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Accutane (Isotretinoin) - Warnings and Precautions

 
 



BOX WARNING

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 PRESCRIPTIONAND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.

An Accutane Medication Guide must be given to the patienteach time Accutane is dispensed, as required by law. This AccutaneMedication Guide is an important part of the risk management programfor the patient.

 

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 hasbeen established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should readthe brochure, Recognizing PsychiatricDisorders in Adolescents and Young Adults: A Guide for Prescribersof Isotretinoin. Prescribers should be alert to the warningsigns of psychiatric disorders to guide patients to receive the helpthey need. Therefore, prior to initiation of Accutane therapy, patientsand family members should be asked about any history of psychiatricdisorder, and at each visit during therapy patients should be assessedfor symptoms of depression, mood disturbance, psychosis, or aggressionto determine if further evaluation may be necessary. Signs and symptomsof depression, as described in the brochure ("Recognizing PsychiatricDisorders in Adolescents and Young Adults"), include sad mood, hopelessness,feelings of guilt, worthlessness or helplessness, loss of pleasureor interest in activities, fatigue, difficulty concentrating, changein sleep pattern, change in weight or appetite, suicidal thoughtsor attempts, restlessness, irritability, acting on dangerous impulses,and persistent physical symptoms unresponsive to treatment. Patientsshould stop Accutane and the patient or a family member should promptlycontact their prescriber if the patient develops depression, mooddisturbance, psychosis, or aggression, without waiting until the nextvisit. Discontinuation of Accutane therapy may be insufficient; furtherevaluation may be necessary. While such monitoring may be helpful,it may not detect all patients at risk. Patients may report mentalhealth problems or family history of psychiatric disorders. Thesereports should be discussed with the patient and/or the patient'sfamily. A referral to a mental health professional may be necessary.The physician should consider whether Accutane therapy is appropriatein this setting; for some patients the risks may outweigh the benefitsof Accutane therapy.

Pseudotumor Cerebri

Accutane use has been associatedwith a number of cases of pseudotumor cerebri (benign intracranialhypertension), 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 withthese symptoms should be screened for papilledema and, if present,they should be told to discontinue Accutane immediately and be referredto a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

Pancreatitis

Acute pancreatitis has been reported in patients with either elevated or normal serumtriglyceride levels. In rare instances,fatal hemorrhagic pancreatitis has been reported. Accutaneshould be stopped if hypertriglyceridemia cannot be controlled atan acceptable level or if symptoms of pancreatitis occur.

Lipids

Elevations of serum triglycerides in excess of 800mg/dL have been reported in patients treated with Accutane. Markedelevations of serum triglycerides were reported in approximately 25%of patients receiving Accutane in clinical trials. In addition, approximately15% developed a decrease in high-density lipoproteins and about 7%showed an increase in cholesterol levels. In clinical trials, theeffects on triglycerides, HDL, and cholesterol were reversible uponcessation of Accutane therapy. Some patients have been able to reversetriglyceride elevation by reduction in weight, restriction of dietaryfat and alcohol, and reduction in dose while continuing Accutane.[ 5 ]

Blood lipid determinationsshould be performed before Accutane is given and then at intervalsuntil the lipid response to Accutane is established, which usuallyoccurs within 4 weeks. Especially careful consideration must be givento risk/benefit for patients who may be at high risk during Accutanetherapy (patients with diabetes, obesity, increased alcohol intake,lipid metabolism disorder or familial history of lipid metabolismdisorder). If Accutane therapy is instituted, more frequent checksof serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: LaboratoryTests).

The cardiovascularconsequences of hypertriglyceridemia associated with Accutane areunknown. Animal Studies: Inrats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times therecommended clinical dose of 1.0 mg/kg/day after normalization fortotal body surface area) for 18 months or longer, the incidences offocal calcification, fibrosis and inflammation of the myocardium,calcification of coronary, pulmonary and mesenteric arteries, andmetastatic calcification of the gastric mucosa were greater than incontrol rats of similar age. Focal endocardial and myocardial calcificationsassociated with calcification of the coronary arteries were observedin two dogs after approximately 6 to 7 months of treatment with isotretinoinat a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommendedclinical dose of 1.0 mg/kg/day, respectively, after normalizationfor total body surface area).

Hearing Impairment

Impaired hearing has been reported in patients takingAccutane; in some cases, the hearing impairment has been reportedto persist after therapy has been discontinued. Mechanism(s) and causalityfor this event have not been established. Patients who experiencetinnitus or hearing impairment should discontinue Accutane treatmentand be referred for specialized care for further evaluation (see ADVERSE REACTIONS:Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probablyrelated to Accutane therapy has been reported. Additionally, mildto moderate elevations of liver enzymes have been observed in approximately15% of individuals treated during clinical trials, some of which normalizedwith dosage reduction or continued administration of the drug. Ifnormalization does not readily occur or if hepatitis is suspectedduring treatment with Accutane, the drug should be discontinued andthe etiology further investigated.

