Risperdal

Do Other Drugs Affect the Way Risperidone Works?

Many drugs may affect the way risperidone works, and the drug could also interfere with other medications. It's very important to let your doctor know about everything you take, including illegal drugs and any over-the-counter medications, herbs, or supplements.

Types of drugs that interact with risperidone (Risperdal) include:

• Antidepressants, such as paroxetine (Paxil) and fluoxetine (Sarafem, Prozac)
• Heartburn medications, such as ranitidine (Zantac) and cimetidine (Tagamet)
• Certain drugs used to treat Parkinson's disease, including the dopamine agonists bromocriptine (Parlodel), cabergoline (Dostinex), and levodopa (Dopar, Larodopa)
• Some drugs used to treat high blood pressure
• Anti-seizure drugs, such as carbamazepine (Tegretol), phenobarbital (Luminal, Solfoton), and phenytoin (Dilantin)
• Other medications for mental illness, including clozapine (Clozaril)
• Certain antibiotics, such as rifampin (Rifadin, Rimactane)
• Sedatives, sleeping pills, and tranquilizers

Should I Avoid Any Food, Drink, or Activity While Taking Risperidone?

Risperidone can make you feel sleepy. Don't drive or operate machinery until you know how the drug will affect you. Drinking alcohol can make you feel even more tired, so it's important to avoid alcohol while taking this medication.

Risperdal is a prescription medication used to treat schizophrenia. It is also used to treat manic or mixed episodes associated with Bipolar I Disorder. Risperdal also is used to treat behavioral symptoms associated with autism.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Janssen Pharmaceuticals, Inc.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Risperdal there are no specific foods that you must exclude from your diet when receiving Risperdal.

• Risperdal comes as a tablet and in an oral solution (liquid) to take by mouth.
• It is usually taken once or twice a day with or without food. Take Risperdal at around the same time(s) every day.
• Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.
• Take Risperdal exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

• Risperdal Tablets should be stored at controlled room temperature 15°–25°C (59°–77°F). Protect from light and moisture.
• Risperdal Oral Solution should be stored at controlled room temperature 15°–25°C (59°–77°F). Protect from light and freezing.
• Keep out of reach of children.

Benzisothiazol-derivative; atypical or second-generation antipsychotic agent.1 2 3 5 6 7 8 9 10 11 12 13 60

• Exact mechanism of antipsychotic action has not been fully elucidated; may involve antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors.1 2 3 8 10 12 13 15 103

• Antagonism at other receptors (e.g., α1- and α2-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).1 103

• Exhibits low to moderate affinity for other serotonin receptor subtypes (e.g., 5HT1C, 5HT1A, 5HT1D), and weak affinity for dopamine D1 receptors and the haloperidol-sensitive sigma site.1 103 Possesses no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors.1 103

This section provides information on the proper use of a number of products that contain risperidone. It may not be specific to Risperdal. Please read with care.

Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

You may take this medicine with or without food.

When using the oral liquid:

• Measure the dose with the measuring device provided with the container.
• Take the medicine directly from the measuring device or mix the liquid with a beverage (eg, water, coffee, orange juice, or low-fat milk). Do not mix the liquid with cola or tea. Drink all of the mixture.
• Rinse the empty measuring device with water. Place it back in its storage case. Put the plastic cap back on the bottle of medicine.

When using the orally disintegrating tablet:

• Do not open the package until you are ready to take the medicine. To remove one tablet, separate one of the 4 tablets by tearing it apart on the perforations.
• Bend the corner as shown on the package. Peel back the foil. Do not push the tablet through the foil because that could damage the tablet.
• With dry hands, take the tablet out of the package. Place it immediately on your tongue. Do not store the tablet once it is removed from the package.
• The tablet will disintegrate in seconds after it is placed on the tongue.
• You may swallow the tablet with or without liquid. Do not split or chew the tablet.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (solution, tablets, or orally disintegrating tablets):
  • For bipolar disorder:
    • Adults—At first, 2 to 3 milligrams (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 6 mg per day.
    • Older adults—At first, 0.5 mg two times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 6 mg per day.
    • Children 10 to 17 years—At first, 0.5 mg once a day, in the morning or evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 6 mg per day.
    • Children younger than 10 years—Use and dose must be determined by your doctor.
  • For irritability associated with autistic disorder:
    • Children 5 to 16 years weighing 20 kilograms (kg) or greater—At first, 0.5 milligrams (mg) per day. Your doctor may adjust your dose as needed.
    • Children 5 to 16 years weighing less than 20 kg—At first, 0.25 mg per day. Your doctor may adjust your dose as needed.
    • Children younger than 5 years—Use and dose must be determined by your doctor.
  • For schizophrenia:
    • Adults—At first, 2 milligrams (mg) per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 16 mg per day.
    • Older adults—At first, 0.5 mg two times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 6 mg per day.
    • Children 13 to 17 years—At first, 0.5 mg once a day, in the morning or evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 6 mg per day.
    • Children younger than 13 years—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Aggressive behavior
• agitation
• anxiety
• changes in vision, including blurred vision
• difficulty concentrating
• difficulty speaking or swallowing
• inability to move the eyes
• increase in amount of urine
• loss of balance control
• mask-like face
• memory problems
• muscle spasms of the face, neck, and back
• problems with urination
• restlessness or need to keep moving (severe)
• shuffling walk
• skin rash or itching
• stiffness or weakness of the arms or legs
• tic-like or twitching movements
• trembling and shaking of the fingers and hands
• trouble sleeping
• twisting body movements

