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 Sotret 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 isotretinoin capsules given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.
There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin capsules. The effect of multiple courses of Sotret on epiphyseal closure is unknown.
Visual problems should be carefully monitored. All Sotret patients experiencing visual difficulties should discontinue Sotret treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).
Corneal opacities have occurred in patients receiving isotretinoin capsules 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 isotretinoin capsules 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 has been reported during isotretinoin capsules 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.
Sotret must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret 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 isotretinoin only from wholesalers registered with iPLEDGE.
For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Sotret, 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:
- Registering prior to distributing isotretinoin and reregistering 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
- 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 reregister annually
- Providing product flow data to manufacturer (or delegate) as detailed in the wholesalers agreement
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 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.
- Register each patient in the iPLEDGE program.
- Confirm monthly that each patient has received counseling and education.
- 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 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 CLIA-certified laboratory. The interval between the 2 tests should be at least 19 days.
- 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 CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified 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.
- Stop taking isotretinoin immediately, if on therapy
- Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse
- Start using 2 forms of effective contraception simultaneously again for 1 month before resuming isotretinoin therapy
- 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.
|Primary forms||Secondary forms|
|Barrier forms (always used with spermicide):|
|• tubal sterilization||• male latex condom|
|• partner’s vasectomy||• diaphragm|
|• intrauterine device||• cervical cap|
|• hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring)||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 isotretinoin capsules. 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 Sotret (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 pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).
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