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CLARAVIS
(isotretinoin) Capsules USP
WARNING
CONTRAINDICATIONS AND WARNINGS
Claravis™ 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 Claravis 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 is otretinoin 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); cardiovas cular 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 Claravis, Claravismust be discontinued immediately and she should be referred to an Obstetrician- Gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Because of is otretinoin's teratogenicity and to minimize fetal exposure, Claravis is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Claravis 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
| Females of Reproductive Potential | Male Patients, and Females of Non-Reproductive 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 |
Isotretinoin, USP a retinoid, is available as Claravis™ (isotretinoin capsules USP), in 10 mg, 20 mg, 30 mg and 40 mg hard gelatin capsules for oral administration. 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. The structural formula is:
 |
Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, titanium dioxide, white wax (beeswax), and vitamin E.
In addition, the 10 mg capsule contains black iron oxide and FD&C yellow no. 6. The 20 mg capsule contains black iron oxide, red iron oxide and yellow iron oxide. The 30 mg capsule contains red iron oxide and yellow iron oxide. The 40 mg capsule contains FD&C yellow no. 6.
The edible imprinting ink contains: 10 mg strength, D&C red no. 7 calcium lake, FD&C yellow no. 6 aluminum lake, propylene glycol, shellac glaze, and titanium dioxide; 20 mg strength, ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide; 30 mg strength, D&C yellow no. 10 aluminum lake, FD&C blue no.1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide black, propylene glycol, and shellac glaze; 40 mg strength, ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze.
Meets dissolution test 2.
Claravis (isotretinoin capsules USP) 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, Claravis should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Claravis is indicated only for those female patients who are not pregnant, because Claravis 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 Claravis. 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).
Claravis should be administered with a meal (see PATIENT INFORMATION).
The recommended dosage range for Claravis is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects - some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Claravis with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.
The safety of once daily dosing with Claravis has not been established. Once daily dosing is not recommended.
If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Claravis, even in low doses, has not been studied, and is not recommended. It is important that Claravis be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Claravis on bone loss is unknown (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis and Premature Epiphyseal Closure).
Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS).
Table 4: Claravis Dosing by Body Weight (Based on
Administration With Food)
| Body Weight | Total mg/day | |||
| kilograms | pounds | 0.5 mg/kg | 1 mg/kg | 2 mg/kg * |
| 40 | 88 | 20 | 40 | 80 |
| 50 | 110 | 25 | 50 | 100 |
| 60 | 132 | 30 | 60 | 120 |
| 70 | 154 | 35 | 70 | 140 |
| 80 | 176 | 40 | 80 | 160 |
| 90 | 198 | 45 | 90 | 180 |
| 100 | 220 | 50 | 100 | 200 |
| * See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day. | ||||
Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866- 495-0654) to obtain an authorization and the “do not dis pense to patient after” date. Claravis must only be dispensed in no more than a 30 day supply.
REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.
A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patient.
REFERENCES
8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.
Claravis™ (isotretinoin capsules USP) is available as:
| 10 mg: | Two-piece hard gelatin capsule with light gray opaque cap and light gray opaque body filled with yellow oily dispersion. Imprinted in red ink barr on one piece and 934 on the other piece. |
| Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1054-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1054-56). | |
| 20 mg: | Two-piece hard gelatin capsule with brown opaque cap and brown opaque body filled with yellow oily dispersion. Imprinted in white ink barr on one piece and 935 on the other piece. |
| Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1055-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1055-56). | |
| 30 mg: | Two-piece hard gelatin capsule with orange opaque cap and orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 454 on the other piece. |
| Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1056-86). | |
| 40 mg: | Two-piece hard gelatin capsule with light orange opaque cap and light orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 936 on the other piece. |
| Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1057-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1057-56). |
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from light.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
REFERENCES
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.
2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.
3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980.
4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980.
TEVA PHARMACEUTICALS USA, INC., North Wales, PA 19454. Revised: Aug 2016
The adverse reactions listed below reflect the experience from investigational studies of Claravis, and the postmarketing experience. The relationship of some of these events to Claravis therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Claravis are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes).
Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).
Allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS, Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss.
Palpitation, tachycardia, vascular thrombotic disease, stroke.