• Back pain
• chest pain
• speech or vision problems
• sudden weakness or numbness in the face, arms, or legs

• Confusion
• dizziness
• drowsiness
• extreme thirst
• fast, shallow breathing
• fast, weak heartbeat
• headache
• increased thirst
• lip smacking or puckering
• loss of appetite
• muscle cramps
• pale, clammy skin
• poor coordination
• prolonged, painful, inappropriate erection of the penis
• puffing of the cheeks
• rapid or worm-like movements of the tongue
• shivering
• talking, feeling, and acting with excitement and activity that cannot be controlled
• uncontrolled chewing movements
• uncontrolled twisting movements of neck, trunk, arms, or legs
• unusual bleeding or bruising
• unusual facial expressions or body positions

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Constipation
• cough
• diarrhea
• dry mouth
• headache
• heartburn
• increased dream activity
• increased length of sleep
• nausea
• sleepiness or unusual drowsiness
• sore throat
• stuffy or runny nose
• unusual tiredness or weakness
• weight gain

• Absent, missed, or irregular menstrual periods
• body aches or pain
• breast swelling or soreness
• chills
• dandruff
• darkening of skin color
• decreased interest in sexual intercourse
• dry skin
• ear congestion
• fever
• inability to have or keep an erection
• increase in body movements
• increased watering of the mouth
• joint pain
• loss in sexual ability, desire, drive, or performance
• loss of voice
• oily skin
• pain or tenderness around the eyes and cheekbones
• shortness of breath or troubled breathing
• sneezing
• stomach pain
• stopping of menstrual bleeding
• tightness in the chest
• toothache
• unusual breast milk production
• vomiting
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death 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 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus Risperdal® when compared to patients treated with Risperdal® alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

Risperdal® (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperdal® is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1)]

Neuroleptic Malignant Syndrome

Antipsychotic drugs including Risperdal® can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, prescribe Risperdal® in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with Risperdal®, consider drug discontinuation. However, some patients may require treatment with Risperdal® despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, 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.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including Risperdal®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including Risperdal®, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including Risperdal®, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including Risperdal®, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including Risperdal®, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including Risperdal®, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of Risperdal®.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

In longer-term, controlled and uncontrolled studies, Risperdal® was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

In longer-term, uncontrolled, open-label extension pediatric studies, Risperdal® was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

In longer-term, controlled and uncontrolled studies, Risperdal® was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5.

In longer-term, uncontrolled, open-label extension pediatric studies, Risperdal® was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

In longer-term, controlled and uncontrolled studies, Risperdal® was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7.

In longer-term, uncontrolled, open-label extension pediatric studies, Risperdal® was associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of Risperdal® treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of Risperdal® treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to Risperdal®. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the Risperdal® groups than the placebo group, but not dose related (1.90 kg in the Risperdal® 0.5–2.5 mg group, 1.44 kg in the Risperdal® 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with Risperdal® for any indication, weight gain should be assessed against that expected with normal growth.

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, Risperdal® elevates prolactin levels and the elevation persists during chronic administration. Risperdal® is associated with higher levels of prolactin elevation than other antipsychotic agents.

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.

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 contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. 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; the available evidence is considered too limited to be conclusive at this time.

Orthostatic Hypotension

Risperdal® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of Risperdal®-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The 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 [see Dosage and Administration (2.1, 2.4)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperdal® should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of Risperdal® and antihypertensive medication.

Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including Risperdal®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including Risperdal®. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Risperdal® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Risperdal® and have their WBC followed until recovery.

Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction associated with Risperdal® treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (Risperdal® 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of Risperdal® 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since Risperdal® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Risperdal® therapy does not affect them adversely.

Seizures

During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of Risperdal®-treated patients, two in association with hyponatremia. Risperdal® should be used cautiously in patients with a history of seizures.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Risperdal® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see Boxed Warning and Warnings and Precautions (5.1)]

Priapism

Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.

Body Temperature Regulation

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral Risperdal® use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

Patients with Phenylketonuria

Inform patients that Risperdal® M-TAB® Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each 4 mg Risperdal® M-TAB® Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg Risperdal® M-TAB® Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg Risperdal® M-TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg Risperdal® M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg Risperdal® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.

Mechanism of Action

The mechanism of action of Risperdal®, in schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from Risperdal® results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the other effects of Risperdal®.

Pharmacodynamics

Risperdal® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors. Risperdal® acts as an antagonist at other receptors, but with lower potency. Risperdal® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.

Pharmacokinetics

Absorption

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Pharmacokinetic studies showed that Risperdal® M-TAB® Orally Disintegrating Tablets and Risperdal® Oral Solution are bioequivalent to Risperdal® Tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5–6 days (measured in extensive metabolizers).

Food Effect

Food does not affect either the rate or extent of absorption of risperidone. Thus, Risperdal® can be given with or without meals.

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1–2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%–8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given Risperdal® do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with Risperdal® may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions (7)].

In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, Risperdal® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, Risperdal® did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.

The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Drug-Drug Interaction Studies

[See Drug Interactions (7)].

Specific Populations

Renal and Hepatic Impairment

[See Use in Specific Populations (8.6 and 8.7)].

