ASENAPINE (Page 3 of 8)
5.6 Hypersensitivity Reactions
Hypersensitivity reactions have been observed in patients treated with asenapine. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.
5.7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects
Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In short-term bipolar mania adult trials, syncope was reported in 0.2% (1/620) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of asenapine, compared to 0% (0/329) of patients treated with placebo. During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with asenapine.
Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medications, patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Asenapine should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions ( 7.1)] . Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.
Asenapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
5.9 Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including asenapine. Agranulocytosis (including fatal cases) has been reported with other agents in the class.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug induced leukopenia/neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) during the first few months of therapy. In such patients, consider discontinuation of asenapine at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue asenapine in patients with severe neutropenia (absolute neutrophil count <1000/mm 3) and follow their WBC until recovery.
5.10 QT Prolongation
The effects of asenapine on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved asenapine doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with another indication, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with asenapine experienced QTc increases ≥60 msec from baseline measurements, nor did any patient experience a QTc of ≥500 msec.
Electrocardiogram (ECG) measurements were taken at various time points during the asenapine clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for asenapine and placebo in these short-term trials. There were no reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular repolarization.
The use of asenapine should be avoided in combination with other drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). Asenapine should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.
Like other drugs that antagonize dopamine D 2 receptors, asenapine can elevate prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. In asenapine adult pre-marketing clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent , a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
Seizures were reported in 0% and 0.3% (0/572, 1/379) of adult patients treated with doses of 5 mg and 10 mg twice daily of asenapine, respectively, compared to 0% (0/203) of patients treated with placebo in pre-marketing short-term bipolar mania trials. During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1953) of patients treated with asenapine.
As with other antipsychotic drugs, asenapine should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.As with other antipsychotic drugs, asenapine should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
5.13 Potential for Cognitive and Motor Impairment
Somnolence was reported in patients treated with asenapine. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, placebo-controlled bipolar mania adult trials of therapeutic doses (5-10 mg twice daily), somnolence was reported in 23% (145/620) of patients on asenapine compared to 5% (18/329) of placebo patients. In another study, somnolence occurred at a lower rate in the 5 mg twice daily dose 20% (24/122) versus the 10 mg twice daily dose 26% (31/119) compared to 4% (5/126) in placebo patients. During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with asenapine. Somnolence led to discontinuation in 0.6% (12/1953) of patients in short-term, placebo-controlled trials.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that asenapine therapy does not affect them adversely.
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