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.
Zenatane causes serious birth defects at any dosage (see BOXED
Category X. See BOXED CONTRAINDICATIONS AND WARNINGS.
Allergic ReactionsZenatane is contraindicated in patients who are hypersensitive to this medication or to any of its components. (see PRECAUTIONS: Hypersensitivity).
The adverse reactions listed below reflect the experience from investigational studies of Zenatane, and the post-marketing experience. The relationship of some of these events to Zenatane therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Zenatane 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).
Dose RelationshipCheilitis 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).
Body as a Wholeallergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascularpalpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolichypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)
Gastrointestinalinflammatory 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
Hematologicallergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.
Musculoskeletalskeletal 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).
Neurologicalpseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness
Psychiatricsuicidal 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.
Reproductive Systemabnormal menses
Respiratorybronchospasms (with or without a history of asthma), respiratory infection, voice alteration
Skin and Appendagesacne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas7,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 SensesHearing
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 Systemglomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)
LaboratoryElevation 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.
Zenatane 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 definition2, means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Zenatane should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Zenatane is indicated only for those female patients who are not pregnant, because Zenatane 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 patients1,3,4. 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 while off Zenatane. 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).
Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a highfat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Zenatane 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 Zenatane 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, Zenatane 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)
| Zenatane 2 x 40 mg Capsules | AUC0-∞ (ng•hr/mL) |
Cmax (ng/mL) | T max (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.
MetabolismFollowing 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-oxotretinoin). 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 Zenatane 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.
EliminationFollowing 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 Zenatane to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t½) 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.
Zenatane (isotretinoin capsules USP) 10 mg are opaque blue elliptical soft gelatin capsules imprinted with black ink, “R135” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and in boxes of 100 containing 10 prescription packs of 10 capsules, as unit dose blisters
Boxes of 30 (3 Prescription Packs of 10 capsules) NDC
55111-135-81
Boxes of 100 (10 Prescription Packs of 10 capsules) NDC
55111-135-78
Zenatane (isotretinoin capsules USP) 20 mg are opaque pink elliptical soft gelatin capsules imprinted with black ink, “R136” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and in boxes of 100 containing 10 prescription packs of 10 capsules, as unit dose blisters
Boxes of 30 (3 Prescription Packs of 10 capsules) NDC
55111-136-81
Boxes of 100 (10 Prescription Packs of 10 capsules) NDC
55111-136-78
Zenatane (isotretinoin capsules USP) 40 mg are opaque green elliptical soft gelatin capsules imprinted with black ink, “R137” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and 100 containing 10 prescription packs of 10 capsules, as unit dose blisters.
Boxes of 30 (3 prescription packs of 10 capsules) NDC
55111-137-81
Boxes of 100(10 prescription packs of 10 capsules) NDC
55111-137-78
Store at 68° to 77°F (20° to 25°C). Protect from light.
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-cisretinoic 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.
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.
Manufactured by: Cipla Limited, Kurkumbh Village, Pune – 413 802 INDIA. Manufactured for: Dr. Reddy's Laboratories Limited, Bachupally – 500 090 INDIA. Issued: 01/13
Zenatane 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 Zenatane 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 Zenatane 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 Zenatane 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 Zenatane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Zenatane therapy.
Pseudotumor CerebriZenatane 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 Zenatane immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).
Serious Skin ReactionsThere have been post-marketing reports of erythema multiforme and severe skin reactions [eg, 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 Zenatane should be considered if warranted.
PancreatitisAcute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Zenatane should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.
LipidsElevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Zenatane. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Zenatane 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 Zenatane 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 Zenatane5.
Blood lipid determinations should be performed before Zenatane is given and then at intervals until the lipid response to Zenatane 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 Zenatane therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Zenatane 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 Zenatane are unknown.
Animal StudiesIn 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 ImpairmentImpaired hearing has been reported in patients taking Zenatane; 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 Zenatane treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).
HepatotoxicityClinical hepatitis considered to be possibly or probably related to Zenatane 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 Zenatane, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel DiseaseZenatane 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 Zenatane treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Zenatane immediately (see ADVERSE REACTIONS: Gastrointestinal).
Skeletal Bone Mineral DensityEffects of multiple courses of Zenatane 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 Zenatane 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 to18 years, who started a second course of Zenatane four 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 Zenatane population. While causality to Zenatane has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Zenatane be given at the recommended doses for no longer than the recommended duration.
HyperostosisA 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 keratinization6. 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 Zenatane 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 Zenatane given in two divided doses. Hyperostosis may require a longer time frame to appear. Â The clinical course and significance remain unknown.
Premature Epiphyseal ClosureThere are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Zenatane. The effect of multiple courses of Zenatane on epiphyseal closure is unknown.
Vision ImpairmentVisual problems should be carefully monitored. All Zenatane patients experiencing visual difficulties should discontinue Zenatane treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).
Corneal OpacitiesCorneal opacities have occurred in patients receiving Zenatane 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 Zenatane 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 VisionDecreased night vision has been reported during Zenatane 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.
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.
PRECAUTIONSZenatane must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Zenatane 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 Zenatane only from wholesalers registered with iPLEDGE.
iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below:
WholesalersFor the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Zenatane, 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 patient of childbearing 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:
| Primary forms | Secondary forms |
|
Barrier: |
|
|
| 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 Zenatane. 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 Zenatane (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 Zenatane treatment, Zenatane 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 Zenatane 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 PatientsIsotretinoin 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, female patients of childbearing 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:
Zenatane must only be dispensed:
An Zenatane Medication Guide must be given to the patient each time Zenatane is dispensed, as required by law. This Zenatane Medication Guide is an important part of the risk management program for the patients.
Zenatane must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Zenatane products must be distributed, prescribed, dispensed, and used. Patients must fill Zenatane 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.
Zenatane should be administered with a meal (see PATIENT INFORMATION).
The recommended dosage range for Zenatane 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/day8, 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 Zenatane 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 Zenatane 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 Zenatane, even in low doses, has not been studied, and is not recommended. It is important that Zenatane be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Zenatane 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: Zenatane 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 (1-866495-0654) to obtain an authorization and the “do not dispense to patient after” date. Zenatane 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 Zenatane medication guide must be given to the patient each time Zenatane are dispensed, as required by law. This Zenatane Medication Guide is an important part of the risk management program for the patient.
The adverse reactions listed below reflect the experience from investigational studies of Zenatane, and the post-marketing experience. The relationship of some of these events to Zenatane therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Zenatane 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).
Dose RelationshipCheilitis 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).
Body as a Wholeallergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascularpalpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolichypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)
Gastrointestinalinflammatory 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
Hematologicallergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.
Musculoskeletalskeletal 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).
Neurologicalpseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness
Psychiatricsuicidal 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.
Reproductive Systemabnormal menses
Respiratorybronchospasms (with or without a history of asthma), respiratory infection, voice alteration
Skin and Appendagesacne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas7,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 SensesHearing
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 Systemglomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)
LaboratoryElevation 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.
DRUG INTERACTIONS