Elderly

In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Use in Specific Populations (8.5)].

Pediatric

The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.

Race and Gender Effects

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 2, 9, and 38 times the maximum recommended human dose (MRHD) for schizophrenia of 16 mg/day on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 body surface basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m2 (mg/kg) basis at which these tumors occurred.

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5–6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.6)].

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the Ames gene mutation test, the mouse lymphoma assay, the in vitro rat hepatocyte DNA-repair assay, the in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in human lymphocytes or Chinese hamster ovary cells.

Impairment of Fertility

Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m2 body surface area basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 body surface area basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

Animal Toxicology

Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were observed with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma AUC levels of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was observed in females only with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose of 1.25 mg/kg/day. This dose produced plasma AUC levels of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe drowsiness, fast heart rate, feeling light-headed, fainting, and restless muscle movements in your eyes, tongue, jaw, or neck.

Applies to risperidone: intramuscular powder for injection extended release, oral solution, oral tablet, oral tablet disintegrating

General

IM Injection: The most commonly reported side effects include tremor, headache, parkinsonism, akathisia, and dizziness.

Oral: The most commonly reported side effects included sedation, increased appetite, extrapyramidal symptoms, and parkinsonism.[Ref]

Nervous system

IM Injection:
Very common (10% or more): Tremor (up to 24%), headache (up to 21%), parkinsonism (up to 15%), akathisia (up to 11%), dizziness (up to 11%)
Common (1% to 10%): Abnormal gait, bradykinesia, cogwheel rigidity, disturbance in attention, drooling, dyskinesia, dystonia, hypoesthesia, hypokinesia, sedation, somnolence, syncope, tardive dyskinesia
Uncommon (0.1% to 1%): Abnormal coordination, balance disorder, cerebral ischemia, convulsion, dysarthria, dysgeusia, loss of consciousness, paresthesia, postural dizziness, psychomotor hyperactivity, vertigo
Rare (0.01% to 0.1%): Cerebrovascular disorder, depressed level of consciousness, diabetic coma, head titubation, neuroleptic malignant syndrome, unresponsive to stimuli
Frequency not reported: Abnormal glabellar reflex, akinesia, athetosis, cerebrovascular accident, choreoathetosis, emprosthotonus, extrapyramidal disorder, facial spasm, gait disturbance, grand mal convulsion, head titubation, hyperkinesia, hypertonia, masked facies, movement disorder, myoclonus, myotonia, opisthotonos, parkinsonian gait, parkinsonian rest tremor, pleurothotonus, restless legs syndrome, risus sardonicus, speech disorder, tongue paralysis, transient ischemic attack

Oral:
Very common (10% or more): Sedation (up to 63%), extrapyramidal symptoms (up to 35%), parkinsonism (up to 28%), somnolence (up to 26.5%), headache (up to 22.4%), dizziness (up to 16%), drooling (up to 12%), tremor (up to 11%), akathisia (up to 10.1%)
Common (1% to 10%): Balance disorder, cerebrovascular accident, depressed level of consciousness, disturbance in attention, dysarthria, dyskinesia, dystonia, gait disturbance, hypersomnia, lethargy, postural dizziness, syncope, transient ischemic attack
Uncommon (0.1% to 1%): Abnormal coordination, abnormal gait, cerebral ischemia, convulsion, dysgeusia, hypoesthesia, loss of consciousness, paresthesia, psychomotor hyperactivity, speech disorder, tardive dyskinesia, unresponsive to stimuli, vertigo
Rare (0.01% to 0.1%): Cerebrovascular disorder, diabetic coma, head titubation, neuroleptic malignant syndrome
Frequency not reported: Abnormal glabellar reflex, akinesia, athetosis, bradykinesia, chorea, choreoathetosis, cogwheel rigidity, emprosthotonus, facial spasm, grand mal convulsion, hyperkinesia, hypertonia, hypokinesia, masked facies, movement disorder, myoclonus, myotonia, opisthotonos, parkinsonian rest tremor, Parkinson's disease, pleurothotonus, restless legs syndrome, risus sardonicus, tongue paralysis
Postmarketing reports: Seizure[Ref]

Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson's disease. Akathisia includes akathisia and restlessness. Dystonia includes muscle spasms, involuntary muscle contractions, muscle contracture, oculogyration, tongue paralysis. Tremor includes parkinsonian rest tremor.

In randomized placebo-controlled trials in elderly patients with dementia-related psychosis, cerebrovascular adverse events occurred more frequently in patients treated with atypical antipsychotics than those receiving placebo. Pooled data from 6 trials mainly in elderly patients older than 65 years showed that cerebrovascular events occurred in 3.3% (33 of 1009) of patients treated with risperidone compared with 1.2% (8 of 712) of placebo-treated patients. The mechanism for this risk is unknown. The risk for a cerebrovascular event was significantly higher in patients with mixed or vascular type dementia compared with Alzheimer's dementia.[Ref]

Metabolic

IM Injection:
Common (1% to 10%): Anorexia, decreased appetite, decreased weight, hyperglycemia, increased appetite, increased weight
Uncommon (0.1% to 1%): Blood cholesterol increased, blood triglycerides increased, diabetes mellitus
Rare (0.01% to 0.1%): Hyperinsulinemia, hypoglycemia, polydipsia, water intoxication
Very rare (less than 0.01%): Diabetic ketoacidosis
Frequency not reported: Blood glucose increased, tetany, thirst
Postmarketing reports: Aggravated diabetes mellitus

