Source: FDA, National Drug Code (US) Revision Year: 2024
RISVAN is contraindicated in patients with a known hypersensitivity to either risperidone, its metabolite, paliperidone or to any of the components in the formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone [see Adverse Reactions (6.2)].
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 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 oral risperidone when compared to patients treated with oral risperidone 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.
RISVAN is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].
Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients given placebo. RISVAN is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].
NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue RISVAN and provide symptomatic treatment and monitoring.
Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the 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.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible is believed to increase as the duration of treatment and the total 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) 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, RISVAN should be prescribed in a manner most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should. Periodically reassess the need for continued treatment.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISVAN, drug discontinuation should be considered. However, some patients may require treatment with RISVAN despite the presence of the syndrome.
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 drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
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 risperidone. 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 hyperglycemiarelated adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related 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 RISVAN, 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 RISVAN, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISVAN, 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 RISVAN, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.
Data from a 12-week double-blind, placebo-controlled study with RISVAN in adults with schizophrenia are presented in Table 1.
Table 1. Changes in Fasting Glucose and Postbaseline Abnormal Values of Glucose > 126 mg/dL from Baseline to End of Treatment in a 12-Week Double Blind, Placebo-Controlled Study in Adults with Schizophrenia:
| RISVAN 75 mg N = 144 | RISVAN 100 mg N = 146 | Placebo N = 147 | |
|---|---|---|---|
| Serum Glucose, mg/dL, mean† Mean Change from Baseline to End of Treatment | 6.0 (n= 129) | 1.80 (n = 125) | 0.3 (n = 119) |
| Glucose, > 126 mg/dL Proportion of patients with Postbaseline Abnormal Values‡ | 22/142 (15.5%) | 27/142 (19%) | 8/109 (7.3%) |
† The "n"s in the Serum Glucose mean row are the number of patients with data at baseline and end of treatment visits.
‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator
In longer-term, controlled and uncontrolled studies, oral risperidone 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).
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including risperidone.
Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
Weight gain has been observed with atypical antipsychotic use. Monitor weight at baseline and frequently thereafter.
Data from a 12-week double-blind, placebo-controlled study with RISVAN in adults with schizophrenia are presented in Table 2.
Table 2. Mean Change in Body Weight from Baseline to End of Study and ≥ 7% Increase from Baseline in a 12-Week Double Blind, Placebo-Controlled Study in Adults with Schizophrenia:
| RISVAN 75mg | RISVAN 100mg | Placebo | |
|---|---|---|---|
| Weight (kg)† Change from baseline | n=129 2.2 | n=126 2.0 | n=121 0.2 |
| Weight (kg)‡ ≥ 7% increase from baseline | 15/129 (11.6%) | 20/126 (15.9%) | 5/121 (4.1%) |
† The "n"s in the Weight Change mean row are the number of patients with data at baseline and end of treatment visits.
‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator.
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. In an openlabel, 12-month long-term safety study, mean weight increased by approximately 0.4 kg from baseline to Day 85 and 1.1 kg from baseline to Day 365 in patients receiving RISVAN.
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic gonadotropin releasing hormone, resulting in reduced pituitary gonadotropin secretion. This 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.
RISVAN may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of patients treated with oral risperidone in Phase 2 and 3 studies in adults with schizophrenia.
RISVAN should be used with particular caution in (1) 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, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.
Antipsychotics, including RISVAN, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other fall-related injuries. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of risperidone. 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.
In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of druginduced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of RISVAN at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue RISVAN in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC until recovery.
Somnolence, sedation, and dizziness were reported as adverse reactions in patients treated with RISVAN [see Adverse Reactions (6.1)]. Antipsychotics, including RISVAN, have the potential to impair judgment, thinking, or motor skills.
In a 12-week, double-blind, placebo-controlled study, sedation (including somnolence) was reported by 4%, 6%, and 3% of patients treated with 75 mg of RISVAN, 100 mg of RISVAN, and placebo, respectively. Dizziness was reported by 4%, 4%, and 3% of 75 mg of RISVAN, 100 mg of RISVAN, and placebo, respectively.
Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that RISVAN does not adversely affect them.
During premarketing studies of oral risperidone in adult patients with schizophrenia, seizures occurred in 0.3% of patients (9 out of 2,607 patients), two in association with hyponatremia. Use RISVAN cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
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. Antipsychotic drugs, including RISVAN, should be used cautiously in patients at risk for aspiration .
Priapism has been reported during postmarketing surveillance for other risperidone products. Severe priapism may require surgical intervention.
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use RISVAN with caution in patients who may experience these conditions.
The following are discussed in more detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of RISVAN for the treatment of schizophrenia in adults is based on adequate and well controlled studies of oral risperidone in studies of patients with schizophrenia and other indications as well as in one 12-week placebo-controlled trial of RISVAN in adult patients with schizophrenia [see Clinical Studies (14)].
The safety of RISVAN was evaluated in a total of 562 adult patients with schizophrenia who received at least 1 dose of RISVAN during the clinical development program. Of the 386 patients with schizophrenia who received one dose of Risvan during the 12-week, placebo-controlled trial, 168 patients received at least 13 doses of RISVAN during the double-blind and open label extension (OLE) phases. During double-blind period, RISVAN 75 mg was administered to 144 patients and RISVAN 100 mg to 146 patients. During the OLE period, RISVAN 75 mg was administered to 116 patients and RISVAN 100 mg to 99 patients.
Adverse Reactions in the 12-Week Placebo-Controlled Trial in Adults with Schizophrenia
The safety data presented below are derived from the 12-week double-blind placebo-controlled study of RISVAN in adult patients with schizophrenia.
Adverse reactions that led to discontinuation in RISVAN-treated patients in the 12-week placebo-controlled trial in adults with schizophrenia include abscess limb (0.3%), skin infection (0.3%), fall (0.3%), humerus fracture (0.3%), liver function test increased (0.3%), neutrophil count decreased (0.3%), mental impairment (0.3%), erectile dysfunction (0.3%), galactorrhea (0.3%), lactation disorder (0.3%), and pruritis (0.3%).
The most frequently reported adverse reactions (≥5% and twice placebo) are blood prolactin increase, hyperprolactinemia, akathisia, headache, sedation (including somnolence), weight increased, injection site pain, and alanine aminotransferase increased.
Table 3 shows the incidence of adverse reactions that occurred in ≥2% of patients treated with RISVAN and at a greater frequency than placebo.
Table 3. Adverse Reactions Occurring in ≥ 2% of RISVAN-Treated Adult Patients and at a Greater Frequency than Placebo in a 12-Week Placebo-Controlled Study in Schizophrenia:
| System Organ Class Preferred Term | RISVAN 75 mg (n = 146) % | RISVAN 100 mg (n = 144) % | Placebo (n = 147) % |
|---|---|---|---|
| Cardiac disorders | |||
| Tachycardia | 1 | 3 | 0 |
| Endocrine disorders | |||
| Hyperprolactinemia | 6 | 9 | 1 |
| Gastrointestinal disorders | |||
| Constipation | 3 | 1 | 1 |
| General disorders and administration site conditions | |||
| Injection site pain | 6 | 3 | 3 |
| Infections and infestations | |||
| Nasopharyngitis | 4 | 3 | 0 |
| Investigations | |||
| Blood prolactin increased | 9 | 14 | 0 |
| Weight increased | 7 | 6 | 2 |
| Alanine aminotransferase increased | 3 | 5 | 2 |
| Aspartate aminotransferase increased | 1 | 3 | 2 |
| Blood triglycerides increased | 3 | 2 | 1 |
| Blood creatine phosphokinase increased | 2 | 1 | 1 |
| Blood cholesterol increased | 0 | 2 | 0 |
| Musculoskeletal and connective tissue disorders | |||
| Myalgia | 2 | 1 | 0 |
| Muscle tightness | 2 | 0 | 0 |
| Nervous system disorders | |||
| Headache | 10 | 8 | 3 |
| Akathisia | 4 | 8 | 2 |
| Sedation1 | 4 | 6 | 3 |
| Dizziness | 4 | 4 | 3 |
| Dystonia2 | 4 | 4 | 1 |
1 Sedation includes sedation and somnolence
2 Dystonia includes dystonia and oromandibular dystonia
Other adverse reactions of <2% incidence but greater than placebo are shown below. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) which are part of the disease state, 3) for which a drug cause was remote, 4) which were so general as to be uninformative, or 5) which were not considered to have significant clinical implications.
