ASENAPINE (Page 7 of 8)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: In a lifetime carcinogenicity study in CD-1 mice asenapine was administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD of 10 mg twice daily. The incidence of malignant lymphomas was increased in female mice, with a no-effect dose resulting in plasma levels estimated to be 1.5 times those in humans receiving the MRHD. The mouse strain used has a high and variable incidence of malignant lymphomas, and the significance of these results to humans is unknown. There were no increases in other tumor types in female mice. In male mice, there were no increases in any tumor type.
In a lifetime carcinogenicity study in Sprague-Dawley rats, asenapine did not cause any increases in tumors when administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD.
Mutagenesis: No evidence for genotoxic potential of asenapine was found in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assays in human lymphocytes, the in vitro sister chromatid exchange assay in rabbit lymphocytes, or the in vivo micronucleus assay in rats.
Impairment of Fertility: Asenapine did not impair fertility in rats when tested at doses up to 11 mg/kg twice daily given orally. This dose is 10 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m 2 basis.
14 CLINICAL STUDIES
Efficacy of asenapine was established in the following trials:
- One flexible-dose, short-term trial in adult patients with manic or mixed episode associated with bipolar I disorder as adjunctive treatment to lithium or valproate [see Clinical Studies ( 14.2)]
14.2 Bipolar I Disorder
Adjunctive Therapy:The efficacy of asenapine as an adjunctive therapy in acute mania was established in a 12-week, placebo-controlled trial with a 3-week primary efficacy endpoint involving 326 adult patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially responsive to lithium or valproate monotherapy after at least 2 weeks of treatment. All patients randomized to asenapine were initially administered 5 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Asenapine was statistically superior to placebo in the reduction of manic symptoms (measured by the YMRS total score) as an adjunctive therapy to lithium or valproate monotherapy at Week 3 (Trial 5 Adjunctive in Table 14).
| Study Number | Treatment Group | Primary Efficacy Measure: YMRS Total Score | ||
| Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference a (95% CI) | ||
| Trial 5 (Adjunctive) | Asenapine 5-10 mg* twice daily + lithium/Valproate | 28.0 (5.6) | -10.3 (0.8) | -2.4 (-4.4, -0.3) |
| Lithium/Valproate | 28.2 (5.8) | -7.9 (0.8) | — | |
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses that are demonstrated to be effective.
16 HOW SUPPLIED/STORAGE AND HANDLING
Asenapine sublingual tablets are supplied as:
5 mg Tablets, black cherry flavor
White, Round, FFBE Tablets, debossed “Σ” on one side and “16” on the other side.
Child-resistant packaging
Bottle of 10 tablets NDC 42794-016-22
Bottle of 30 tablets NDC 42794-016-08
Bottle of 60 tablets NDC 42794-016-10
10 mg Tablets, black cherry flavor
White, Round, FFBE Tablets, debossed “Σ” on one side and “17” on the other side.
Child-resistant packaging
Bottle of 10 tablets NDC 42794-017-22
Bottle of 30 tablets NDC 42794-017-08
Bottle of 60 tablets NDC 42794-017-10
Storage
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature] excursions permitted to 15°-30°C (59°-86°F). Store Asenapine sublingual tablet(s) in its original container.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Dosage and Administration
Counsel patients on proper sublingual administration of Asenapine sublingual tablet(s) and advise them to read the FDA-approved patient labeling (Instructions for Use). When initiating treatment with asenapine, provide dosage escalation instructions [see Dosage and Administration ( 2)].
Hypersensitivity Reactions
Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms [see Contraindications ( 4), Warnings and Precautions ( 5.6) and Adverse Reactions ( 6)].
Application Site Reactions
Inform patients that application site reactions, primarily in the sublingual area, including oral ulcers, blisters, peeling/sloughing and inflammation have been reported. Instruct patients to monitor for these reactions [see Adverse Reactions ( 6.2)]. Inform patients that numbness or tingling of the mouth or throat may occur directly after administration of Asenapine sublingual tablet(s) and usually resolves within 1 hour [ see Adverse Reactions ( 6.1)] .
Neuroleptic Malignant Syndrome
Counsel patients about a potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their health care provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions ( 5.3)] .
Tardive Dyskinesia
Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions ( 5.4)].
Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions ( 5.5)].
Orthostatic Hypotension
Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions ( 5.7)].
Leukopenia/Neutropenia
Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking asenapine [see Warnings and Precautions ( 5.9)].
Hyperprolactinemia
Counsel patients on the signs and symptoms of Hyperprolactinemia and to contact their health care provider if these abnormalities occur [see Warnings and Precautions ( 5.11)].
Interference with Cognitive and Motor Performance
Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that asenapine therapy does not affect them adversely [see Warnings and Precautions ( 5.13)].
Heat Exposure and Dehydration
Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.14)].
Concomitant Medications
Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions ( 7.1)].
Pregnancy
Advise patients that asenapine may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations ( 8.1)].
Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy [see Use in Specific Populations ( 8.1)].
Sigmapharm Laboratories, LLC
Bensalem, PA 19020
OS017-11 REV.1220
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