Amnesteem

isotretinoin

Dosage Form: capsule

 

CONTRAINDICATIONS AND WARNINGS

Amnesteem must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Amnesteem in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

Birth defects which have been documented following Amnesteem exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion and premature births have been reported.

Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted.

If pregnancy does occur during treatment of a female patient who is taking Amnesteem, Amnesteem must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Special Prescribing Requirements

Because of Amnesteem’s teratogenicity and to minimize fetal exposure, Amnesteem is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Amnesteem must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Amnesteem must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS).

Table 1. Monthly Required iPLEDGE Interactions

	Female Patients of Childbearing Potential	Male Patients, and Female Patients not of Childbearing Potential
PRESCRIBER
Confirms patient counseling	X	X
Enters the two contraception methods chosen by the patient	X
Enters pregnancy test results	X
PATIENT
Answers educational questions before every prescription	X
Enters two forms of contraception	X
PHARMACIST
Contacts system to get an authorization	X	X

Amnesteem Description

Isotretinoin, USP a retinoid, is available as Amnesteem (isotretinoin capsules, USP) in 10 mg, 20 mg and 40 mg soft gelatin capsules for oral administration. Each capsule contains yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil and soybean oil. Gelatin capsules contain glycerin, with the following dye systems: 10 mg – red iron oxide paste and black ink; 20 mg – red iron oxide paste, yellow iron oxide paste, titanium dioxide and black ink; 40 mg – red iron oxide paste, yellow iron oxide paste, titanium dioxide and black ink.

USP Dissolution Test Pending.

Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

Amnesteem - Clinical Pharmacology

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Amnesteem, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Amnesteem under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high fat meal when compared with Amnesteem given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Amnesteem capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Table 2. Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N = 74

* Eating a standardized high fat meal
Amnesteem 2 x 40 mg Capsules	AUC0-∞ (ng•hr/mL)	Cmax (ng/mL)	Tmax (hr)	t1/2 (hr)
Fed*	10,004 (22%)	862 (22%)	5.3 (77%)	21 (39%)
Fasted	3,703 (46%)	301 (63%)	3.2 (56%)	21 (30%)

 

Distribution

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

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of Amnesteem to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (≥ 18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Amnesteem to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥ 18 years) who received Amnesteem for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38*

* The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2. † Median (range)
Parameter	Isotretinoin (Single Dose)	Isotretinoin (Steady-State)
Cmax (ng/mL) AUC(0 to 12) (ng.hr/mL) AUC(0 to 24) (ng.hr/mL) Tmax (hr)† Cssmin (ng/mL) T1/2 (hr) CL/F (L/hr)	573.25 (278.79) 3033.37 (1394.17) 6003.81 (2885.67) 6 (1 - 24.6) – – –	731.98 (361.86) 5082 (2184.23) – 4 (0 to 12) 352.32 (184.44) 15.69 (5.12) 17.96 (6.27)

 In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

Indications and Usage for Amnesteem

Severe Recalcitrant Nodular Acne

Amnesteem 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, Amnesteem should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Amnesteem is indicated only for those female patients who are not pregnant, because Amnesteem can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Amnesteem. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).  

Contraindications

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

Amnesteem is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS: Hypersensitivity).

Warnings

Psychiatric Disorders

Amnesteem may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Amnesteem therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Amnesteem and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Amnesteem therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether Amnesteem therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Amnesteem therapy.

Pseudotumor Cerebri

Amnesteem 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 Amnesteem immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

Serious Skin Reactions

There have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization or disability. Patients should be monitored closely for severe skin reactions and discontinuation of Amnesteem should be considered if warranted.

Pancreatitis

Acute pancreatitishas been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Amnesteem should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Lipids

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Amnesteem. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Amnesteem 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 Amnesteem therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Amnesteem.5

Blood lipid determinations should be performed before Amnesteem is given and then at intervals until the lipid response to Amnesteem 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 Amnesteem therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Amnesteem therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).

The cardiovascular consequences of hypertriglyceridemia associated with Amnesteem are unknown.

Animal Studies

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

Hearing Impairment

Impaired hearing has been reported in patients taking Amnesteem; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Amnesteem treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to Amnesteem therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Amnesteem, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

Amnesteem has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Amnesteem treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Amnesteem immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of Amnesteem on the developing musculoskeletal system are unknown. There is some evidence that long-term, high dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N = 217) of a single course of therapy with Amnesteem for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in five of eight patients (62.5%).

In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Amnesteem 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use). 

Spontaneous reports of osteoporosis, osteopenia, bone fractures and delayed healing of bone fractures have been seen in the Amnesteem population. While causality to Amnesteem has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration.