Inflammatory Bowel Disease

Accutane has been associated with inflammatory boweldisease (including regional ileitis) in patients without a prior historyof intestinal disorders. In some instances, symptoms have been reportedto persist after Accutane treatment has been stopped. Patients experiencingabdominal pain, rectal bleeding or severe diarrhea should discontinueAccutane immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of Accutane on the developingmusculoskeletal system are unknown. There is some evidence that long-term,high-dose, or multiple courses of therapy with isotretinoin have moreof an effect than a single course of therapy on the musculoskeletalsystem. In an open-label clinical trial (N=217) of a single courseof therapy with Accutane for severe recalcitrant nodular acne, bonedensity measurements at several skeletal sites were not significantlydecreased (lumbar spine change >-4% and total hip change >-5%) orwere increased in the majority of patients. One patient had a decreasein lumbar spine bone mineral density >4% based on unadjusted data.Sixteen (7.9%) patients had decreases in lumbar spine bone mineraldensity >4%, and all the other patients (92%) did not have significantdecreases or had increases (adjusted for body mass index). Nine patients(4.5%) had a decrease in total hip bone mineral density >5% basedon unadjusted data. Twenty-one (10.6%) patients had decreases in totalhip bone mineral density >5%, and all the other patients (89%) didnot have significant decreases or had increases (adjusted for bodymass index). Follow-up studies performed in 8 of the patients withdecreased bone mineral density for up to 11 months thereafter demonstratedincreasing bone density in 5 patients at the lumbar spine, while theother 3 patients had lumbar spine bone density measurements belowbaseline 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 monthsafter the first course, two patients showed a decrease in mean lumbarspine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).

Spontaneous reports of osteoporosis,osteopenia, bone fractures, and delayed healing of bone fractureshave been seen in the Accutane population. While causality to Accutanehas not been established, an effect cannot be ruled out. Longer termeffects have not been studied. It is important that Accutane be givenat the recommended doses for no longer than the recommended duration.

Hyperostosis

A high prevalence of skeletal hyperostosis was notedin clinical trials for disorders of keratinization with a mean doseof 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in6 of 8 patients in a prospective study of disorders of keratinization.[ 6 ] Minimal skeletal hyperostosis and calcificationof ligaments and tendons have also been observed by x-ray in prospectivestudies of nodular acne patients treated with a single course of therapyat recommended doses. The skeletal effects of multiple Accutane treatmentcourses for acne are unknown.

In a clinicalstudy of 217 pediatric patients (12 to 17 years) with severe recalcitrantnodular acne, hyperostosis was not observed after 16 to 20 weeks oftreatment with approximately 1 mg/kg/day of Accutane given in twodivided doses. Hyperostosis may require a longer time frame to appear.The clinical course and significance remain unknown.

Premature Epiphyseal Closure

There are spontaneous reports of premature epiphysealclosure in acne patients receiving recommended doses of Accutane.The effect of multiple courses of Accutane on epiphyseal closure isunknown.

Vision Impairment

Visual problems should becarefully monitored. All Accutane patients experiencing visual difficultiesshould discontinue Accutane treatment and have an ophthalmologicalexamination (see ADVERSE REACTIONS: Special Senses).

Corneal Opacities

Corneal opacities have occurred in patients receivingAccutane for acne and more frequently when higher drug dosages wereused in patients with disorders of keratinization. The corneal opacitiesthat have been observed in clinical trial patients treated with Accutanehave either completely resolved or were resolving at follow-up 6 to7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).

Decreased Night Vision

Decreased night vision has been reported during Accutanetherapy and in some instances the event has persisted after therapywas discontinued. Because the onset in some patients was sudden, patientsshould be advised of this potential problem and warned to be cautiouswhen driving or operating any vehicle at night.

PRECAUTIONS

Accutane must only be prescribed by prescribers whoare registered and activated with the iPLEDGE program. Accutane mustonly 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 fromwholesalers registered with iPLEDGE.

iPLEDGEprogram requirements for wholesalers, prescribers, and pharmacistsare described below:

Wholesalers:

For the purpose of the iPLEDGE program, the termwholesaler refers to wholesaler, distributor, and/or chain pharmacydistributor. To distribute Accutane, wholesalers must be registeredwith iPLEDGE, and agree to meet all iPLEDGE requirements for wholesaledistribution of isotretinoin products. Wholesalers must register withiPLEDGE by signing and returning the iPLEDGE wholesaler agreementthat affirms they will comply with all iPLEDGE requirements for distributionof isotretinoin. These include:

