Risperidone Depot Product Monograph

RECENT MAJOR LABEL CHANGES

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TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ..................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION .............................................................. 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics ........................................................................................................... 4

1.2 Geriatrics ........................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................ 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ..................................................... 5

4 DOSAGE AND ADMINISTRATION .............................................................................. 5

4.1 Dosing Considerations ....................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment Schizophrenia .......................... 5

4.3 Administration .................................................................................................... 8

5 OVERDOSAGE ........................................................................................................... 16

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .................... 17

7 WARNINGS AND PRECAUTIONS ............................................................................. 17

7.1 Special Populations ......................................................................................... 25

7.1.1 Pregnant Women ............................................................................................. 25

7.1.2 Breast-feeding ................................................................................................. 25

7.1.3 Pediatrics ......................................................................................................... 26

7.1.4 Geriatrics ......................................................................................................... 26

8 ADVERSE REACTIONS ............................................................................................. 27

8.1 Clinical Trial Adverse Reactions ...................................................................... 27

8.2 Less Common Clinical Trial Adverse Reactions (≤ 1%) Schizophrenia ........... 38

8.3 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................ 41

8.4 Post-Market Adverse Reactions ...................................................................... 42

9 DRUG INTERACTIONS .............................................................................................. 44

9.1 Overview ......................................................................................................... 44

9.2 Drug-Drug Interactions .................................................................................... 45

9.3 Drug-Food Interactions .................................................................................... 49

9.4 Drug-Herb Interactions .................................................................................... 49

9.5 Drug-Laboratory Test Interactions ................................................................... 49

9.6 Drug-Lifestyle Interactions ............................................................................... 49

10 ACTION AND CLINICAL PHARMACOLOGY ............................................................ 49

10.1 Mechanism of Action ....................................................................................... 49

10.2 Pharmacokinetics ............................................................................................ 50

11 STORAGE, STABILITY AND DISPOSAL .................................................................. 52

12 SPECIAL HANDLING INSTRUCTIONS ..................................................................... 52

PART II: SCIENTIFIC INFORMATION ................................................................................... 53

13 PHARMACEUTICAL INFORMATION ........................................................................ 53

14 CLINICAL TRIALS ...................................................................................................... 53

14.1 Clinical Trials by Indications ........................................................................ 53

14.2 Comparative Bioavailability Studies ........................................................... 56

15 MICROBIOLOGY ........................................................................................................ 56

16 NON-CLINICAL TOXICOLOGY .................................................................................. 56

17 SUPPORTING PRODUCT MONOGRAPHS ............................................................... 59

PATIENT MEDICATION INFORMATION .............................................................................. 60

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Adults

Schizophrenia and Related Disorders

Risperidone Depot (risperidone for prolonged-release injectable suspension) is indicated for the management of the manifestations of schizophrenia and related psychotic disorders. Risperidone Depot was found to improve both positive and negative symptoms of schizophrenia.

The efficacy of risperidone for prolonged-release injectable suspension 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 risperidone in this population.

The effectiveness of risperidone for prolonged-release injectable suspension 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 maintaining clinical improvement during long-term therapy (1 year). Patients should be periodically reassessed to determine the need for continued treatment (see DOSAGE AND ADMINISTRATION).

Bipolar Disorder

Risperidone Depot is indicated as monotherapy maintenance treatment in patients with bipolar I disorder, who have previously responded to oral antipsychotics or other anti-manic treatment, to delay occurrence of manic episodes.

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

1.1 Pediatrics

Pediatrics (< 18 years of age): No data available and its use is not recommended. See WARNINGS AND PRECAUTIONS, Special Populations.

1.2 Geriatrics

Geriatrics (> 65 years of age): See SERIOUS WARNINGS AND PRECAUTIONS BOX and WARNINGS AND PRECAUTIONS, Special Populations.

2 CONTRAINDICATIONS

Risperidone Depot is contraindicated in patients who are hypersensitive to risperidone, paliperidone, or to any other ingredient in the formulation or component of the container (see WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity, and ADVERSE REACTIONS, Post-Market Adverse Reactions). For a complete listing of ingredients, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Risperidone Depot is a treatment option for patients where the risk of relapse requires intervention according to clinical judgment. For patients who have never taken oral risperidone, tolerability with oral risperidone should be established prior to initiating treatment with Risperidone Depot.

Very rare cases of severe hypersensitivity after injection with risperidone for prolonged-release injectable suspension have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Care should be taken to avoid exposure to those that are suspected to be hypersensitive or have shown hypersensitivity reactions to any of the excipients (see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

• Patients prone to hypotension
• Geriatrics
• Patients with renal impairment
• Patients with hepatic impairment

4.2 Recommended Dose and Dosage Adjustment Schizophrenia

The recommended dose is 25 mg IM every 2 weeks. Although dose response for effectiveness has not been established for Risperidone Depot, 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 Depot every 2 weeks. No additional benefit was observed with dosages greater than 50 mg risperidone for prolonged-release injectable suspension in clinical trials in patients with schizophrenia; however, a higher incidence of adverse effects was observed.

Although no controlled studies have been conducted to answer the question of how long patients should be treated with risperidone for prolonged-release injectable suspension, oral risperidone has been shown to be effective in maintaining clinical improvement during long-term therapy (1 year) in patients with schizophrenia. It is recommended that responding patients be continued on treatment with Risperidone Depot at the lowest dose needed. Patients should be periodically reassessed to determine the need for continued treatment.

Bipolar Disorder

The recommended dose is 25 mg IM every 2 weeks. Although dose response for effectiveness has not been established for Risperidone Depot, some patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. In clinical trials the majority of patients were treated with the 25 mg dose. The maximum dose should not exceed 50 mg Risperidone Depot every 2 weeks. Doses above 50 mg have not been studied in this population. It is recommended that responding patients be continued with the lowest dose needed and reassessed periodically to determine the need for continued treatment.

Risperidone Depot is not indicated as adjunctive treatment in patients with bipolar disorder.

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 (see below), 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 Depot and 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 ACTION AND CLINICAL PHARMACOLOGY).

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 for 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.

Two different dose strengths of Risperidone Depot should not be combined in a single administration.

Pediatrics

Risperidone for prolonged-release injectable suspension has not been studied in children younger than 18 years old.

Geriatrics

For elderly patients treated with Risperidone Depot, 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 Depot 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 ACTION AND CLINICAL PHARMACOLOGY).

Risperidone for prolonged-release injectable suspension has not been studied in elderly patients with bipolar disorder. 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, Cardiovascular).

Patients with Hepatic Impairment

Risperidone for prolonged-release injectable suspension has not been studied in hepatically impaired patients.

Risperidone Depot should be used with caution in patients with hepatic impairment.

Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone and this may result in an enhanced effect. If hepatically impaired patients require treatment with Risperidone Depot, a starting dose of 0.5 mg b.i.d. oral risperidone is recommended during the first week. In the second week, 1 mg b.i.d. or 2 mg q.d. can be given. If an oral dose of at least 2 mg is well tolerated, an injection of 25 mg Risperidone Depot can be administered every 2 weeks. Alternatively, a starting dose of 12.5 mg Risperidone Depot may be appropriate (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions). 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

Risperidone for prolonged-release injectable suspension has not been studied in renally impaired patients. Risperidone Depot should be used with caution in patients with renal impairment.

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than normal adults. If renally impaired patients require treatment with Risperidone Depot, a starting dose of 0.5 mg b.i.d. oral risperidone is recommended during the first week. In the second week, 1 mg b.i.d. or 2 mg q.d. can be given. If an oral dose of at least 2 mg is well tolerated, an injection of 25 mg Risperidone Depot can be administered every 2 weeks. Alternatively, a starting dose of 12.5 mg Risperidone Depot may be appropriate (see WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions). 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.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients from other antipsychotics to Risperidone Depot, or concerning concomitant administration with other antipsychotics. Previous antipsychotics should be gradually discontinued to ensure that therapeutic concentrations are maintained during the 3 weeks after the first injection of Risperidone Depot 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 Depot. As recommended with other antipsychotic medications, the need for continuing existing EPS medication should be re-evaluated periodically.

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

4.3 Administration

Risperidone Depot should be administered every 2 weeks by deep intramuscular gluteal or deltoid injection. Each injection should be administered by a healthcare professional using the appropriate enclosed safety needle (see Instructions for Use). When selecting an intramuscular site for injection, it is recommended that the healthcare professional conduct an assessment of the patient and site characteristics considering such factors as age, physical condition, skin integrity and size of the muscle.

For gluteal administration, use the 2-inch needle alternating injections between the two buttocks. For deltoid administration, use the 1-inch needle alternating injections between the two arms. Prior to each administration, the site of injection should be examined for any signs of clinically significant or persistent local reaction. If such signs are present, an alternate site should be chosen for injection. Care must be taken to avoid inadvertent injection of Risperidone Depot into a blood vessel. Do not administer intravenously (see WARNINGS AND PRECAUTIONS, General and Instructions for Use).

While gluteal and deltoid injections of risperidone for prolonged-release injectable suspension have demonstrated bioequivalence under the recommended injection parameters, the tolerability of repeated injections of risperidone for prolonged-release injectable suspension in the deltoid muscle for more than 8 weeks has not been systematically studied.

Instructions for Use

Important information

Risperidone Depot requires close attention to these step-by-step Instructions for Use to help ensure successful administration.

Wait 30 minutes

Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting.

Do not warm any other way.

Use components provided

The components in this dose pack are specifically designed for use with Risperidone Depot. Risperidone Depot must be reconstituted only in the diluent supplied in the dose pack.

Do not substitute ANY components of the dose pack.

Do not store suspension after reconstitution

Administer dose as soon as possible after reconstitution to avoid settling.

Proper dosing

The entire contents of the vial must be administered to ensure intended dose of Risperidone Depot is delivered.

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.

SINGLE-USE DEVICE

Dose pack contents

Take out dose pack

Connect vial adapter to vial

Wait 30 minutes Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting.

Do not warm any other way.

Remove cap from vial

Flip off colored cap from vial.

Wipe top of the grey stopper with an alcohol swab.

Allow to air dry.

Do not remove grey rubber stopper.

Prepare vial adapter Hold sterile blister as shown.

Peel back and remove paper backing.

Do not remove vial adapter from blister.

Do not touch spike tip at any time. This will result in contamination.

Connect vial adapter to vial Place vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place.

Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial.

