Zenatane
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Questions & Answers
Side Effects & Adverse Reactions
Special Patient Populations
Pediatric Patients
The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received Zenatane 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(0-12) (ng⋅hr/mL) | 3033.37 (1394.17) | 5082 (2184.23) |
| AUC(0-24) (ng⋅hr/mL) | 6003.81 (2885.67) | – |
| Tmax (hr)† | 6(1 to 24.6) | 4 (0 to12) |
| Cssmin (ng/mL) | – | 352.32 (184.44) |
| T1/2 (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 (t1/2) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
Zenatane ay 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 is appropriate in this setting; for some patients the risks may outweigh the benefits of Zenatane therapy.
Zenatane 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).
There 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.
Acute 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.
Elevations 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 Zenatane 5.
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: LaboratoryTests).
The cardiovascular consequences of hypertriglyceridemia associated with Zenatane are unknown.
Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 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 1.0 mg/kg/day, respectively, after normalization for total body surface area).
Impaired 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 ADVERSEREACTIONS: SpecialSenses).
Clinical 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.
Zenatane 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 ADVERSEREACTIONS: Gastrointestinal).
Bone Mineral Density
Effects 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 13-18 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.
Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple 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. The clinical course and significance remain unknown.
Premature Epiphyseal Closure
There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Zenatane. The effect of multiple courses of Zenatane on epiphyseal closure is unknown.
Visual problems should be carefully monitored. All Zenatane patients experiencing visual difficulties should discontinue Zenatane treatment and have an ophthalmological examination (see ADVAERSE REACTIONS: Special Senses).
Corneal Opacities
Corneal 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 ADVERSEREACTIONS: Special Senses).
Decreased Night Vision
Decreased 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.
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Severe Recalcitrant Nodular Acne
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 definition,2 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 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 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).
History
There is currently no drug history available for this drug.
Other Information
Isotretinoin USP, a retinoid, is available as Zenatane (isotretinoin capsules USP) in 10 mg, 20 mg and 40 mg soft gelatin capsules for oral administration. Each capsule contains butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil (Type-I and Type-II), medium chain triglyceride, refined soybean oil and white wax. Gelatin capsules contain gelatin, glycerin, methylparaben, propyl paraben, lake blend blue(LB-332) containing D&C Yellow No.10, FD&C Blue No.1 (for 10 mg), lake blend red (LB-1574) containing D&C Red No.27, D&C Red No.30 (for 20 mg), lake blend green (LB-333) containing D&C Yellow No.10, FD&C Blue No.1 (for 40 mg), lake blend white (TLB-1774) containing FD&C Blue No.2, titanium dioxide, and opacode black S-1-27794 containing iron oxide black, N-butyl alcohol, propylene glycol, industrial methylene spirit and shellac.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow or light orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform; sparingly soluble in alcohol, in isopropyl alcohol and in polyethylene glycon 400. The structural formula is:
Sources
Zenatane Manufacturers
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Physicians Total Care, Inc.
![Zenatane (Isotretinoin) Capsule, Gelatin Coated [Physicians Total Care, Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Zenatane | Physicians Total Care, Inc.
Zenatane should be administered with a meal (see PRECAUTIONS: Informationfor Patients).
The recommended dosage range for Zenatane is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 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 2.0 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: BoneMineral 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.
INFORMATION FOR PHARMACISTS 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. -
Dr. Reddy’s Laboratories Limited
Zenatane | Sun Pharma Global Fze
2.1 Important Administration InstructionsQuetiapine fumarate tablets can be taken with or without food.
2.2 Recommended DosingThe recommended initial dose, titration, dose range and maximum quetiapine fumarate tablets dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies (14.1 and 14.2)].
Table 1: Recommended Dosing for Quetiapine Fumarate Tablets * N/A Not applicable Indication
Initial Dose and Titration
Recommended Dose
Maximum Dose
Schizophrenia-Adults
Day 1: 25 mg twice daily.
Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4.
Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days.
150 to 750 mg/day
750 mg/day
Schizophrenia- Adolescents (13 to 17 years)
Day 1: 25 mg twice daily.
Day 2: Twice daily dosing totaling 100 mg.
Day 3: Twice daily dosing totaling 200 mg.
Day 4: Twice daily dosing totaling 300 mg.
Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 800 mg/day. Based on response and tolerability, may be administered three times daily.
400 to 800 mg/day
800 mg/day
Schizophrenia-Maintenance
N/A*
400 to 800 mg/day
800 mg/day
Bipolar Mania- Adults
Monotherapy or as an
adjunct to lithium or
divalproex
Day 1: Twice daily dosing totaling 100 mg.
Day 2: Twice daily dosing totaling 200 mg.
Day 3: Twice daily dosing totaling 300 mg.
Day 4: Twice daily dosing totaling 400 mg.
Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.
400 to 800 mg/day
800 mg/day
Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy
Day 1: 25 mg twice daily.
Day 2: Twice daily dosing totaling 100 mg.
Day 3: Twice daily dosing totaling 200 mg.
Day 4: Twice daily dosing totaling 300 mg.
Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day.
Based on response and tolerability, may be administered three times daily.
400 to 600 mg/day
600 mg/day
Bipolar Depression- Adults
Administer once daily at bedtime.
Day 1: 50 mg
Day 2: 100 mg
Day 3: 200 mg
Day 4: 300 mg
300 mg/day
300 mg/day
Bipolar I Disorder Maintenance Therapy- Adults
Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized.
400 to 800 mg/day
800 mg/day
Maintenance Treatment for Schizophrenia and Bipolar I Disorder
Maintenance Treatment—Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].
2.3 Dose Modifications in Elderly PatientsConsideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.
Elderly patients should be started on quetiapine fumarate tablets 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.
2.4 Dose Modifications in Hepatically Impaired PatientsPatients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
2.5 Dose Modifications when used with CYP3A4 InhibitorsQuetiapine fumarate tablets dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine fumarate tablets should be increased by 6 fold [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].
2.6 Dose Modifications when used with CYP3A4 InducersQuetiapine fumarate tablets dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate tablets should be reduced to the original level within 7 to 14 days [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].
2.7 Reinitiation of Treatment in Patients Previously DiscontinuedAlthough there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine fumarate tablets for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate tablets for less than one week, gradual dose escalation may not be required and the maintenance dose may be reinitiated.
2.8 Switching from AntipsychoticsThere are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate tablets, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate tablets therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
![Zenatane (Isotretinoin) Capsule, Gelatin Coated [Dr. Reddy’s Laboratories Limited]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=ffe52b98-9872-48c1-90fd-8fcd37c3432f&name=100mg.jpg)
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