Hyperostosis

A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in six of eight 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 Amnesteem 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 Amnesteem given in two divided 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 epiphyseal closure in acne patients receiving recommended doses of Amnesteem. The effect of multiple courses of Amnesteem on epiphyseal closure is unknown.

Vision Impairment

Visual problems should be carefully monitored. All Amnesteem patients experiencing visual difficulties should discontinue Amnesteem treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).

Corneal Opacities

Corneal opacities have occurred in patients receiving Amnesteem 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 Amnesteem 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 Amnesteem therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.

Precautions

Amnesteem must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Amnesteem 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 Amnesteem only from wholesalers registered with iPLEDGE.

iPLEDGE program requirements for wholesalers, prescribers and pharmacists are described below:

Wholesalers

For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor and/or chain pharmacy distributor. To distribute Amnesteem, 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 re-registering annually thereafter


• Distributing only FDA approved isotretinoin product


• Only shipping isotretinoin to
  
  • wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer or
  
  
  • pharmacies licensed in the US and registered and activated in the iPLEDGE program
  
  


• Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order isotretinoin


• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the isotretinoin manufacturer (or delegate)


• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not reregister annually

Prescribers

To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know 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 Guide to Best Practices for the iPLEDGE Program and The iPLEDGEProgram Prescriber Contraception Counseling Guide.


• Before beginning treatment of female patients of child bearing 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 capsules and another pregnancy test one month later.


• I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or one month after the last dose to the pregnancy registry.

To prescribe isotretinoin, the Prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

1. Register each patient in the iPLEDGE program.


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


3. For female patients of childbearing potential:
   
   • Enter patient’s two chosen forms of contraception each month.
   
   

Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies that she:

• Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.


• Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two 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 immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one 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 two forms of effective contraception simultaneously, at least one 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 two forms of effective contraception for at least one month prior to initiation of isotretinoin therapy, during isotretinoin therapy and for one month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.

If the patient has unprotected heterosexual intercourse at any time one month before, during or one month after therapy, she must:

1. Stop taking Amnesteem immediately, if on therapy


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


3. Start using two forms of effective contraception simultaneously again for one month before resuming Amnesteem therapy


4. Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether she has regular menses or not.

Effective forms of contraception include both primary and secondary forms of contraception:

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 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 Amnesteem. 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 two 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 Amnesteem (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 Amnesteem treatment, Amnesteem 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 one month after Amnesteem 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).

All Patients

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

• Must be registered with the iPLEDGE program by the prescriber


• Must understand that severe birth defects can occur with the use of isotretinoin by female patients


• Must be reliable in understanding and carrying out instructions


• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin


• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test for female patients of child bearing potential


• Must fill and pick up the prescription within 30 days of the office visit for male patients and females patients not of child bearing potential


• Must not donate blood while on isotretinoin and for one month after treatment has ended


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

Female Patients of Childbearing Potential

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

• Must NOT be pregnant or breast-feeding


• Must comply with the required pregnancy testing at a CLIA-certified laboratory


• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test


• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse and understand behaviors associated with an increased risk of pregnancy


• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy


• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin


• Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy and one month after the last dose to answer questions on the program requirements and to enter the patient’s two chosen forms of contraception


• Must have been informed of the purpose and importance of providing information to the iPLEDGE program should she become pregnant while taking isotretinoin or within one month of the last dose

Pharmacists

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

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

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


• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE program requirements.


• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program.


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


• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.


• I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually.


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

To dispense isotretinoin, the pharmacist must:

1. be trained by the Responsible Site Pharmacist concerning the iPLEDGE program requirements.


2. obtain authorization from the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive Amnesteem.


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

Amnesteem must only be dispensed:

• in no more than a 30 day supply


• with an Amnesteem Medication Guide


• after authorization from the iPLEDGE program


• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and female patients not of child bearing potential and within 7 days of the date of specimen collection for female patients of child bearing potential)


• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

An Amnesteem Medication Guide must be given to the patient each time Amnesteem is dispensed, as required by law. This Amnesteem Medication Guide is an important part of the risk management program for the patients.

Amnesteem must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Amnesteem products must be distributed, prescribed, dispensed and used. Patients must fill Amnesteem prescriptions only at U.S. licensed pharmacies.

A description of the iPLEDGE program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE program requirements and to reinforce the educational messages.

1. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Amnesteem prescription.


2. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.


3. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.


4. The iPLEDGE program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE program includes information on the risks and benefits of Amnesteem which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.


5. Female patients not of childbearing potential and male patients, and female patients of childbearing potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form and a toll-free line which provides isotretinoin information in two languages.