Connect prefilled syringe to vial adapter

Remove sterile blister Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove. Do not shake. Do not touch exposed luer opening on vial adapter. This will result in contamination.	Use proper grip Hold by white collar at the tip of the syringe. Do not hold syringe by the glass barrel during assembly.	Remove cap Holding the white collar, snap off the white cap. Do not twist or cut off the white cap. Do not touch syringe tip. This will result in contamination. The broken-off cap can be discarded.	Connect syringe to vial adapter Hold vial adapter by skirt to keep stationary. Hold syringe by white collar then insert tip into the luer opening of the vial adapter. Do not hold the glass syringe barrel. This may cause the white collar to loosen or detach. Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug. Do not over-tighten. Over-tightening may cause the syringe tip to break.

Inject diluent

Inject entire amount of diluent from syringe into the vial.

Suspend microspheres in diluent Continuing to hold

down the plunger rod, shake vigorously for at least 10 seconds, as shown.

Check the suspension. When properly mixed, the suspension appears uniform, thick and milky in color.

Microspheres will be visible in the liquid. Immediately proceed to the next step so

suspension does not settle.

Transfer suspension to syringe

Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe.

Remove vial adapter

Hold white collar on the syringe and unscrew from vial adapter.

Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes.

Discard both vial and vial adapter appropriately.

Step 3	Attach needle
Select appropriate needle Choose needle based on injection location (gluteal or deltoid).		Attach needle Peel blister pouch open part way and use to grasp the base of the needle, as shown. Holding the white collar on the syringe, attach syringe to needle luer connection with a	Resuspend microspheres Fully remove the blister pouch. Just before injection, shake syringe vigorously again, as some settling will have occurred.
		firm clockwise twisting
		motion until snug.
		Do not touch needle luer
		opening. This will result in
		contamination.

Remove transparent needle protector Move the needle safety device back towards the syringe,

as shown. Then hold white collar on syringe and carefully pull the transparent needle protector straight off.

Do not twist transparent needle protector, as the luer connection may loosen.

Remove air bubbles Hold syringe

upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air.

Inject Immediately inject entire contents of syringe intramuscularly (IM) into the gluteal or deltoid muscle of the patient.

Gluteal injection should be made into the upper- outer quadrant of the gluteal area. Do not administer intravenously.

Secure needle in safety device Using one hand, place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device.

Avoid needle stick injury: Do not use two hands.

Do not intentionally disengage or mishandle the needle safety device.

Do not attempt to straighten the needle or engage the safety device

if the needle is bent or damaged.

Properly dispose of needles

Check to confirm needle safety device is fully engaged.

Discard in an approved sharps container.

Also discard the unused needle provided in the dose pack.

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

Reconstitution:

5 OVERDOSAGE

Human Experience

No cases of overdose were reported in premarketing studies with risperidone for prolonged-release injectable suspension. Because Risperidone Depot is to be administered by healthcare professionals, the potential for overdosage by patients is low.

Cases of overdose have been reported with oral risperidone; the estimated doses were between 20 and 360 mg. In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, namely drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. In overdose, QT-prolongation, widened QRS complex, convulsions, hyponatremia and hypokalemia were also reported. Torsade de pointes has been reported in association with combined overdose of oral risperidone and paroxetine.

Treatment of Overdosage

In case of acute overdosage, establish and maintain an airway to ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to Risperidone Depot. 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Dosage Forms and Packaging

Risperidone Depot is available in dosage strengths of 12.5, 25, 37.5, or 50 mg risperidone. It is provided as a kit, and includes a vial containing the risperidone microspheres, a prefilled syringe containing 2 mL of diluent for Risperidone Depot, one Vial Adaptor, and two Terumo SurGuard^®-3 Injection Needles for intramuscular injection (a 20G TW 2-inch needle for gluteal administration and a 21G TW 1-inch needle for deltoid administration). The colour of the vial cap varies by dosage strength: purple (12.5 mg), red (25 mg), green (37.5 mg), or blue (50 mg).

Composition

Risperidone Depot is a combination of prolonged-release microspheres for injection and diluent for parenteral use.

The prolonged-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-co-glycolide (PLG) at a concentration of 381 mg risperidone per gram of microspheres.

The diluent for parenteral use is a clear, colourless solution in a prefilled syringe. Composition of the diluent includes polysorbate 20, sodium carboxymethylcellulose, 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.

7 WARNINGS AND PRECAUTIONS

Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.

General

Administration

Risperidone Depot should be injected into the gluteal or deltoid muscle, and care must be taken to avoid inadvertent injection of Risperidone Depot into a blood vessel (see DOSAGE AND

ADMINISTRATION and ADVERSE REACTIONS, Post-Market Adverse Reactions [retinal artery occlusion]).

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing Risperidone Depot for patients who will be experiencing conditions which may contribute to an elevation or reduction of core body temperature, e.g., exercising strenuously, exposure to extreme heat or cold, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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 Depot and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Falls

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

Carcinogenesis and Mutagenesis

Osteodystrophy and Tumours in Animals

Risperidone for prolonged-release injectable suspension 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 for prolonged-release injectable suspension produced renal tubular tumours (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 for prolonged-release injectable suspension produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumour-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 relevance of these findings to human risk is unknown.

The effect dose for osteodystrophy and the tumour 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 tumours, nor osteodystrophy, was 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.

For additional animal data regarding the renal tubular and adrenomedullary tumors in male rats, as well as additional animal data regarding the carcinogesis studies, please refer to the NON-CLINICAL TOXICOLOGY section.

Cardiovascular

Risperidone Depot may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499) of patients treated with risperidone for prolonged-release injectable suspension in repeated-dose studies. Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment.

Risperidone Depot should be used with caution in the elderly and patients with renal or hepatic impairment, as well as those with cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, cerebrovascular disease, conduction abnormalities), and conditions such as dehydration and hypovolemia. Special care should be taken to avoid hypotension in patients with a history of cerebrovascular insufficiency or ischemic heart disease, and in patients taking medications to lower blood pressure. Monitoring of cardiovascular signs should be considered in all such patients.

QT Interval

As with other antipsychotics, caution should be exercised when Risperidone Depot is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome, and in concomitant use with drugs known to prolong the QT interval.

Risperidone Depot 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. The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg risperidone for prolonged-release injectable suspension and 98 schizophrenic patients treated with placebo in a 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 for prolonged-release injectable suspension.

The electrocardiograms of 227 patients were evaluated in the 24-month double-blind, placebo- controlled treatment period of a trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. There were no clinically relevant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone for prolonged-release injectable suspension compared to placebo.

Endocrine and Metabolism

Dyslipidemia

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

Hyperglycemia and Diabetes Mellitus

As with some other antipsychotics, hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes, in some cases serious and associated with ketoacidosis or hyperosmolar coma or death, have been reported during the use of oral risperidone (see ADVERSE REACTIONS, Post-Market Adverse Reactions).

Diabetic ketoacidosis (DKA) has occurred in patients treated with antipsychotics with no reported history of hyperglycemia. Appropriate clinical monitoring of patients treated with antipsychotics is advisable in accordance with utilized antipsychotic guidelines.

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.

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

Hyperprolactinemia

As with other atypical antipsychotics that antagonize dopamine D₂ receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, Risperidone Depot should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks. Caution should also be exercised when considering Risperidone Depot treatment in patients with pituitary tumours. Possible manifestations associated with elevated prolactin levels are galactorrhoea, nonpuerperal lactation, amenorrhea, gynecomastia, abnormal sexual function, ejaculation failure, decreased libido, and impotence. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects.

As is common with compounds that increase prolactin release, increases in pituitary gland, mammary gland, and adrenal medullary neoplasia, as well as endocrine pancreatic islet cell hyperplasia and/or neoplasia, were observed with oral risperidone and risperidone for prolonged-release injectable suspension in carcinogenicity studies conducted in mice and rats (see NON-CLINICAL TOXICOLOGY, Carcinogenicity). 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.

Weight Gain

Significant weight gain has been reported in both clinical trials and post-marketing. Monitoring weight gain is advised when risperidone is being used (see ADVERSE REACTIONS, Post- Market Adverse Reactions).

In the 12-week, placebo-controlled study in patients with schizophrenia, 9% of patients treated with risperidone for prolonged-release injectable suspension (25 mg or 50 mg) and 6% of placebo-treated patients met a weight gain criterion of >7%. With continued treatment, weight gain (mean: 2.6 kg in the long-term study) has been seen.

In the 24-month, double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 11.6% of patients treated with risperidone for prolonged-release injectable suspension compared with 2.8% of patients treated with placebo experienced a weight gain of >7% of body weight at endpoint.

Gastrointestinal

Antiemetic Effect

Consistent with its dopamine antagonistic effects, Risperidone Depot may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage with other drugs, or may mask symptoms of disease such as brain tumour, intestinal obstruction or Reye's syndrome.

Genitourinary

Priapism

Drugs with alpha-adrenergic-blocking effects have been reported to induce priapism. Priapism has been reported with risperidone during post-marketing surveillance. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment.

Hematologic

Leukopenia, Neutropenia, and Agranulocytosis Class Effect

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Granulocytopenia and agranulocytosis have also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of risperidone 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 < 1 x 10⁹/L) should discontinue risperidone and have their WBC followed until recovery (see ADVERSE REACTIONS, Post-Market Adverse Reactions).

Venous Thromboembolism

Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including Risperidone Depot, in case reports and/or observational studies. When prescribing Risperidone Depot all potential risk factors for VTE should be identified and preventative measures undertaken.

Hepatic/Biliary/Pancreatic

Use in Patients with Hepatic Impairment

Whereas the pharmacokinetics of oral risperidone in patients with hepatic impairment were comparable to those in young volunteers, the mean free fraction of risperidone was increased by about 35%. Although patients with hepatic impairment were not studied with risperidone for prolonged-release injectable suspension, it is recommended that patients with any degree of hepatic impairment be carefully titrated on oral risperidone before treatment with Risperidone Depot is initiated at a dose of 25 mg. Alternatively, a starting dose of 12.5 mg Risperidone Depot may be appropriate (see DOSAGE AND ADMINISTRATION).