  • Registering prior to distributing isotretinoin and re-registeringannually thereafter
  • Distributing only FDA approved isotretinoin product
  • Only shipping isotretinoin to
      –wholesalers registered in the iPLEDGEprogram with prior written consent from the manufacturer or
    • –pharmacies licensed in the US andregistered and activated in the iPLEDGE program
  • Notifying the isotretinoin manufacturer (or delegate) of anynon-registered and/or non-activated pharmacy or unregistered wholesalerthat attempts to order isotretinoin
  • Complying with inspection of wholesaler records for verificationof compliance with the iPLEDGE program by the isotretinoin manufacturer(or delegate)
  • Returning to the manufacturer (or delegate) any undistributedproduct if registration is revoked by the manufacturer or if the wholesalerchooses to not re-register annually
  • Providing product flow data to manufacturer (or delegate) asdetailed in the wholesalers agreement

Prescribers:

To prescribe isotretinoin, the prescriber must beregistered and activated with the pregnancy risk management programiPLEDGE. Prescribers can register by signing and returning the completedregistration form. Prescribers can only activate their registrationby affirming that they meet requirements and will comply with alliPLEDGE requirements by attesting to the following points:

  • I know the risk and severity of fetal injury/birth defects fromisotretinoin.
  • I know the risk factors for unplanned pregnancy and the effectivemeasures for avoidance of unplanned pregnancy.
  • I have the expertise to provide the patient with detailed pregnancyprevention counseling or I will refer her to an expert for such counseling,reimbursed by the manufacturer.
  • I will comply with the iPLEDGE program requirements describedin the booklets entitled The Guide toBest Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception CounselingGuide.
  • Before beginning treatment of female patients of childbearingpotential with isotretinoin and on a monthly basis, the patient willbe counseled to avoid pregnancy by using two forms of contraceptionsimultaneously and continuously one month before, during, and onemonth after isotretinoin therapy, unless the patient commits to continuousabstinence.
  • I will not prescribe isotretinoin to any female patient ofchildbearing potential until verifying she has a negative screeningpregnancy test and monthly negative CLIA-certified (Clinical LaboratoryImprovement Amendment) pregnancy tests. Patients should have a pregnancytest at the completion of the entire course of isotretinoin and anotherpregnancy test 1 month later.
  • I will report any pregnancy case that I become aware of whilethe female patient is on isotretinoin or 1 month after the last doseto the pregnancy registry.

To prescribe isotretinoin, the prescriber must accessthe 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 receivedcounseling and education.
  • 3)For femalepatients of childbearing potential:
      Enter patient's two chosen forms of contraception each month.
    • Enter monthly result from CLIA-certified laboratory conductedpregnancy test.

Isotretinoin must only be prescribed to female patientswho are known not to be pregnant as confirmed by a negative CLIA-certifiedlaboratory conducted pregnancy test.

Isotretinoinmust only be dispensed by a pharmacy registered and activated withthe pregnancy risk management program iPLEDGE and only when the registeredpatient meets all the requirements of the iPLEDGE program. Meetingthe requirements for a female patient of childbearing potential signifiesthat she:

  • Has been counseledand has signed a Patient Information/Informed Consent About BirthDefects (for female patients who can get pregnant) form that containswarnings about the risk of potential birth defects if the fetus isexposed to isotretinoin. The patient must sign the informed consentform before starting treatment and patient counseling must also bedone at that time and on a monthly basis thereafter.
  • Has had two negativeurine or serum pregnancy tests with a sensitivity of at least 25 mIU/mLbefore receiving the initial isotretinoin prescription. The firsttest (a screening test) is obtained by the prescriber when the decisionis made to pursue qualification of the patient for isotretinoin. Thesecond pregnancy test (a confirmation test) must be done in a CLIA-certifiedlaboratory. The interval between the 2 tests should be at least 19days.
      –For patients with regular menstrualcycles, the second pregnancy test should be done during the first5 days of the menstrual period immediately preceding the beginningof isotretinoin therapy and after the patient has used 2 forms ofcontraception for 1 month.
    • –For patients with amenorrhea, irregularcycles, or using a contraceptive method that precludes withdrawalbleeding, the second pregnancy test must be done immediately precedingthe beginning of isotretinoin therapy and after the patient has used2 forms of contraception for 1 month.
  • Has had a negativeresult from a urine or serum pregnancy test in a CLIA-certified laboratorybefore receiving each subsequent course of isotretinoin. A pregnancytest must be repeated every month, in a CLIA-certified laboratory,prior to the female patient receiving each prescription.
  • Has selected and hascommitted to use 2 forms of effective contraception simultaneously,at least 1 of which must be a primary form, unless the patient commitsto continuous abstinence from heterosexual contact, or the patienthas undergone a hysterectomy or bilateral oophorectomy, or has beenmedically confirmed to be post-menopausal. Patients must use 2 formsof effective contraception for at least 1 month prior to initiationof isotretinoin therapy, during isotretinoin therapy, and for 1 monthafter discontinuing isotretinoin therapy. Counseling about contraceptionand behaviors associated with an increased risk of pregnancy mustbe repeated on a monthly basis.