General Disorders and Administration Site Conditions: asthenia, fatigue, injection site reaction (including injection site erythema, swelling and discomfort)
Metabolism and Nutrition Disorders: diabetes mellitus, increased appetite
Nervous System Disorders: dysarthria, dyskinesia, drooling, mental impairment, restless legs syndrome
Psychiatric Disorders: anorgasmia, enuresis, restlessness, tension
Renal and Urinary disorders: glycosuria, micturition urgency
Reproductive System and Breast Disorders: amenorrhea, dysmenorrhea, erectile dysfunction, galactorrhea
Vascular Disorders: hypotension, orthostatic hypotension
The following is a list of adverse reactions that are not reported in Table 3 above for RISVAN and occurred at an incidence of 2% or more in oral risperidone-treated adult patients and greater than placebo during the clinical trial evaluation of oral risperidone:
Eye Disorders: blurred vision
Gastrointestinal Disorders: nausea, dyspepsia, dry mouth, abdominal discomfort, salivary hypersecretion, diarrhea
General Disorders: fatigue, chest pain, asthenia
Infections and Infestations: upper respiratory tract infection, sinusitis, urinary tract infection
Investigations: heart rate increased
Musculoskeletal and Connective Tissue Disorders: back pain, arthralgia, pain in extremity
Nervous System Disorders: parkinsonism (includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease), tremor (includes tremor and parkinsonian rest tremor), dizziness postural
Psychiatric Disorders: insomnia, anxiety
Respiratory, Thoracic and Mediastinal Disorders: nasal congestion, dyspnea, epistaxis
Skin and Subcutaneous Tissue Disorders: rash, dry skin
The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence:
Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia
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: edema peripheral, 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, electrocardiogram abnormal, heart rate increased, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia
Musculoskeletal, Connective Tissue, and Bone Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, muscle contracture, rhabdomyolysis
Nervous System Disorders: balance disorder, 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, hypoesthesia, tardive dyskinesia, muscle contractions involuntary, Parkinson’s 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, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence
Reproductive System and Breast Disorders: menstrual irregular, gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea, epistaxis, wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: rash, dry skin, erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular
Vascular Disorders: flushing
In the 12-week double-blind, placebo-controlled study, there was an increase in mean prolactin levels in fasting blood samples from baseline to end of the study in both the RISVAN 75 mg and 100 mg groups, while mean prolactin for the placebo group decreased during the study. Changes in mean prolactin were dose-dependent. See Table 3 for the percentage of RISVAN-treated patients with hyperprolactinemia with an incidence of greater than or equal to 2% and greater than placebo.
Several methods were used to measure EPS, including: (1) the Barnes Akathisia Rating Scale (BARS) global clinical rating score which evaluates akathisia, (2) the Abnormal Involuntary Movement Scale (AIMS) scores which evaluates dyskinesia, (3) the Simpson-Angus Scale (SAS) global score which broadly evaluates parkinsonism, and (4) the incidence of spontaneous reports of EPS-related adverse reactions.
In the 12-week double-blind, placebo-controlled study, the mean changes from baseline in BARS, AIMS, and SAS total scores were comparable between RISVAN- and placebo-treated patients. At all postbaseline assessments, mean changes from baseline were between 0.0 and 0.1 (inclusive) for the BARS, between 0.1 and -0.1(inclusive) for the AIMS, and between 0.1 and 0.2 (inclusive) for the SAS.