Immune

Hypersensitivity

There have been very rare spontaneous post-marketing reports of severe hypersensitivity (e.g., anaphylaxis, angioedema, anaphylactic shock) in some patients after injection with Risperidone Depot. It is unknown how many of these patients previously tolerated oral risperidone or paliperidone. However, anaphylactic-type reactions have occurred after injection with Risperidone Depot in patients who have previously tolerated oral risperidone or oral paliperidone. Symptoms of anaphylaxis include skin rash, hives, peripheral edema, swollen eye, tongue and face, hyperhidrosis, dyspnea, and hypotension. Further treatment with Risperidone Depot should be discontinued if such symptoms occur. Patients with hypersensitivity to oral risperidone, paliperidone, or to any other ingredient of the formulation or component of the container, should not be treated with Risperidone Depot (see CONTRAINDICATIONS). Caution should also be exercised in patients who have had serious allergic reactions to other medications. Prior to initiating treatment with Risperidone Depot, tolerability with oral risperidone should be established (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS, Post-Market Adverse Reactions). For a complete listing of ingredients, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Neurologic

Extrapyramidal Symptoms and Psychostimulants

Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of one or both treatments should be considered (see DRUG INTERACTIONS, Drug-Drug Interactions).

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including risperidone.

Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular blood pressure, tachycardia, cardiac arrhythmias, and diaphoresis). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. 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 all antipsychotic drugs including Risperidone Depot, 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. After the last administration of Risperidone Depot, plasma levels of risperidone are present for up to a minimum of 6 weeks.

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 recurrence of NMS has been reported.

Potential for Cognitive and Motor Impairment

Somnolence was reported by 5% of patients treated with risperidone for prolonged-release injectable suspension in repeated-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 Depot does not affect them adversely.

Seizures

During premarketing testing, seizures occurred in 0.3% (5/1499) of patients treated with risperidone for prolonged-release injectable suspension. Therefore, Risperidone Depot should be used cautiously in patients with a history of seizures.

Tardive Dyskinesia (TD)

A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although TD appears to be most prevalent in the elderly, especially elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD. It has been suggested that the occurrence of parkinsonian side effects is a predictor for the development of TD. In clinical studies with oral risperidone, the observed incidence of drug-induced parkinsonism was lower with risperidone than with haloperidol. In the optimal clinical dose range, the difference between risperidone and haloperidol was significant. The risk of developing TD may be less with oral risperidone and Risperidone Depot.

The risk of developing TD 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 less commonly, after relatively brief periods of treatment at low doses. There is no known treatment for established cases of TD. The syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. However, antipsychotic drug treatment itself may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown.

In view of these considerations, Risperidone Depot should be prescribed in a manner that is most likely to minimize the risk of TD. As with any antipsychotic drug, Risperidone Depot should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of TD develop during treatment with Risperidone Depot, withdrawal of the drug should be considered. However, some patients may require treatment with Risperidone

Depot despite the presence of the syndrome.

Use in Patients with Parkinson’s Disease or Dementia with Lewy Bodies (DLB)

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including Risperidone Depot, to patients with Parkinson’s Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Ophthalmologic

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including risperidone for prolonged-release injectable suspension (see ADVERSE REACTIONS, Post-Market Adverse Reactions).

This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Psychiatric

Suicide

The possibility of suicide or attempted suicide is inherent in psychosis and bipolar disorder, and thus, close supervision and appropriate clinical management of high-risk patients should accompany drug therapy. Risperidone Depot is to be administered by a healthcare professional (see DOSAGE AND ADMINISTRATION); therefore, suicide due to an overdose is unlikely.

Renal

Use in Patients with Renal Impairment

The pharmacokinetics of oral risperidone were significantly altered in patients with renal disease. In a study with oral risperidone in patients with moderate to severe renal disease, clearance of risperidone and its active metabolite 9-hydroxyrisperidone combined decreased by 60% compared to young healthy subjects (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions). Although patients with renal impairment were not studied with risperidone for prolonged-release injectable suspension, it is recommended that patients with any degree of renal impairment be carefully titrated on oral risperidone with lower starting doses and lower maximal doses, before treatment with Risperidone Depot is initiated at a dose of 25 mg. Alternatively, a starting dose of 12.5 mg Risperidone Depot may be appropriate. It may also be useful to monitor renal function in these patients (see DOSAGE AND ADMINISTRATION).

Skin

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life threatening adverse drug reactions that have been reported with atypical antipsychotic exposure. SCARs commonly present as a combination of the following symptoms: malaise, mucosal ulceration, extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. Discontinue Risperidone Depot if severe cutaneous adverse reactions occur (see ADVERSE REACTIONS, Post-Market Adverse Reactions).

7.1 Special Populations

7.1.1 Pregnant Women

Teratogenic Effects

The safety of risperidone for prolonged-release injectable suspension during pregnancy has not been established. No clinical studies have been conducted with risperidone for prolonged-release injectable suspension. Risperidone Depot should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.

A retrospective observational cohort study based on a US claims database compared the risk of congenital malformations for live births among women with and without antipsychotic use during the first trimester of pregnancy. Compared to no antipsychotic exposure, the relative risk of congenital malformations with risperidone, after adjusting for confounder variables available in the database, was statistically significant (relative risk=1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain these findings and teratogenic effects have not been observed in non-clinical studies. Based on the findings of this single observational study, a causal relationship between in utero exposure to risperidone and congenital malformations has not been established.

In animal studies, risperidone did not show direct reproductive toxicity. However, due to its prolactin-elevating and CNS-depressant activities, reproductive performance and pup survival were adversely affected in rats. Risperidone was not teratogenic in either rats or rabbits. The microspheres are hydrolyzed to the endogenous components of lactic acid and hydroxyacetic acid, which are not teratogenic.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to risperidone therapy is unknown (see NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

Non-Teratogenic Effects

Neonates exposed to antipsychotic drugs (including risperidone) during the third trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

7.1.2 Breast-feeding

Risperidone appeared in the milk of lactating dogs. The concentration of risperidone was similar in milk and plasma, while that of 9-hydroxyrisperidone was higher in milk than in plasma. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk.

Breast-feeding should not be undertaken while a patient is receiving Risperidone Depot and for at least 12 weeks after the last injection.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of risperidone for prolonged-release injectable suspension in children under the age of 18 have not been established and its use is not recommended.

Weight gain has been observed with atypical antipsychotic use in pediatric and adolescent patient populations. Independent of any drug-specific effects, weight gain can be associated with adverse changes in other metabolic parameters (e.g., glucose and lipid metabolism). Abnormal childhood weight and metabolic status can have adverse effects on cardiovascular outcomes in adulthood. Weight gain and adverse effects on other metabolic parameters associated with typical antipsychotics can be more frequent or more severe in pediatric and adolescent patients than in the adult patients.

The long-term safety, including cardiometabolic effects and effects on growth, maturation and behavioural development in patients under 18 years of age has not been systematically evaluated.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): Geriatric patients generally have decreased renal, hepatic and cardiac function, and an increased tendency to postural hypotension. Therefore, lower starting doses, lower rates of dose adjustment and lower maximal doses are recommended in these patients.

Risperidone is substantially excreted by the kidneys. Thus, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, caution should be taken in dose selection and titration. It may also be useful to monitor renal function in these patients (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

In an open-label study, 57 clinically stable elderly patients with schizophrenia (≥ 65 years old) received risperidone for prolonged-release injectable suspension every 2 weeks for up to 12 months. In general, no differences in the tolerability of risperidone for prolonged-release injectable suspension were observed between otherwise healthy elderly and nonelderly patients. Risperidone for prolonged-release injectable suspension has not been studied in elderly patients with bipolar disorder. 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 (see WARNINGS AND PRECAUTIONS, Cardiovascular, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Use in Geriatric Patients with Dementia

Overall Mortality

Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. In six placebo-controlled trials with oral risperidone in this population, the incidence of mortality was 4.0% for risperidone -treated patients compared to 3.1% for placebo- treated patients.

Concomitant Use with Furosemide

In the oral risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70-96), furosemide alone (4.1%; mean age 80 years, range 67-90) or placebo without furosemide (2.9%; mean age 88 years, range 71-100). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death has been observed. Nevertheless, caution should be exercised and the risks and benefits of this combination should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular Adverse Events (CVAEs) in Elderly Patients with Dementia

In placebo-controlled trials in elderly patients with dementia, there was a significantly higher incidence of cerebrovascular adverse events (stroke and transient ischemic attacks) including fatalities in patients (mean age 85 years; range 73-97) treated with oral risperidone compared to patients receiving placebo. There is insufficient information to determine whether CVAEs in elderly patients with dementia are associated specifically with risperidone or other antipsychotic agents.

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 Depot and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

8 ADVERSE REACTIONS

8.1 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The prescriber should be aware that the numbers in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trial. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

Schizophrenia

The safety of risperidone for prolonged-release injectable suspension was evaluated from a clinical trial database consisting of 1499 patients exposed to one or more doses of risperidone for prolonged-release injectable suspension for the treatment of schizophrenia. Of these 1499 patients, 332 were patients who received risperidone for prolonged-release injectable suspension while participating in a 12-week, double-blind, placebo-controlled trial. A total of 202 of the 332 were patients with schizophrenia who received 25 mg or 50 mg risperidone for prolonged-release injectable suspension. The conditions and duration of treatment with risperidone for prolonged-release injectable suspension 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.

Adverse findings were assessed by spontaneous reports of adverse events, laboratory tests, vital signs, body weight, and ECGs. Adverse events were classified using the World Health Organization preferred terms. Treatment-emergent adverse events were defined as those events with an onset between the first dose and 49 days after the last dose.

Adverse Events Associated with Discontinuation of Treatment

Risperidone for prolonged-release injectable suspension is generally well tolerated at doses of 12.5 mg to 50 mg. In the 12- week, placebo-controlled trial in patients with schizophrenia who received 25 mg or 50 mg, the incidence of patients who discontinued treatment due to an adverse event was lower with risperidone for prolonged-release injectable suspension (11%; 22/202 patients) than with placebo (13%; 13/98 patients). The more common adverse events causing discontinuation included: psychiatric (17% vs. 11% placebo): primarily psychosis, hallucination, agitation, suicide attempt, and anxiety; neurological (1.4% vs. 1% placebo): primarily hyperkinesia. No adverse events leading to discontinuation were found to be unexpected nor were considered to be clinically relevant to risperidone for prolonged-release injectable suspension.

Commonly Observed Adverse Events in the Controlled Clinical Trial

Table 1.1 enumerates adverse events that occurred at an incidence of 2% or more, and were at least as frequent among schizophrenic patients treated with 25 mg or 50 mg risperidone for prolonged-release injectable suspension as patients treated with placebo in the 12-week, placebo-controlled trial. This table shows the percentage of patients in each dose group who spontaneously reported at least one episode of an event at some time during double-blind treatment. All patients were titrated to a dose of 4 mg oral risperidone during a one-week run-in period. Patients who received risperidone for prolonged-release injectable suspension were given doses of oral risperidone (2 mg for patients in the 25 mg group, and 4 mg for patients in the 50 mg group) during the 3 weeks after the first injection to provide therapeutic levels until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.

