Dosage Form: injection
FULL PRESCRIBING INFORMATION
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. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1)]
Indications and Usage for Risperdal Consta
Schizophrenia
RISPERDAL® CONSTA® (risperidone) is indicated for the treatment of schizophrenia [see Clinical Studies (14.1)].
Bipolar Disorder
RISPERDAL® CONSTA® is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2, 14.3)].
Risperdal Consta Dosage and Administration
For patients who have never taken oral RISPERDAL®, it is recommended to establish tolerability with oral RISPERDAL® prior to initiating treatment with RISPERDAL® CONSTA®.
RISPERDAL® CONSTA® should be administered every 2 weeks by deep intramuscular (IM) deltoid or gluteal injection. Each injection should be administered by a health care professional using the appropriate enclosed safety needle [see Dosage and Administration (2.8)]. For deltoid administration, use the 1-inch needle alternating injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between the two buttocks. Do not administer intravenously.
Schizophrenia
The recommended dose for the treatment of schizophrenia is 25 mg IM every 2 weeks. Although dose response for effectiveness has not been established for RISPERDAL® CONSTA®, some patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg RISPERDAL® CONSTA® every 2 weeks. No additional benefit was observed with dosages greater than 50 mg RISPERDAL® CONSTA®; however, a higher incidence of adverse effects was observed.
The efficacy of RISPERDAL® CONSTA® in the treatment of schizophrenia has not been evaluated in controlled clinical trials for longer than 12 weeks. Although controlled studies have not been conducted to answer the question of how long patients with schizophrenia should be treated with RISPERDAL® CONSTA®, oral risperidone has been shown to be effective in delaying time to relapse in longer-term use. It is recommended that responding patients be continued on treatment with RISPERDAL® CONSTA® at the lowest dose needed. The physician who elects to use RISPERDAL® CONSTA® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Bipolar Disorder
The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in this population. The physician who elects to use RISPERDAL® CONSTA® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
General Dosing Information
A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic or renal impairment, for certain drug interactions that increase risperidone plasma concentrations [see Drug Interactions (7.11)] or in patients who have a history of poor tolerability to psychotropic medications. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Oral RISPERDAL® (or another antipsychotic medication) should be given with the first injection of RISPERDAL® CONSTA® and continued for 3 weeks (and then discontinued) to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site [see Clinical Pharmacology (12.3)].
Upward dose adjustment should not be made more frequently than every 4 weeks. The clinical effects of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose.
In patients with clinical factors such as hepatic or renal impairment or certain drug interactions that increase risperidone plasma concentrations [see Drug Interactions (7.11)], dose reduction as low as 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Do not combine two different dose strengths of RISPERDAL® CONSTA® in a single administration.
Dosage in Special Populations
Elderly
For elderly patients treated with RISPERDAL® CONSTA®, the recommended dosage is 25 mg IM every 2 weeks. Oral RISPERDAL® (or another antipsychotic medication) should be given with the first injection of RISPERDAL® CONSTA® and should be continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site [see Clinical Pharmacology (12.3)].
Renal or Hepatic Impairment
Patients with renal or hepatic impairment should be treated with titrated doses of oral RISPERDAL® prior to initiating treatment with RISPERDAL® CONSTA®. The recommended starting dose is 0.5 mg oral RISPERDAL® twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a total daily dose of at least 2 mg oral RISPERDAL® is well tolerated, an injection of 25 mg RISPERDAL® CONSTA® can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection until the main release of risperidone from the injection site has begun. In some patients, slower titration may be medically appropriate. Alternatively, a starting dose of RISPERDAL® CONSTA® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Patients with renal impairment may have less ability to eliminate risperidone than normal adults. Patients with impaired hepatic function may have an increase in the free fraction of the risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)]. Elderly patients and patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). These patients should avoid sodium depletion or dehydration, and circumstances that accentuate hypotension (alcohol intake, high ambient temperature, etc.). Monitoring of orthostatic vital signs should be considered [see Warnings and Precautions (5.7)].
Reinitiation of Treatment in Patients Previously Discontinued
There are no data to specifically address reinitiation of treatment. When restarting patients who have had an interval off treatment with RISPERDAL® CONSTA®, supplementation with oral RISPERDAL® (or another antipsychotic medication) should be administered.
Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients from other antipsychotics to RISPERDAL® CONSTA®, or concerning concomitant administration with other antipsychotics. Previous antipsychotics should be continued for 3 weeks after the first injection of RISPERDAL® CONSTA® to ensure that therapeutic concentrations are maintained until the main release phase of risperidone from the injection site has begun [see Clinical Pharmacology (12.3)]. For patients who have never taken oral RISPERDAL®, it is recommended to establish tolerability with oral RISPERDAL® prior to initiating treatment with RISPERDAL® CONSTA®. As recommended with other antipsychotic medications, the need for continuing existing EPS medication should be re-evaluated periodically.
Co-Administration of RISPERDAL® CONSTA® with Certain Other Medications
Co-administration of carbamazepine and other CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RISPERDAL® CONSTA® treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.11)]. At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Fluoxetine and paroxetine, CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. [see Drug Interactions (7.11)]
Instructions for Use
Dose pack components include:
RISPERDAL® CONSTA® requires close attention to the step-by-step 'Instructions for Use' to help avoid difficulties in the use of the kit.
RISPERDAL® CONSTA® must be reconstituted only in the diluent supplied in the dose pack, and must be administered with only the appropriate needle supplied in the dose pack for gluteal (2-inch needle) or deltoid (1-inch needle) administration. All components are required for administration. Do not substitute any components of the dose pack. To assure that the intended dose of risperidone is delivered, the full contents from the vial must be administered. Administration of partial contents may not deliver the intended dose of risperidone. It is recommended to administer immediately after reconstitution.
Remove the dose pack of RISPERDAL® CONSTA® from the refrigerator and allow it to come to room temperature for approximately 30 minutes prior to reconstitution.
- Flip off the plastic colored cap from the vial. Do not remove the grey rubber stopper. Wipe the top of the grey rubber stopper with an alcohol wipe and allow to dry.
- Peel back the blister pouch and remove the SmartSite® Needle-Free Vial Access Device by holding between the white luer cap and the skirt. Do not touch the spike tip of the access device at any time.
- It is very important that the SmartSite® Needle-Free Vial Access Device be placed on the vial correctly or the diluent could leak upon transfer to the vial
Place the vial on a hard surface. Hold the base of the vial. Orient the SmartSite® Needle-Free Vial Access Device vertically over the vial so that the spike tip is at the center of the vial's rubber stopper.
With a straight downward push, press the spike tip of the SmartSite® Needle-Free Vial Access Device through the center of the vial's rubber stopper until the device securely snaps onto the vial top. - Hold the base of the vial and swab the syringe connection point (blue circle) of the SmartSite® Needle-Free Vial Access Device with an alcohol wipe and allow to dry prior to attaching the syringe to the SmartSite® Needle-Free Vial Access Device.
- The prefilled syringe has a white tip consisting of 2 parts: a white collar and a smooth white cap. To open the syringe, hold the syringe by the white collar and snap off the smooth white cap (DO NOT TWIST OR CUT OFF THE WHITE CAP). Remove the white cap together with the rubber tip cap inside.
For all syringe assembly steps, hold the syringe only by the white collar located at the tip of the syringe. Holding the white collar will help to prevent the white collar from getting detached and ensure a good connection to the syringe. Be careful to not overtighten components when assembling. Overtightening connections may cause syringe component parts to loosen from the syringe body. - While holding the white collar of the syringe, insert and press the syringe tip into the blue circle of the SmartSite® Needle-Free Vial Access Device and twist in a clockwise motion to secure the connection of the syringe to the SmartSite® Needle-Free Vial Access Device (avoid over-twisting). Hold the skirt of the SmartSite® Needle-Free Vial Access Device during attachment to prevent it from spinning.
Keep the syringe and SmartSite® Needle-Free Vial Access Device aligned. - Inject the entire contents of the syringe containing the diluent into the vial.
- Shake the vial VIGOROUSLY while holding the plunger rod down with the thumb for a minimum of 10 seconds to ensure a homogeneous suspension. When properly mixed, the suspension appears uniform, thick, and milky in color. The microspheres will be visible in liquid, but no dry microspheres remain.
DO NOT STORE THE VIAL AFTER RECONSTITUTION OR THE SUSPENSION MAY SETTLE. - Invert the vial completely and SLOWLY withdraw the entire content of the suspension from the vial into the syringe. Tear the section of the vial label at the perforation and apply the detached label to the syringe for identification purposes.
