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Risperidone Long-Acting Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


Increased Mortality in Elderly Patients with Dementia–Related Psychosis

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen 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. Risperidone is not approved for the treatment of patients with Dementia-Related Psychosis.


 

1. DESCRIPTION

Risperidone is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives.

The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:

Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.

Risperidone long-acting injection is a combination of extended release microspheres for injection and diluent for parenteral use.

The extended release microspheres formulation is a white to off-white, free-flowing powder that is available in dosage strengths of 12.5, 25, 37.5, or 50 mg risperidone per vial. Risperidone is micro-encapsulated in 7525 polylactide-coglycolide (PLG) at a concentration of 381 mg risperidone per gram of microspheres.

The diluent for parenteral use is a clear, colorless solution. Composition of the diluent includes polysorbate 20, sodium carboxymethyl cellulose, disodium hydrogen phosphate dihydrate, citric acid anhydrous, sodium chloride, sodium hydroxide, and water for injection. The microspheres are suspended in the diluent prior to injection.

Risperidone injection is provided as a dose pack, consisting of a vial containing the microspheres, a pre-filled syringe containing the diluent, a SmartSite® Needle-Free Vial Access Device, and one Needle-Pro® 20 G TW safety needle.

2. INDICATIONS AND USAGE

2.1 Schizophrenia

Risperidone is indicated for the treatment of schizophrenia.

2.2 Bipolar Disorder

Risperidone is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder.

3. DOSAGE AND ADMINISTRATION

For patients who have never taken oral risperidone, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with risperidone injection.

Risperidone injection 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]. 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.

3.1 Schizophrenia

The recommended dose is 25 mg IM every 2 weeks. Although dose response for effectiveness has not been established for risperidone injection, 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 risperidone injection every 2 weeks. No additional benefit was observed with dosages greater than 50 mg risperidone injection; however, a higher incidence of adverse effects was observed.

The efficacy of risperidone injection 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 risperidone injection, 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 risperidone injection at the lowest dose needed. The physician who elects to use risperidone injection for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

3.2 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 risperidone injection for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

3.3 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] 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 risperidone (or another antipsychotic medication) should be given with the first injection of risperidone 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.

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], 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 risperidone injection in a single administration.

3.4 Dosage in Special Populations

Elderly

For elderly patients treated with risperidone injection, the recommended dosage is 25 mg IM every 2 weeks. Oral risperidone (or another antipsychotic medication) should be given with the first injection of risperidone 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.

Renal or Hepatic Impairment

Patients with renal or hepatic impairment should be treated with titrated doses of oral risperidone prior to initiating treatment with risperidone injection. The recommended starting dose is 0.5 mg oral risperidone 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 risperidone is well tolerated, an injection of 25 mg risperidone 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 risperidone 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. 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.

3.5 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 risperidone injection, supplementation with oral risperidone (or another antipsychotic medication) should be administered.

3.6 Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone injection, or concerning concomitant administration with other antipsychotics. Previous antipsychotics should be continued for 3 weeks after the first injection of risperidone to ensure that therapeutic concentrations are maintained until the main release phase of risperidone from the injection site has begun. For patients who have never taken oral risperidone, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with risperidone injection. As recommended with other antipsychotic medications, the need for continuing existing EPS medication should be re-evaluated periodically.

3.7 Co-Administration of Risperidone Injection 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 risperidone injection 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]. 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 risperidone injection may need to be adjusted. A dose increase, or additional oral risperidone, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of risperidone injection should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of risperidone injection 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 risperidone injection 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 risperidone injection dose to 12.5 mg or necessitates interruption of risperidone injection 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 risperidone injection. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of risperidone injection 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 risperidone injection, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the risperidone injection dose to 12.5 mg or necessitates interruption of risperidone injection treatment. When risperidone injection 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].

3.8 Instructions for Use

Dose pack components include:

 


Risperidone injection 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.


 

Remove the dose pack of risperidone injection 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. Hold the base of the vial. Orient the SmartSite® 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® Access Device through the center of the vial’s rubber stopper until the device securely snaps onto the vial top.

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. 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 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. Be careful to not overtighten components when assembling. Overtightening connections may cause syringe component parts to loosen from the syringe body.

6. While holding the white collar of the syringe, insert and press the syringe tip into the blue circle of the SmartSite® Access Device and twist in a clockwise motion to secure the connection of the syringe to the SmartSite® Access Device (avoid over-twisting). Hold the skirt of the SmartSite® Access Device during attachment to prevent it from spinning. Keep the syringe and SmartSite® Access Device aligned.

