start acting on dangerous impulses

• start seeing or hearing things that are not real

After stopping Accutane, you may also need follow-up mental health care if you

had any of these symptoms.

What is Accutane?

Accutane is a medicine taken by mouth to treat the most severe form of acne

(nodular acne) that cannot be cleared up by any other acne treatments, including

antibiotics. Accutane can cause serious side effects (see “What is the most

important information I should know about Accutane?â€). Accutane can only

be:

• prescribed by doctors that are registered in the iPLEDGE program

• dispensed by a pharmacy that is registered with the iPLEDGE program

• given to patients who are registered in the iPLEDGE program and agree to do

everything required in the program

What is severe nodular acne?

Severe nodular acne is when many red, swollen, tender lumps form in the skin.

These can be the size of pencil erasers or larger. If untreated, nodular acne can

lead to permanent scars.

Who should not take Accutane?

• Do not take Accutane if you are pregnant, plan to become pregnant, or

become pregnant during Accutane treatment. Accutane causes severe birth

defects. See “What is the most important information I should know

about Accutane?â€

41

• Do not take Accutane if you are allergic to anything in it. Accutane

contains parabens as the preservative. See the end of this Medication Guide

for a complete list of ingredients in Accutane.

What should I tell my doctor before taking Accutane?

Tell your doctor if you or a family member has any of the following health

conditions:

• mental problems

• asthma

• liver disease

• diabetes

• heart disease

• bone loss (osteoporosis) or weak bones

• an eating problem called anorexia nervosa (where people eat too little)

• food or medicine allergies

Tell your doctor if you are pregnant or breastfeeding. Accutane must not be

used by women who are pregnant or breastfeeding.

Tell your doctor about all of the medicines you take including prescription

and non-prescription medicines, vitamins and herbal supplements. Accutane

and certain other medicines can interact with each other, sometimes causing

serious side effects. Especially tell your doctor if you take:

• Vitamin A supplements. Vitamin A in high doses has many of the same side

effects as Accutane. Taking both together may increase your chance of getting

side effects.

• Tetracycline antibiotics. Tetracycline antibiotics taken with Accutane can

increase the chances of getting increased pressure in the brain.

• Progestin-only birth control pills (mini-pills). They may not work while

you take Accutane. Ask your doctor or pharmacist if you are not sure what

type you are using.

• Dilantin (phenytoin). This medicine taken with Accutane may weaken your

bones.

• Corticosteroid medicines. These medicines taken with Accutane may

weaken your bones.

• St. John’s Wort. This herbal supplement may make birth control pills work

less effectively.

These medicines should not be used with Accutane unless your doctor tells

you it is okay.

Know the medicines you take. Keep a list of them to show to your doctor and

pharmacist. Do not take any new medicine without talking with your doctor.

42

How should I take Accutane?

• You must take Accutane exactly as prescribed. You must also follow all the

instructions of the iPLEDGE program. Before prescribing Accutane, your

doctor will:

• explain the iPLEDGE program to you

• have you sign the Patient Information/Informed Consent (for all patients).

Female patients who can get pregnant must also sign another consent

form.

You will not be prescribed Accutane if you cannot agree to or follow all

the instructions of the iPLEDGE program.

• You will get no more than a 30-day supply of Accutane at a time. This is to

make sure you are following the Accutane iPLEDGE program. You should

talk with your doctor each month about side effects.

• The amount of Accutane you take has been specially chosen for you. It is

based on your body weight, and may change during treatment.

• Take Accutane 2 times a day with a meal, unless your doctor tells you

otherwise. Swallow your Accutane capsules whole with a full glass of

liquid. Do not chew or suck on the capsule. Accutane can hurt the tube that

connects your mouth to your stomach (esophagus) if it is not swallowed

whole.

• If you miss a dose, just skip that dose. Do not take 2 doses at the same time.

• If you take too much Accutane or overdose, call your doctor or poison control

center right away.

• Your acne may get worse when you first start taking Accutane. This should

last only a short while. Talk with your doctor if this is a problem for you.

• You must return to your doctor as directed to make sure you don’t have signs

of serious side effects. Your doctor may do blood tests to check for serious

side effects from Accutane. Female patients who can get pregnant will get a

pregnancy test each month.

