CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`18-662 I S-038
`
`Trade Name:
`
`Accutane
`
`Generic Name: (isotretinoin)
`
`Sponsor:
`
`Hoffman La Roche Inc.
`
`Approval Date: May 1, 2000
`
`CFAD VI 1029-0001
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`
`18-662 I S-038
`
`CONTENTS
`
`~ Reviews I Information Included in this NDA Review.
`
`Final Printed Labelin
`Medical Review s
`Chemist Review(s
`EA/FON SI
`Pharmacolo · Review s
`Statistical. Review s)
`
`x
`
`x
`
`Administrative and Corres ondence Document(s
`
`X
`
`CFAD VI 1029-0002
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`APPLICA TI0N NUMBER:
`
`18-662 I S-038
`18-662 / S-038
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`CFAD VI 1029-0003
`
`CFAD VI 1029-0003
`
`

`

`!tbJ., I
`
`MAY I
`
`2000
`
`NDA 18-662/S-038
`
`Hoffmann-La Roche Inc.
`Attention: Betty Holland, M.S.
`Program Director
`340 Kingsland Street
`Nutley, New Jersey 07110-1199
`
`Dear Ms. Holland:
`
`Please refer to your supplemental new drug applications dated September 10, 1999, received
`September 13, 1999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act. for.Accutane (isotretinoin) Capsules, 10 mg, 20 mg, and 40 mg,
`
`~
`
`We acknqyvJedge receipt of your submissions dated December 22, 1999; and January 17 and 26,
`FebruaryJfg and 24, and April 6 and 18, 2000.
`..
`This supplemen~l new drug application provides for revisions to the labeling regarding the use
`o~contra,ceptive methods .
`. :-~ .. ·......
`·. ~
`
`.~..:·
`
`We have'completed the review of this supplemental application, as amended, and have
`concluded that adequate informati.on has been presented to demonstrate that the drug product is
`safe and effective for use as recommended in the agreed upon enclosed labeling text.
`Accordingly, this supplemental application is approved effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package
`insert).
`
`Please submit 20 copies of the FPL as soon as it is available, in no case more than 30 days after
`it is printed to each application. Please individually mount ten of the copies on heavy-weight
`. paper or similar :material. For administrative purposes, this submission should be designated
`"FPL for approved Supplement NDA 18--662/S-038. II Approval of this submission by FDA is not
`required before the labeling is used.
`
`If a letter communicating important information about this drug product (i.e., a "Dear Health
`Care Practitioner" letter) is issued to physicians and others responsible for patient care, we
`request that you submit a copy of the letter to this NDA and a copy to the following address:
`
`MEDW ATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`)
`
`CFAD VI 1029-0004
`
`

`

`NDA 18-662/S-038
`Page2
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21CFR314.80 and 314.81.
`
`If you have any questions, call Kevin Darryl White, Project Manager, at (301) 827-2920.
`
`Sincerely,
`
`(J -!_J s/1(00
`Jonat~n K. Wilkin, M.D.
`
`Director
`Division of Dermatologic and Dental Drug Products
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`CFAD VI 1029-0005
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`APPLICA TI0N NUMBER:
`
`18-662 I S-038
`18-662 / 8-038
`
`APPROVED LABELING
`APPROVED LABELING
`
`CFAD V1 1029-0006
`
`CFAD VI 1029-0006
`
`

`

`MAY l
`
`2000
`
`'·-Accutane 04/18100
`
`, ACCUTANE®
`(isotretinoin)
`CAPSULES
`
`A void Pregnancy
`
`CONTRAINDICATIONS AND WARNINGS: Accutane must not be used by
`females who are pregnant or who may become pregnant while undergoing
`treatment. Although not every fetus exposed to Accutane has resulted in a deformed
`child, there is an extremely high risk that a deformed infant can result if pregnancy
`occurs while taking Accutane in any amou~t even for short periods of time.
`Potentially any fetus exposed during pregn_;incy can be affected. Presently, there are
`no accurate means of determining after At'cutane exposure which fetus has been
`affected and which fetus has not been affected.
`
`Accutane is contraindicate.d in females of childbearing potential unless the patient
`meets all of the following conditions:
`
`• must have severe disfiguring nodular acne that is recalcitrant to standard
`therapies (see INDICATIONS AND USAGE for definition)
`
`• must be reliable in understanding and carrying out instructions
`
`• must be capable of complying with the mandatory contraceptive measures
`required ff?r Accutane therapy and understand behaviors associated with an
`increased risk of pregnancy
`
`• must have received both oral and written warnings of the hazards of taking
`Accutane during pregnancy and exp_o.sing a fetus to the drug
`
`• must have received both oral and written information on the types of
`contraceptive methods and warnings about the rates of possible contraceptive
`failure, ·and-~f the need to use two separate, effective forms of contraception
`simultaneously, unless abstinence is the chosen method, or the patient has
`undergone a hysterectomy and has acknowledged in writing her understanding
`of the information and warnings and.of the need for using two contraceptive
`methods· simultaneously
`
`CFAD VI 1029-0007
`
`

