risperidone (Rx)

>10%

Somnolence (40-45%)

Insomnia (26-30%)

Agitation (20-25%)

Anxiety (10-15%)

Headache (10-15%)

Rhinitis (10-15%)

Fatigue (18-31%)

Parkinsonism (28-62%)

Akathisia (5-11%)

Increased appetite (4-44%)

Vomiting (10-20%)

Drooling (<12%)

Urinary incontinence (5-22%)

Tremor (11-24%)

Nasopharyngitis (4-19%)

Rhinorrhea (4-12%)

Enuresis (1-16%)

ER suspension

• Increased weight (12.8-13%)

1-10%

Constipation (5-10%)

Dyspepsia (5-10%)

Nausea (5-10%)

Abdominal pain (1-5%)

Aggressive reaction (1-5%)

Facial edema (<4%)

QT prolongation (<4%)

Dizziness (1-5%)

Extrapyramidal symptoms (EPS; 1-5%)

Gynecomastia in children (1-5%)

Rash (1-5%)

Tachycardia (1-5%)

Syncope (1-2%)

Bradycardia (<4%)

Palpitation (<4%)

Chest pain (<4%)

Agitation (<4%)

Postural dizziness (<4%)

Pruritus (<4%)

Acne (1-2%)

Hyperprolactinemia (<4%)

Sexual dysfunction (<4%)

Xerostomia (7-10%)

ER suspension

• Sedation (7-7.7%)
• Pain in extremity (0.9-7.7%)
• Constipation (7-7/7%)
• Anxiety (2.6-6.8%)
• Akathisia (2.6-6.8%)
• Back pain (3.5-6.8%)
• Musculoskeletal pain (5.2%)
• Extrapyramidal disorder (1.7-4.3%)
• Increased appetite (1.7-3.4%)
• Musculoskeletal stiffness (0.9-2.6%)
• Abdominal discomfort (2.6%)
• Muscle spasms (0-2.6%)
• Dry mouth (1.7-2.6%)

<1%

Agranulocytosis

Cholesterol increased

Delirium

Ketoacidosis

Orthostatic hypotension

Seizures

Frequency Not Defined

Diabetes mellitus

Hyperthermia

Hypoglycemia

Hypothermia

Myelosuppression

Neuroleptic malignant syndrome (NMS)

Priapism

Prolonged QT interval

Tardive dyskinesia

Thrombotic thrombocytopenic purpura (TTP)

Sleep apnea syndrome

Urinary retention

Blood and lymphatic system disorders: Anemia, granulocytopenia

Cardiac disorders: Tachycardia, sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and labyrinth disorders: Ear pain, tinnitus

Eye Disorders: Vision blurred, oculogyration, ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal disorders: Dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General disorders: Thirst, gait disturbance, chest pain, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune system disorders: Drug hypersensitivity

Infections and infestations: Nasopharyngitis, upper respiratory tract infection, sinusitis, urinary tract infection, pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations: Body temperature increased, alanine aminotransferase increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and nutrition disorders: Polydipsia, anorexia

Musculoskeletal, connective tissue, and bone disorders: Joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, muscle contracture, rhabdomyolysis

Nervous system disorders: Dizziness postural, disturbance in attention, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, bradykinesia, transient ischemic attack, coordination abnormal, cerebrovascular accident, masked facies, speech disorder, syncope, loss of consciousness, muscle contractions involuntary, Parkinson disease, tongue paralysis, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric disorders: Agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness

Renal and urinary disorders: Enuresis, dysuria, pollakiuria, urinary incontinence Reproductive system and breast disorders: Vaginal discharge, menstrual disorder, retrograde ejaculation, sexual dysfunction

Postmarketing Reports

Falls

Alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN), and water intoxication

Contraindications

Documented hypersensitivity

Cautions

Increased incidence of cerebrovascular disease reported; may alter cardiac conduction; life threatening arrhythmias reported with therapeutic doses of antipsychotics

May cause anticholinergic effects including blurred vision, urinary retention, agitation, confusion, blurred vision, and xerostomia

Use with caution in patients with history of seizures, Parkinson disease, Lewy body dementia, cardiovascular disease, hypovolemia, dehydration