• Female patients who can get pregnant must agree to use 2 separate forms of

effective birth control at the same time 1 month before, while taking, and for 1

month after taking Accutane. You must access the iPLEDGE system to

answer questions about the program requirements and to enter your 2

chosen forms of birth control. To access the iPLEDGE system, go to

www.ipledgeprogram.com or call 1-866-495-0654.

You must talk about effective birth control methods with your doctor or go for

a free visit to talk about birth control with another doctor or family planning

43

expert. Your doctor can arrange this free visit, which will be paid for by the

company that makes Accutane.

If you have sex at any time without using 2 forms of effective birth

control, get pregnant, or miss your expected period, stop using Accutane

and call your doctor right away.

What should I avoid while taking Accutane?

• Do not get pregnant while taking Accutane and for 1 month after stopping

Accutane. See “What is the most important information I should know

about Accutane?â€

• Do not breast feed while taking Accutane and for 1 month after stopping

Accutane. We do not know if Accutane can pass through your milk and harm

the baby.

• Do not give blood while you take Accutane and for 1 month after stopping

Accutane. If someone who is pregnant gets your donated blood, her baby may

be exposed to Accutane and may be born with birth defects.

• Do not take other medicines or herbal products with Accutane unless you

talk to your doctor. See “What should I tell my doctor before taking

Accutane?â€

• Do not drive at night until you know if Accutane has affected your vision.

Accutane may decrease your ability to see in the dark.

• Do not have cosmetic procedures to smooth your skin, including waxing,

dermabrasion, or laser procedures, while you are using Accutane and for

at least 6 months after you stop. Accutane can increase your chance of

scarring from these procedures. Check with your doctor for advice about when

you can have cosmetic procedures.

• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines

use ultraviolet lights. Accutane may make your skin more sensitive to light.

• Do not share Accutane with other people. It can cause birth defects and

other serious health problems.

What are the possible side effects of Accutane?

• Accutane can cause birth defects (deformed babies), loss of a baby before

birth (miscarriage), death of the baby, and early (premature) births. See

“What is the most important information I should know about

Accutane?â€

• Accutane may cause serious mental health problems. See “What is the

most important information I should know about Accutane?â€

44

• serious brain problems. Accutane can increase the pressure in your brain.

This can lead to permanent loss of eyesight and, in rare cases, death. Stop

taking Accutane and call your doctor right away if you get any of these signs

of increased brain pressure:

• bad headache

• blurred vision

• dizziness

• nausea or vomiting

• seizures (convulsions)

• stroke

• stomach area (abdomen) problems. Certain symptoms may mean that your

internal organs are being damaged. These organs include the liver, pancreas,

bowel (intestines), and esophagus (connection between mouth and stomach).

If your organs are damaged, they may not get better even after you stop taking

Accutane. Stop taking Accutane and call your doctor if you get:

• severe stomach, chest or bowel pain

• trouble swallowing or painful swallowing

• new or worsening heartburn

• diarrhea

• rectal bleeding

• yellowing of your skin or eyes

• dark urine

• bone and muscle problems. Accutane may affect bones, muscles, and

ligaments and cause pain in your joints or muscles. Tell your doctor if you

plan hard physical activity during treatment with Accutane. Tell your doctor if

you get:

• back pain

• joint pain

• broken bone. Tell all healthcare providers that you take Accutane if you

break a bone.

Stop Accutane and call your doctor right away if you have muscle

weakness. Muscle weakness with or without pain can be a sign of

serious muscle damage.

Accutane may stop long bone growth in teenagers who are still growing.

• hearing problems. Stop using Accutane and call your doctor if your hearing

gets worse or if you have ringing in your ears. Your hearing loss may be

permanent.

• vision problems. Accutane may affect your ability to see in the dark. This

condition usually clears up after you stop taking Accutane, but it may be

permanent. Other serious eye effects can occur. Stop taking Accutane and call

45

your doctor right away if you have any problems with your vision or dryness

of the eyes that is painful or constant. If you wear contact lenses, you may

have trouble wearing them while taking Accutane and after treatment.