    If the patient has unprotectedheterosexual intercourse at any time 1 month before, during, or 1month after therapy, she must:

      Stop taking Accutane immediately, if on therapy
    • Have a pregnancy test at least 19 days after the last act ofunprotected heterosexual intercourse
    • Start using 2 forms of effective contraception simultaneouslyagain for 1 month before resuming Accutane therapy
    • Have a second pregnancy test after using 2 forms of effectivecontraception for 1 month as described above depending on whethershe has regular menses or not.

    Effective forms of contraception include both primaryand secondary forms of contraception:

    Primary forms
    • tubal sterilization
    • partner's vasectomy
    • intrauterine device
    • hormonal (combination oral contraceptives, transdermal patch,injectables, implantables, or vaginal ring)
    Secondary forms
    Barrier:
    • male latex condom with or without spermicide
    • diaphragm with spermicide
    • cervical cap with spermicide
    Other:
    • vaginal sponge (contains spermicide)

Any birth control method can fail. There have beenreports of pregnancy from female patients who have used oral contraceptives,as well as transdermal patch/injectable/implantable/vaginal ring hormonalbirth control products; these pregnancies occurred while these patientswere taking Accutane. These reports are more frequent for female patientswho use only a single method of contraception. Therefore, it is criticallyimportant that female patients of childbearing potential use 2 effectiveforms of contraception simultaneously. Patients must receive writtenwarnings about the rates of possible contraception failure (includedin patient education kits).

Using two formsof contraception simultaneously substantially reduces the chancesthat a female will become pregnant over the risk of pregnancy witheither form alone. A drug interaction that decreases effectivenessof hormonal contraceptives has not been entirely ruled out for Accutane(see PRECAUTIONS: Drug Interactions). Although hormonalcontraceptives are highly effective, prescribers are advised to consultthe package insert of any medication administered concomitantly withhormonal contraceptives, since some medications may decrease the effectivenessof these birth control products.

Patients shouldbe prospectively cautioned not to self-medicate with the herbal supplementSt. John's Wort because a possible interaction has been suggestedwith hormonal contraceptives based on reports of breakthrough bleedingon oral contraceptives shortly after starting St. John's Wort. Pregnancieshave been reported by users of combined hormonal contraceptives whoalso used some form of St. John's Wort.

Ifa pregnancy does occur during isotretinoin treatment, isotretinoinmust be discontinued immediately. The patient should be referred toan Obstetrician-Gynecologist experienced in reproductive toxicityfor further evaluation and counseling. Any suspected fetal exposureduring or 1 month after isotretinoin therapy must be reported immediatelyto the FDA via the MedWatch number 1-800-FDA-1088 and also to theiPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

Isotretinoin is contraindicated in female patientswho are pregnant. To receive isotretinoin all patients must meet allof the following conditions:

  • Must be registeredwith the iPLEDGE program by the prescriber
  • Must understand thatsevere birth defects can occur with the use of isotretinoin by femalepatients
  • Must be reliable inunderstanding and carrying out instructions
  • Must sign a PatientInformation/Informed Consent (for all patients) form that containswarnings about the potential risks associated with isotretinoin
  • Must fill and pickup the prescription within 7 days of the date of specimen collectionfor the pregnancy test for female patients of childbearing potential
  • Must fill and pickup the prescription within 30 days of the office visit for male patientsand female patients not of childbearing potential
  • Must not donate bloodwhile on isotretinoin and for 1 month after treatment has ended
  • Must not share isotretinoinwith anyone, even someone who has similar symptoms

Female Patients of ChildbearingPotential

Isotretinoin is contraindicated in female patientswho are pregnant. In addition to the requirements for all patientsdescribed above, female patients of childbearing potential must meetthe following conditions:

  • Must NOT be pregnantor breast-feeding
  • Must comply with therequired pregnancy testing at a CLIA-certified laboratory
  • Must filland pick up the prescription within 7 days of the date of specimencollection for the pregnancy test

  • Must be capable ofcomplying with the mandatory contraceptive measures required for isotretinointherapy, or commit to continuous abstinence from heterosexual intercourse,and understand behaviors associated with an increased risk of pregnancy
  • Must understand thatit is her responsibility to avoid pregnancy one month before, duringand one month after isotretinoin therapy
  • Must have signed anadditional 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 ifthe fetus is exposed to isotretinoin
  • Must access the iPLEDGEsystem via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654),before starting isotretinoin, on a monthly basis during therapy, and1 month after the last dose to answer questions on the program requirementsand to enter the patient's two chosen forms of contraception
  • Must have been informedof the purpose and importance of providing information to the iPLEDGEprogram should she become pregnant while taking isotretinoin or within1 month of the last dose

Pharmacists:

To dispense isotretinoin, pharmacies must be registeredand activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacyby signing and returning the completed registration form. After registration,the Responsible Site Pharmacist can only activate the pharmacy registrationby affirming that they meet requirements and will comply with alliPLEDGE requirements by attesting to the following points:

  • I know the risk and severity of fetal injury/birth defects fromisotretinoin.
  • I will train all pharmacists, who participate in the fillingand dispensing of isotretinoin prescriptions, on the iPLEDGE programrequirements.
  • I will comply and seek to ensure all pharmacists who participatein the filling and dispensing of isotretinoin prescriptions complywith the iPLEDGE program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program.
  • I will obtain Accutane product only from iPLEDGE registeredwholesalers.
  • I will not sell, buy, borrow, loan or otherwise transfer isotretinoinin any manner to or from another pharmacy.
  • I will return to the manufacturer (or delegate) any unused productif registration is revoked by the manufacturer or if the pharmacychooses to not reactivate annually.
  • I will not fill isotretinoin for any party other than a qualifiedpatient.

To dispense isotretinoin, the pharmacist must:

  • 1)be trained by the Responsible Site Pharmacistconcerning the iPLEDGE program requirements.
  • 2)obtain authorization from the iPLEDGE programvia the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654)for every isotretinoin prescription. Authorization signifies thatthe patient has met all program requirements and is qualified to receiveisotretinoin.
  • 3)write the Risk Management Authorization(RMA) number on the prescription.

Accutane must only be dispensed:

  • in no more than a 30-day supply
  • with an Accutane Medication Guide
  • after authorization from the iPLEDGE program
  • prior to the "do not dispense to patient after" date providedby the iPLEDGE system (within 30 days of the office visit for malepatients and female patients not of childbearing potential and within7 days of the date of specimen collection for female patients of childbearingpotential)
  • with a new prescription for refills and another authorizationfrom the iPLEDGE program (No automatic refills are allowed)

An Accutane Medication Guide must be given to thepatient each time Accutane is dispensed, as required by law. ThisAccutane Medication Guide is an important part of the risk managementprogram for the patients.

Accutane must notbe prescribed, dispensed or otherwise obtained through the internetor any other means outside of the iPLEDGE program. Only FDA-approvedAccutane products must be distributed, prescribed, dispensed, andused. Patients must fill Accutane prescriptions only at US licensedpharmacies.

A description of the iPLEDGE programeducational materials available with iPLEDGE is provided below. Themain goal of these educational materials is to explain the iPLEDGEprogram requirements and to reinforce the educational messages.

  • 1) The Guideto Best Practices for the iPLEDGE Program includes: isotretinointeratogenic potential, information on pregnancy testing, and the methodto complete a qualified isotretinoin prescription.
  • 2) The iPLEDGEProgram Prescriber Contraception Counseling Guide includes:specific information about effective contraception, the limitationsof contraceptive methods, behaviors associated with an increased riskof contraceptive failure and pregnancy and the methods to evaluatepregnancy risk.
  • 3) The PharmacistGuide for the iPLEDGE Program includes: isotretinoin teratogenicpotential and the method to obtain authorization to dispense an isotretinoinprescription.
  • 4)The iPLEDGE program is a systematic approachto comprehensive patient education about their responsibilities andincludes education for contraception compliance and reinforcementof educational messages. The iPLEDGE program includes informationon the risks and benefits of isotretinoin which is linked to the MedicationGuide dispensed by pharmacists with each isotretinoin prescription.
  • 5)Female patients not of childbearing potentialand male patients, and female patients of childbearing potential areprovided with separate booklets. Each booklet contains informationon isotretinoin therapy including precautions and warnings, a PatientInformation/Informed Consent (for all patients) form, and a toll-freeline which provides isotretinoin information in 2 languages.
  • 6)The booklet for female patients not ofchildbearing potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and FemalePatients Who Cannot Get Pregnant, also includes informationabout male reproduction and a warning not to share isotretinoin withothers or to donate blood during isotretinoin therapy and for 1 monthfollowing discontinuation of isotretinoin.
  • 7) The booklet for female patients of childbearingpotential, The iPLEDGE Program Guideto Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraceptioncounseling, 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 informationon the types of contraceptive methods, the selection and use of appropriate,effective contraception, the rates of possible contraceptive failureand a toll-free contraception counseling line.
  • 9)In addition, there is a patient educationalDVD 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 notestablished, physicians should use caution when prescribing Accutaneto patients with a genetic predisposition for age-related osteoporosis,a history of childhood osteoporosis conditions, osteomalacia, or otherdisorders of bone metabolism. This would include patients diagnosedwith anorexia nervosa and those who are on chronic drug therapy thatcauses drug-induced osteoporosis/osteomalacia and/or affects vitaminD metabolism, such as systemic corticosteroids and any anticonvulsant.

