asenapine

Saphris

Pharmacologic class: Dibenzooxepino pyrrole

Therapeutic class: Atypical antipsychotic

Pregnancy risk category C

FDA Box Warning

• Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk for death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in the drug-treated patients of between 1.6 and 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although causes of death were varied, most deaths appeared to be either cardiovascular (for example, heart failure, sudden death) or infectious (for example, pneumonia) in nature.

• Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional antipsychotics may increase mortality.

• The extent to which findings of increased mortality in observational studies may be attributed to the antipsychotic as opposed to some characteristic(s) of the patients isn't clear.

• Asenapine isn't approved for treatment of patients with dementia-related psychosis.

Action

Unknown. May be mediated through a combination of antagonistic activity at D₂ and 5-HT_2A receptors.

Availability

Tablet (sublingual): 5 mg, 10 mg

Indications and dosages

➣ Acute treatment of schizophrenia in adults

Adults: 5 mg S.L. b.i.d.

➣ Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults

Adults: Initially, 10 mg S.L. b.i.d.; may be decreased to 5 mg S.L. b.i.d. if adverse reactions occur

Dosage adjustment

• Hypotension

• Severe neutropenia

Contraindications

None

Precautions

Use cautiously in:

• severe hepatic impairment (use not recommended)

• neuroleptic malignant syndrome, tardive dyskinesia, history of seizures or conditions that potentially lower seizure threshold (such as Alzheimer's dementia)

• diabetes mellitus

• dysphagia, patients at risk for aspiration pneumonia (avoid use)

• leukopenia, neutropenia

• antipsychotic-naïve patients

• cerebrovascular or cardiovascular disease; patients with risk factors for prolonged QT interval; concomitant use of drugs known to prolong QT interval, including Class 1A and Class III antiarrhythmics, other antipsychotics, and some antibiotics (avoid use)

• concomitant use of fluvoxamine (a CYP1A2 inhibitor), drugs that are both substrates and inhibitors of CYP2D6 (such as paroxetine), other centrally acting drugs, certain antihypertensives, alcohol

• patients who experience conditions that may contribute to core body temperature elevation (such as strenuous exercise, exposure to extreme heat, concomitant medication with anticholinergic activity, dehydration)

• elderly patients with dementia-related psychosis

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Don't give within 10 minutes of a meal.

• Don't give water for at least 10 minutes following sublingual dose.

Adverse reactions

CNS: headache, somnolence, insomnia, fatigue, anxiety, depression, irritability, dizziness, syncope, akathisia, extrapyramidal symptoms other than akathisia (including dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor), neuroleptic malignant syndrome, seizures

CV: hypertension, orthostatic hypotension, QT-interval prolongation

GI: constipation, dry mouth, oral hypoesthesia, dysphagia, salivary hypersecretion, vomiting, increased appetite, dyspepsia

Hematologic: leukopenia, neutropenia, agranulocytosis

Metabolic: hyperglycemia, hyperprolactinemia

Musculoskeletal: arthralgia, extremity pain

Other: weight gain, toothache, dysgeusia

Interactions

Drug-drug. Antibiotics (such as gatifloxacin, moxifloxacin), antipsychotics (such as chlorpromazine, thioridazine, ziprasidone), Class 1A antiarrhythmics (such as procainamide, quinidine), Class III antiarrhythmics (such as amiodarone, sotalol): increased risk of QT-interval prolongation

Antihypertensives: possible enhanced effects of these agents

CYP1A2 inhibitors (such as fluvoxamine), other centrally acting drugs: possible increased asenapine plasma concentration

CYP2D6 substrates and inhibitors (such as paroxetine): possible enhanced inhibitory effects of paroxetine on its own metabolism

Drug-food. Any food: decreased asenapine effect

Drug-behaviors. Alcohol: possible enhanced alcohol effects

Patient monitoring

See Immediately discontinue drug and closely monitor patient if signs and symptoms of neuroleptic malignant syndrome occur, such as hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs and symptoms may include elevated creatine kinase level, myoglobinuria (rhabdomyolysis), and acute renal failure.

See Discontinue drug if signs and symptoms of tardive dyskinesia occur (syndrome of potentially irreversible, involuntary, dyskinetic movement).

See Watch closely for suicide attempt in patients with inherent psychotic illnesses and bipolar disorder.

• Monitor blood glucose level closely in patient with or at risk for diabetes mellitus.

• Carefully monitor CBC with differential for neutropenia (fever or other signs and symptoms of infection) and treat promptly if such signs or symptoms occur. Discontinue drug immediately if WBC count decreases in absence of other causative factors or if severe neutropenia occurs (absolute neutrophil count less than 1,000/mm³).

• Carefully evaluate patient for history of drug abuse; if history exists, observe patient for signs and symptoms of misuse or abuse (such as drug-seeking behavior and increases in dosage).

• Monitor liver function tests closely.

Patient teaching

• Instruct patient not to remove tablet from packet until ready to take.

• Instruct patient to gently remove medication from packaging by peeling back tab with dry hands and not to push tablet through packaging.