• lipid (fats and cholesterol in blood) problems. Accutane can raise the level

of fats and cholesterol in your blood. This can be a serious problem. Return to

your doctor for blood tests to check your lipids and to get any needed

treatment. These problems usually go away when Accutane treatment is

finished.

• serious allergic reactions. Stop taking Accutane and get emergency care

right away if you develop hives, a swollen face or mouth, or have trouble

breathing. Stop taking Accutane and call your doctor if you get a fever, rash,

or red patches or bruises on your legs.

• blood sugar problems. Accutane may cause blood sugar problems including

diabetes. Tell your doctor if you are very thirsty or urinate a lot.

• decreased red and white blood cells. Call your doctor if you have trouble

breathing, faint, or feel weak.

• The common, less serious side effects of Accutane are dry skin, chapped

lips, dry eyes, and dry nose that may lead to nosebleeds. Call your doctor if

you get any side effect that bothers you or that does not go away.

These are not all of the possible side effects with Accutane. Your doctor or

pharmacist can give you more detailed information.

How should I store Accutane?

• Store Accutane at room temperature, between 59° and 86°F. Protect from

light.

• Keep Accutane and all medicines out of the reach of children.

General Information about Accutane

Medicines are sometimes prescribed for conditions that are not mentioned in

Medication Guides. Do not use Accutane for a condition for which it was not

prescribed. Do not give Accutane to other people, even if they have the same

symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about

Accutane. If you would like more information, talk with your doctor. You can ask

your doctor or pharmacist for information about Accutane that is written for

health care professionals. You can also call iPLEDGE program at 1-866-495-

0654 or visit www.ipledgeprogram.com.

46

What are the ingredients in Accutane?

Active Ingredient: Isotretinoin

Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium,

hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil.

Gelatin capsules contain glycerin and parabens (methyl and propyl), with the

following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg —

FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C

Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.This Medication Guide has been approved by the U.S. Food and Drug

Administration.

Dilantin is a registered trademark of Warner-Lambert Company LLC.

Distributed by:

27898954

Revised: August 2005

Copyright © 2000-2005 by Roche Laboratories Inc. All rights reserved.

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so basically accutane causes birth defects and depression. thanks for the new info ;)

sorry, but i still think accutane is a good med as long as it is used properly. (not while pregnant) and as long as you are aware of the side effects, and what to look for.

this is information that people taking accutane are well aware of. (it's on the box.)

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so basically accutane causes birth defects and depression. thanks for the new info ;)

sorry, but i still think accutane is a good med as long as it is used properly. (not while pregnant) and as long as you are aware of the side effects, and what to look for.

this is information that people taking accutane are well aware of. (it's on the box.)

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from the iPLEDGE materials

Unlike in female patients, there is no pattern of birth defects in babies whose father were taking isotretinoin. approximately 3-5 babies in 100 are born with some kind of birth defect from other causes, not from isotretinoin.

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i did, i was on retin a 3 different antibiotics, diet, countless topicals, and nicomide. accutane has helped the most.

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maybe we wouldn't have to watch our lipids and liver

if there wasn't hydrogenated this and that in the med...HA!!!!!!!!!!!

maybe we could suggest using olive oil or coconut oil

hehe

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i did, i was on retin a 3 different antibiotics, diet, countless topicals, and nicomide. accutane has helped the most.

good but you know there are people who have never stepped foot into a derm's office in their life for acne

that are wanting to get put on this stuff on day 1

will you be able to get off someday? i see you alternate dosages?

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The point of this thread is to inform people that accutane isnt all candy and roses, there are real risks involved and they should not be shoved under the carpet in the name of clear skin.

Its a big decision not to be taken lightly.

This thread is about real education about the truth, for people that are willing to listen and learn.

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Well the risks exist, but most people do not get the serious side effects - they are extremely rare. Most people only experience the dryness and lipid elevations which correct after the treatment is over.

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The point of this thread is to inform people that accutane isnt all candy and roses, there are real risks involved and they should not be shoved under the carpet in the name of clear skin.

Its a big decision not to be taken lightly.

This thread is about real education about the truth, for people that are willing to listen and learn.

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I talked to her about it. 2Bacnefree did not mean to offend anyone with her posts, she just got a little zealous with the package insert and has said that she's not posting this stuff anymore. Let it go, please.

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