In the 12-week double-blind, placebo-controlled study, there was a higher incidence of akathisia in RISVAN 100 mg (8%) compared with the RISVAN 75 mg (4%) and the placebo group (2%); reports of extrapyramidal disorders were higher in the RISVAN 100 mg group (12%) compared with the RISVAN 75 mg (8%) and the placebo group (3%).
Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Local injection site pain was assessed using a subject-reported VAS scale (0 = no pain to 10 = unbearably painful) administered approximately 1 hour after each injection. In the 12-week, double-blind placebo-controlled study, the mean subject-reported injection site pain VAS scores were similar for all treatment groups after each of the three injections. Median VAS scores were 1 for all treatment groups after each of the three injections. In the 12-month, long-term safety study, the injection site pain VAS scores were highest on day 1 (mean of 1.8) and tended to lessen over time (mean of 1.5 at day 337).
The most commonly reported injection site related adverse reaction was pain. Throughout the double-blind placebocontrolled study and the long-term safety study, 14 out of 386 patients (4%) reported 18 cases of injection site pain after 2,827 injections (1%) of RISVAN. Of the 18 cases of injection site pain, 15 were rated as mild, and 3 were rated as moderate. Less common injection site adverse reactions were swelling (n=3, 1%), erythema (n=1, 0%), and discomfort (n=1, 0%), with all cases rated as mild in severity.
The local injection site was assessed by site investigators. Throughout the double-blind placebo-controlled study (n=290 receiving RISVAN), 7% of patients had redness, 2% had swelling, and 1% had induration. Throughout the long-term safety study (n=215 receiving RISVAN), 3% of patients had redness, 0.5% had swelling, and no patients had induration.
The following adverse reactions have been identified during post approval use of oral risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, 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, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.
Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.
The interactions of RISVAN with coadministration of other drugs have not been evaluated. The drug interaction data provided in this section is based on studies with oral risperidone.
Clinically significant drug interactions with RISVAN are shown in Table 4.
Table 4. Clinically Important Drug Interactions with RISVAN:
| Strong CYP2D6 Inhibitors | |
| Clinical Impact: | Concomitant use of RISVAN with strong CYP2D6 inhibitors may increase the plasma exposure of risperidone and lower the plasma exposure of a major active metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. |
| Intervention: | When used concomitantly with strong CYP2D6 inhibitors, the recommended dose of RISVAN is 75 mg started at least 4 weeks before the planned start of strong CYP2D6 inhibitors to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving RISVAN 75 mg, it is recommended to continue treatment with 75 mg unless clinical judgment necessitates interruption of RISVAN treatment. The effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9- hydroxyrisperidone have not been studied [see Clinical Pharmacology (12.3)]. |
| Strong CYP3A4 Inducers | |
| Clinical Impact: | Concomitant use of RISVAN and a strong CYP3A4 inducer may cause decreases in the combined plasma concentrations of risperidone and 9- hydroxyrisperidone which could lead to decreased efficacy of RISVAN [see Clinical Pharmacology (12.3)]. |
| Intervention: | Changes in efficacy and safety should be carefully monitored with any dose adjustment of RISVAN. At the initiation of therapy with a strong CYP3A4 inducer, patients should be closely monitored during the first 4 to 8 weeks. In patients receiving RISVAN 75 mg, increase the dose to 100 mg. In patients receiving RISVAN 100 mg, additional oral risperidone therapy may need to be considered. On discontinuation of a strong CYP3A4 inducer, the dosage of RISVAN or any additional oral risperidone therapy should be reevaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone and 9-hydroxyrisperidone. For patients treated with RISVAN 75 mg and discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the 75 mg dose unless clinical judgment necessitates interruption of RISVAN treatment [see Dosage and Administration (2.4)]. |
| Centrally-Acting Drugs and Alcohol | |
| Clinical Impact: | Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders. |
| Intervention: | Caution should be used when RISVAN is administered in combination with other centrally-acting drugs or alcohol. |
| Hypotensive Agents | |
| Clinical Impact: | Because of its potential for inducing hypotension, RISVAN may enhance the hypotensive effects of other therapeutic agents with this potential. |
| Intervention: | Caution should be used when RISVAN is administered in combination with other therapeutic agents with hypotensive effects. |
| Dopamine Agonists | |
| Clinical Impact: | Agents with central antidopaminergic activity such as RISVAN may antagonize the pharmacologic effects of dopamine agonists. |
| Intervention: | Caution should be used when RISVAN is administered in combination with levodopa and dopamine agonists. |
| Methylphenidate | |
| Clinical Impact: | Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) [see Adverse Reactions (6.2)]. |
| Intervention: | Monitor for symptoms of EPS with concomitant use of RISVAN and methylphenidate. |
Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of RISVAN is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate and moderate CYP3A4 inhibitors (erythromycin). Additionally, no dosage adjustment is necessary for lithium, valproate, topiramate, digoxin and CYP2D6 substrates (donepezil and galantamine) when coadministered with RISVAN [see Clinical Pharmacology (12.3)].