Hypertriglyceridemia (see WARNINGS, Lipids), alterations in blood sugar levels (see PRECAUTIONS, Laboratory Tests).
Inflammatory bowel disease (see WARNINGS, Inflammatory Bowel Disease), hepatitis (see WARNINGS, Hepatotoxicity), pancreatitis (see WARNINGS, Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.
Allergic reactions (see PRECAUTIONS, Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS, Laboratory Tests for other hematological parameters.
Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS, Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS, Laboratory Tests).
Pseudotumor cerebri (see WARNINGS, Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.
Suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS, Psychiatric Disorders), emotional instability. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.
Abnormal menses.
Bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.
Acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS, Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION).
Special Senses : Hearing: hearing impairment (see WARNINGS, Hearing Impairment), tinnitus.
Vision: corneal opacities (see WARNINGS, Corneal Opacities), decreased night vision which may persist (see WARNINGS, Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances.
Urinary System: glomerulonephritis (see PRECAUTIONS, Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS, Laboratory Tests for other urological parameters).
Elevation of plasma triglycerides (see WARNINGS, Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment.
Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS, Hepatotoxicity).
Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS, Laboratory Tests), hyperuricemia.
Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.
White cells in the urine, proteinuria, microscopic or gross hematuria.
REFERENCES
7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.
Claravis may cause depression, psychos is 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 Claravis therapy, patients and family members should be as ked 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 ”), includes ad mood, hopelessness, feelings of guilt, worthlessness or helplessness, los s 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 Claravis 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 Claravis 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 Claravis therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Claravis therapy.
Claravis 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 Claravis immediately and be referred to a neurologis t for further diagnosis and care (see ADVERSE REACTIONS, Neurological).
There have been postmarketing 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 Claravis should be considered if warranted.
Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Claravis should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Claravis. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Claravis in clinical trials. In addition, approximately 15% developed a decrease in highdensity 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 Claravis 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 Claravis.5
Blood lipid determinations should be performed before Claravis is given and then at intervals until the lipid response to Claravis 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 Claravis therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Claravis 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 Claravis are unknown.
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).
Impaired hearing has been reported in patients taking Claravis; 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 Claravis treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS, Special Senses).
Clinical hepatitis considered to be possibly or probably related to Claravis 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 Claravis, the drug should be discontinued and the etiology further investigated.
Claravis 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 Claravis treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Claravis immediately (see ADVERSE REACTIONS, Gastrointestinal).
Effects of multiple courses of Claravis 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 Claravis 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 Claravis 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 Claravis population. While causality to Claravis has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Claravis be given at the recommended doses for no longer than the recommended duration.
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 Claravis 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 Claravis 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 Claravis. The effect of multiple courses of Claravis on epiphyseal closure is unknown.
Visual problems should be carefully monitored. All Claravis patients experiencing visual difficulties should discontinue Claravis treatment and have an ophthalmological examination (see ADVERSE REACTIONS, Special Senses).
Corneal opacities have occurred in patients receiving Claravis 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 Claravis 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 Claravis 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.
Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Claravis 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.
iPLEDGE Program requirements for wholesalers, prescribers, and pharmacists are described below:
For the purpose of the iPLEDGE Program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Claravis, 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:
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:
To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:
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 of reproductive potential signifies that she:
If the patient has unprotected heterosexual intercourse at any time one month before, during, or one month after therapy, she must:
Effective forms of contraception include both primary and secondary forms of contraception:
Barrier Forms
Other
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 Claravis. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive 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 Claravis (see 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 one month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA- 1088 and also the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).
Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:
Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential must meet the following conditions:
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:
To dispense isotretinoin, the pharmacist must:
Claravis must only be dispensed:
A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patients.
Claravis must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used. Patients must fill isotretinoin prescriptions only at US licensed pharmacies.
A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages.
Although an effect of Claravis on bone loss is not established, physicians should use caution when prescribing Claravis to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.
Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Claravis or following cessation of therapy with Claravis while involved in these activities. While causality to Claravis has not been established, an effect must not be ruled out.
See PRECAUTIONS and BOXED CONTRAINDICATIONS AND WARNINGS.
Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.
Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Claravis is established. The incidence of hypertriglyceridemia is one patient in four on Claravis therapy (see WARNINGS, Lipids).
Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Claravis has been established (see WARNINGS, Hepatotoxicity).
Some patients receiving Claravis have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Claravis therapy, although no causal relationship has been established.
Some patients undergoing vigorous physical activity while on Claravis therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.
In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Claravis therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Category X
See BOXED CONTRAINDICATIONS AND WARNINGS.
It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Claravis.
The use of isotretinoin in pediatric patients less than 12 years of age has not been studied. The use of isotretinoin for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS, General). Use of isotretinoin in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients ( ≥ 18 years). Results from this study demonstrated that isotretinoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients.
In studies with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).
In an open-label clinical trial (N = 217) of a single course of therapy with Claravis 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. Twentyone (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 isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS, Skeletal, Bone Mineral Density).
Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS).
REFERENCES
5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980.
6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.
The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.
Claravis causes serious birth defects at any dosage (see BOXED CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the BOXED CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.
Category X
See BOXED CONTRAINDICATIONS AND WARNINGS.
Claravis is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS, Hypersensitivity).
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.
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 Claravis, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1
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 Claravis 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 Claravis 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, Claravis 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 Is otretinoin
Mean (%CV), N = 74
| Claravis 2 x 40 mg Capsules | AUC0-∞ (ng • hr/mL) | Cmax (ng/mL) | Tmax (hr) | t½ (hr) |
| Fed* | 10,004 (22%) | 862 (22%) | 5.3 (77%) | 21 (39%) |
| Fasted | 3,703 (46%) | 301 (63%) | 3.2 (56%) | 21 (30%) |
| *Eating a standardized high fat meal | ||||
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
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 isotretinoin 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.
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 isotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (tmax) 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.
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 isotretinoin 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
| Parameter | Isotretinoin (Single Dose) | Isotretinoin (Steady State) |
| Cmax (ng/mL) | 573.25 (278.79) | 731.98 (361.86) |
| AUC(0 to 12) (ng•hr/mL) | 3033.37 (1394.17) | 5082 (2184.23) |
| AUC(0 to 24) (ng•hr/mL) | 6003.81 (2885.67) | -- |
| Tmax (hr)† | 6 (1 to 24.6) | 4 (0 to 12) |
| CSSmin (ng/mL) | -- | 352.32 (184.44) |
| H ½( hr) | -- | 15.69 (5.12) |
| CL/F (L/hr) | -- | 17.96 (6.27) |
| *The single and multiple dose data in this table were
obtained following a non-standardized meal that is not comparable to the high
fat meal that was used in the study in Table 2. †Median (range) |
||
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxoisotretinoin 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.
REFERENCES
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.
To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor.
Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent.
_______________________________________________(Patient's Name)
1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin.
Initial: __________
2. I understand that I must not get pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin.
Initial: __________
3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective forms of birth control (contraception) at the s ame time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am postmenopausal.
Initial: __________
4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use two different birth control methods at the same time, starting one month before, during, and for one month after stopping therapy every time I have sexual intercourse, even if one of the methods I choose is hormonal birth control.
Initial: __________
5. I understand that the following are effective forms of birth control:
Primary forms
Secondary forms
Barrier forms:
Other:
A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm. I understand that at least one of my two forms of birth control must be a primary method.
Initial: __________
6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products.
Initial: __________
7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation.
Initial: __________
8. I must begin using the birth control methods I have chosen as described above at least one month before I start taking isotretinoin.
Initial: __________
9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment or as instructed by my doctor. I will then have one pregnancy test; in a lab.
I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab.
Initial:__________
10. I have read and understand the materials my doctor has provided to me, including The iPLEDGE Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The iPLEDGE Program Patient Introductory Brochure. My doctor provided me and asked me to watch a video about birth control and a video about birth defects and isotretinoin.
I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control.
Initial: __________
11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control, or have sexual intercourse without using my two birth control methods at any time.
Initial: __________
12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin, and government health regulatory authorities.
Initial: __________
13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I:
Initial: ______
My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to get pregnant one month before, during isotretinoin treatment, or for one month after I stop taking is otretinoin.
Initial: ______
I now authorize my doctor ________________ to begin my treatment with isotretinoin.