Serious Adverse Events

In the 12-week, placebo-controlled trial, the most frequently reported serious adverse events during the double-blind period among schizophrenic patients were psychosis, hallucination, agitation, suicide attempt, and anxiety. No serious adverse events were found to be unexpected nor were considered to be clinically relevant to risperidone for prolonged-release injectable suspension.

^a Includes adverse events of bradykinesia, extrapyramidal disorder, and hypokinesia.

^b Not Otherwise Specified

Adverse Reactions During Long-Term Treatment

The long-term safety of risperidone for prolonged-release injectable suspension was evaluated in 615 patients with schizophrenia treated up to one year with 25 mg, 50 mg, or 75 mg in an open trial. A total of 400 patients completed the one-year trial. The most frequently reported adverse events (> 10%) for all dose groups combined were anxiety, psychosis, insomnia, depression, headache, hyperkinesia and rhinitis.

Bipolar Disorder

Safety data are presented from a clinical trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension as monotherapy maintenance treatment in patients with bipolar I disorder. Patients who met criteria for a stable response to treatment with risperidone for prolonged-release injectable suspension during a 26- week open label stabilization period were randomized into a 24-month double-blind placebo- controlled period in which they received risperidone for prolonged-release injectable suspension (n=154) or placebo (n=149) as monotherapy. The majority of patients were treated with the 25 mg dose of risperidone for prolonged-release injectable suspension (see CLINICAL TRIALS).

Safety data are also presented from a clinical trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension when administered as adjunctive maintenance treatment in patients with bipolar disorder. In this study, patients who met criteria for stable remission following 16 weeks of open label treatment with risperidone for prolonged-release injectable suspension, while continuing treatment as usual (mood stabilizers, antidepressants, and/or anxiolytics), were randomized to risperidone for prolonged-release injectable suspension or placebo, as adjunct to their treatment as usual, for up to 52 weeks. risperidone for prolonged-release injectable suspension is not indicated as adjunctive maintenance treatment in bipolar disorder.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of patients experiencing adverse events, events were grouped into standardized categories using MedDRA terminology.

Monotherapy

Adverse Events Associated with Discontinuation of Treatment

In the 24-month, double-blind, placebo-controlled trial evaluating risperidone for prolonged-release injectable suspension as monotherapy maintenance treatment in patients with bipolar I disorder per study protocol, an adverse event was not recorded as the reason for discontinuation when a patient experienced a mood-related adverse event in association with relapse. One patient (0.6%) in the risperidone for prolonged-release injectable suspension group experienced an adverse event, hyperglycemia, that led to discontinuation and was not associated with relapse. Thirty-three patients (22%) in the placebo group and 15 patients (9.7%) in the risperidone for prolonged-release injectable suspension group who discontinued double- blind treatment due to relapse had adverse events with action taken of permanent stop. For the majority of patients in both treatment groups these adverse events were psychiatric. Depression was the only psychiatric adverse event associated with discontinuation of more relapsed patients in the risperidone for prolonged-release injectable suspension group than in the placebo group (5% risperidone for prolonged-release injectable suspension versus 2% placebo).

Commonly Observed Adverse Events in the Controlled Clinical Trial

Table 1.2 enumerates adverse events that occurred at an incidence of 2% or more, and were at least as frequent among bipolar patients treated with risperidone for prolonged-release injectable suspension as patients treated with placebo in the 24-month, double-blind treatment period of the trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder.

Serious Adverse Events

In the 24-month, placebo-controlled monotherapy trial, the most frequently reported serious adverse events in the risperidone for prolonged-release injectable suspension group during the double-blind period were psychiatric disorders: depression (3% risperidone for prolonged-release injectable suspension versus 1% placebo), Bipolar I disorder (2% risperidone for prolonged-release injectable suspension versus 6% placebo), and mania (2% risperidone for prolonged-release injectable suspension versus 7% placebo).

Adjunctive Therapy

Adverse Events Associated with Discontinuation of Treatment

In the 52-week, double-blind phase of the placebo-controlled trial in which risperidone for prolonged-release injectable suspension was administered as adjunctive therapy to patients with bipolar disorder in addition to their treatment as usual, approximately 4% (3/72) of patients treated with risperidone for prolonged-release injectable suspension discontinued due to an adverse event, compared with 1.5% (1/67) of placebo- treated patients. Adverse events that led to discontinuation that occurred more frequently in the risperidone for prolonged-release injectable suspension group were hypokinesia, tardive dyskinesia and hypertensive heart disease (1.4%, one patient each).

Commonly Observed Adverse Events in the Controlled Clinical Trial

Table 1.3 enumerates adverse events that occurred at an incidence of 2% or more, and were at least as frequent among bipolar patients treated with risperidone for prolonged-release injectable suspension as patients treated with placebo in the 52-week trial in which risperidone for prolonged-release injectable suspension was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual. Risperidone Depot is not indicated as adjunctive maintenance treatment in bipolar disorder.

Serious Adverse Events

In the 52-week, placebo-controlled adjunctive therapy trial, the most frequently reported serious adverse events in the risperidone for prolonged-release injectable suspension group during the double-blind period was mania (4% risperidone for prolonged-release injectable suspension versus 6% placebo).

Adverse Events Observed Across Indications

Extrapyramidal Symptoms

Schizophrenia

Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week, placebo- controlled trial comparing three doses of risperidone for prolonged-release injectable suspension (25 mg, 50 mg, and 75 mg) with placebo including: 1) the incidence of spontaneous reports of EPS symptoms; and 2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS).

As shown in Table 1.1, the overall incidence of EPS-related adverse events (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg risperidone for prolonged-release injectable suspension was comparable to that of patients treated with placebo; the incidence of EPS-related adverse events was higher in patients treated with 50 mg risperidone for prolonged-release injectable suspension.

The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with risperidone for prolonged-release injectable suspension compared with patients treated with placebo: 0 (placebo group); -1 (25 mg group, significantly less than the placebo group); and 0 (50 mg group).

Bipolar Disorder

There were no clinically meaningful changes from baseline to study endpoint for mean ESRS total score during any phase of the monotherapy study. Similarly, there were no meaningful changes from baseline to study endpoint on dyskinetic symptoms (measured using the Abnormal Involuntary Movement Scale), akathisia symptoms (Barnes Akathisia Scale) or Parkinsonian symptoms (Simpson-Angus Rating Scale) during any phase of the adjunctive therapy study. As shown in Table 1.3, a higher incidence of EPS-related adverse events was noted in the adjunctive therapy study, predominantly tremor.

Vital Sign Changes

Hypotension (including orthostatic) and tachycardia have been observed following the administration of risperidone for prolonged-release injectable suspension. In the placebo-controlled trial in patients with schizophrenia, orthostatic hypotension was observed in 2% of patients treated with 25 mg or 50 mg risperidone for prolonged-release injectable suspension (see WARNINGS AND PRECAUTIONS, Cardiovascular).

Weight Changes

In the 12-week, placebo-controlled trial, 9% of patients with schizophrenia treated with risperidone for prolonged-release injectable suspension (25 or 50 mg), compared with 6% of patients treated with placebo, experienced a weight gain of >7% of body weight at endpoint.

In the 24-month, double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 11.6% of patients treated with risperidone for prolonged-release injectable suspension compared with 2.8% of patients treated with placebo experienced a weight gain of >7% of body weight at endpoint (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

ECG Changes

Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone for prolonged-release injectable suspension in the 12-week, placebo-controlled trial in patients with schizophrenia (see WARNINGS AND PRECAUTIONS, General, QT Interval).

The electrocardiograms of 227 patients were evaluated in the 24-month double-blind, placebo- controlled treatment period of a trial assessing the efficacy and safety of risperidone for prolonged-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. There were no clinically relevant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone for prolonged-release injectable suspension compared to placebo (see WARNINGS AND PRECAUTIONS, General, QT Interval).

Pain Assessment and Local Injection Site Reactions

Gluteal

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 for prolonged-release injectable suspension experienced redness, swelling, or induration at the injection site.

Deltoid

In a separate study to observe local-site tolerability, risperidone for prolonged-release injectable suspension was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, (patients received up to 2 injections per arm as alternate arms were injected). No patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site was observed in subjects treated with 37.5 mg or 50 mg risperidone for prolonged-release injectable suspension at 2 hours after deltoid injection. All ratings returned to baseline at the predose assessment of the next injection 2 weeks later. No moderate or severe reactions were observed in any subject.

The tolerability of repeated injections of risperidone for prolonged-release injectable suspension in the deltoid muscle for more than 8 weeks has not been systematically studied.

Hyperprolactinemia

Risperidone Depot elevated plasma prolactin levels. Possible manifestations associated with elevated prolactin levels are nonpuerperal lactation, amenorrhea, abnormal sexual function, ejaculation failure, decreased libido, and impotence.

Other Adverse Events

As with other antipsychotics, cases of water intoxication, either due to polydipsia or to syndrome of inappropriate secretion of antidiuretic hormone (SIADH), have occasionally been reported during treatment with risperidone.

Adverse Reactions Reported with Paliperidone and Oral Risperidone

Paliperidone is the active metabolite of risperidone. Therefore, the adverse reaction profiles of both the oral and injectable formulations of paliperidone are relevant to one another and, also, to risperidone. In addition to the above adverse reactions, the following adverse reactions, classified using MedDRA terminology, have been noted with the use of paliperidone and /or risperidone products and can be expected to occur with both the oral and injectable formulations of risperidone.