`

`Accutane 04/18/00
`
`ACCUTANE® (isotretinoin)
`
`• must have had a negative urine or serum pregnan~y test with a sensitivity of at
`least 50 mlU/IltL when the patient is qualified for Accutane therapy by the
`prescriber, and must have had a second negative urine or serum pregnancy test
`on tb,e second day of the next normal menstrual period or at least 11 days after
`the last unprotected aci of sexual intercourse, whichever is later
`
`•
`
`·must understand and agree that her prescriber will issue her a prescription for
`Accutane only after she has contacted the prescriber to confirm that she has
`obtained a negative result forthe second urine pregnancy test which is to be
`·conducted on _the second day of the next normal menstrual period or at least 11
`. days after the last unprotected act of sexual intercourse, whichever is later
`
`• must have received instruction to join the Accutane Survey and have watched .a
`videotape, provided by Roche to her prescriber, that provides information about
`contraceptive methods, possible reasons for contraceptive failure, and
`importance of using effective contraception when taking teratogenic drugs.
`Major human fetal abnormalities related· to Accutane administration have been
`documented,: CNS abnormalities (including cerebral abnormalities, cerebellar
`malformation, hydrocephalus, microcephaly, cranial nerve deficit); skull
`abnormality; external ear abnormalities (including anotia, micropinna, small or
`absent external auditory canals); eye abnormalities (including microphthalmia);
`cardiovascular abnormalities; facial dysmorphia; cleft palate; thymus gland
`abnormality; parathyroid hormone deficiency. In some cases death has occurred
`with certain of the abnormalities previously noted. Cases of IQ scores less than 85
`with or without obvious CNS abnormalities have also be_en reported. There is an
`increased risk of spontaneous abortion. In addition, premature births have been
`reported.
`
`It is strongly recommended that a prescription for Acciltane should :not ·be issued by
`. the prescriber until a femahfpatient bas had negative results from two urine or
`serum pregnancy tests, on~ of which is performed in the prescriber's office when the
`patient is qualified for Accutane therapy, the second of which is performed on the
`second <lay of the next normal menstrual period or 11 days after the last
`unprotected act of sexual intercourse, w~ichever is later. It is also recommended
`that pregnancy testing and counseling ab~ut contraception and behaviors associated
`with an increased risk of pregnancy be repeated on a monthly basis.To assure
`compliance, the prescriber should not issue a prescription for a female patient, until
`after the second nega_tive pregnancy test result is .obtained. In a~dition, the
`prescriber shouid prescribe no more than a 1-month supply of t~e drug.for all
`.Accutane patients and no automatic refills should be permitted. Roche will supply
`urine pregnancy test kits for female Accutane patients for the initial, second, and
`monthly testing during therapy.
`
`Effective contraception must be used for at least 1 month before beginning Accutane
`therapy, during therapy, and for 1 month following discontinuation of therapy even
`
`CFAD VI 1029-0008
`
`