Oral:
Very common (10% or more): Increased appetite (up to 44%)
Common (1% to 10%): Decreased appetite, increased weight, thirst
Uncommon (0.1% to 1%): Anorexia, blood cholesterol increased, blood triglycerides increased, decreased weight, diabetes mellitus, hyperglycemia, polydipsia
Rare (0.01% to 0.1%): Hyperinsulinemia, hypoglycemia, water intoxication
Very rare (less than 0.01%): Diabetic ketoacidosis
Frequency not reported: Blood glucose increased, tetany[Ref]

Psychiatric

IM Injection:
Common (1% to 10%): Agitation, anxiety, decreased libido, depression, insomnia, sleep disorder
Uncommon (0.1% to 1%): Anorgasmia, confusional state, mania, nervousness, nightmare
Rare (0.01% to 0.1%): Blunted affect, drug withdrawal syndrome, neonatal drug withdrawal syndrome
Frequency not reported: Initial insomnia, listlessness, middle insomnia, restlessness

Oral:
Very common (10% or more): Insomnia (up to 32%), anxiety (up to 16%)
Common (1% to 10%): Agitation, confusional state, depression, listlessness, mild insomnia, nervousness, sleep disorder
Uncommon (0.1% to 1%): Decreased libido, mania, nightmare
Rare (0.01% to 0.1%): Anorgasmia, blunted affect, drug withdrawal syndrome, neonatal drug withdrawal syndrome
Frequency not reported: Initial insomnia, middle insomnia[Ref]

Other

IM Injection:
Common (1% to 10%): Asthenia, extremity pain, fall, fatigue, pain, pyrexia
Uncommon (0.1% to 1%): Body temperature increased, chills, ear infection, ear pain, feeling abnormal, malaise, procedural pain, tinnitus
Rare (0.01% to 0.1%): Body temperature decreased, discomfort, hypothermia, peripheral coldness
Frequency not reported: Chronic otitis media, otitis media, sluggishness, sudden death

Oral:
Very common (10% or more): Fatigue (up to 31%), pyrexia (up to 16%)
Common (1% to 10%): Asthenia, ear infection, ear pain, fall, feeling abnormal, increased body temperature, pain, sluggishness
Uncommon (0.1% to 1%): Chills, discomfort, malaise, procedural pain, tinnitus
Rare (0.01% to 0.1%): Decreased body temperature, hypothermia, peripheral coldness
Frequency not reported: Adverse reaction, chronic otitis media, otitis media
Postmarketing reports: Body temperature dysregulation, sudden death[Ref]

Gastrointestinal

IM Injection:
Common (1% to 10%): Abdominal discomfort, abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, gastroenteritis, nausea, salivary hypersecretion, toothache, vomiting
Uncommon (0.1% to 1%): Dysphagia, fecal incontinence, flatulence
Rare (0.01% to 0.1%): Cheilitis, fecaloma, intestinal obstruction, pancreatitis, swollen tongue
Very rare (less than 0.01%): Ileus
Frequency not reported: Aptyalism, gastritis, lip swelling, stomach discomfort, tongue spasm, upper abdominal pain

Oral:
Very common (10% or more): Vomiting (up to 20%), constipation (up to 17%), nausea (up to 16%), upper abdominal pain (up to 16%), dry mouth (up to 10%), dyspepsia (up to 10%), salivary hypersecretion (up to 10%)
Common (1% to 10%): Abdominal discomfort/pain, diarrhea, dysphagia, fecaloma, stomach discomfort, toothache
Uncommon (0.1% to 1%): Fecal incontinence, flatulence, gastroenteritis
Rare (0.01% to 0.1%): Cheilitis, intestinal obstruction, lip swelling, pancreatitis, swollen tongue
Very rare (less than 0.01%): Ileus
Frequency not reported: Aptyalism, gastritis, tongue protrusion, tongue spasm[Ref]

Respiratory

IM Injection:
Common (1% to 10%): Bronchitis, cough, dyspnea, nasal congestion, pharyngolaryngeal pain, pneumonia, sinus congestion, sinusitis, upper respiratory tract infection
Uncommon (0.1% to 1%): Epistaxis, hyperventilation, respiratory tract congestion/infection, tonsillitis, wheezing
Rare (0.01% to 0.1%): Aspiration pneumonia, dysphonia, laryngospasm, oropharyngeal spasm, pulmonary congestion, pulmonary embolism, rales, respiratory disorder, sleep apnea syndrome
Frequency not reported: Bronchopneumonia, lower respiratory tract infection, nasal edema, nasopharyngitis, pharyngitis, productive cough, rhinitis, rhinorrhea, tracheobronchitis

Oral:
Very common (10% or more): Nasopharyngitis (up to 19%), cough (up to 17%), rhinorrhea (up to 12%), nasal congestion (up to 10%), pharyngolaryngeal pain (up to 10%)
Common (1% to 10%): Bronchitis, dyspnea, epistaxis, pneumonia, pulmonary congestion, rhinitis, sinus congestion, sinusitis, upper respiratory tract infection
Uncommon (0.1% to 1%): Aspiration pneumonia, dysphonia, rales, respiratory disorder, respiratory tract congestion/infection, tonsillitis, wheezing
Rare (0.01% to 0.1%): Hyperventilation, pulmonary embolism, sleep apnea syndrome
Frequency not reported: Bronchopneumonia, laryngospasm, lower respiratory tract infection, nasal edema, oropharyngeal spasm, pharyngitis, productive cough, tracheobronchitis[Ref]