Patients may be at increased risk when participating insports with repetitive impact where the risks of spondylolisthesiswith and without pars fractures and hip growth plate injuries in earlyand late adolescence are known. There are spontaneous reports of fracturesand/or delayed healing in patients while on therapy with Accutaneor following cessation of therapy with Accutane while involved inthese activities. While causality to Accutane has not been established,an effect must not be ruled out.

Information for Patients

See PRECAUTIONS and Boxed CONTRAINDICATIONS ANDWARNINGS.

  • Patients must be instructed to read the Medication Guide suppliedas required by law when Accutane is dispensed. The complete text ofthe Medication Guide is reprinted at the end of this document. Foradditional information, patients must also be instructed to read theiPLEDGE program patient educational materials. All patients must signthe Patient Information/Informed Consent (for all patients) form.
  • Female patients of childbearing potential must be instructedthat they must not be pregnant when Accutane therapy is initiated,and that they should use 2 forms of effective contraception simultaneouslyfor 1 month before starting Accutane, while taking Accutane, and for1 month after Accutane has been stopped, unless they commit to continuousabstinence from heterosexual intercourse. They should also sign asecond Patient Information/Informed Consent About Birth Defects (forfemale patients who can get pregnant) form prior to beginning Accutanetherapy. They should be given an opportunity to view the patient DVDprovided by the manufacturer to the prescriber. The DVD includes informationabout contraception, the most common reasons that contraception fails,and the importance of using 2 forms of effective contraception whentaking teratogenic drugs and comprehensive information about typesof potential birth defects which could occur if a female patient whois pregnant takes Accutane at any time during pregnancy. Female patientsshould be seen by their prescribers monthly and have a urine or serumpregnancy test, in a CLIA-certified laboratory, performed each monthduring treatment to confirm negative pregnancy status before anotherAccutane 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 milliontimes lower than an oral dose of 40 mg. While the no-effect limitfor isotretinoin induced embryopathy is unknown, 20 years of postmarketingreports include 4 with isolated defects compatible with features ofretinoid 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 psychiatricdisorders to guide patients to receive the help they need. Therefore,prior to initiation of Accutane treatment, patients and family membersshould be asked about any history of psychiatric disorder, and ateach visit during treatment patients should be assessed for symptomsof depression, mood disturbance, psychosis, or aggression to determineif further evaluation may be necessary. Signs and symptoms of depression include sad mood, hopelessness,feelings of guilt, worthlessness or helplessness, loss of pleasureor interest in activities, fatigue, difficulty concentrating, changein sleep pattern, change in weight or appetite, suicidal thoughtsor attempts, restlessness, irritability, acting on dangerous impulses,and persistent physical symptoms unresponsive to treatment. Patients should stop Accutane and the patient or a family membershould promptly contact their prescriber if the patient develops depression,mood disturbance, psychosis, or aggression, without waiting untilthe next visit. Discontinuation of Accutane treatment may be insufficient;further evaluation may be necessary. While such monitoring may behelpful, it may not detect all patients at risk. Patients may reportmental health problems or family history of psychiatric disorders.These reports should be discussed with the patient and/or the patient'sfamily. A referral to a mental health professional may be necessary.The physician should consider whether Accutane therapy is appropriatein this setting; for some patients the risks may outweigh the benefitsof Accutane therapy.
  • Patients must be informed that some patients, while taking Accutaneor soon after stopping Accutane, have become depressed or developedother 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, schoolor work performance going down, or trouble concentrating. Some patientstaking Accutane have had thoughts about hurting themselves or puttingan end to their own lives (suicidal thoughts). Some people tried toend their own lives. And some people have ended their own lives. Therewere reports that some of these people did not appear depressed. Therehave been reports of patients on Accutane becoming aggressive or violent.No one knows if Accutane caused these behaviors or if they would havehappened even if the person did not take Accutane. Some people havehad other signs of depression while taking Accutane.
  • Patients must be informed that they must not share Accutanewith anyone else because of the risk of birth defects and other seriousadverse events.
  • Patients must be informed not to donate blood during therapyand for 1 month following discontinuation of the drug because theblood might be given to a pregnant female patient whose fetus mustnot 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, patientsshould 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 least6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS: Skin andAppendages).
  • Patients should be advised to avoid prolonged exposure to UVrays or sunlight.
  • Patients should be informed that they may experience decreasedtolerance to contact lenses during and after therapy.
  • Patients should be informed that approximately 16% of patientstreated with Accutane in a clinical trial developed musculoskeletalsymptoms (including arthralgia) during treatment. In general, thesesymptoms were mild to moderate, but occasionally required discontinuationof the drug. Transient pain in the chest has been reported less frequently.In the clinical trial, these symptoms generally cleared rapidly afterdiscontinuation of Accutane, but in some cases persisted (see ADVERSE REACTIONS:Musculoskeletal). There have been rare postmarketingreports of rhabdomyolysis, some associated with strenuous physicalactivity (see Laboratory Tests: CPK).
  • Pediatric patients and their caregivers should be informed thatapproximately 29% (104/358) of pediatric patients treated with Accutanedeveloped back pain. Back pain was severe in 13.5% (14/104) of thecases and occurred at a higher frequency in female patients than malepatients. Arthralgias were experienced in 22% (79/358) of pediatricpatients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriateevaluation of the musculoskeletal system should be done in patientswho present with these symptoms during or after a course of Accutane.Consideration should be given to discontinuation of Accutane if anysignificant abnormality is found.
  • Neutropenia and rare cases of agranulocytosis have been reported.Accutane should be discontinued if clinically significant decreasesin white cell counts occur.