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISVAN, during pregnancy. Healthcare providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/.
Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including RISVAN, during pregnancy (see Clinical Considerations).
Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human oral dose (MRHD) of 16 mg/day with maternal toxicity observed at 4-times MRHD based on mg/m² body surface area. Risperidone did not cause malformations in rats or rabbits when orally administered risperidone at doses up to 6-times the oral MRHD based on mg/m² body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the oral MRHD based on mg/m² body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the oral MRHD and offspring mortality increased at doses 0.1 to 3 times the oral MRHD based on mg/m² body surface area.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
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.
Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.
Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1566 women exposed to risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.
No developmental toxicity studies were conducted with RISVAN.
Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3- times the oral MRHD of 16 mg/day based on mg/m² body surface area; maternal toxicity occurred at 4-times the oral MRHD. Risperidone did not cause malformations when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6-times the oral MRHD based on mg/m² body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6-times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2-times the oral MRHD based on mg/m² body surface area; postnatal development and growth of the offspring were also delayed.
Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1-to 3-times the oral MRHD based on mg/m² body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5-times the oral MRHD based on mg/m² body surface area.
In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3-times the oral MRHD based on mg/m² and the only dose tested in the study.
Limited data from published literature report 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. There is no information on the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RISVAN and any potential adverse effects on the breastfed child from RISVAN or from the mother’s underlying condition.
Infants exposed to RISVAN through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms tremors and abnormal muscle movements).
Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with RISVAN may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.7)].
The safety and effectiveness of RISVAN have not been established in pediatric patients.
No juvenile animal studies were conducted with intramuscular risperidone suspension. Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day. In addition, sexual maturation was delayed 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.
Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day.
Clinical studies of RISVAN in the treatment of schizophrenia did not include patients older than 65 years to determine whether they respond differently from younger patients.
In general, dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting a decreased pharmacokinetic clearance in geriatric patients, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Risperidone is substantially excreted by the kidneys, and the risk of reactions may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection for RISVAN, and it may be useful to monitor renal function [see Dosage and Administration (2.2), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].
Elderly patients with dementia-related psychosis treated with RISVAN are at an increased risk of death compared to placebo. RISVAN is not approved for the treatment of patients with dementia related psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].
In patients with renal impairment, titrate with oral risperidone (up to at least 3 mg) before initiating treatment with RISVAN at a dose of 75 mg [see Dosage and Administration (2.3)].
RISVAN was not studied in patients with renal impairment; however, such effect has been investigated with oral risperidone [see Clinical Pharmacology (12.3)].
In patients with hepatic impairment, titrate with oral risperidone (up to at least 3 mg) before initiating treatment with RISVAN at a dose of 75 mg [see Dosage and Administration (2.3)].
RISVAN was not studied in patients with hepatic impairment; however, such effect has been investigated with oral risperidone [see Clinical Pharmacology (12.3)].
Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to RISVAN.
Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.
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