Blood and Lymphatic System Disorders: Eosinophil count increased, Hematocrit decreased, Neutropenia, White blood cell count decreased

Cardiac Disorders: Atrioventricular block, Postural orthostatic tachycardia syndrome, Sinus arrhythmia

Ear and Labyrinth Disorders: Tinnitus

Endocrine Disorders: Glucose urine present

Eye Disorders: Dry eye, Eye movement disorder, Eye rolling, Eyelid margin crusting,

Glaucoma, Lacrimation increased, Ocular hyperemia

Gastrointestinal Disorders: Cheilitis, Dysphagia, Fecal incontinence, Fecaloma, Flatulence, Gastroenteritis, Intestinal obstruction, Swollen tongue

General Disorders and Administration Site Conditions: Body temperature decreased, Body temperature increased, Chills, Discomfort, Drug withdrawal syndrome, Face edema, Induration, Malaise, Peripheral coldness, Thirst

Hepatobiliary disorders: Transaminases increased

Infections and Infestations: Acarodermatitis, Bronchitis, Cellulitis, Cystitis, Eye infection, Localised infection, Respiratory tract infection, Subcutaneous abscess, Tonsillitis, Viral infection

Injury, Poisoning and Procedural Complications: Fall, Procedural pain

Immune System Disorders: Anaphylactic reaction

Metabolism and Nutrition Disorders: Blood cholesterol increased, Blood triglycerides increased, Hyperinsulinaemia, Polydipsia

Musculoskeletal, Connective Tissue, and Bone Disorders: Blood creatine phosphokinase increased, Joint swelling, Neck pain, Posture abnormal, Rhabdomyolysis

Nervous System Disorders: Balance disorder, Cerebrovascular accident, Cerebrovascular disorder, Convulsion (includes Grand mal convulsion), Coordination abnormal, Depressed level of consciousness, Diabetic coma, Dystonia (includes blepharospasm, cervical spasm, emprosthotonus, facial spasm, hypertonia, laryngospasm, muscle contractions involuntary, myotonia, oculogyration, opisthotonus, oropharyngeal spasm, pleurothotonus, risus sardonicus, tetany, tongue paralysis, tongue spasm, torticollis, trismus), Head titubation, Loss of consciousness, Neuroleptic malignant syndrome, Psychomotor hyperactivity, Unresponsive to stimuli

Psychiatric Disorders: Anorgasmia, Blunted affect

Renal and Urinary Disorders: Dysuria, Pollakiuria

Reproductive System and Breast Disorders: Breast discharge, Breast engorgement, Breast enlargement, Gynecomastia, Menstrual disorder (includes Menstruation irregular, Oligomenorrhea), Menstruation delayed, Sexual dysfunction, Vaginal discharge

Respiratory, Thoracic and Mediastinal Disorders: Dysphonia, Hyperventilation, Pneumonia aspiration, Pulmonary congestion, Rales, Respiratory disorder, Respiratory tract congestion

Skin and Subcutaneous Disorders: Drug eruption, Eczema, Erythema, Hyperkeratosis, Skin discolouration, Skin lesion, Urticaria

8.2 Less Common Clinical Trial Adverse Reactions (≤ 1%) Schizophrenia

During its premarketing assessment, risperidone for prolonged-release injectable suspension was administered to 1499 patients in multiple-dose studies. The conditions and duration of exposure to risperidone for prolonged-release injectable suspension varied greatly, and included (in overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and short-term and long-term exposure studies. In all studies, untoward events associated with this exposure were obtained by spontaneous report and were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the listings that follow, spontaneously reported adverse events were classified using World Health Organization (WHO) preferred terms. The frequencies presented, therefore, represent the proportion of the 1499 patients exposed to multiple doses of risperidone for prolonged-release injectable suspension who experienced an event of the type cited on at least one occasion while receiving risperidone for prolonged-release injectable suspension. All reported events are included except those already listed in Table 1.1, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the reported events occurred during treatment with risperidone for prolonged-release injectable suspension, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from the placebo-controlled trial appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients.

Application Site Disorders: Frequent: injection site pain. Infrequent: injection site reaction.

Body as a Whole/General Disorders: Frequent: back pain, chest pain, asthenia, edema.

Infrequent: malaise, choking, hypersensitivity.

Cardiovascular Disorders: Frequent: hypotension. Infrequent: postural hypotension.

Central and Peripheral Nervous System Disorders: Frequent: hypertonia, dystonia. Infrequent: dyskinesia, vertigo, leg cramps, tardive dyskinesia^a, involuntary muscle contractions, paresthesia, abnormal gait, bradykinesia, convulsions, hypokinesia, ataxia, fecal incontinence, oculogyric crisis, tetany, apraxia, dementia, migraine. Rare: neuroleptic malignant syndrome.

^aIn the integrated database of multiple-dose studies (1499 patients with schizophrenia or schizoaffective disorder), 9 patients (0.6%) treated with RISPERDAL CONSTA^® (all dosages combined) experienced an adverse event of tardive dyskinesia.

Endocrine Disorders: Infrequent: hyperprolactinemia, gynecomastia, hypothyroidism.

Gastrointestinal Disorders: Frequent: nausea, vomiting, abdominal pain. Infrequent: gastritis, gastroesophageal reflux, flatulence, hemorrhoids, melena, dysphagia, rectal hemorrhage, stomatitis, colitis, gastric ulcer, gingivitis, irritable bowel syndrome, ulcerative stomatitis.

Hearing and Vestibular Disorders: Infrequent: earache, deafness, hearing decreased.

Heart Rate and Rhythm Disorders: Frequent: tachycardia, electrocardiogram abnormal. Infrequent: bradycardia, AV block, palpitation, bundle branch block, conduction disorder, electrocardiogram QT prolonged. Rare: T-wave inversion.

Liver and Biliary System Disorders: Frequent: increased hepatic enzymes. Infrequent: hepatomegaly, increased SGPT. Rare: bilirubinemia, increased GGT, hepatitis, hepatocellular damage, jaundice, fatty liver, increased SGOT.

Metabolic and Nutritional Disorders: Infrequent: hyperuricemia, hyperglycemia, hyperlipemia, hypokalemia, glycosuria, hypercholesterolemia, obesity, dehydration, diabetes mellitus, hyponatremia.

Musculoskeletal System Disorders: Frequent: arthralgia, skeletal pain. Infrequent: torticollis, arthrosis, muscle weakness, tendinitis, arthritis, arthropathy.

Myo-, Endo-, and Pericardial and Valve Disorders: Infrequent: myocardial ischemia, angina pectoris, myocardial infarction.

Platelet, Bleeding and Clotting Disorders: Infrequent: purpura, epistaxis. Rare: pulmonary embolism, hematoma, thrombocytopenia.

Psychiatric Disorders: Frequent: anxiety, psychosis, depression, agitation, nervousness, paranoid reaction, delusion, apathy. Infrequent: anorexia, impaired concentration, impotence, emotional lability, manic reaction, decreased libido, increased appetite, amnesia, confusion, euphoria, depersonalization, paroniria, delirium, psychotic depression.

Red Blood Cell Disorders: Frequent: anemia.

Reproductive Disorders, Female: Frequent: amenorrhea. Infrequent: nonpuerperal lactation, vaginitis, dysmenorrhea, breast pain, leukorrhea.

Reproductive Disorders, Male: Infrequent: ejaculation failure.

Resistance Mechanism Disorders: Infrequent: abscess, infection.

Respiratory System Disorders: Frequent: dyspnea. Infrequent: pneumonia, stridor, hemoptysis. Rare: pulmonary edema.

Skin and Appendage Disorders: Frequent: rash. Infrequent: eczema, pruritus, erythematous rash, dermatitis, alopecia, seborrhea, photosensitivity reaction, increased sweating.

Urinary System Disorders: Frequent: urinary incontinence. Infrequent: hematuria, micturition frequency, renal pain, urinary retention.

Vascular (Extracardiac) Disorders: Infrequent: phlebitis. Rare: intermittent claudication, flushing, thrombophlebitis.

Vision Disorders: Infrequent: conjunctivitis, eye pain, abnormal accommodation, photophobia.

White Cell and Resistance Disorders: Infrequent: lymphadenopathy, leukopenia, cervical lymphadenopathy. Rare: granulocytopenia, leukocytosis, lymphopenia.

Bipolar Disorder

Monotherapy

All reported events in the risperidone for prolonged-release injectable suspension group during the double-blind treatment period of the monotherapy trial reported at least as frequently in the placebo group are listed below except those already listed in Table 1.2.

Blood and lymphatic disorders: Anemia, Lymphadenitis.

Cardiac disorders: Bundle branch block right, Myocardial ischemia.

Ear and labyrinth disorders: Ear pain.

Eye disorders: Conjunctivitis, Visual disturbance.

Gastrointestinal disorders: Abdominal pain, Constipation, Dry mouth, Duodenal ulcer, Gastritis, Gingival bleeding, Hemorrhoids, Mouth ulceration, Salivary hypersecretion, Tooth loss, Vomiting.

General disorders and administration site conditions: Pyrexia, Feeling cold, Pain, Thirst.

Immune system disorders: Hypersensitivity.

Infections and infestations: Bronchitis, Anogenital warts, Bacteriuria, Ear infection, Fungal infection, Furuncle, Gastroenteritis viral, Influenza, Onychomycosis, Papilloma viral infection, Paronychia, Pharyngitis streptococcal, Sinusitis, Tinea infection, Urinary tract infection, Viral upper respiratory tract infection.

Investigations: Electrocardiogram QT prolonged, Electrocardiogram T wave abnormal, Alanine aminotransferase increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased.

Metabolism and nutrition disorders: Decreased appetite, Dehydration, Hyperglycemia, Anorexia, Diabetes mellitus, Hypertriglyceridemia, Increased appetite, Obesity, Type 2 diabetes mellitus.

Musculoskeletal and connective tissue disorders: Musculoskeletal pain, Myalgia.

Nervous system disorders: Akathisia, Dyskinesia, Parkinsonism, Hypoesthesia, Radiculitis, Sedation, Sinus headache, Somnolence, Tremor.

Psychiatric disorders: Depressed mood, Libido decreased, Drug dependence.

Renal and urinary disorders: Stress urinary incontinence.

Reproductive system and breast disorders: Erectile dysfunction, Sexual dysfunction, Ejaculation disorder.

Respiratory, thoracic and mediastinal disorders: Cough, Nasal congestion, Nasal polyps, Pharyngolaryngeal pain, Sinus congestion.

Skin and subcutaneous tissue disorders: Dermatitis, Dermatitis contact.

Adjunctive Therapy

All reported events in the risperidone for prolonged-release injectable suspension group during the double-blind treatment period of the adjunctive therapy trial reported at least as frequently in the placebo group are listed below except those already listed in Table 1.3.

General disorders and administration site conditions: Chest pain, Malaise, Pain.

Blood and lymphatic disorders: Anemia.

Cardiac disorders: Hypertensive heart disease. Endocrine disorders: Hypothyroidism.

Eye disorders: Cataract.

Gastrointestinal disorders: Hemorrhoidal hemorrhage, Hemorrhoids, Halitosis, Tongue Disorder.

