Asenapine (Page 3 of 10)

5.6 Hypersensitivity Reactions

Hypersensitivity reactions have been observed in patients treated with asenapine sublingual tablets. 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 schizophrenia adult trials, syncope was reported in 0.2% (1/572) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of asenapine sublingual tablets, compared to 0.3% (1/378) of patients treated with placebo. 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 sublingual tablets, compared to 0% (0/329) of patients treated with placebo. During adult pre-marketing clinical trials with asenapine sublingual tablets, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1,953) of patients treated with asenapine sublingual tablets. In a 3-week, bipolar mania pediatric trial, syncope was reported in 1% (1/104) of patients treated with asenapine sublingual tablets 2.5 mg twice daily, 1% (1/99) of patients treated with asenapine 5 mg twice daily, and 0% (0/99) for patients treated with asenapine sublingual tablets 10 mg twice daily compared to 0% (0/101) for patients treated with placebo. 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 sublingual tablets 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.

5.8 Falls

Asenapine sublingual tablets 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 sublingual tablets. 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 sublingual tablets at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

3) and follow their WBC until recovery.

5.10 QT Prolongation

The effects of asenapine sublingual tablets on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved asenapine sublingual tablets doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with schizophrenia, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, asenapine sublingual tablets was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with asenapine sublingual tablets 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 sublingual tablets 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 sublingual tablets 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.

5.11 Hyperprolactinemia

Like other drugs that antagonize dopamine D2 receptors, asenapine sublingual tablets 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 sublingual tablets adult pre-marketing clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo. In a 3-week, bipolar mania pediatric trial, the incidence of adverse events related to abnormal prolactin levels were 0% in the asenapine sublingual tablets 2.5 mg twice daily treatment group, 2% in the asenapine sublingual tablets 5 mg twice daily treatment group, and 1% in the asenapine sublingual tablets 10 mg twice daily treatment group versus to 1% for patients treated with placebo [see Adverse Reactions (6.1)]. 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.

5.12 Seizures

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 sublingual tablets, respectively, compared to 0% (0/503, 0/203) of patients treated with placebo in pre-marketing short-term schizophrenia and bipolar mania trials, respectively. During adult pre-marketing clinical trials with asenapine sublingual tablets, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1,953) of patients treated with asenapine sublingual tablets. There were no reports of seizures in pediatric patients treated with asenapine sublingual tablets in a 3-week-term, bipolar mania trial. As with other antipsychotic drugs, asenapine sublingual tablets 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 sublingual tablets. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, fixed-dose, placebo-controlled schizophrenia adult trials, somnolence was reported in 15% (41/274) of patients on asenapine sublingual tablets 5 mg twice daily and in 13% (26/208) of patients on asenapine sublingual tablets 10 mg twice daily compared to 7% (26/378) of placebo patients. 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 sublingual tablets compared to 5% (18/329) of placebo patients. In the 3-week fixed-dose study, somnolence occurred at a lower rate in the 5mg twice daily dose 20% (24/122) versus the 10mg twice daily dose 26% (31/119) compared to 4% (5/126) in placebo patients. During adult pre-marketing clinical trials with asenapine sublingual tablets, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1,953) of patients treated with asenapine sublingual tablets. Somnolence led to discontinuation in 0.6% (12/1,953) of patients in short-term, placebo-controlled trials.

In a 3-week, placebo-controlled, bipolar I pediatric trial, the incidence of somnolence (including sedation and hypersomnia) for placebo, asenapine sublingual tablets 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, was 12% (12/101), 46% (48/104), 53% (52/99), and 49% (49/99), respectively. Somnolence led to discontinuation in 0%, 3%, 1%, and 2% of patients treated with placebo, and asenapine sublingual tablets 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, respectively.

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