Leukopenia/neutropenia and agranulocytosis reported; possible risk factors for leukopenia/neutropenia include preexisting low white blood cell (WBC) count and history of drug-induced leukopenia/neutropenia

If patient has history of clinically significant low WBC count or drug-induced leukopenia/neutropenia, monitor complete blood count (CBC) frequently during first few months of therapy; discontinue drug at first sign of clinically significant WBC decline <1000/μL in absence of other causative factors, and continue monitoring WBC count until recovery

May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; perform complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

Use caution in patients at risk of pneumonia; esophageal dysmotility and aspiration reported with antipsychotic use

May cause extrapyramidal symptoms including acute dystonic reactions, akathisia, pseudoparkinsonism, and tardive dyskinesia

Intraoperative floppy iris syndrome reported in patients receiving risperidone therapy

Monitor for fever, mental status changes, muscle rigidity and or autonomic instability; neuroleptic malignant syndrome (NMS) associated with risperidone use; if NMS suspected, discontinue therapy immediately and provide symptomatic treatment and monitoring

Use with caution in children <15 kg

Cases of priapism reported with therapy

Prolactin elevations occur and persist during chronic administration; risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents

Use caution when operating heavy machinery

FDA warning regarding off-label use for dementia in elderly

Seizures observed during premarketing studies of risperidone in adult patients with schizophrenia

Esophageal dysmotility and aspiration have been associated with antipsychotic use

Disruption of body temperature regulation has been attributed to antipsychotic agents

Tardive dyskinesia

• A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs; although prevalence appears to be highest among elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome; whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown
• Risk of developing tardive dyskinesia and likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment
• Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued; antipsychotic treatment, itself, however, may suppress (or partially suppress) signs and symptoms of the syndrome, possibly masking the underlying process
• Therapy should be prescribed in a manner that is most likely to minimize occurrence of tardive dyskinesia; chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness known to respond to antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate
• In patients who do require chronic treatment, use lowest dose and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued treatment;
• If signs and symptoms of tardive dyskinesia appear in a patient receiving therapy, consider discontinuing drug; however, some patients may require treatment with the drug despite the presence of the syndrome

Orthostatic hypotension

• May induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties
• risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment
• Risk of orthostatic hypotension and syncope may be minimized by limiting initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment
• Consider monitoring orthostatic vital signs in patients at risk; consider dose reduction if hypotension occurs
• Use caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions that would predispose patients to hypotension, eg, dehydration and hypovolemia, and in the elderly and patients with renal or hepatic impairment
• Consider monitoring for orthostatic vital signs if hypotension occurs; clinically significant hypotension observed with concomitant use of drug and antihypertensive medication

Metabolic changes

• Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk (eg, hyperglycemia, dyslipidemia, and body weight gain)
• In some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with ketoacidosis, hyperosmolar coma, or death
• In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy

Healthcare professionals are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research programs/ pregnancyregistry/

Infertility

• Based on the pharmacologic action of risperidone, treatment may result in an increase in serum prolactin levels, which may lead to reversible reduction in fertility in females of reproductive potential

Disease-associated maternal and/or embryo/fetal risk

• There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide
• Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth It is not known if this is a direct result of the illness or other comorbid factors

Fetal/neonatal adverse reactions

• Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy; symptoms varied
• Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately

Lactation

Limited data from published literature reports the presence of risperidone and its metabolite, 9- hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3 and 4.7% of the maternal weight-adjusted dosage

Reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug 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

Has high affinity for serotonin type 2 (5-HT2) receptors; binds to dopamine D2 receptors with 20 times lower affinity than that for 5-HT2 receptors; antagonizes alpha1-adrenergic, alpha2-adrenergic, and histaminergic receptors; has moderate affinity for serotonin type 1 (5-HT1C, 5-HT1D, 5-HT1A) receptors; has weak affinity for dopamine D1 receptors; has no affinity for muscarinic, beta1-adrenergic, and beta2-adrenergic receptors

Absorption

Peak plasma time, steady-state: 4-6 hr (SC)

Peak plasma concentration: 6.33-10.9 ng/mL (risperidone, 9-hydroxyrisperidone)