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 microspheres will be visible in liquid, but no dry microspheres 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 into the syringe. Tear section of the vial label at the perforation and apply detached label to syringe for identification purposes.

11. While holding the white collar of the syringe, unscrew the syringe from the SmartSite® Access Device. Discard both the vial and vial access device appropriately.

12. Select the appropriate needle:

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)

13. 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.

14. 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.

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

16. 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.

17. Tap the syringe gently to make any air bubbles rise to the top. Remove air in syringe by depressing the plunger rod 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 within 2 minutes to avoid settling. 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.

18. After 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 table top or other hard, 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.

Upon suspension of the microspheres in the diluent, it is recommended to use risperidone injection immediately. If risperidone injection is not administered within 2 minutes of reconstitution, settling of the microspheres will occur and resuspension by shaking is necessary prior to administration. Keeping the vial upright, shake vigorously back and forth for as long as it takes to resuspend the microspheres. Once in suspension, the product may remain at room temperature (do not expose to temperatures above 77ºF (25ºC)). Risperidone injection must be used within 6 hours of suspension.

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

4. CONTRAINDICATIONS

Risperidone is contraindicated in patients with a known hypersensitivity to the product or any of its components.

5. MECHANISM OF ACTION

The mechanism of action of risperidone, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug’s therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

6.2 Nursing Mothers

Risperidone and 9–hydroxyrisperidone are excreted in human breast milk. Therefore, women receiving risperidone should not breast-feed.

6.3 Pediatric Use

Risperidone has not been studied in children younger than 18 years old.

6.4 Geriatric Use

In general, no differences in the tolerability of risperidone injection were observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise healthy elderly patients are the same as for nonelderly patients. Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients, elderly 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). In addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom orthostatic hypotension is of concern.

Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis

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 oral placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of oral risperidone regardless of concomitant use with furosemide. Risperidone injection is not approved for the treatment of patients with dementia-related psychosis.

7. WARNINGS AND PRECAUTIONS

7.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Risperidone injection is not approved for the treatment of dementia-related psychosis (see Boxed Warning).

7.2 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].

7.3 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.

7.4 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, risperidone injection 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 risperidone injection, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.

7.5 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 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 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 risperidone, 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 risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone, 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 risperidone, 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 antidiabetic treatment despite discontinuation of risperidone.

In longer-term, controlled and uncontrolled studies in adult subjects, 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).

Dyslipidemia

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

In longer-term, controlled and uncontrolled studies, risperidone 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.

In an uncontrolled, longer-term, open-label study, risperidone injection 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).

7.6 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. 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.

7.7 Orthostatic Hypotension

Risperidone injection 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 risperidone injection 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).

Risperidone injection 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.

7.8 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 risperidone injection. 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 risperidone injection 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 risperidone injection and have their WBC followed until recovery.

7.9 Potential for Cognitive and Motor Impairment

Somnolence was reported by 5% of patients treated with risperidone injection 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 risperidone injection does not affect them adversely.

7.10 Seizures

During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with risperidone injection. Therefore, risperidone injection should be used cautiously in patients with a history of seizures.

7.11 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. Risperidone injection and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see also Boxed Warning and Warnings and Precautions].

7.12 Priapism

Priapism has been reported during postmarketing surveillance [see Adverse Reactions]. Severe priapism may require surgical intervention.

7.13 Thrombotic Thrombocytopenic Purpura (TTP)

A single case of TTP was reported in a 28 year-old female patient receiving oral risperidone in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to risperidone therapy is unknown.

7.14 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 risperidone or risperidone injection use. Caution is advised when prescribing risperidone injection for patients who will be exposed to temperature extremes.

7.15 Administration

Risperidone injection 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 and Adverse Reactions].

7.16 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.

7.17 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. Risperidone injection is to be administered by a health care professional [see Dosage and Administration]; therefore, suicide due to an overdose is unlikely.

7.18 Use in Patients with Concomitant Illness

Clinical experience with risperidone injection in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including risperidone injection, 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 risperidone injection in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone injection 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 risperidone; 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 risperidone before treatment with risperidone injection 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].

7.19 Osteodystrophy and Tumors in Animals

Risperidone injection 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.

Risperidone injection 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, risperidone injection 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.