`

`Accutane 04/18/00
`
`ACCUT ANE® (isotretinoin)
`
`where there has been a history of infertility, unless due to hysterectomy. The
`patient must be counseled about and understand the limitations of any chosen
`' contraceptive method. The patient must also understand the risks associated with
`not using two contraceptive methods, even when one of the chosen methods is a
`hormonal contraceptive method.
`
`Any birth control method can fail. Therefore, it is critically important that women
`of childbearing potential use two effective forms of contraception simultaneously,
`unless absolute abstinence is the chosen method, even when one ofthe forms is a
`hormonal contraceptive method. Although hormonal contraceptives are highly
`effective, there have been reports of pregnancy from women who have used oral
`contraceptives, as well as injectable/implantable contraceptive products. These
`reports are more frequent for women who use only a single method of
`contraception. It is not known if hormonal contraceptives differ in their
`· effectiveness when used with Accutane.
`
`If a pregnancy does occur during treatment, the prescriber and patient should
`discuss the desirability of continuing the pregnancy. Prescribers are encouraged to
`report all cases of pregnancy with specificJnformation about the contraceptive
`forms used during Accutane therapy and for 1 month following therapy, either to
`the Roche MedicalServices@ 1-800-526-6367 or to the Food and Drug
`Administration MedWatch Program@ 1-800-FDA-10~8.
`
`Accutane should be prescribed only by prescribers who have special competence in
`the diagnosis and treatment of severe recalcitrant nodular acne, are experienced in
`the use of systemic retinoids, and understand the risk of teratogenicity if Accutane is
`used during pregnancy.
`
`Prescribers who prescribe Accutane should use the Pregnancy Prevention
`· Program8
`M kit provided by Roche for the counseling of patients, should instruct the
`patient to participate in. the A'C~utane Survey, and should receive medical education
`sponsored by Roche about effective contraception, the limitations of contraceptive
`methods and behaviors associated with an increased risk of contraceptive failure·
`and pregnancy.
`
`DESCRIPTION: Isotretinoin, a retinoid, fa available as Accutane in 10-mg, 20-mg and
`40-mg soft gelatin capsules for oral administration. Each capsule also 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 rrig-iron oxide (red)
`and titanium diOxide; 20 mg-FD&C Red No. 3, FD&C Blue No. i, and ti~anium
`dioxide; 40 mg - FD&C Yellow No. 6, D&C Yellow No. 10, arid titanium dioxide.
`
`Chemically, isotretinoin is 13-cis-retinoic aCid and is related to both retinoic acid and
`retinol (vitamin A). It is a yellow-orange to orange crystalline powder with a molecular
`weight of 300.44. The structural formula is:
`
`,
`
`I
`
`CFAD VI 1029-0009
`
`

`

`Accutane 04/18/00
`
`ACCUTANE® (isotretinoin)
`
`.~ ~ ~
`COOH
`
`.
`
`.
`
`.
`
`CLINICAL _PJIARMACOLOGY: Isotretinoin is a retinoid, which when adi:riiriistered
`inpharma~ofogic dosages of0.5 to 2.0 mg/kg/day, inhibits sebaceous gland function and
`keratinization. The exact mechanism of action of Accutane is unknown.
`
`Nodular Acne: Clinical improvement in nodular acne patients occurs in association with
`a reduction in seblim 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: Absorptii>n: Oral absorption of isotretinoin is optimal when taken
`with food or milk. After administration of a single 80-mg oral dose (two 40-mg capsules)
`ofisotretinoin to 15 healthy male subjects, maximum blood concentrations ranged from
`167 to 459 ng/mL (rriean 256 ng/mL) and were achieved in 1 to 6 hours (mean 3.2 hours).
`The oral absorption of isotretinoin is consist~nt with first-order kinetics and can be
`described with a linear two-compartment rnqpel. Nodular acne does not alter the
`absorption of the drug: In a 27-day study ofisotretinoin in 10 male patients with nodular
`acne treated with an oral dose of 40 mg bid, the mean peak concentration ranged from
`·98 ng/mL to 535 ng/mL (mean 262 ng/mL) and occurred at 2 to 4 hours after
`administration (mean 2.9 hours). In these patients, the mean± SD minimum steady-state
`blood concentration of isotretinoin was 160 ± 19 ng/mL. The terminal elimination half(cid:173)
`life was consistent with that observed in normal subjects.
`
`Distribution: Isotretinoin is more than 99.9% bound to plasma proteins, primarily
`albumin.
`
`Metabolism: After oral administration of isotretinoin, 4-oxo-isotretinoin is the major
`metabolite identified in the blood. Maximum concentrations of 4.;oxo-isotretinoin (87 to
`399 ng/mL) were achieved at 6 to 20 hour5 after oral administration of two 40-mg
`capsules; the blood concentration of the major metabolite generally exceeded that of
`isotretinoin after 6 hours. Isotretinoin also undergoes isomerization to the all-trans(cid:173)
`isomer, tretinoin; which is then metabolized to its corresponding 4-oxo-metabolite; both
`have been detected. Both parent compomicf_and metabolites are further metabolized into
`conjugates which are excreted.
`
`Elimination: Following administration of an 80-mg liquid suspension oral dose of 14C(cid:173)
`isotretinoin, 14C:activity in blood declined with a half-life of90 hou~s. The metabolites of
`isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively
`. equal amounts (total of 65% to 83%). The terminal elimination half-life of isotretinoin
`ranges from 10 to 20 hours. The mean elimination half-life of4-oxo-isotretinoin is 25
`hours (range 17 to 50 hours). After both single and multiple doses, the accumulation ratio
`of 4-oxo-isotretinoin to parent compound is 3 to 3.5.
`
`CFAD VI 1029-0010
`
`