- While holding the white collar of the syringe, unscrew the syringe from the SmartSite® Needle-Free Vial Access Device. Discard both the vial and vial access device appropriately.
- Select the appropriate needle provided with the kit:
For GLUTEAL injection, select the 20G TW 2-inch needle (longer needle with yellow colored hub in blister with yellow print)
For DELTOID injection, select the 21G UTW 1-inch needle (shorter needle with green colored hub in blister with green print) - Peel the blister pouch of the Needle-Pro® safety device open halfway. Grasp the transparent needle sheath using the plastic peel pouch. To prevent contamination, be careful not to touch the orange Needle-Pro® safety device's luer connector. While holding the white collar of the syringe, attach the luer connection of the orange Needle-Pro® safety device to the syringe with an easy clockwise twisting motion.
- While continuing to hold the white collar of the syringe, grasp the transparent needle sheath and seat the needle firmly on the orange Needle-Pro® safety device with a push and a clockwise twist. Seating the needle is an important step to secure the connection between the needle and the orange Needle-Pro® safety device.
- RESUSPENSION OF RISPERDAL® CONSTA® WILL BE NECESSARY PRIOR TO ADMINISTRATION, AS SETTLING WILL OCCUR OVER TIME ONCE PRODUCT IS RECONSTITUTED. RESUSPEND THE MICROSPHERES IN THE SYRINGE BY SHAKING VIGOROUSLY.
- While holding the white collar of the syringe, pull the transparent needle sheath straight away from the needle. DO NOT TWIST the sheath as the luer connections may be loosened.
- Tap the syringe gently to make any air bubbles rise to the top. Remove air in syringe by depressing the plunger rod, carefully and slowly, while holding the needle in an upright position. Inject the entire contents of the syringe intramuscularly (IM) into the selected gluteal or deltoid muscle of the patient immediately. Gluteal injection should be made into the upper-outer quadrant of the gluteal area. DO NOT ADMINISTER INTRAVENOUSLY.
WARNING: To avoid a needle stick injury with a contaminated needle:- Do not use free hand to press the Needle-Pro® safety device over the needle.
- Do not intentionally disengage the Needle-Pro® safety device.
- Do not attempt to straighten the needle or engage Needle-Pro® safety device if the needle is bent or damaged.
- Do not mishandle the Needle-Pro® safety device, as it may cause the needle to protrude from the Needle-Pro® safety device.
- After the injection is complete, press the needle into the orange Needle-Pro® safety device using a one-handed technique. Perform a one-handed technique by GENTLY pressing the orange Needle-Pro® safety device against a flat surface. AS THE ORANGE NEEDLE-PRO® SAFETY DEVICE IS PRESSED, THE NEEDLE WILL FIRMLY ENGAGE INTO THE ORANGE NEEDLE-PRO® SAFETY DEVICE. Visually confirm that the needle is fully engaged into the orange Needle-Pro® safety device before discarding. Discard needle appropriately. Also discard the other (unused) needle provided in the dose pack.
Stability after reconstitution: Once in suspension, the product may remain at room temperature (do not expose to temperatures above 77°F (25°C)). RISPERDAL® CONSTA® must be used within 6 hours of suspension, but should always be resuspended prior to administration if not used immediately.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Do Not Reuse: Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to re-process the device for subsequent re-use may adversely affect the integrity of the device or lead to deterioration in performance.
Dosage Forms and Strengths
RISPERDAL® CONSTA® is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg risperidone. It is provided as a dose pack, consisting of a vial containing the risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for RISPERDAL® CONSTA®, a SmartSite® Needle-Free Vial Access Device, and two Needle-Pro® safety needles for intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration).
Contraindications
RISPERDAL® CONSTA® (risperidone) is contraindicated in patients with a known hypersensitivity to the product.
Warnings and Precautions
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. RISPERDAL®CONSTA®(risperidone) is not approved for the treatment of dementia-related psychosis (see Boxed Warning).
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) 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 events in patients treated with oral risperidone compared to patients treated with placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis [See also Boxed Warning and Warnings and Precautions (5.1)]
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, 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.