Infections and infestations: Fungal infection, Furuncle, Pneumonia, Sinusitis, Tuberculosis

Injury, poisoning and procedural complications: Blister.

Investigations: Corneal reflex decreased, urine analysis abnormal.

Metabolism and nutrition disorders: Anorexia, Hyperlipidemia.

Musculoskeletal and connective tissue disorders: Pain in extremity, Posture abnormal.

Nervous system disorders: Cogwheel rigidity, Drooling, Neuritis, Tardive dyskinesia.

Psychiatric disorders: Anxiety, Libido decreased, Middle insomnia, Panic attack, Suicide attempt.

Renal and urinary disorders: Enuresis.

Reproductive system and breast disorders: Menorrhagia, Menstrual disorder

Respiratory, thoracic and mediastinal disorders: Dyspnea.

Skin and subcutaneous tissue disorders: Alopecia areata, Dry skin, Face edema, Pain of skin, Seborrhoeic dermatitis.

Vascular disorders: Hypotension.

8.3 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The percentage of patients treated with risperidone for prolonged-release injectable suspension who experienced potentially important changes in routine serum chemistry, hematology, or urinalysis parameters was similar to or less than that of placebo patients. Additionally, no patients discontinued treatment due to changes in serum chemistry, hematology, or urinalysis parameters.

In one study with oral risperidone in which testosterone levels were measured, testosterone decreased below the normal range in 6 out of 85 patients.

8.4 Post-Market Adverse Reactions

Adverse events first identified during post-marketing experience with risperidone are included in Table 1.4. In Table 1.4, ADRs are presented by frequency category based on spontaneous reporting rates according to the following convention:

Very Common ≥ 1/10

Common ≥ 1/100 and < 1/10

Uncommon ≥ 1/1000 and < 1/100

Rare ≥ 1/10000 and < 1/1000

Very rare < 1/10000, including isolated reports

Not known data Cannot be estimated from the available data

In addition, adverse events reported with risperidone treatment since market introduction which were temporally related to risperidone therapy include the following: agitation, skin manifestations of allergy, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), systemic manifestations of allergy including a case of anaphylactic shock, apnea, benign pituitary adenomas, and Parkinson’s disease aggravated. Cerebrovascular adverse events, including cerebrovascular accidents and transient ischemic attacks, have been reported during treatment with risperidone (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics, Use in Geriatric Patients with Dementia, Cerebrovascular Adverse Events (CVAEs) in Elderly Patients with Dementia). Hyperglycemia and exacerbation of pre-existing diabetes have been reported during treatment with risperidone (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

As with other neuroleptics, sudden deaths have been reported during treatment with risperidone. Most of the patients had pre-existing cardiovascular disease or were morbidly obese. A relationship to risperidone has not been established at this time.

Retinal artery occlusion after injection of risperidone for prolonged-release injectable suspension has been reported very rarely during post-marketing surveillance. Risperidone Depot should be injected into the gluteal or deltoid muscle, and care must be taken to avoid inadvertent injection of Risperidone Depot into a blood vessel (see DOSAGE AND ADMINISTRATION).

Injection site reactions including injection site abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with risperidone for prolonged-release injectable suspension. These events were reported as serious. Isolated cases required surgical intervention.

As with other neuroleptics, sudden death, torsades de pointes, ventricular tachycardia, arrhythmia, cardiopulmonary arrest and QT prolongation have been reported during treatment with risperidone. Many of the patients had pre-existing cardiovascular disease, were on concomitant medications known to prolong the QT interval, had risk factors for QT prolongation, took an overdose of risperidone, and/or were morbidly obese. Very rarely, QT prolongation has been reported in the absence of confounding factors.

Significant weight gain has been reported in both clinical trials and post-marketing (see

WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Granuloycytopenia and agranulocytosis have also been reported (see WARNINGS AND PRECAUTIONS, Hematologic).

In post-marketing experience, drug withdrawal syndrome neonatal has been reported very rarely.

Atypical antipsychotic drugs, such as risperidone, have been associated with cases of sleep apnea, with or without concomitant weight gain. In patients who have a history of, or that are at risk of, sleep apnea, Risperidone Depot should be prescribed with caution.

Risks of somnambulism (sleep walking) and sleep-related eating disorder have been associated with the use of atypical antipsychotics including Risperidone Depot.

Hypersensitivity

There have been very rare spontaneous reports of severe hypersensitivity (e.g., anaphylaxis, angioedema, anaphylactic shock) in some patients after injection with risperidone for prolonged-release injectable suspension.

Symptoms of anaphylaxis include skin rash, hives, peripheral edema, swollen eye, tongue and face, hyperhidrosis, dyspnea, and hypotension. It is unknown as to how many of these patients previously tolerated oral risperidone or paliperidone. However, anaphylactic-type reactions have occurred after injection with risperidone for prolonged-release injectable suspension in patients who have previously tolerated oral risperidone or oral paliperidone (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity and DOSAGE AND ADMINISTRATION).

9 DRUG INTERACTIONS

The interactions of risperidone for prolonged-release injectable suspension with co-administration of other drugs have not been systematically evaluated. The drug interaction data provided in this section are based on studies with oral risperidone.

9.1 Overview

Centrally-acting Drugs and Alcohol

Given the primary central nervous system effects of Risperidone Depot, caution should be used when it is taken in combination with other centrally acting drugs and alcohol.

Levodopa and Dopamine Agonists

Risperidone Depot may antagonize the effects of levodopa and dopamine agonists.

Drugs with Hypotensive Effects

Because of its potential for inducing hypotension, Risperidone Depot may enhance the hypotensive effects of other therapeutic agents.

Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive medications.

Drugs Known to Prolong the QT interval

Caution is advised when prescribing Risperidone Depot with drugs known to prolong the QT interval.

9.2 Drug-Drug Interactions

Risperidone is mainly metabolized through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P- glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.

Strong CYP2D6 Inhibitors

Co-administration of Risperidone Depot with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction (risperidone and 9-hydroxyrisperidone combined). Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g., paroxetine, see below). When concomitant paroxetine or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone Depot.

CYP3A4 and/or P-gp Inhibitors

Co-administration of Risperidone Depot with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone Depot.

CYP3A4 and/or P-gp Inducers

Co-administration of Risperidone Depot with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone Depot.

Highly Protein-bound Drugs

When Risperidone Depot is taken together with highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosages.

Concomitant Use with Furosemide

See WARNINGS AND PRECAUTIONS regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide and oral risperidone.

The Effect of Other Drugs on the Metabolism of Risperidone

SSRIs and Tricyclic Antidepressants

Fluoxetine

Fluoxetine, a strong CYP 2D6 inhibitor, increases the plasma concentration of risperidone but less so of risperidone and 9-hydroxyrisperidone combined. Pharmacokinetic interaction with fluoxetine was examined in a study which measured steady-state plasma levels of oral risperidone and its metabolites before and following 3 weeks of co-treatment with fluoxetine (n=10). The addition of fluoxetine resulted in about a 2- to 3-fold increase in peak and AUC levels of risperidone and about a 50% increase in peak and AUC levels for risperidone and 9- hydroxyrisperidone combined.

Paroxetine

Paroxetine, a strong CYP 2D6 inhibitor, increases the plasma concentration of risperidone but, at dosages up to 20 mg/day, less so of risperidone and 9-hydroxyrisperidone combined. However, higher doses of paroxetine may elevate concentrations of the risperidone active antipsychotic fraction. Pharmacokinetic interaction with paroxetine was examined in a study which measured steady-state plasma levels of risperidone and its metabolites before and following 4 weeks of co-treatment with paroxetine (n=10). After 4 weeks of paroxetine treatment, the sum of the concentrations of risperidone and 9-hydroxyrisperidone increased significantly by 45% over baseline.

When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg of Risperidone Depot, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the Risperidone Depot dose to 12.5 mg or necessitates interruption of treatment with Risperidone Depot. When Risperidone Depot 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 DOSAGE AND ADMINISTRATION).

Tricyclic antidepressants

Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.

Sertraline

Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.

Antibacterials

Erythromycin

Erythromycin, a moderate CYP 3A4 inhibitor, did not change the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined. Risperidone was administered as a single dose of 1 mg with multiple doses of erythromycin (500 mg q.i.d.) in healthy volunteers (n=18).

Rifampicin

Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentrations of the active antipsychotic fraction.

Anticholinesterases

Galantamine and Donepezil

Galantamine (n=15) and donepezil (n=24), both CYP2D6 and CYP3A4 substrates, did not show an effect on the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined. Galantamine 12 mg o.d. was co-administered with risperidone 0.5 mg o.d. in healthy elderly volunteers. Donepezil 5 mg o.d. was co-administered with risperidone 0.5 mg b.i.d. in healthy male volunteers.

Antiepileptics

Carbamazepine and Other CYP 3A4 Enzyme Inducers

Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown to decrease substantially the plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone (n=11). Similar effects may be observed with other CYP 3A4 hepatic enzyme inducers. Consequently, in the presence of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dose of Risperidone Depot may have to be adjusted. At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored for the first 4–8 weeks, since the dose of Risperidone Depot 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 inducers, the dosage of Risperidone Depot should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of Risperidone Depot between 2 and 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 (25 mg) of Risperidone Depot, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the Risperidone Depot dose to 12.5 mg or necessitates interruption of Risperidone Depot treatment (see DOSAGE AND ADMINISTRATION). The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Topiramate

Healthy Volunteers: A drug-drug interaction study between risperidone and topiramate was conducted in 12 healthy volunteers (6 males, 6 females), ages 28–40 years, with single-dose administration of risperidone (2 mg) and multiple doses of topiramate (titrated up to 200 mg/day). In the presence of topiramate, systemic exposure of risperidone and 9- hydroxyrisperidone combined was reduced such that mean AUC_0-4 was 11% lower and mean C_max was statistically significantly (18%) lower. In the presence of topiramate, systemic exposure of risperidone was statistically significantly reduced such that mean C_max and AUC_0-4 were 29% and 23% lower, respectively. The pharmacokinetics of 9-hydroxyrisperidone were unaffected. The effects of a single dose (2 mg/day) of risperidone on the pharmacokinetics of multiple doses of topiramate have not been studied.

