DRUG INFORMATION
Class
Second Generation Antipsychotic
Neuroscience-based Nomenclature (NbN)
Pharmacological Target
Dopamine, serotonin, norepinephrine
Mode of Action
Receptor Antagonist (D2, 5-HT2, NE alpha-2)
Brand Name
Saphris, Sycrest
Monograph
DOSING AND ADMINISTRATION
Therapeutic Dose Range
Schizophrenia: 5 mg given twice daily
Bipolar Disorder: 5 mg twice daily. The dose can be increased to 10 mg twice daily, based on individual clinical response and tolerability.
Time of Day
Twice daily
Effect of food
May be taken with or without food
Effect of smoking
Asenapine undergoes CYP1A2 metabolism, however smoking does not appear to effect its clearance.
ADVERSE EFFECTS
Adverse Reactions
Sedation
Dizziness
Weight gain
EPS
Galactorrhea
Risk of tardive dyskinesia
NMS
Warnings
Class Warning: Increased Mortality in Elderly Patients with Dementia Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Class Warning: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Smoking
A population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, had no effect on the clearance of asenapine in smokers. In a crossover study in which 24 healthy male subjects (who were smokers) were administered a single 5 mg sublingual dose, concomitant smoking had no effect on the pharmacokinetics of asenapine.
PHARMACOKINETICS
Bioavailability
35% (estimated for 5 mg SL tablet) <2% when swallowed
Volume of distribution (Vd)
20-25 L/Kg
Protein binding
95%
Elimination half-life
24 hours
Time to peak (Tmax)
0.5-1.5 hours
Metabolism
Direct glucuronidation by UGT1A4 and oxidative metabolism by CYP1A2
Excretion
Following administration of a single radiolabeled dose, about 90% of the dose was recovered; approximately 40% recovered in feces and 50% in urine.
MORE INFORMATION
Renal impairment
No dosage adjustment of asenapine is required for patients with renal impairment.
Hepatic impairment
No dosage adjustment of asenapine is required for patients with mild to moderate hepatic impairment. In subjects with severe hepatic impairment (Child-Pugh C), a 7-fold increase in asenapine exposure was observed. Thus, asenapine is not recommended in patients with severe hepatic impairment.
DRUG-DRUG INTERACTIONS
Potential of Other Drugs to Affect Asenapine
Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors and an inducer of several of these enzyme pathways on asenapine pharmacokinetics were studied. With the exception of fluvoxamine (strong CYP1A2 inhibitor), none of the drugs resulted in clinically relevant alterations in asenapine pharmacokinetics. Coadministration of fluvoxamine 25 mg twice daily for 8 days with asinine 5 mg (single dose) increased Cmax (13%) and UAC (29%). Coadminister with caution.
Asenapine undergoes CYP1A2 metabolism, however smoking does not appear to effect its clearance.
Potential for Asenapine to Affect Other Drugs
Because of its alpha-1 adrenergic antagonism with potential for inducing orthostatic hypotension, asenapine may enhance the effects of certain antihypertensive agents.
In vitro studies indicate that asenapine weakly inhibits CYP2D6. Following co-administration of dextromethorphan and asenapine in healthy subjects, the ratio of dextrorphan (a metabolite of dextrometorphan) and dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with asenapine 5 mg twice daily resulted in a 2.5-fold decrease in DX/DM ratio. In the same study, treatment with paroxetine 20 mg daily produced a more pronounced, 30-fold decrease in the DX/DM ratio. In a separate study, co- administration of a single 75 mg dose of imipramine with a single 5 mg dose of asenapine did not affect the plasma concentrations of the metabolite desipramine (a CYP2D6 substrate). Coadministration of a single 20-mg dose of paroxetine (a CYP2D6 substrate and inhibitor) during treatment with 5 mg asenapine twice daily in 15 healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure. In vivo asenapine appears to be at most a weak inhibitor of CYP2D6. However, asenapine may enhance the inhibitory effects of paroxetine on its own metabolism. Therefore, asenapinpe should be co-administered cautiously with drugs that are both substrates and inhibitors for CYP2D6.