Genitourinary

Risperidone (the active ingredient contained in Risperdal) is associated with higher levels of prolactin elevation than other antipsychotic drugs. Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH) resulting in reduced pituitary gonadotropin secretion and in turn inhibit reproductive function by impairing gonadal steroidogenesis. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.[Ref]

IM Injection:
Common (1% to 10%): Amenorrhea, erectile dysfunction, galactorrhea, menstrual disorder, sexual dysfunction, urinary incontinence, urinary tract infection
Uncommon (0.1% to 1%): Breast discomfort/pain/discharge, delayed menstruation, dysuria, ejaculation disorder, pollakiuria, urinary retention
Rare (0.01% to 0.1%): Breast discharge/engorgement/enlargement
Frequency not reported: Anovulation, delayed ejaculation, ejaculation failure, enuresis, fertility disorder, irregular menstruation, menstrual disturbances, oligomenorrhea, retrograde ejaculation, vaginal discharge
Postmarketing reports: Priapism

Oral:
Very common (10% or more): Enuresis (up to 16%), urinary tract infection (up to 12.9%)
Common (1% to 10%): Ejaculation failure, galactorrhea, pollakiuria, urinary incontinence
Uncommon (0.1% to 1%): Amenorrhea, breast discomfort, breast pain, dysuria, ejaculation disorder, erectile dysfunction, menstrual disorder, sexual dysfunction, urinary retention, vaginal discharge
Rare (0.01% to 0.1%): Breast discharge/engorgement/enlargement, delayed menstruation, priapism
Frequency not reported: Abnormal sexual dysfunction, anovulation, fertility disorder, irregular menstruation, oligomenorrhea, retrograde ejaculation[Ref]

Musculoskeletal

IM Injection:
Very common (10% or more): Muscle rigidity (up to 11%)
Common (1% to 10%): Abnormal posture, arthralgia, back pain, muscle spasms, muscle twitching, musculoskeletal pain
Uncommon (0.1% to 1%): Blood creatine phosphokinase increased, joint stiffness, joint swelling, muscular weakness, neck pain
Rare (0.01% to 0.1%): Rhabdomyolysis
Frequency not reported: Buttock pain, involuntary muscle contractions, muscle contracture, muscle rigidity, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, nuchal rigidity, torticollis, trismus

Oral:
Common (1% to 10%): Abnormal posture, arthralgia, back pain, blood creatine phosphokinase increased, extremity pain, joint swelling, muscle spasms, musculoskeletal pain, myalgia, neck pain
Uncommon (0.1% to 1%): Joint stiffness, muscular weakness
Rare (0.01% to 0.1%): Rhabdomyolysis
Frequency not reported: Buttock pain, cervical spasm, involuntary muscle contractions, muscle contracture, muscle rigidity, muscle tightness, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus[Ref]

Cardiovascular

IM Injection:
Common (1% to 10%): Chest pain, edema, electrocardiogram QT prolonged, hypertension, hypotension, orthostatic hypotension, peripheral edema, right bundle branch block, tachycardia
Uncommon (0.1% to 1%): Abnormal electrocardiogram, atrial fibrillation, atrioventricular block, bradycardia, chest discomfort, conduction disorder, palpitations
Rare (0.01% to 0.1%): Flushing, sinus arrhythmias, venous thrombosis/thromboembolism
Frequency not reported: Cardiac arrest, decreased blood pressure, deep vein thrombosis, first degree atrioventricular block, generalized edema, increased heart rate, left bundle branch block, pitting edema, postural orthostatic tachycardia syndrome, sinus bradycardia, sinus tachycardia, Torsade de pointes, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia

Oral:
Common (1% to 10%): Chest discomfort/pain, edema, hypertension, hypotension, increased heart rate, orthostatic hypotension, palpitations, peripheral edema, pitting edema, tachycardia
Uncommon (0.1% to 1%): Abnormal electrocardiogram, atrial fibrillation, atrioventricular block/first degree atrioventricular block, bradycardia, bundle branch block/left bundle branch block/right bundle branch block, conduction disorder, electrocardiogram QT prolonged, flushing, palpitations
Rare (0.01% to 0.1%): Sinus arrhythmia, venous thrombosis/thromboembolism
Frequency not reported: Decreased blood pressure, generalized edema, postural orthostatic tachycardia syndrome, sinus bradycardia, sinus tachycardia, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, Torsade de pointes
Postmarketing reports: Cardiac/cardiopulmonary arrest, deep vein thrombosis[Ref]

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents, including risperidone, for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug- treated patient than in the placebo- treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Similar results (i.e., increased risk of mortality with atypical antipsychotics) were reported in another meta-analysis involving elderly dementia patients that consisted of 15 randomized, placebo-controlled trials (n=3353) of 10 to 12 weeks in duration. Risperidone is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia. However, in contrast, the results of another meta-analysis of 6 randomized, double-blind, placebo-controlled, clinical trials (n=1721) found a nonsignificant increase in overall mortality in elderly dementia patients treated with risperidone.