Hypersensitivity

Anaphylactic reactions and other allergic reactionshave been reported. Cutaneous allergic reactions and serious casesof allergic vasculitis, often with purpura (bruises and red patches)of the extremities and extracutaneous involvement (including renal)have been reported. Severe allergic reaction necessitates discontinuationof therapy and appropriate medical management.

Drug Interactions

  • Vitamin A: Because ofthe relationship of Accutane to vitamin A, patients should be advisedagainst taking vitamin supplements containing vitamin A to avoid additivetoxic effects.
  • Tetracyclines: Concomitanttreatment with Accutane and tetracyclines should be avoided becauseAccutane use has been associated with a number of cases of pseudotumorcerebri (benign intracranial hypertension), some of which involvedconcomitant use of tetracyclines.
  • Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations ("minipills" that do not containan estrogen) may be an inadequate method of contraception during Accutanetherapy. Although other hormonal contraceptives are highly effective,there have been reports of pregnancy from female patients who haveused combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginalring hormonal birth control products. These reports are more frequentfor female patients who use only a single method of contraception.It is not known if hormonal contraceptives differ in their effectivenesswhen used with Accutane. Therefore, it is critically important forfemale patients of childbearing potential to select and commit touse 2 forms of effective contraception simultaneously, at least 1of which must be a primary form (see PRECAUTIONS).
  • Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrantnodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptiveagent, Accutane at the recommended dose of 1 mg/kg/day, did not induceclinically relevant changes in the pharmacokinetics of ethinyl estradioland norethindrone and in the serum levels of progesterone, follicle-stimulatinghormone (FSH) and luteinizing hormone (LH). Prescribers are advisedto consult the package insert of medication administered concomitantlywith hormonal contraceptives, since some medications may decreasethe 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-medicatewith the herbal supplement St. John's Wort because a possible interactionhas been suggested with hormonal contraceptives based on reports ofbreakthrough bleeding on oral contraceptives shortly after startingSt. John's Wort. Pregnancies have been reported by users of combinedhormonal contraceptives who also used some form of St. John's Wort.
  • Phenytoin: Accutane hasnot been shown to alter the pharmacokinetics of phenytoin in a studyin seven healthy volunteers. These results are consistent with thein vitro finding that neither isotretinoin nor its metabolites induceor inhibit the activity of the CYP 2C9 human hepatic P450 enzyme.Phenytoin is known to cause osteomalacia. No formal clinical studieshave been conducted to assess if there is an interactive effect onbone loss between phenytoin and Accutane. Therefore, caution shouldbe exercised when using these drugs together.
  • Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formalclinical studies have been conducted to assess if there is an interactiveeffect 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 orserum pregnancy tests with a sensitivity of at least 25 mIU/mL beforereceiving the initial Accutane prescription. The first test (a screeningtest) is obtained by the prescriber when the decision is made to pursuequalification of the patient for Accutane. The second pregnancy test(a confirmation test) must be done in a CLIA-certified laboratory.The interval between the two tests must be at least 19 days.
    • –For patients with regular menstrualcycles, the second pregnancy test must be done during the first 5days of the menstrual period immediately preceding the beginning ofAccutane therapy and after the patient has used 2 forms of contraceptionfor 1 month.
    • –For patients with amenorrhea, irregularcycles, or using a contraceptive method that precludes withdrawalbleeding, the second pregnancy test must be done immediately precedingthe beginning of Accutane therapy and after the patient has used 2forms of contraception for 1 month.
    • –Each month of therapy, patients musthave a negative result from a urine or serum pregnancy test. A pregnancytest must be repeated each month, in a CLIA-certified laboratory,prior to the female patient receiving each prescription.
  • Lipids: Pretreatmentand follow-up blood lipids should be obtained under fasting conditions.After consumption of alcohol, at least 36 hours should elapse beforethese determinations are made. It is recommended that these testsbe performed at weekly or biweekly intervals until the lipid responseto Accutane is established. The incidence of hypertriglyceridemiais 1 patient in 4 on Accutane therapy (see WARNINGS: Lipids).
  • Liver Function Tests: Since elevations of liver enzymes have been observed during clinicaltrials, and hepatitis has been reported, pretreatment and follow-upliver function tests should be performed at weekly or biweekly intervalsuntil the response to Accutane has been established (see WARNINGS: Hepatotoxicity).
  • Glucose: Some patientsreceiving Accutane have experienced problems in the control of theirblood sugar. In addition, new cases of diabetes have been diagnosedduring Accutane therapy, although no causal relationship has beenestablished.
  • CPK: Some patients undergoingvigorous physical activity while on Accutane therapy have experiencedelevated CPK levels; however, the clinical significance is unknown.There have been rare postmarketing reports of rhabdomyolysis, someassociated with strenuous physical activity. In a clinical trial of217 pediatric patients (12 to 17 years) with severe recalcitrant nodularacne, transient elevations in CPK were observed in 12% of patients,including those undergoing strenuous physical activity in associationwith reported musculoskeletal adverse events such as back pain, arthralgia,limb injury, or muscle sprain. In these patients, approximately halfof the CPK elevations returned to normal within 2 weeks and half returnedto normal within 4 weeks. No cases of rhabdomyolysis were reportedin this trial.

