asenapine transdermal (Rx)

>10%

Application site reactions (14-15%)

Extrapyramidal symptoms (8-13%)

1-10%

Headache (9%)

Increased weight (4-6%)

Constipation (4-5%)

Akathisia (4%)

Somnolence (3-4%)

Increased hepatic transaminases >3x ULN (1.6-3.1%)

Dyspepsia (1-3%)

Diarrhea (1-3%)

Blood glucose increased (1-3%)

Dystonia (1-3%)

Nasopharyngitis (1-3%)

Upper respiratory tract infection (1-3%)

Creatine kinase elevations ≥3 x ULN at any time (1.6-2.1%)

Hypertension (2%)

Vomiting (<2%)

Dry mouth (<2%)

Asthenia (<2%)

Myalgia (<2%)

Increased prolactin levels (1.3%)

<1%

Anemia

Temporary bundle-branch block

Accommodation disorder

Swollen tongue

Hyponatremia

Dysarthria

Thrombocytopenia

Postmarketing Reports

Choking

Contraindications

Severe hepatic impairment (Child-Pugh C)

Hypersensitivity to asenapine or any components of the transdermal system

Cautions

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; in placebo-controlled trials, patients, especially those taking atypical antipsychotic drugs, showed an increased risk of death in treated patients (1.6-1.7x) compared with placebo patients

Neuroleptic malignant syndrome associated with use; monitor for symptoms; discontinue if suspected, and provide intensive symptomatic treatment and monitoring

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke

Not approved for treatment of dementia-related psychosis

Atypical antipsychotic drugs, including asenapine transdermal, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain

Hypersensitivity reactions have been observed

Atypical antipsychotics cause orthostatic hypotension and syncope; risk is greatest during initial dose titration and when increasing the dose

May cause somnolence, postural hypotension, motor instability, and sensory instability, which may lead to falls and, consequently, fractures or other injuries; complete fall risk assessments in patients with diseases, conditions, or medications that could exacerbate these effects, when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

Leukopenia, neutropenia, and agranulocytosis reported with use; perform a CBC count during first few months of therapy; in such patients, consider discontinuation of therapy at first sign of clinically significant decline in WBC count in absence of other causative factors

Possible prolongation of QTc interval; avoid in patients with history of cardiac arrhythmias or other conditions that increase risk of torsades de pointes (eg, bradycardia, hypokalemia, hypomagnesemia)

Can elevate prolactin levels, and elevation can persist during long-term 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

Use 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

Potential disruption of body temperature regulation

Inherent suicide risk with population treated warrants close supervision when drug therapy is changed

Dysphagia, esophageal dysmotility, and aspiration may occur

Both the rate and extent of absorption are increased when heat is applied to application; avoid exposing patch to direct external heat sources (eg, hair dryers, heating pads, electric blankets, heated water beds)

Local skin reactions, such as irritation, were reported

Tardive dyskinesia

• Tardive dyskinesia may develop in patients treated with antipsychotic drugs, including asenapine transdermal
• Risk appears highest among elderly patients, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome
• Reserve long-term antipsychotic treatment for patients who have a chronic illness that is responsive to antipsychotic drugs, or in patients in whom effective alternative therapies are not available or appropriate
• In patients who do require long-term treatment, use lowest dose and shortest duration of treatment producing a satisfactory clinical response; periodically reassess if it needs to be continued
• If signs and symptoms of tardive dyskinesia appear, consider discontinuing treatment

Drug interaction overview

• Asenapine is a CYP1A2 and UGT1A4 substrate; weak CYP2D6 inhibitor
• Coadministration of asenapine with a CYP1A2 inhibitor increases AUC and plasma levels of asenapine; reduce dose based on clinical response, if necessary
• Owing to its alpha1-adrenergic antagonism with potential for inducing hypotension, asenapine may enhance the effects of certain antihypertensive agents; monitor blood pressure and adjust dosage of antihypertensive drug accordingly
• Coadministration with other drugs that prolong QTc interval may result in life-threatening arrhythmias (eg, class 1A antiarrhythmics [quinidine, procainamide], class 3 antiarrhythmics [amiodarone, sotalol], antipsychotics [ziprasidone, chlorpromazine, thioridazine], and antibiotics [moxifloxacin])
• Asenapine may enhance inhibitory effects of paroxetine on its own metabolism by CYP2D6; concomitant use with paroxetine increases paroxetine AUC and plasma levels; reduce paroxetine dose by half when used in combination with asenapine

Pregnancy

Studies have not been conducted in pregnant women

No human data available informing the drug-associated risk

Animal data

• In a pre-and post-natal study in rats, IV administration of asenapine at doses up to 0.7 times the MRHD of 10 mg of sublingual asenapine twice daily produced increases in postimplantation loss and early pup deaths, and decreases in subsequent pup survival and weight gain
• Doses were up to 1.1x the maximum recommended human dose (MRHD) of 12.8 mg transdermal asenapine daily.
• Advise pregnant women of the potential risk to a fetus

Pregnancy exposure registry

• Monitors pregnancy outcomes in women exposed to atypical antipsychotics during pregnancy
• For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/

Clinical considerations

• Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy
• Symptoms have varied in severity
• Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization; monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately

Lactation

Studies have not been conducted to assess the presence of asenapine in human milk, the effects of asenapine on the breastfed infant, or the effects of asenapine on milk production

Asenapine is excreted in rat milk

Consider developmental and health benefits of breastfeeding along with the mother's clinical need for asenapine transdermal and any potential adverse effects on the breastfed infant from asenapine transdermal or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Mechanism of action is unknown

Efficacy thought to be mediated via combined antagonist activity at dopamine D2 and serotonin type 2 (5-HT2) receptors

Absorption

Peak plasma time: 12-24 hr

Steady-state plasma concentrations are achieved in ~72 hr after the first application

Application of a heating pad on asenapine transdermal patch for 8 hr led to a faster absorption rate (median peak plasma time ~8 hr) as compared with no heating pad

Distribution

Protein bound: 95% (including albumin and alpha1-acid glycoprotein)

Vd: 20-25 L/kg

Metabolism

Direct glucuronidation by UGT1A4

Oxidative metabolism predominantly by CYP1A2

Elimination

Half-life: 30 hr

Excretion: Urine (~50%); feces (40%)

Transdermal Administration

Transdermal use only

Apply patch every 24 hr; do not wear longer than 24 hr

Apply to clean, dry, and intact skin at the selected application sites: hip, abdomen, upper arm, or upper back area

Wear only 1 patch at any time

Apply to a different application site each time a new patch is applied

Do not cut open the pouch until ready to apply; do not use if the individual pouch seal is broken or appears to be damaged

Apply whole transdermal patch; do not cut

If patch lifts at the edges, reattach by pressing firmly and smoothing down the edges of the patch

If patch comes off completely, apply a new one

After use, fold used patch so that the adhesive side sticks to itself and safely discard

If irritation or a burning sensation occurs while wearing patch, remove and apply a new patch to a new application site

Showering is permitted, but use during swimming or taking a bath has not been evaluated

Do not apply external heat sources (eg, heating pad) over the patch

Storage

Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)