Patients with Bipolar Disorder: A drug-drug interaction study conducted in 52 patients with various types of bipolar disorder (24 males, 28 females), ages 19–56 years, evaluated the steady-state pharmacokinetics of risperidone and topiramate when administered concomitantly. Eligible subjects were stabilized on a risperidone dose of 1–6 mg/day for 2 to 3 weeks. Topiramate was then titrated up to escalating doses of 100, 250 and 400 mg/day along with risperidone for up to 6 weeks. Risperidone was then tapered and discontinued over 4 weeks while maintaining topiramate (up to 400 mg/day). There was a statistically significant reduction in risperidone systemic exposure (16% and 33% for AUC₁₂ and 13% and 34% for C_max at the 250 and 400 mg/day doses, respectively). Minimal alterations were observed in the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined and 9-hydroxyrisperidone. Topiramate systemic exposure was slightly reduced (12.5% for mean C_max and 11% for mean AUC₁₂) in the presence of risperidone, which achieved statistical significance. There were no clinically significant changes in the systemic exposure of risperidone and 9-hydroxyrisperidone combined or of topiramate. The effects of higher doses of topiramate (> 400 mg/day) are unknown. Therefore, if combination therapy is chosen, patients receiving both risperidone and topiramate should be closely monitored.

Antifungals

Itraconazole

Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.

Ketoconazole

Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxyrisperidone.

Antipsychotics

Phenothiazines

Phenothiazines may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

Clozapine

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

Antivirals

Protease inhibitors

No formal study data are available; however, since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction.

Beta-Blockers

Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

Calcium Channel Blockers

Verapamil

A moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases the plasma concentration of risperidone and the active antipsychotic fraction.

Gastrointestinal Drugs

Cimetidine and Ranitidine (H2-receptor antagonists)

Risperidone was administered as a single dose of 1 mg with multiple doses of either cimetidine (400 mg b.i.d.) or ranitidine (150 mg b.i.d.), both weak inhibitors of CYP2D6 and CYP3A4, in healthy young volunteers (n=12). The effect of the drug interaction of cimetidine and ranitidine on risperidone and 9-hydroxyrisperidone combined was minimal.

Effects of Risperidone on the Metabolism of Other Drugs

Aripiprazole

A CYP2D6 and CYP3A4 substrate; Risperidone tablets or injections did not affect the pharmacokinetics of the sum of aripiprazole and its active metabolite, dehydroaripiprazole.

Lithium

Oral risperidone (3 mg b.i.d.) did not show an effect on the pharmacokinetics of lithium (400, 450, or 560 b.i.d.) (n=13).

Valproate

Oral risperidone (4 mg o.d.) did not show an effect on the pharmacokinetics of valproate (1000 mg/day) (n=9). However, more subjects reported adverse events with the risperidone- valproate therapy compared to the placebo-valproate group in the clinical trial.

Digoxin

The effect of oral risperidone (0.5 mg/day administered b.i.d.) on the steady-state plasma concentrations of digoxin (0.125 mg/day) was examined in a double-blind, two-way crossover trial in 19 healthy elderly volunteers (median age 68 years, range 61 to 75 years). Risperidone did not affect the steady-state pharmacokinetics of digoxin, and concurrent administration of the two drugs was well tolerated.

In vitro studies, in which risperidone was given in the presence of various highly protein-bound agents, indicated that clinically relevant changes in protein binding would not occur either for risperidone for prolonged-release injectable suspension or for any of the drugs tested.

Concomitant use of Risperidone with psychostimulants

The combined use of psychostimulants (e.g. methylphenidate) with risperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see WARNINGS AND PRECAUTIONS, Neurologic).

9.3 Drug-Food Interactions

Interactions with food have not been established.

9.4 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.5 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

9.6 Drug-Lifestyle Interactions

Centrally-acting Drugs and Alcohol

Given the primary central nervous system effects of risperidone, caution should be used when it is taken in combination with other centrally acting drugs and alcohol.

10 ACTION AND CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Risperidone, a benzisoxazole derivative, is a novel antipsychotic drug which binds with high affinity to serotonin type 2 (5-HT2), dopamine type 2 (D2), and α1-adrenergic receptors. Risperidone binds with a lower affinity to the α2-adrenergic and histamine H1 receptors. Risperidone does not bind to dopamine D1 receptors and has no affinity (when tested at concentrations > 10^-5 M) for muscarinic cholinergic receptors. Due to the lack of muscarinic receptor binding, risperidone is not expected to produce anticholinergic adverse effects.

Receptor occupancy was also demonstrated in vivo in humans. Using positron emission tomography, risperidone was shown to block both 5-HT2A and dopamine D2 receptors in three healthy volunteers. Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy in animal models than classical antipsychotics. Risperidone has also been found to be one of the most potent known antagonists of 5-HT2A (cloned human receptor); 5-HT2A antagonism has been shown to reverse deficits in several in vivo animal models predictive of novel antipsychotic activity (PCP-induced social deficit, microdialysis assessment of dopamine output in prefrontal cortex, glutamate antagonist-induced hyperlocomotion). Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability.

10.2 Pharmacokinetics

Risperidone is well absorbed, 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 urine and 14% in feces.

Absorption

After a single intramuscular injection of Risperidone Depot, there is a small initial release of the drug (< 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from week 3 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 Depot 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 for prolonged-release injectable suspension, 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 Depot 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 Depot, plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are linear. The half-life of risperidone plus 9-hydroxyrisperidone is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3 to 6 days is related to the erosion of the microspheres and subsequent absorption of risperidone. The elimination phase is complete approximately 7 to 8 weeks after the last injection.

After repeated IM injections of 25 mg or 50 mg risperidone for prolonged-release injectable suspension every 2 weeks, median trough and peak plasma concentrations of risperidone plus 9-hydroxyrisperidone fluctuated between 9.9 ng/mL to 19.2 ng/mL and 17.9 ng/mL to 45.5 ng/mL, respectively. Fluctuations in plasma concentrations were lower with risperidone for prolonged-release injectable suspension than with risperidone oral tablets. Median Cmax/Cmin ratios for risperidone were approximately 2 after IM injection and 20– 30 after oral intake; median C_max/C_min ratios for risperidone plus 9-hydroxyrisperidone were approximately 2 after IM injection and 3–4 after oral intake.

Gluteal and deltoid intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.

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 88%, and that of 9-hydroxyrisperidone is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites.

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, cytochrome P₄₅₀IID₆ (CYP 2D6). A minor metabolic pathway is through N-dealkylation. The main metabolite, 9- hydroxyrisperidone, has similar pharmacological activity to risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9- hydroxyrisperidone. The hydroxylation of risperidone is dependent upon debrisoquine 4-hydroxylase, i.e., the metabolism of risperidone is sensitive to debrisoquine hydroxylation type genetic polymorphism. Consequently, the concentrations of parent drug and active metabolite differ substantially in extensive and poor metabolizers. However, the concentration of risperidone and 9-hydroxyrisperidone combined did not differ substantially between extensive and poor metabolizers, and elimination half-lives were similar in all subjects (approximately 20 to 24 hours).

Excretion

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 of risperidone for prolonged-release injectable suspension.

Special Populations and Conditions

Pediatrics: No data available.

Geriatrics: In an open-label trial, steady-state concentrations of risperidone plus 9- hydroxyrisperidone in otherwise healthy elderly patients (≥ 65 years old) treated with risperidone powder for injectable prolonged-release suspension for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. For these reasons, dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients (see DOSAGE AND ADMINISTRATION).

Sex: No specific pharmacokinetic study was conducted to investigate gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (with or without correction for body weight).

Race: No specific pharmacokinetic study was conducted to investigate race effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to race.

Hepatic Insufficiency: Whereas 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 powder for injectable prolonged-release suspension, it is recommended that patients with hepatic impairment be carefully titrated on oral risperidone before treatment with Risperidone Depot is initiated at a dose of 25 mg. Alternatively, a starting dose of 12.5 mg Risperidone Depot may be appropriate (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and DOSAGE AND ADMINISTRATION).

Renal Insufficiency: In patients with moderate to severe renal disease treated with oral risperidone, clearance of risperidone and 9-hydroxyrisperidone combined was decreased by about 60%, C_max and AUC were increased by about 40% and 160% respectively, and half-life was prolonged by about 60% compared with young healthy subjects. Although patients with renal impairment were not studied with risperidone powder for injectable prolonged-release suspension, it is recommended that patients with renal impairment be carefully titrated on oral risperidone before treatment with Risperidone Depot is initiated at a dose of 25 mg.

Alternatively, a starting dose of 12.5 mg Risperidone Depot may be appropriate (see WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION).

11 STORAGE, STABILITY AND DISPOSAL

The entire kit should be stored in the refrigerator (2°C–8°C) and protected from light.

If refrigeration is unavailable, kit can be stored at temperatures not exceeding 25°C for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C. Protect from light.

Risperidone Depot must be suspended only in the diluent supplied in the dose pack. The entire volume of diluent (2 mL) must be used for suspension of the microspheres.

Upon suspension in the diluent, it is recommended to use Risperidone Depot immediately. Risperidone Depot must be used within 6 hours of suspension. Resuspension of Risperidone Depot will be necessary prior to administration as settling will occur over time since the product is in suspension. Keeping the vial upright, shake vigorously for at least 10 seconds to resuspend the microspheres. Reconstituted product in syringe must be resuspended by shaking vigorously. Once in suspension, the product should not be exposed to temperatures above 25°C.

Risperidone Depot should be kept out of the sight and reach of children.

The vial and syringe stoppers and syringe tip cap are not made with natural rubber latex.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: risperidone

Chemical name: 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

Molecular formula and molecular mass: C₂₃H₂₇FN₄O₂, 410.48 Structural formula:

Physicochemical properties: Risperidone is practically insoluble in water, freely soluble in methylene chloride, and sparingly soluble in ethanol.

pKa: 6.51

Partition Coefficient: log P = 6.58

Melting Point: 165 - 172°C

14 CLINICAL TRIALS

14.1 Clinical Trials by Indications

Schizophrenia

The effectiveness of risperidone for prolonged-release injectable suspension in the treatment of schizophrenia was established, in part, on the basis of extrapolation from the established effectiveness of the oral formulation of risperidone. In addition, the effectiveness of risperidone for prolonged-release injectable suspension in the treatment of schizophrenia was established in a 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.

Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of either 25, 50, or 75 mg risperidone for prolonged-release injectable suspension or placebo every 2 weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral risperidone. Patients who received risperidone for prolonged-release injectable suspension were given doses of oral risperidone (2 mg for patients in the 25 mg group, 4 mg for patients in the 50 mg group, and 6 mg for patients in the 75 mg group) for the 3 weeks after the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item inventory composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.

The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study was 81.5.

Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic patients treated with each dose of risperidone for prolonged-release injectable suspension (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no statistically significant differences between the treatment effects for the three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose group.