7.20 Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

8. ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling [see Warnings and Precautions]:

• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions]

• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis

• Neuroleptic malignant syndrome

• Tardive dyskinesia

• Metabolic changes

• Hyperprolactinemia

• Orthostatic hypotension

• Leukopenia/Neutropenia and Agranulocytosis

• Potential for cognitive and motor impairment

• Seizures • Dysphagia

• Priapism

• Thrombotic Thrombocytopenic Purpura (TTP)

• Disruption of body temperature regulation

• Avoidance of inadvertent injection into a blood vessel

• Antiemetic effect

• Suicide

• Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies

• Diseases or conditions that could affect metabolism or hemodynamic responses

• Osteodystrophy and tumors in animals

The most common adverse reactions in clinical trials in patients with schizophrenia (≥5%) were: headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity, and dry mouth. The most common adverse reactions in the double-blind, placebo-controlled periods of the bipolar disorder trials were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥10% in the adjunctive treatment trial).

The most common adverse reactions that were associated with discontinuation from the 12week double-blind, placebo-controlled trial in patients with schizophrenia (causing discontinuation in ≥ 1% of patients) were agitation, depression, anxiety, and akathisia. Adverse reactions that were associated with discontinuation from the double-blind, placebo-controlled periods of the bipolar disorder trials were hyperglycemia (one patient in the monotherapy trial) and hypokinesia and tardive dyskinesia (one patient each in the adjunctive treatment trial).

The data described in this section are derived from a clinical trial database consisting of 2392 patients exposed to one or more doses of risperidone injection for the treatment of schizophrenia. Of these 2392 patients, 332 were patients who received risperidone injection while participating in a 12-week double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mg risperidone injection. The conditions and duration of treatment with risperidone injection in the other clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

The majority of all adverse reactions were mild to moderate in severity.

8.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia

Table 1 lists the adverse reactions reported in 2% or more of risperidone injection-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial.

Table 1. Adverse Reactions in ≥ 2% of Risperidone Injection-Treated Patients with Schizophrenia in a 12Week Double-Blind, Placebo-Controlled Trial

* Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia. Akathisia includes akathisia and restlessness. Sedation includes sedation and somnolence.

________________________________________________________________________

8.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder

Table 2 lists the treatment-emergent adverse reactions reported in 2% or more of risperidone injection-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone injection when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder.

Table 2. Adverse Reactions in ≥ 2% of Patients with Bipolar I Disorder Treated with Risperidone Injection as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial

8.3 Discontinuations Due to Adverse Reactions

Schizophrenia

Approximately 11% (22/202) of risperidone injection-treated patients in the 12-week double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse event, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more risperidone injection-treated patients were: agitation (3%), depression (2%), anxiety (1%), and akathisia (1%).

Bipolar Disorder

In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone injection when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 risperidone injection-treated patients discontinued due to an adverse reaction (hyperglycemia).

In the 52-week double-blind phase of the placebo-controlled trial in which risperidone injection was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual, approximately 4% (3/72) of risperidone injection-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in risperidone injection-treated patients were: hypokinesia (one patient) and tardive dyskinesia (one patient).

8.4 Changes in ECG

The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg risperidone injection and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone injection.

8.5 Pain Assessment and Local Injection Site Reactions

The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg risperidone injection experienced redness, swelling, or induration at the injection site.

8.6 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during postapproval use of risperidone injection: cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated.

Retinal artery occlusion after injection of risperidone injection has been reported during postmarketing surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis.

Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with risperidone injection during postmarketing surveillance. Isolated cases required surgical intervention.

9. OVERDOSAGE

No cases of overdose were reported in premarketing studies with risperidone injection. Because risperidone injection is to be administered by health care professionals, the potential for overdosage by patients is low.

Premarketing experience included eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience includes reports of acute risperidone overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse events reported since market introduction which were temporally (but not necessarily causally) related to risperidone overdose, include torsade de pointes, prolonged QT interval, convulsions, cardiopulmonary arrest, and rare fatality associated with multiple drug overdose.

Management of Overdosage

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Because of the rapid disintegration of risperidone orally disintegrating tablets, pill fragments may not appear in gastric contents obtained with lavage.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.

There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

10. DRUG INTERACTIONS

The interactions of risperidone injection and other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, caution should be used when risperidone injection is administered in combination with other centrally-acting drugs or alcohol.

Because of its potential for inducing hypotension, risperidone injection may enhance the hypotensive effects of other therapeutic agents with this potential.

Levodopa and dopamine: Risperidone injection may antagonize the effects of levodopa and dopamine agonists.

Amitriptyline: Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety.