• Tell patient to place tablet under the tongue and allow it to dissolve completely; caution patient not to chew, crush, or swallow tablet whole.

• Instruct patient not to eat or drink anything for 10 minutes after taking this medication.

See Instruct patient to immediately discontinue drug and notify prescriber if the following signs or symptoms occur: overheating, muscle rigidity, altered mental status, irregular pulse or blood pressure, rapid or irregular heart beat, excessive sweating, or involuntary muscle movements.

See Advise patient or caregiver to immediately notify prescriber if suicidal thoughts or behavior develops.

• Advise patient to avoid alcoholic beverages.

• Caution patient to avoid driving and other hazardous activities until drug's effects on concentration and alertness are known.

• Inform patient that drug may elevate body temperature and to avoid activities that may cause overheating and dehydration (such as strenuous work or exercise in hot weather, using hot tubs) and to seek immediate medical attention if fever, mental or mood change, headache, or dizziness occurs.

• Inform patient to move slowly when rising to avoid dizziness from sudden blood pressure decrease.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, foods, and behaviors mentioned above.

asenapine

(a-sen-a-peen) asenapine,

Saphris

(trade name)

Classification

Therapeutic: antipsychotics
Pharmacologic: dibenzo oxepino pyrroles
Pregnancy Category: C

Indications

Acute and maintenance treatment of schizophrenia.Acute treatment of manic/mixed episodes associated with bipolar I disorder (as monotherapy or with lithium or valproate).

Action

May act through combined antagonism of dopaminergic (D₂) and 5-HT_2A receptors.

Therapeutic effects

Decreased symptoms of acute schizophrenia and mania/mixed episodes of bipolar I disorder.

Pharmacokinetics

Absorption: 35% absorbed following SL administration.Distribution: Rapidly distributed throughout the body. Vd is approximately 20–25 L/kg; 95% bound to plasma proteins.Metabolism and Excretion: Highly metabolized; primarily by CYP1A2 and UGTA14 enzyme systems 50% excreted in urine, 40% in feces, primarily as metabolites.Half-life: 24 hr.

Time/action profile (antipsychotic effect)

ROUTE	ONSET	PEAK	DURATION
SL	unknown	0.5–1.5 hr†	12–24 hr

† Blood levels.

Contraindications/Precautions

Contraindicated in: Hypersensitivity;Dementia-related psychoses;Severe hepatic impairment; Lactation: Avoid use.Use Cautiously in: History of cardiac arrhythmias, congenital QT prolongation, electrolyte abnormalities (especially hypomagnesemia or hypokalemia; correct prior to use) or concurrent use of medications known to prolong the QTc interval (may ↑ risk of life-threatening arrhythmias);History of seizures or conditions/medications known to ↓ seizure threshhold;History of leukopenia/neutropenia;Strenuous exercise, exposure to extreme heat, concurrent medications with anticholinergic activity, or risk of dehydration;History of suicide attempt; Geriatric: ↑ risk of adverse reactions; consider age-related ↓ in hepatic function, cardiovascular status, and concurrent medications; Geriatric: ↑ risk of mortality in elderly patients treated for dementia-related psychosis; Obstetric: Neonates at ↑ risk for extrapyramidal symptoms and withdrawal after delivery when exposed during the 3rd trimester; use only if benefit outweighs risk to fetus; Pediatric: Safety and effectiveness not established.

Adverse Reactions/Side Effects

Central nervous system

neuroleptic malignant syndrome (life-threatening)
seizures (life-threatening)
suicidal thoughts (life-threatening)
akathisia (most frequent)
dizziness (most frequent)
drowsiness (most frequent)
extrapyramidal symptoms (most frequent)
anxiety
fatigue
syncope
tardive dyskinesia

Cardiovascular

bradycardia
orthostatic hypotension
QTc interval prolongation
tachycardia

Gastrointestinal

oral hypoesthesia (most frequent)
dry mouth
dyspepsia
oral blisters
oral inflammation
oral peeling/sloughing
oral ulcers

Endocrinologic

hyperglycemia
hyperprolactinemia

Metabolic

weight gain (most frequent)
↑ appetite

Miscellaneous

hypersensitivity (including anaphylaxis, angioedema, hypotension, tachycardia, dyspnea, wheezing, and rash) (life-threatening)
angioedema (life-threatening)

Interactions

Drug-Drug interaction

Concurrent use of QTc interval prolonging drugs including Class 1A antiarrhythmics such as quinidine and procainamide or Class 3 antiarrhythmics including amiodarone and sotalol or other antipsychotics including ziprasidone, chlorpromazine or thioridazine or certain antibiotics such as moxifloxacin ; may ↑ risk of torsade de pointes and/or sudden death. Concurrent use should be avoided.Fluvoxamine, a strong inhibitor of CYP1A2, ↑ levels and risk of toxicity; use cautiously.Similar effects may occur with paroxetine, a CYP2D6 substrate and inhibitor. Drugs having similar properties (substrates/inhibitors of CYP2D6 ) should also be used cautiously with asenapine.↑ risk of CNS depression with other CNS depressants including antihistamines, some antidepressants, sedative/hypnotics, and alcohol.