The results of a large retrospective cohort study appear to indicate that atypical antipsychotic agents (i.e., risperidone, olanzapine, clozapine, quetiapine) increase the risk of venous thromboembolism in elderly patients; however, these events seem to be rare.

Based on data from four placebo controlled trials conducted in elderly patients (n=1230), cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in elderly patients with dementia- related psychosis. In placebo controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone has not been shown to be safe or effective in the treatment of patients with dementia- related psychosis. Additional information on these and other clinical trials conducted in elderly patients can be obtained by calling 1-800- JANSSEN (800-526-7736). However, the association between the use of atypical antipsychotics (i.e., risperidone, olanzapine) and the risk of cerebrovascular events appears to be somewhat controversial. The results of a case-control study found no increased risk of cerebrovascular events in elderly patients treated with atypical antipsychotics.[Ref]

Dermatologic

IM Injection:
Common (1% to 10%): Acne, dry skin, rash
Uncommon (0.1% to 1%): Acarodermatitis, alopecia, cellulitis, eczema, erythema, facial edema, induration, onychomycosis, pruritus, seborrheic dermatitis, skin discoloration, subcutaneous abscess
Rare (0.01% to 0.1%): Dandruff, drug eruption, hyperkeratosis, skin disorder, skin lesion, urticaria
Frequency not reported: Erythematous rash, generalized pruritus, generalized rash, maculopapular rash, papular rash

Oral:
Common (1% to 10%): Acne, cellulitis, dandruff, dry skin, erythema, hyperkeratosis, pruritus, rash, seborrheic dermatitis
Uncommon (0.1% to 1%): Acarodermatitis, alopecia, eczema, facial edema, onychomycosis, skin discoloration, skin disorder, skin lesion, urticaria
Rare (0.01% to 0.1%): Drug eruption, induration
Frequency not reported: Erythematous rash, generalized rash, maculopapular rash, papular rash, subcutaneous abscess[Ref]

Ocular

IM Injection:
Common (1% to 10%): Blurred vision, reduced visual acuity
Uncommon (0.1% to 1%): Conjunctivitis, dry eye, eye infection, lacrimation disorder, ocular hyperemia
Rare (0.01% to 0.1%): Eye movement disorder, eye rolling, eyelid margin crusting, glaucoma, intraoperative floppy iris syndrome, photophobia, retinal artery occlusion
Frequency not reported: Eye discharge, eye swelling, eyelid edema, increased lacrimation

Oral:
Common (1% to 10%): Blurred vision, conjunctivitis
Uncommon (0.1% to 1%): Dry eye, eye discharge, eye infection, eye swelling, increased lacrimation, ocular hyperemia, photophobia
Rare (0.01% to 0.1%): Eye movement disorder, eye rolling, eyelid margin crusting, glaucoma, intraoperative floppy iris syndrome, reduced visual acuity
Frequency not reported: Blepharospasm, eyelid edema, oculogyration[Ref]

Immunologic

IM Injection:
Common (1% to 10%): Infection, influenza, viral infection
Frequency not reported: Influenza-like illness

Oral:
Common (1% to 10%): Influenza/influenza-like illness
Uncommon (0.1% to 1%): Viral infection
Frequency not reported: Infection[Ref]

Endocrine

IM Injection:
Common (1% to 10%): Hyperprolactinemia
Uncommon (0.1% to 1%): Gynecomastia
Rare (0.01% to 0.1%): Inappropriate antidiuretic hormone secretion
Frequency not reported: Blood prolactin increased

Oral:
Common (1% to 10%): Blood prolactin increased, hyperprolactinemia
Uncommon (0.1% to 1%): Gynecomastia
Rare (0.01% to 0.1%): Inappropriate antidiuretic hormone secretion
Postmarketing reports: Pituitary adenoma, precocious puberty[Ref]

Risperidone is associated with higher levels of prolactin elevation than other antipsychotic drugs. Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH) resulting in reduced pituitary gonadotropin secretion and in turn inhibit reproductive function by impairing gonadal steroidogenesis. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.[Ref]

Renal

IM Injection:
Uncommon (0.1% to 1%): Cystitis, glucose urine present

Oral:
Uncommon (0.1% to 1%): Cystitis
Rare (0.01% to 0.1%): Glucose urine present[Ref]

Hematologic

IM Injection:
Common (1% to 10%): Anemia
Uncommon (0.1% to 1%): Decreased hematocrit, decreased white blood cell count, thrombocytopenia
Rare (0.01% to 0.1%): Agranulocytosis, increased eosinophil count, neutropenia
Frequency not reported: Decreased hemoglobin, granulocytopenia, thrombocytopenia

Oral:
Common (1% to 10%): Anemia
Uncommon (0.1% to 1%): Decreased hematocrit, decreased white blood cell count, increased eosinophil count, neutropenia, thrombocytopenia
Rare (0.01% to 0.1%): Agranulocytosis
Frequency not reported: Decreased hemoglobin, granulocytopenia
Postmarketing reports: Thrombotic thrombocytopenic purpura[Ref]

Hepatic

IM Injection:
Common (1% to 10%): Gamma-glutamyltransferase increased, increased transaminases
Uncommon (0.1% to 1%): Hepatic enzymes increased
Rare (0.01% to 0.1%): Jaundice
Frequency not reported: ALT increased, AST increased