`

`Accutane 04/18/00
`
`ACCUT ANE® (isotretinoin)
`
`- 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 severe nodular acne who are unresponsive to conventional
`therapy, including systemic antibiotics. fu addition, for female patients of childbearing
`potential, Accutane is indicated only for those females who are not pregnant (see boxed
`CONTRAINDICATIONS AND WARNINGS).
`
`A single course of therapy for 15 to 20 weeks has been shown to result in complete ~d
`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: 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 and suicide. Discontinuation of Accutane
`therapy may be insufficient; further evaluation may be necessary. No mechanism-of
`action has been established for these events (see ADVERSE REACTIONS:
`Psychiatric).
`
`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 ifhypertriglyceridemia cannot be controlled _
`at an acceptable level or if symptoms of pancreatitis occuL
`·
`
`CFAD VI 1029-0011
`
`

`

`Accutane 04/18/00
`
`ACCUT ANE® (isotretinoin)
`
`Lipids: Elevations of serum triglycerides have been reported in patients treated with
`Accutane, Marked elevations of serum triglycerides in excess of 800 IIig/dL 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 conti1rning 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 oflipid metabolism
`disorder). If Accutane therapy is instituted, more frequent checks of serum values for
`lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).
`
`The cardiovascular consequences ofhypertti:glyceridemia associated with Accutane are
`unknown. Animal Studies: In rats given 8 or;32 mg/kg/day ofisotretinoin (O.Tor 2.7
`times the maxinium clinical dose 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 (15 to 30 times the maximum clinical
`dos.e, 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. Meehanism(s) and causality for .this event have not been established.
`Patients who -experience tinnitus or hearing impairment should discontinue Accutane
`treatment and be referred to 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% ofindividuals treated during clinical
`trials, some Of which normalized with dosage reduction or continued administration of
`· the drug. If nornialization 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 (inducting regional ileitis) in patients without a prior history of intestinal
`disorders, In some instances, symptoms have been reported to persist after Accutane
`
`CFAD VI 1029-0012
`
`

`

`Accutane 04/18/00
`
`ACCUTANE® (isotretinoin).
`
`treatment has been stopped. Patients experiencing-abdominal pain, rectal bleeding or
`severe diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS:
`' Gastrointestinal).
`Skeff!iat: Hyperostosis: A high prevale1we of skeletal hyperostosis was noted in clinical
`trials for disorders of keratinization with a mean dose of2.24 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 ofligaments and tendons
`have also beeli 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.
`
`Premature Epiphyseal Closure: There are spontaneous reports of premature epiphyseal ·
`closure in acne patients receiving recommended doses, but it is not known ifthere is a
`causal relationship with Accutane. In clinical trials for disorders ofkeratinization with a
`mean dose of 2.24 mg/kg/day, two children showed x-ray findings suggestive of
`premature epiphyseal closure. The skeletal effects ofmultiple Accutane treatment courses
`.,
`for acne are unknown.
`
`Vision Impairment: Visual problems should be carefully monitored. All Accutane
`patients experiencing visual difficulties should disco.ntinue 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.
`ofkeratinization. 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 Aq;utane
`therapy and in some instanc.es the event has persisted after therapy was discontinued~
`Because the onset· in some patients was sudden, patients should he advised of this
`potential problem and warned to be cautious when driving or operating any vehicle at
`night.
`
`PRECAUTIONS: Information for Patients and Prescribers: Females of childbearing
`potential should be instructed that they must not be pregnant when Accutane
`therapy is initiated, and that they should use effective contraception while taking
`Accutane and for l month after Accutane has been stopped. They should also sign a
`consent form prior to beginning Accutane therapy. They should be instructed to
`join the Accutane Survey and to review the patient videotape provided by Roche to
`the prescriber that provides information about contraception, the most common
`reasons that contraception fails, and the importance of using effective contraception
`when taking teratogenic drugs. Female patients should also be seen monthly and
`have a urine or serum pregnancy test performed each month during treatment to
`
`CFAD VI 1029-0013
`
`