Patient Signature:_____________________________________ Date: ______
Parent/Guardian Signature (if under age 18):________________ Date:______
Please print: Patient Name and Address_______________________________
______________________________ Telephone _______________________
I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to females of reproductive potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability.
Doctor Signature: __________________________________ Date: ______
PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD.
PLEASE PROVIDE A COPY TO THE PATIENT.
Patient Information/Informed Consent (for all patients )
To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.
Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement.
Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin.
1. I,___________________________________________(Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: __________
2. My doctor has told me about my choices for treating my acne.
Initials: __________
3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)].
Initials: __________
4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below).
Initials: __________
5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there.
Initials: __________
6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems.
Initials: __________
7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I:
Initials: __________
8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects.
Initials: __________
9. Isotretinoin will be prescribed just for me - I will not share isotretinoin with other people because it may cause serious side effects, including birth defects.
Initials: __________
10. I will not give blood while taking isotretinoin or for one month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects.
Initials: __________
11. I have read the The iPLEDGE Program Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received.
Initials: __________
12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin.
Initials: __________
I now allow my doctor _______________________ to begin my treatment with isotretinoin.
Patient Signature:_________________________________Date:____________________
Parent/Guardian Signature (if under age 18):____________________Date: ___________
Patient Name (print)__________________________________
Patient Address___________________________________ Telephone (____-____-____)
I have:
Doctor Signature:_______________________________________Date:___________
PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT.
MEDICATION GUIDE
CLARAVIS
(klar-uh-vis )
(isotretinoin) Capsules USP
Read the Medication Guide that comes with Claravis before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.
What is the most important information I should know about Claravis ?
Birth defects (deformed babies ), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. Female patients who are pregnant or who plan to become pregnant must not take Claravis. Female patients must not get pregnant:
If you get pregnant while taking Claravis, s top taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to:
2. Serious mental health problems. Claravis may cause:
Stop Claravis and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis :
After stopping Claravis, you may also need follow-up mental health care if you had any of these symptoms.
What is Claravis ?
Claravis is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Claravis can cause serious side effects (see “What is the most important information I should know about Claravis ?”). Claravis can only be:
What is severe nodular acne?
Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars.
Who should not take Claravis ?
What should I tell my doctor before taking Claravis ?
Tell your doctor if you or a family member has any of the following health conditions :
Tell your doctor if you are pregnant or breastfeeding. Claravis must not be used by women who are pregnant or breastfeeding.
Tell your doctor about all of the medicines you take including pres cription and nonprescription medicines, vitamins and herbal supplements. Claravis and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take:
These medicines should not be used with Claravisunless your doctor tells you it is okay.
Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.
How should I take Claravis ?
You will not be prescribed Claravis if you cannot agree to or follow all the instructions of the iPLEDGE Program.
You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes Claravis.
If you have sex at any time without using two forms of effective birth control, get pregnant, or miss your expected period, stop using Claravis and call your doctor right away.
What should I avoid while taking Claravis ?
What are the possible side effects of Claravis ?
Stop Claravis and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage.
Claravis may stop long bone growth in teenagers who are still growing.
These are not all of the possible side effects with Claravis. Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Claravis ?
General Information about Claravis.
Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Claravis for a condition for which it was not prescribed. Do not give Claravis to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Claravis. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Claravis that is written for healthcare professionals. You can also call iPLEDGE Program at 1-866-495-0654 or visit www.ipledgeprogram.com.
What are the ingredients in Claravis ?
Active Ingredient: Isotretinoin
Inactive Ingredients : Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, titanium dioxide, white wax (beeswax), and vitamin E.
In addition, the 10 mg capsule contains black iron oxide and FD&C yellow no. 6. The 20 mg capsule contains black iron oxide, red iron oxide and yellow iron oxide. The 30 mg capsule contains red iron oxide and yellow iron oxide. The 40 mg capsule contains FD&C yellow no. 6.
The edible imprinting ink contains: 10 mg strength, D&C red no. 7 calcium lake, FD&C yellow no. 6 aluminum lake, propylene glycol, shellac glaze, and titanium dioxide; 20 mg strength, ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide; 30 mg strength, D&C yellow no. 10 aluminum lake, FD&C blue no.1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide black, propylene glycol, and shellac glaze; 40 mg strength, ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