Subgroup analyses did not indicate any differences in treatment outcome as a function of age, race, or gender.

Maintenance Treatment in Bipolar I Disorder – Monotherapy

The effectiveness of risperidone for prolonged-release injectable suspension when administered as monotherapy for the maintenance treatment of bipolar I disorder was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, and at time of screening were either experiencing an acute manic or mixed episode or were already stabilized on either risperidone or other anti-manic medications. Acutely ill patients and patients stabilized on other anti-manic medications initiated the study by receiving 3 weeks of open-label treatment with oral risperidone to control acute manic symptoms and to discontinue other anti-manic medications.

A total of 501 patients were treated during a 26-week open-label stabilization phase with risperidone for prolonged-release injectable suspension (starting dose of 25 mg, and titrated, if deemed clinically necessary, to 37.5 mg or 50 mg; for patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). For the 3 weeks after the first injection or after dose increases patients received supplementary doses of oral risperidone to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. In the open-label stabilization phase, 303 (60%) patients who received a stable dose of risperidone for prolonged-release injectable suspension for the last 8 weeks of the open-label phase and continued to meet the protocol-specified criteria for response were randomized to double-blind treatment with either the same dose of risperidone for prolonged-release injectable suspension or placebo injection. Non-response during the open label phase was defined by meeting any of the following criteria: met DSM-IV-TR criteria for manic, hypomanic, mixed or depressed episode; needed treatment intervention with a mood stabilizer, antipsychotic, benzodiazepine, or antidepressant; required hospitalization for any bipolar mood episode; or had a YMRS total score > 12, a MADRS score > 12 or a CGI-S score > 4 at any single visit.

After randomization patients were monitored for relapse for up to 24-months. The primary endpoint was time to relapse to any mood episode (depression, mania, hypomania, or mixed) during double-blind treatment phase. Relapse during the double-blind phase was defined by meeting any of the same criteria used to define non-response during the open label phase or by the need for an increase in risperidone for prolonged-release injectable suspension dose, supplementation with oral risperidone, or addition of another antipsychotic or mood stabilizer. Secondary endpoints included the change in YMRS, MADRS and CGI-BP-S scores, from double-blind baseline to double-blind endpoint.

Time to relapse was delayed in patients receiving risperidone for prolonged-release injectable suspension monotherapy as compared to placebo (p < 0.001) (Figure 2.1). In the 24-month, double-blind phase, 30% of patients in the risperidone for prolonged-release injectable suspension group and 56% of patients in the placebo group relapsed. The majority of relapses were due to manic rather than depressive episodes. Based on their bipolar disorder history, subjects entering this study had, on average, more manic episodes than depressive episodes, and patients who entered the study during an acute episode were experiencing either manic or mixed episodes. Therefore, there are insufficient data to evaluate the effect of risperidone for prolonged-release injectable suspension with regard to the occurrence of depressive episodes in patients with bipolar I disorder. Secondary endpoints evaluating psychiatric symptoms severity, such as change in YMRS and CGI-S-BP during double-blind treatment, were consistent with the maintained treatment response that was observed with risperidone for prolonged-release injectable suspension compared to placebo.

Figure 2.1: Kaplan-Meier Curves of Time to Relapse During Double-Blind Treatment with risperidone for prolonged-release injectable suspension

Deltoid and Gluteal Administration

Deltoid injection has been shown to be bioequivalent to gluteal injection. In an 8-week clinical trial evaluating multiple dose tolerability of deltoid injections (n = 53), patients received up to 4 injections (up to 2 injections per arm at two week intervals) into the deltoid muscle.

14.2 Comparative Bioavailability Studies

An open label, randomized, multiple dose, steady state, two-way, crossover, multi-center bioequivalence study of Risperidone Depot 25 mg/vial (SteriMax Inc.) and RISPERDAL CONSTA^® 25 mg/vial (Janssen Pharmaceuticals Inc.) was conducted in Asian male and female patients with schizophrenia or bipolar I disorder. Comparative bioavailability data from the 75 subjects that were included in the statistical analysis are presented in the following table:

Table 1.5 – Summary Table of the Comparative Bioavailability Data

¹ Risperidone Depot (risperidone for prolonged-release injectable suspension), 25 mg/vial (SteriMax, Inc.)

² RISPERDAL CONSTA® (risperidone) powder for injectable prolonged-release suspension, 25 mg/vial (Janssen Pharmaceuticals, USA.)

³ Expressed as the arithmetic mean (CV%) only.

15 MICROBIOLOGY

Not applicable.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

In acute toxicity studies, after 14 days of administration to mice, rats and dogs, toxicity was manifested by symptoms such as palpebral ptosis, prostration, catalepsy, sedation, hypothermia, and hypotonia at all doses, and clonic convulsions and loss of righting reflex at near lethal and lethal doses. Occasionally, signs of gastrointestinal disturbance were present. Autopsy occasionally revealed gastric lesions and bleeding in rodents. All survivors recovered within the 14-day observation period.

The acute oral toxicity of 9-hydroxyrisperidone in rats was similar to that of the parent drug.

Chronic toxicity studies up to 12 months in length, both in rats and dogs, of risperidone for prolonged-release injectable suspension did not result in unexpected risperidone-related findings when compared to the oral risperidone toxicity studies. The findings were mainly the result of prolactin-mediated effects, (α-lytic effects) or they were related to exaggerated pharmacological effects of risperidone.

In addition, a powdery deposit, histologically evidenced as encapsulation of the microspheres, and an inflammatory reaction at the administration site, after either subcutaneous or intramuscular administration, were found in all groups, including the vehicle group. This was considered to be related to the gradual biodegradation of the microspheres.

No no-toxic-effect doses could be established in both species.

Carcinogenicity Studies

Oral carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg body weight administered per day for 18 months to mice and for 25 months to rats. These doses were equivalent to 2.4, 9.4, and 37.5 times the oral maximum recommended human dose (MRHD) (16 mg/day) on a mg/kg basis, or 0.2, 0.75, and 3 times the oral MRHD (mice) or 0.4, 1.5, and 6 times the oral MRHD (rats) on a mg/m² basis. A maximum tolerated dose was not achieved in male mice. There was a significant increase in pituitary gland adenomas in female mice at doses 0.75 and 3 times the oral MRHD on a mg/m² basis. There was a significant increase in endocrine pancreatic adenomas in male rats at doses 1.5 and 6 times the oral MRHD on a mg/m² basis. Mammary gland adenocarcinomas were significantly increased in female mice at all doses tested (0.2, 0.75, and 3 times the oral MRHD on a mg/m² basis), in female rats at all doses tested (0.4, 1.5, and 6 times the oral MRHD on a mg/m² basis), and in male rats at a dose 6 times the oral MRHD on a mg/m² basis.

Risperidone for prolonged-release injectable suspension was evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were treated every 2 weeks with IM injections of either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m² basis. A control group received injections of 0.9% NaCl, and a vehicle control group was injected with placebo microspheres. There was a significant increase in pituitary gland adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m² basis. The incidence of mammary gland adenocarcinomas was significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m² basis). A significant increase in renal tubular tumours (adenomas, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m² basis. Plasma exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM MRHD.

Dopamine D2 receptor antagonists have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the carcinogenicity studies of oral risperidone; however, measurements taken during subchronic toxicity studies showed that oral risperidone elevated serum prolactin levels 5 to 6 fold in mice and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin levels increased in a dose-dependent manner up to 6 and 1.5 fold in male and female rats, respectively, at the end of the 24 month treatment with risperidone for prolonged-release injectable suspension every 2 weeks. Increases in the incidence of pituitary gland, endocrine pancreas, and mammary gland neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and may be prolactin mediated.

Genotoxicity

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

In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for risperidone for prolonged-release injectable suspension.

Reproductive and Developmental Toxicology

A Segment II study was conducted in Sprague-Dawley rats. Groups of 24 female rats received a single IM dose of risperidone powder for injectable prolonged-release suspension at a total body dose of 10 or 20 mg/kg body weight, saline or vehicle. In addition, one group received risperidone 2.5 mg/kg body weight/day by gavage from Day 6 through Day 17 of pregnancy and served as an oral reference group. There was no drug-related mortality.

There were no relevant drug-related effects on pregnancy or litter parameters. No relevant fetal abnormalities were seen in any dosage group.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to risperidone therapy is unknown (see WARNINGS AND PRECAUTIONS, Special Populations).

In a toxicity study in juvenile rats treated with oral risperidone (0, 0.04, 0.16, 0.63 or 2.5/1.25 mg/kg/day), increased pup mortality and a delay in physical development was observed. In a 40-week study with juvenile dogs treated with oral risperidone (0. 0.31, 1.25 or 5 mg/kg/day), sexual maturation was delayed. Based on AUC, long bone growth was not affected in dogs at 3.6-times the maximum human oral exposure in adolescents (1.5 mg/day); while effects on long bones and sexual maturation were observed at 15 times the maximum human oral exposure in adolescents.

Local Tolerance Studies

Several single-dose tolerance studies were performed in dogs, pigs, or rats, in order to examine the local reaction at the administration site and/or systemic reaction after injection of risperidone microspheres. Both in dogs and pigs, the animals treated with risperidone for prolonged-release injectable suspension intramuscularly showed irritation at the injection site, which was evidenced by clinical observations, increases in creatine kinase, and/or histopathological findings (fibro-granulomatous reactions and giant cells with granulocytic infiltration). No systemic reaction was seen in either species.

Mechanistic Studies

Supportive mechanistic studies were performed in dogs to explain the early release noted in some patients in early clinical studies. Several studies were designed mainly to test two effects, i.e. local inflammation and allergy/anaphylactic reaction, which could result in faster release of risperidone out of the microspheres. A dog model was chosen as a worst case model. The dog appeared to be more sensitive than humans to an early release of risperidone from the microspheres. Moreover, this phenomenon was seen neither in rats nor in pigs. Possible influencing factors, including volume, mass, or concentration of risperidone, repeated injections at the same site, and different diluents, were studied. The results of the different studies showed that a local inflammation, probably worsened by degradation of polysorbate 20, which is present in the diluents, could explain the observed phenomena.

17 SUPPORTING PRODUCT MONOGRAPHS

^PrRISPERDAL CONSTA^® (risperidone powder for injectable prolonged-release suspension, 12.5 mg, 25 mg, 37.5 mg and 50 mg), control 241839, Product Monograph, Janssen Inc. (2020-12-18)