Oral:
Uncommon (0.1% to 1%): Hepatic enzymes increased, increased ALT, increased AST, increased transaminases, gamma glutamyltransferase increased
Rare (0.01% to 0.1%): Jaundice[Ref]

Local

IM Injection:
Common (1% to 10%): Injection site reaction
Uncommon (0.1% to 1%): Localized infection
Frequency not reported: Injection site induration, injection site pain, injection site swelling
Postmarketing reports: Injection site abscess, injection site cellulitis, injection site cyst, injection site hematoma, injection site necrosis, injection site nodule, injection site ulcer

Oral:
Uncommon (0.1% to 1%): Localized infection[Ref]

Hypersensitivity

There have been post marketing reports of anaphylactic reaction in patients who had previously tolerated oral risperidone (the active ingredient contained in Risperdal) [Ref]

IM Injection:
Uncommon (0.1% to 1%): Hypersensitivity
Rare (0.01% to 0.1%): Anaphylactic reaction
Very rare (less than 0.01%): Angioedema
Frequency not reported: Drug hypersensitivity

Oral:
Common (1% to 10%): Angioedema, hypersensitivity
Rare (0.01% to 0.1%): Anaphylactic reaction
Frequency not reported: Drug hypersensitivity[Ref]

Some side effects of Risperdal may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

• Relieves psychotic symptoms such as hallucinations, delusions, confusion, disturbed thoughts and lack of insight or self-awareness.
• Used either alone or in combination with other medicines for the treatment of schizophrenia, acute mania or mixed episodes in bipolar disorder.
• Risperdal in small dosages also relieves irritability and symptoms of aggression, temper tantrums, and mood fluctuations in children with autistic disorder.

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Comments: -Due to lack of published data and the potential for serious adverse reaction in nursing infants, other agents may be preferred, especially while nursing a newborn or preterm infant. -Women should not breastfeed for at least 12 weeks after receiving a long-acting injection of the drug.

An exclusively breastfed infant may expect to receive 4.3% of the maternal weight-adjusted drug dosage. This calculation is based on a study in 1 mother receiving risperidone 6 mg daily and having her milk and serum levels of risperidone and its active metabolite (9-hydroxyrisperidone) measured over 24 hours.

Summary of Use during Lactation

Limited information indicates that maternal risperidone doses of up to 6 mg daily produce low levels in milk. Because there is little published experience with risperidone during breastfeeding and little long-term follow-up data, other agents may be preferred, especially while nursing a newborn or preterm infant. Systematic reviews of second-generation antipsychotics concluded that risperidone seemed to be a second-line agent during breastfeeding because of the limited data available and higher excretion into milk relative to other agents.[1][2]

Drug Levels

Maternal Levels. One mother taking risperidone 6 mg daily had milk and serum levels of risperidone and its active metabolite, 9-hydroxyrisperidone, measured over 24 hours. Results indicated that an exclusively breastfed infant would receive 0.84% of the maternal weight-adjusted dosage of risperidone and another 3.46% as 9-hydroxyrisperidone for a total of 4.3% of the maternal weight-adjusted dosage.[3]

Two breastfeeding women taking 2 mg twice daily and 1.5 mg daily in 2 divided doses, respectively, and another with risperidone-induced galactorrhea taking 3 mg once daily were studied. Both risperidone and 9-hydroxyrisperidone were measured in milk. Milk levels of the drugs were rather flat during the 12 to 24 hours after the dose. The mean dose that an exclusively breastfed infant would receive was calculated to be 3.3% (range 2.2 to 4.7%) of the maternal weight-adjusted dosage.[4]

A woman who was 1 week postpartum was started on oral risperidone 2 mg daily and increased to 3 mg once daily. On day 6 of therapy (dosage 2 mg daily) average milk levels at 3 hours after a dose were risperidone 2.5 mcg/L and 9-hydroxyrisperidone 10 mcg/L. On day 10 (dosage 2 mg daily) at 15 hours after a dose 9-hydroxyrisperidone averaged 1.2 mcg/L and risperidone was undetectable. On day 20 of therapy (dosage 3 mg daily) average milk levels at 16 hours after a dose were risperidone 0.1 mcg/L and 9-hydroxyrisperidone 2.5 mcg/L.[5]

A woman took risperidone during pregnancy and breastfeeding. At 3 months postpartum, she provided 6 foremilk samples over a 24-hour period after her daily dose while she was taking a dose of 1 mg daily. Milk was analyzed for risperidone and 9-hydroxyrisperidone by HPLC. Risperidone could not be detected in milk (assay limit not specified). Breastmilk 9-hydroxyrisperidone was about 3 mcg/L at 1 and 24 hours later; its concentration was about 4 mcg/L at 2, 4, 8, 18 and 23 hours after the dose. The authors estimated that a fully breastfed infant would receive 4.7% of the maternal weight-adjusted dosage as 9-hydroxyrisperidone.[6]

Infant Levels. In 2 breastfed infants (6 weeks and 3.3 months old) whose mothers were taking 2 mg twice daily and 1.5 mg daily in 2 divided doses, respectively, risperidone and 9-hydroxyrisperidone were both undetectable (<1 mcg/L) in the serums of the infants.[4]

