RISPERDAL® CONSTA (risperidone) is indicated for the treatment of schizophrenia.

The efficacy of RISPERDAL® CONSTA® is based in part on a 12-week, placebo-controlled trial in schizophrenic inpatients or outpatients, along with extrapolation from the established efficacy of oral RISPERDAL® in this population.

The effectiveness of RISPERDAL® CONSTA® in longer-term use, that is, more than 12 weeks, has not been systematically evaluated in controlled trials. However, oral risperidone has been shown to be effective in delaying time to relapse in longer-term use. Patients should be periodically reassessed to determine the need for continued treatment (see 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® (risperidone).

RISPERDAL® CONSTA® should be administered every 2 weeks by deep intramuscular (IM) gluteal injection. Each injection should be administered by a health care professional using the enclosed safety needle (see HOW SUPPLIED). Injections should alternate between the two buttocks. Do not administer intravenously.

The recommended dose 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.

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 PRECAUTIONS - DRUG INTERACTIONS), 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).

Upward dosage 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 PRECAUTIONS - DRUG INTERACTIONS), 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 dosage strengths of RISPERDAL® CONSTA® in a single administration.

Pediatric Use

RISPERDAL® CONSTA® has not been studied in children younger than 18 years old.

Dosage in Special Populations

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).

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 RISPERDALR b.i.d. during the first week, which can be increased to 1 mg b.i.d. or 2 mg once daily during the second week. If a total daily dose of at least 2 mg oral RISPERDALR is well tolerated, an injection of 25 mg RISPERDAL CONSTA can be administered every 2 weeks. 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.

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.

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). 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 PRECAUTIONS).

Maintenance Therapy

Although no controlled studies have been conducted to answer the question of how long patients 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. Patients should be periodically reassessed to determine the need for continued treatment.

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 schizophrenic 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). For schizophrenic 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 active moiety (the sum of risperidone and 9-hydroxyrisperidone), 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 CLINICAL PHARMACOLOGY and PRECAUTIONS). 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® CONSTAR may need to be adjusted. A dose increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYO 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® CONSTAR between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme 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® CONSTAR and discontinuing from carbamazepine or other CYP 3A4 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 and 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.

Instructions for Use

Remove the dose pack of RISPERDAL® CONSTA® from the refrigerator and allow it to come to room temperature prior to reconstitution.

1. Flip off the plastic colored cap from the vial.

2. Peel back the blister pouch and remove the SmartSite® Needle-Free Vial Access Device by holding the white luer cap. Do not touch the spike tip of the access device at any time.

3. Place vial on a hard surface. Press the spike tip of the SmartSite® Access Device through the center of the vial's rubber stopper until the device securely snaps into place.

4. Swab the syringe connection point (blue circle) of the SmartSite® Access Device with preferred antiseptic prior to attaching the syringe to the SmartSite® Access Device.

5. Twist off the white cap from the pre-filled syringe and remove together with the rubber tip cap inside.

6. Press the syringe tip into the blue circle of the SmartSite® Access Device and Twist in a clockwise motion to ensure that the syringe is securely attached to the white luer cap of the access device. Keep the syringe and SmartSite® Access Device aligned, and hold the skirt of the access device during attachment to prevent spinning.

7. Inject the entire contents of the syringe containing the diluent into the vial.

8. 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 particles will be visible in liquid, but no dry particles remain.

9. Do not store the vial after reconstitution or the suspension may settle. If 2 minutes pass before injection, re-suspend by shaking vigorously.

10. Invert the vial completely and slowly withdraw the suspension from the vial. Tear section of the vial label at the perforation and apply detached label to syringe for identification purposes.

11. Unscrew the syringe from the SmartSite® access device and discard both the vial and access device appropriately.

12. Peel the blister pouch of the Needle-Pro® device open halfway. Grasp sheath using the plastic peel pouch.

13. Attach the luer connection of the Needle-Pro® device to the syringe with an easy clockwise twisting motion. Seat the needle firmly on the Needle-Pro® device with a push and clockwise twist.

14. If 2 minutes pass before injection, re-suspend by shaking vigorously.

15. Pull sheath away from the needle. Do not twist sheath, as needle may be loosened from Needle-Pro® device. Tap the syringe gently to make any air bubbles rise to the top. De-aerate syringe by moving plunger rod carefully forward, with needle in an upward position. Inject entire contents intramuscularly (IM) into the upper-outer quadrant of the gluteal area within 2 minutes to avoid settling. DO NOT ADMINISTER INTRAVENOUSLY.

WARNING: To avoid a needle stick injury with a contaminated needle, do not:

• intentionally disengage the Needle-Pro® device
• attempt to straighten the needle or engage Needle-Pro® device if the needle is bent or damaged
• mishandle the needle protection device that could lead to protrusion of the needle from it

16. After injection is complete, use only one hand and tabletop or other hard surface to snap needle into the orange needle protector device before discarding. Discard needle appropriately.

Upon suspension in the diluent, it is recommended to use RISPERDAL® CONSTA® immediately. RISPERDAL® CONSTA® must be used within 6 hours of suspension. Resuspension of RISPERDAL® CONSTA® will be necessary prior to administration, as settling will occur over time once the product is in suspension. Keeping the vial upright, shake vigorously back and forth for as long as it takes to resuspend the microspheres. Once in suspension, the product should not be exposed to temperatures above 77° F (25° C).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

RISPERDAL® CONSTA® (risperidone) is available in dosage strengths of 12.5, 25, 37.5, or 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 one Needle-Pro® safety needle for intramuscular injection (20 G TW needle with needle protection device).

12.5-mg vial/kit (NDC 50458-309-11): 12.5 mg of a white to off-white powder provided in a vial with a violet flip-off cap (NDC 50458-309-01).

25-mg vial/kit (NDC 50458-306-11): 25 mg of a white to off-white powder provided in a vial with a pink flip-off cap (NDC 50458-306-01).

37.5-mg vial/kit (NDC 50458-307-11): 37.5 mg of a white to off-white powder provided in a vial with a green flip-off cap (NDC 50458-307-01).

50-mg vial/kit (NDC 50458-308-11): 50 mg of a white to off-white powder provided in a vial with a blue flip-off cap (NDC 50458-308-01).

Storage and Handling

The entire dose pack should be stored in the refrigerator (36° - 46° F; 2° - 8° C) and protected from light.

If refrigeration is unavailable, RISPERDAL® CONSTA® can be stored at temperatures not exceeding 77° F (25° C) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 77° F (25° C).

Keep out of reach of children.

Revised August 2008 ©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2003
Risperidone is manufactured by: Janssen Pharmaceutical Ltd., Wallingstown, Little Island, County Cork, Ireland
Microspheres are manufactured by: Alkermes Controlled Therapeutics II., Wilmington, Ohio
Diluent is manufactured by: Vetter Pharma Fertigung GmbH & Co. KG., Ravensburg, Germany or Cilag, AG Schaffhausen, Switzerland or Ortho Biotech Products, L.P. Raritan, New Jersey
RISPERDAL CONSTA® is is manufactured for: Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560
FDA rev date: 8/14/2008

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