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. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to 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 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, RISPERDAL® CONSTA® should be prescribed 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® CONSTA®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL® CONSTA® 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 3 double-blind, placebo-controlled studies in subjects with schizophrenia and 4 double-blind, placebo-controlled monotherapy studies in subjects with bipolar mania with oral risperidone are presented in Table 1.
| RISPERDAL® | |||
|---|---|---|---|
| Placebo | 1–8 mg/day | >8–16 mg/day | |
| Mean change from baseline (mg/dL) | |||
| n=555 | n=748 | n=164 | |
| Serum Glucose | -1.4 | 0.8 | 0.6 |
| Proportion of patients with shifts | |||
| Serum Glucose | 0.6% | 0.4% | 0% |
| (<140 mg/dL to ≥200 mg/dL) | (3/525) | (3/702) | (0/158) |
In longer-term, controlled and uncontrolled studies in adult subjects, 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).
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 2.
| RISPERDAL® | |||
|---|---|---|---|
| Placebo | 1–8 mg/day | >8–16 mg/day | |
| Mean change from baseline (mg/dL) | |||
| Cholesterol | n=559 | n=742 | n=156 |
| Change from baseline | 0.6 | 6.9 | 1.8 |
| Triglycerides | n=183 | n=307 | n=123 |
| Change from baseline | -17.4 | -4.9 | -8.3 |
| Proportion of patients With Shifts | |||
| Cholesterol | 2.7% | 4.3% | 6.3% |
| (<200 mg/dL to ≥240 mg/dL) | (10/368) | (22/516) | (6/96) |
| Triglycerides | 1.1% | 2.7% | 2.5% |
| (<500 mg/dL to ≥500 mg/dL) | (2/180) | (8/301) | (3/121) |
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).
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data from a placebo-controlled, 12-week, fixed-dose study in adult subjects with schizophrenia are presented in Table 3.
| RISPERDAL® CONSTA® | |||
|---|---|---|---|
| Placebo (n=83) | 25 mg (n=90) | 50 mg (n=87) | |
| Weight (kg) | |||
| Change from baseline | -1.4 | 0.5 | 1.2 |
| Weight Gain | |||
| ≥7% increase from baseline | 6% | 10% | 8% |
In an uncontrolled, longer-term, open-label study, RISPERDAL® CONSTA® was associated with a mean change in weight of +2.1 kg at Week 24 (n=268) and +2.8 kg at Week 50 (n=199).
Hyperprolactinemia
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 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® CONSTA® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period with oral risperidone, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL® CONSTA® in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position).
RISPERDAL® CONSTA® 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 RISPERDAL® and antihypertensive medication.
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® CONSTA®. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a 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® CONSTA® 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® CONSTA® and have their WBC followed until recovery.
Potential for Cognitive and Motor Impairment
Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in multiple-dose trials. Since risperidone 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 treatment with RISPERDAL® CONSTA® does not affect them adversely.
Seizures
During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL® CONSTA®. Therefore, RISPERDAL® CONSTA® 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® CONSTA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see also Boxed Warning and Warnings and Precautions (5.1)]
Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.8)]. Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL® therapy is unknown.
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® or RISPERDAL® CONSTA® use. Caution is advised when prescribing RISPERDAL® CONSTA® for patients who will be exposed to temperature extremes.
Administration
RISPERDAL® CONSTA® should be injected into the deltoid or gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel. [see Dosage and Administration (2) and Adverse Reactions (6.7)]
Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor.
Suicide
There is an increased risk of suicide attempt in patients with schizophrenia or bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. RISPERDAL® CONSTA® is to be administered by a health care professional [see Dosage and Administration (2)]; therefore, suicide due to an overdose is unlikely.
Use in Patients with Concomitant Illness
Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL® CONSTA®, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable when using RISPERDAL® CONSTA® in patients with diseases or conditions that could affect metabolism or hemodynamic responses. RISPERDAL® CONSTA® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) treated with oral RISPERDAL®; an increase in the free fraction of risperidone is also seen in patients with severe hepatic impairment. Patients with renal or hepatic impairment should be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal or hepatic impairment [see Dosage and Administration (2.4)].
Osteodystrophy and Tumors in Animals
RISPERDAL® CONSTA® produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.
RISPERDAL® CONSTA® produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA® produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. (Cellular proliferation was not measured at the low dose or in females in either study.)
The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose (MRHD) (50 mg) on a mg/m2 basis and is associated with a plasma exposure (AUC) 2 times the expected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m2 basis). Plasma exposure (AUC) at the no-effect dose was one third the expected plasma exposure (AUC) at the IM MRHD.
Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study.
The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of Fertility).
The relevance of these findings to human risk is unknown.
Monitoring: Laboratory Tests
No
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