An infant was breastfed 6 times daily during maternal therapy with risperidone 2 mg once daily. Fifteen hours after the mother's last dose, the infant's plasma levels of risperidone was undetectable and 9-hydroxyrisperidone was 0.1 mcg/L.[5]

An infant was exclusively breastfed on demand during maternal therapy with risperidone 1 mg daily. At 3 months of age, risperidone was undetectable in the infant's serum 6 hours after a maternal dose.[6]

Effects in Breastfed Infants

One woman took risperidone 4 mg daily during breastfeeding. Her infant showed no developmental abnormalities on examinations up to 9 months of age. Another mother took risperidone 6 mg daily during breastfeeding. Her infant showed no developmental abnormalities on examinations up to 12 months of age.[7]

Two women taking risperidone 4 mg and 1.5 mg daily breastfed their infants of 3.3 months and 6 weeks of age, respectively, were achieving normal developmental milestones and had no adverse effects reported.[4]

A 1 week postpartum woman was started on risperidone 2 mg daily and increased after 10 days to a dosage of 3 mg daily. She breastfed her infant 6 times daily. The infant was observed for 5 weeks of inpatient therapy and judged normal by a pediatric neurologist. No sedation or other adverse effects were observed in the infant. After 3 months of treatment with risperidone, the mother and infant were judged to be well.[5]

An infant had been exclusively breastfed for 3 months during maternal therapy with risperidone 1 mg daily. A pediatric examination found the infant to have no neurological or physical abnormalities, and appeared to interact appropriately.[6]

In a telephone follow-up study, 124 mothers who took a benzodiazepine while nursing reported whether their infants had any signs of sedation. One mother who was taking 0.75 mg of risperidone daily, flurazepam 15 mg daily, clonazepam 0.25 mg twice daily, and 1 mg of bupropion daily reported sedation in her breastfed infant.[8]

Effects on Lactation and Breastmilk

Risperidone has caused elevated prolactin serum levels, gynecomastia, and galactorrhea in patients taking the drug.[9][10][11][12][13][14][15] In one case, euprolactinemic gynecomastia and galactorrhea occurred in a 19-year-old man who was also taking fluvoxamine.[16] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

Alternate Drugs to Consider

Haloperidol, Olanzapine, Quetiapine

References

1. Uguz F. Second-generation antipsychotics during the lactation period: A comparative systematic review on infant safety. J Clin Psychopharmacol. 2016;36:244-52. PMID: 27028982

2. Pacchiarotti I, Leon-Caballero J, Murru A et al. Mood stabilizers and antipsychotics during breastfeeding: Focus on bipolar disorder. Eur Neuropsychopharmacol. 2016;26:1562-78. PMID: 27568278

3. Hill RC, McIvor RJ, Wojnar-Horton RE, Dip G et al. Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breast-feeding. J Clin Psychopharmacol. 2000;20:285-6. Letter. PMID: 10770482

4. Ilett KF, Hackett LP, Kristensen JH, Vaddadi KS et al. Transfer of risperidone and 9-hydroxyrisperidone into human milk. Ann Pharmacother. 2004;38:273-6. PMID: 14742766

5. Aichhorn W, Stuppaeck C, Whitworth AB. Risperidone and breast-feeding. J Psychopharmacol. 2005;19:211-3. PMID: 15728443

6. Weggelaar NM, Keijer WJ, Janssen PK. A case report of risperidone distribution and excretion into human milk: How to give good advice if you have not enough data available. J Clin Psychopharmacol. 2011;31:129-31. PMID: 21192160

7. Ratnayake T, Libretto SE. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry. 2002;63(1):76-7. PMID: 11838633

8. Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr. 2012;161:448-51. PMID: 22504099

9. Gupta S, Frank B, Madhusoodanan S. Risperidone-associated galactorrhea in a male teenager. J Am Acad Child Adolesc Psychiatry. 2001;40:504-5. Letter. PMID: 11349691

10. Popli A, Gupta S, Rangwani SR. Risperidone-induced galactorrhea associated with prolactin elevation. Ann Clin Psychiatry. 1998;10:31-3. PMID: 9622047

11. Madhusoodanan S, Moise D. Risperidone-induced hyperprolactinemia in adolescents: A case series. J Clin Psychiatry. 2006;67(7):1110-3. PMID: 16889455

12. Afzal KI, Briones DF, DeVargas C. Risperidone-induced polydipsia and polyphagia associated with galactorrhea, abdominal pain, and rapid weight gain in an adolescent Hispanic female. CNS Spectr. 2007;12:818-20. PMID: 17984854

13. Benazzi F. Gynecomastia with risperidone-fluoxetine combination. Pharmacopsychiatry. 1999;32:41. PMID: 10071182

14. Schreiber S, Segman RH. Risperidone-induced galactorrhea. Psychopharmacology (Berl). 1997;130:300-1. PMID: 9151366

15. Holzer L, Eap CB. Risperidone-induced symptomatic hyperprolactinaemia in adolescents. J Clin Psychopharmacol. 2006;26:167-71. PMID: 16633146

16. Pratheesh PJ, Praharaj SK, Srivastava A. Euprolactinemic gynecomastia and galactorrhea with risperidone-fluvoxamine combination. Psychopharmacol Bull. 2011;44:70-3. PMID: 22506441

Substance Name

Risperidone

CAS Registry Number

106266-06-2

Drug Class

Antipsychotic Agents