`

`Accutane 04/18/00
`
`ACCUTANE® (isotretinoin)
`
`confirm negative pregnancy status (see boxed CONTRAINDICATIONS AND'
`WARNINGS).
`.
`
`. ·.·.
`
`• Patients should be informed that they must not share Accutane with anyone else
`because of the risk of birth defects and other serious adverse events .
`
`• Patients should not donate blood during therapy and for I month following
`discontinuance of the drug because the blood might be given to a pregnant woman
`whose fetus must not be exposed to Accutane.
`
`• 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 dermabra!)ion, 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 prol~ged 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
`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: Musculoskelet~l).
`
`· • Neutropema and rare cases of agranulocytosis have been reported. Accutane should
`be discontinued if clinically significant decreases in white cell counts occur.
`
`Hypersensitivity: Anaphylactic reactions ~d 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 (!Ild extracutaneous involvement (including
`renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy .
`and appropriate medical management.
`
`.. ~·._
`
`Drug Interactions:
`
`• Because oftherelationship ofAccutane to vitamin A, patients should be advised
`against taking vitamin supplements containing vitamin A to avoid additive toxic
`·
`effects.
`
`CFAD VI 1029-0014
`
`

`

`Accutane 04118/00
`
`ACCUTANE® (isotretinoin)
`
`• Concomitant treatment with Accutane and tetracyclines should be avoided becat.ise
`Accutane use has been associated with a number of cases of pseudotumor cerebri
`(benign intracranial hypertension), some of which involved concomitant use of
`tetracyclines.
`
`• Microdosed progesterone preparations (minipills) may be an inadequate method of >
`contraception during Accutane therapy. Althou$h other hormonal contraceptives are
`highly effective, there have been reports of pregnancy from women who have·used
`oral contraceptives, as well as injectable/implantable contraceptive products. These
`reports are more frequent for women who use only a. single method of contraception'.
`It is not known if hormonal contraceptives differ in their effectiveness when used
`with Accutane. Therefore, it is critically important that women of childbearing
`potential use two effective forms of contraception simultaneously, unless absolute .
`abstinence is the chosen method, even when one of the forms is a hormonal
`contraceptive method (see boxed CONTRAINDICATIONS AND WARNINGS).
`
`Laboratory Tests:
`
`.,
`• Pregnancy Test: Female patients of childbearing potential must have negative results
`from two urine or serum pregnancy tests with a sensitivity of at least 50 mIU/mL
`before a prescription is given'. The first test is to be performed at the office visit when
`the patient is qualified for Accutane therapy by her prescriber. The second test is to
`be performed on the second day of her next menstrual cycle or 11 days after her last
`unprotect~d act of sexual intercourse, whichever is later. Additional pregnancy tests .
`·
`·
`are to be conducted monthly during treatment.
`
`• 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 hyperlri,glyceridemia is l patient in 4 on Accutane therapy (see
`WARNINGS: Lipids).
`
`. • Liver Function Tests: Since elevations of liver enzyrries have been. observed during .
`clinical trials, and hepatifis has been reported, pretreatment and follow-up liver
`fiinction tests should be performed at weekly or biweekly intervals until the response ·
`to Accutane has been established (see WARNINGS: Hepatotoxicity).
`
`· • Glucose: So.me patients receiving Accutane have experienced problem.sin 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.
`
`CFAD VI 1029-0015
`
`

`

`Accutane 04118100
`
`ACCUTANE® (isotretinoin)
`
`Carcinogenesis, Mutagenesis and Impairment of Fertility: In tnale and female Fischer
`' 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (0. 7 or 2. 7 times the
`maximum clinical dose, respectively, after normalization for total body surface area) for
`greater than)8 months, there was a dose-related increased incidence of
`pheochro:m,oc}'toma relative to controls. The incidence ofadrenal medullary hyperplasia
`·
`was also increased at the higher dosage in both sexes. The relatively high level of
`spontaneous phepchromocytomas occurring in the male Fischer 344 rat makes it an
`equivocal modelfor 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 laborato_ry were negative while in the second laboratory a weakly positive
`response (less than 1.6 x background) was noted in S. typhimurium TAIOO when the
`assay was conducted with metabolic activation. No dose-response 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 D? assay, in vitro
`clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis
`assay) were all negative.
`.:
`·i
`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 (0.2, 0. 7,
`or 2. 7 times the maximuni clinical dose, 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 of20 or 60 mg/kg/day (5or15 times the maximum
`clinical dose, respectively, after normalization for total body surface area). In general,
`there was microscopic evidence f~r 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 66men, 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 spenn 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.
`
`)
`
`ADVERSE REACTIONS: Clinical Trials and Postmarketing Surveillance: The
`adver