Carcinogenesis, Mutagenesisand Impairment of Fertility

In male and female Fischer 344 rats given oral isotretinoinat dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommendedclinical dose of 1.0 mg/kg/day, respectively, after normalizationfor total body surface area) for greater than 18 months, there wasa dose-related increased incidence of pheochromocytoma relative tocontrols. The incidence of adrenal medullary hyperplasia was alsoincreased at the higher dosage in both sexes. The relatively highlevel of spontaneous pheochromocytomas occurring in the male Fischer344 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 inthe second laboratory a weakly positive response (less than 1.6 background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. Nodose-response effect was seen and all other strains were negative.Additionally, other tests designed to assess genotoxicity (Chinesehamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay withhuman-derived lymphocytes, and unscheduled DNA synthesis assay) wereall negative.

In rats, no adverse effects ongonadal function, fertility, conception rate, gestation or parturitionwere 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 treatmentwith oral isotretinoin for approximately 30 weeks at dosages of 20or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0mg/kg/day, respectively, after normalization for total body surfacearea). In general, there was microscopic evidence for appreciabledepression of spermatogenesis but some sperm were observed in alltestes examined and in no instance were completely atrophic tubulesseen. In studies of 66 men, 30 of whom were patients with nodularacne under treatment with oral isotretinoin, no significant changeswere 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 ejaculatevolume, sperm count, total sperm motility, morphology or seminal plasmafructose.

Pregnancy: Category X.

See Boxed CONTRAINDICATIONS AND WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted inhuman milk. Because of the potential for adverse effects, nursingmothers should not receive Accutane.

Pediatric Use

The use of Accutane in pediatric patients less than12 years of age has not been studied. The use of Accutane for thetreatment of severe recalcitrant nodular acne in pediatric patientsages 12 to 17 years should be given careful consideration, especiallyfor those patients where a known metabolic or structural bone diseaseexists (see PRECAUTIONS:General). Use of Accutane in this age group forsevere recalcitrant nodular acne is supported by evidence from a clinicalstudy comparing 103 pediatric patients (13 to 17 years) to 197 adultpatients (≥18 years). Results from this study demonstratedthat Accutane, at a dose of 1 mg/kg/day given in two divided doses,was equally effective in treating severe recalcitrant nodular acnein both pediatric and adult patients.

In studieswith Accutane, adverse reactions reported in pediatric patients weresimilar to those described in adults except for the increased incidenceof 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 courseof therapy with Accutane for severe recalcitrant nodular acne, bonedensity measurements at several skeletal sites were not significantlydecreased (lumbar spine change >-4% and total hip change >-5%) orwere increased in the majority of patients. One patient had a decreasein lumbar spine bone mineral density >4% based on unadjusted data.Sixteen (7.9%) patients had decreases in lumbar spine bone mineraldensity >4%, and all the other patients (92%) did not have significantdecreases or had increases (adjusted for body mass index). Nine patients(4.5%) had a decrease in total hip bone mineral density >5% basedon unadjusted data. Twenty-one (10.6%) patients had decreases in totalhip bone mineral density >5%, and all the other patients (89%) didnot have significant decreases or had increases (adjusted for bodymass index). Follow-up studies performed in 8 of the patients withdecreased bone mineral density for up to 11 months thereafter demonstratedincreasing bone density in 5 patients at the lumbar spine, while theother 3 patients had lumbar spine bone density measurements belowbaseline 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 monthsafter the first course, two patients showed a decrease in mean lumbarspine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).

Geriatric Use

Clinical studies of isotretinoin did not includesufficient numbers of subjects aged 65 years and over to determinewhether they respond differently from younger subjects. Although reportedclinical experience has not identified differences in responses betweenelderly and younger patients, effects of aging might be expected toincrease some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS).

Page last updated: 2009-05-08

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