Cimetidine and ranitidine: Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased the AUC of the active moiety by 20%.

Clozapine: Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Carbamazepine and Other CYP 3A4 Enzyme Inducers

Carbamazepine: During co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite, 9–hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be affected.

CYP 3A4 Enzyme Inducers: Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9–hydroxyrisperidone, which could lead to decreased efficacy of risperidone injection treatment. 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 risperidone injection may need to be adjusted. A dose increase, or additional oral risperidone, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of risperidone injection should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of risperidone injection 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 risperidone injection 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 risperidone injection dose to 12.5 mg or necessitates interruption of risperidone injection treatment. (See also DOSAGE AND ADMINISTRATION.) The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Fluoxetine and Paroxetine

Fluoxetine (20 mg QD) and paroxetine (20 mg QD), 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%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of risperidone injection.

When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of risperidone injection 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 risperidone injection, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the risperidone injection dose to 12.5 mg or necessitates interruption of risperidone injection treatment. When risperidone injection 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. (See also DOSAGE AND ADMINISTRATION.) The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9–hydroxyrisperidone have not been studied.

Lithium

Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13).

Valproate

Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of risperidone.

Digoxin

Risperidone (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

Drugs that Inhibit CYP 2D6 and Other CYP Isozymes

Risperidone is metabolized to 9–hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs. Drug interactions that reduce the metabolism of risperidone to 9–hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9–hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n ≈ 70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.

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

There were no significant interactions between risperidone and erythromycin.

Drugs Metabolized by CYP 2D6

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

11. PHARMACOKINETICS

Absorption

After a single intramuscular (gluteal) injection of risperidone injection, there is a small initial release of the drug (< about 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) injection. Therefore, oral antipsychotic supplementation should be given during the first 3 weeks of treatment with risperidone injection to maintain therapeutic levels until the main release of risperidone from the injection site has begun (see DOSAGE AND ADMINISTRATION). Following single doses of risperidone injection, the pharmacokinetics of risperidone, 9–hydroxyrisperidone (the major metabolite), and risperidone plus 9–hydroxyrisperidone were linear in the dosing range of 12.5 mg to 50 mg.

The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of risperidone injection results in sustained therapeutic concentrations. Steady-state plasma concentrations are reached after 4 injections and are maintained for 4 to 6 weeks after the last injection. Following multiple doses of 25 mg to 50 mg risperidone injection, plasma concentrations of risperidone, 9–hydroxyrisperidone and risperidone plus 9–hydroxyrisperidone were linear.

Distribution

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

Metabolism

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

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

Excretion

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

The apparent half-life of risperidone plus 9–hydroxyrisperidone following risperidone injection administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of risperidone. The clearance of risperidone and risperidone plus 9–hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No accumulation of risperidone was observed during long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or 50 mg risperidone injection. The elimination phase is complete approximately 7 to 8 weeks after the last injection.

Special Populations

Renal Impairment: In patients with moderate to severe renal disease treated with oral risperidone, clearance of the sum of risperidone and its active metabolite decreased by 60% compared with young healthy subjects. Although patients with renal impairment were not studied with risperidone injection, it is recommended that patients with renal impairment be carefully titrated on oral risperidone before treatment with risperidone injection 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 impairment (see PRECAUTIONS – Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION – Dosage in Special Populations).

Hepatic Impairment: While the pharmacokinetics of oral risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Although patients with hepatic impairment were not studied with risperidone injection, it is recommended that patients with hepatic impairment be carefully titrated on oral risperidone before treatment with risperidone injection 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 hepatic impairment (see PRECAUTIONS – Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION – Dosage in Special Populations).

Elderly: In an open-label trial, steady-state concentrations of risperidone plus 9–hydroxyrisperidone in otherwise healthy elderly patients (≥65 years old) treated with risperidone injection for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients (see DOSAGE AND ADMINISTRATION).

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

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: RISPERDAL CONSTA , by Janssen Pharms.

b) Generic drugs: None.

2) How Supplied:

RISPERDAL® CONSTA® (risperidone) is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, 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 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).

12.5-mg vial/kit (NDC 50458-309-11): 41 mg (equivalent to 12.5 mg of risperidone) 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): 78 mg (equivalent to 25 mg of risperidone) 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): 116 mg (equivalent to 37.5 mg of risperidone) 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): 152 mg (equivalent to 50 mg of risperidone) of a white to off-white powder provided in a vial with a blue flip-off cap (NDC 50458-308-01).

3)Storage:

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.

Rx only

Rev 11/11