Route/Dosage

Schizophrenia

Sublingual (Adults) Acute treatment—5 mg twice daily; Maintenance treatment—5 mg twice daily; may ↑ to 10 mg twice daily after 1 wk.

Acute Manic/Mixed Episodes Associated with Bipolar I Disorder

Sublingual (Adults) Monotherapy—10 mg twice daily; may be ↓ to 5 mg twice daily if tolerated poorly; Adjunctive therapy with lithium or valproate—5 mg twice daily; may be ↑ to 10 mg twice daily.

Availability

Sublingual tabletsblack cherry: 5 mg, 10 mg

Nursing implications

Nursing assessment

Assess mental status (orientation, mood, behavior) before and periodically during therapy. Assess for suicidal tendencies. Restrict amount of drug available to patient. Risk may be increased in children, adolescents, and adults ≤24 yrs.
Assess weight and BMI initially and throughout therapy.
Monitor BP (sitting, standing, lying) and pulse before and periodically during therapy.
Observe patient carefully when administering medication to ensure that medication is actually taken and not hoarded or cheeked.
Monitor patient for onset of akathisia (restlessness or desire to keep moving) and extrapyramidal side effects (parkinsonian—difficulty speaking or swallowing, loss of balance control, pill rolling of hands, masklike face, shuffling gait, rigidity, tremors; and dystonic—muscle spasms, twisting motions, twitching, inability to move eyes, weakness of arms or legs) periodically throughout therapy. Report these symptoms.
Monitor for tardive dyskinesia (uncontrolled rhythmic movement of mouth, face, and extremities; lip smacking or puckering; puffing of cheeks; uncontrolled chewing; rapid or worm-like movements of tongue). Notify health care professional immediately if these symptoms occur, as these side effects may be irreversible.
Monitor for development of neuroleptic malignant syndrome (fever, muscle rigidity, altered mental status, respiratory distress, tachycardia, seizures, diaphoresis, hypertension or hypotension, pallor, tiredness, loss of bladder control). Discontinue asenapine and notify health care professional immediately if these symptoms occur.
Monitor for symptoms related to hyperprolactinemia (menstrual abnormalities, galactorrhea, sexual dysfunction).
Assess patient for signs and symptoms of hypersensitivity reactions, including anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.
Lab Test Considerations: Obtain fasting blood glucose and cholesterol levels initially and periodically during therapy.
- Monitor CBC frequently during initial months of therapy in patients with pre-existing or history of low WBC. May cause leukopenia, neutropenia, or agranulocytosis. Monitor patients with neutropenia for fever or other symptoms of infection and treat promptly. Discontinue therapy if ANC <1000/mm³ occurs.
- May cause transient ↑ in serum ALT.

Potential Nursing Diagnoses

Disturbed thought process (Indications)

Implementation

Sublingual: Open packet immediately before use by firmly pressing thumb button and pulling out tablet pack. Do not push tablet through or cut or tear tablet pack. Peel back colored tab and gently remove tablet. Place tablet under tongue and allow to dissolve completely; dissolves in saliva within seconds. Avoid eating or drinking for 10 min after administration. Slide tablet pack back into case until it clicks.

Patient/Family Teaching

Advise patient to take medication as directed and not to skip doses or double up on missed doses. Take missed doses as soon as remembered unless almost time for the next dose.
Inform patient of possibility of extrapyramidal symptoms and tardive dyskinesia. Instruct patient to report these symptoms immediately.
Advise patient to make position changes slowly to minimize orthostatic hypotension.
Medication may cause drowsiness and dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
Advise patient and family to notify health care professional if thoughts about suicide or dying, attempts to commit suicide; new or worse depression; new or worse anxiety; feeling very agitated or restless; panic attacks; trouble sleeping; new or worse irritability; acting aggressive; being angry or violent; acting on dangerous impulses; an extreme increase in activity and talking; other unusual changes in behavior or mood or if signs and symptoms of hypersensitivity reactions (difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded) occur.
Inform patient that oral ulcers, blisters, peeling/sloughing, and inflammation may occur at application site. Advise patient to notify health care professional if these occur, may require discontinuation.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken, to avoid alcohol, and to consult health care professional before taking any new medications and to avoid taking alcohol or other CNS depressants concurrently with this medication.
Advise patient that extremes in temperature should be avoided, because this drug impairs body temperature regulation.
Advise patient to notify health care professional of medication regimen prior to treatment or surgery.
Advise female patients to notify health care professional if pregnancy is planned or suspected and to avoid breast feeding during therapy.
Emphasize the importance of routine follow-up exams and continued participation in psychotherapy as indicated.

Evaluation/Desired Outcomes

Decrease in excitable, paranoic, or withdrawn behavior.
Decrease incidence of mood swings in patients with bipolar disorders.
Decreased agitation associated with schizophrenia or bipolar disorder.