AUC: 2262-3891 ng·hr/mL

Bioavailability: 70%

Peak plasma time: Extensive metabolizers, 3 hr; poor metabolizers, 17 hr

Distribution

Protein bound: Risperidone, 90%; metabolite, 77%

Vd: 1-2 L/kg

Metabolism

Metabolized in liver by CYP2D6

Metabolite: 9-hydroxyrisperidone (paliperidone)

Elimination

Half-life: Extensive metabolizers, 3 hr (parent and metabolite combined); poor metabolizers, 20 hr (parent and metabolite combined); prolonged in renal impairment; free fraction increase in hepatic disease

Half-life: 8-9 days (9-hydroxyrisperidone and total active moiety)

Excretion: Urine (70%), feces (14%)

Oral Administration

Oral solution

• Administer directly from the calibrated pipette, or can be mixed with a beverage prior to administration
• Compatible in the following beverages: Water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea

Orally disintegrating tablets

• Do not open the blister until ready to administer
• For single tablet removal, separate one of the four blister units by tearing apart at the perforations
• Bend the corner where indicated
• Peel back foil to expose the tablet
• DO NOT push the tablet through the foil because this could damage the tablet
• The child-resistant pouch should be torn open at the notch to access the blister; do not open the blister until ready to administer
• Peel back foil from the side to expose the tablet
• DO NOT push the tablet through the foil, because this could damage the tablet
• Using dry hands, remove the tablet from the blister unit and immediately place the entire oral disintegration on the tongue; consumed immediately, as the tablet cannot be stored once removed from the blister unit
• Disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid; patients should not attempt to split or to chew the tablet

SC Preparation

Visually inspect for particulate matter and discoloration prior to administration

Hold powder syringe upright tap the barrel of the syringe to unpack the powder

Remove caps from both powder syringe and diluent syringe

Connect both syringes; do not over tighten

Keep your fingers off the plunger to avoid drug spillage

Mix product

• Failure to fully mix the product could result in incorrect dosage

• Premixing

  • Transfer contents of the liquid syringe into the powder syringe
  • Gently push the powder syringe plunger until you feel resistance (to wet powder and avoid compacting)
  • Repeat this gentle back-and-forth process for 5 cycles

• Complete mixing

  • Continue mixing the syringes for an additional 55 cycles; mixing can be more vigorous than when premixing
  • When fully mixed, the product should be a cloudy suspension that is uniform in color; varies between white to yellow-green in color
  • If mixed drug appears any clear areas in the mixture, continue to mix until the distribution of the color is uniform

SC Administration

For abdominal SC injection, only

Do not administer by any other route

To be administered by a healthcare professional only

Choose an injection site on the abdomen with adequate SC tissue that has no skin conditions (eg, nodules, lesions, excessive pigment); recommended patient be in the supine position; rotate injection sites (refer to prescribing information)

Allow package to come to room temperature for at least 15 minutes prior to preparation

Only prepare medication when you are ready to administer the dose

As a universal precaution, always wear gloves

IM preparation

Remove dose pack from refrigerator; allow to sit at room temperature at least 30 minutes before reconstituting; do not warm any other way

Remove vial cap; connect vial adapter

Keep vial vertical to prevent leakage

Hold base of vial and pull up on the sterile blister to remove; do not shake; do not touch exposed luer opening on vial adapter; this will result in contamination

Remove cap from liquid cap; connect liquid syringe to the vial adapter

Do not hold glass syringe barrel; may cause the white collar to loose or detach Inject diluent, suspend microspheres in diluent

Continuing to hold down the plunger rod, shake vigorously for at least 10 seconds, as shown; check the suspension

Microspheres will be visible in the liquid; immediately proceed to the next step so suspension does not settle

IM Administration

Immediately inject entire contents of syringe IM into the gluteal or deltoid muscle of the patient

Gluteal injection should be made into the upper-outer quadrant of the gluteal area

Do not IV administer

Storage

Tablets and oral disintegrating tablets

• Store at room temperature 15-25°C (59-77°F); protect from light and moisture

Oral solution

• Store at controlled room temperature 15- 25°C (59-77°F); protect from light and freezing

SC and IM kits

• Unopened: Refrigerate 2-8°C (36-46°F); may store at room temperature in its original packaging at 20-25°C (68-77°F) for up to 7 days
• After removal from the refrigerator, discard after 7 days