Okedi Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

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

TABLE OF CONTENTS ............................................................................................................... 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 ............................................................. 4

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

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

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

4.4 Administration ......................................................................................................... 6

4.5 Missed Dose .......................................................................................................... 22

5 OVERDOSAGE ............................................................................................................. 22

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 23

7 WARNINGS AND PRECAUTIONS ................................................................................. 24

7.1 Special Populations................................................................................................ 31

7.1.1 Pregnant Women ............................................................................................ 31

7.1.2 Breast-feeding ................................................................................................. 31

7.1.3 Pediatrics ......................................................................................................... 31

7.1.4 Geriatrics ......................................................................................................... 31

8 ADVERSE REACTIONS ................................................................................................. 32

8.1 Adverse Reaction Overview ................................................................................... 32

8.2 Clinical Trial Adverse Reactions ............................................................................. 33

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 36

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 38

8.5 Post-Market Adverse Reactions ............................................................................ 39

9 DRUG INTERACTIONS ................................................................................................. 40

9.2 Drug Interactions Overview ................................................................................... 40

9.3 Drug-Behavioural Interactions ............................................................................... 40

9.4 Drug-Drug Interactions .......................................................................................... 40

9.5 Drug-Food Interactions .......................................................................................... 43

9.6 Drug-Herb Interactions .......................................................................................... 43

9.7 Drug-Laboratory Test Interactions ......................................................................... 43

10 CLINICAL PHARMACOLOGY ........................................................................................ 43

10.1 Mechanism of Action ....................................................................................... 43

10.2 Pharmacodynamics ......................................................................................... 44

10.3 Pharmacokinetics ............................................................................................ 44

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 47

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 47

PART II: SCIENTIFIC INFORMATION ........................................................................................ 48

13 PHARMACEUTICAL INFORMATION ............................................................................. 48

14 CLINICAL TRIALS ......................................................................................................... 48

14.1 Trial Design and Study Demographics ............................................................. 48

14.2 Study Results ................................................................................................... 49

15 MICROBIOLOGY ......................................................................................................... 50

16 NON-CLINICAL TOXICOLOGY ...................................................................................... 50

PATIENT MEDICATION INFORMATION ................................................................................... 53

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

OKEDI (risperidone for extended-release injectable suspension) is indicated for the treatment of schizophrenia in adults.

The efficacy of OKEDI was demonstrated in a 12-week, placebo-controlled trial in patients with schizophrenia experiencing an acute exacerbation. The effectiveness of OKEDI 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 maintaining clinical improvement during long-term therapy (1 year). Patients should be periodically reassessed for treatment response.

1.1 Pediatrics

Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (>65 years): Clinical studies of OKEDI in the treatment of schizophrenia did not include patients older than 65 years of age. Use with caution in elderly subjects. OKEDI is not approved for the treatment of patients with dementia (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX; 7.1.4 Geriatrics; 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

Risperidone is contraindicated in patients with a known hypersensitivity to risperidone, paliperidone, or to any ingredient in the OKEDI formulation, including any non-medicinal ingredient or component of the container (see 7 WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity, and 8.5 Post-Market Adverse Reactions). For a complete listing of ingredients, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

Increased Mortality in Elderly Patients with Dementia

OKEDI is not approved for the treatment of patients with dementia. Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 13 placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating treatment with OKEDI.
• OKEDI should not be supplemented with oral risperidone.
• Do not administer a loading dose.
• Prior to use, the product is constituted by coupling the liquid and powder syringes and passing the contents back and forth between the syringes (See 4.4 Administration).
• Failure to fully mix the medication could result in incorrect dosage (See 4.4 Administration).
• Caution should be exercised in patients prone to hypotension. Consider using lower starting doses (See 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Orthostatic Hypotension and Syncope).

4.2 Recommended Dose and Dosage Adjustment

Recommended Dose

• Each injection should only be administered by a healthcare professional using the appropriate enclosed needle.
• OKEDI is to be administered as intramuscular deltoid or gluteal injection only. Do not administer by any other route.
• For patients who have never taken risperidone, it is recommended to establish the tolerability with oral risperidone prior to initiating with OKEDI.

• Administer OKEDI at a dose of 75 mg or 100 mg once every 4 weeks by intramuscular injection. Patients should be reassessed periodically for treatment response.

  To avoid missing the 4-week dose interval, patients may be given the injection up to 3 days before the 4-week time-point. The next dose should remain the same as planned (even if the dose was administered up to 3 days in advance).

  If a dose is delayed by 1 week, the median trough concentration decreases by approximately 50% during that week (See 10.3 Pharmacokinetics).

• Dose adjustment cannot be made during the 4-week period immediately after a dose administration. Do not administer more than one dose (75 mg or 100 mg total) per 4 weeks.

• The corresponding doses of OKEDI and oral risperidone needed to maintain approximately similar plasma concentrations of risperidone active moiety (i.e., risperidone plus its active metabolite 9-hydroxyrisperidone) at steady-state are as follows:

  • OKEDI injection 75 mg once every 4 weeks is similar to oral risperidone dose of 3 mg/day.
  • OKEDI injection 100 mg once every 4 weeks is similar to oral risperidone dose of 4 mg/day.
  • Patients who are stable on oral risperidone doses lower than 3 mg/day or higher than 4 mg/day may not be candidates for OKEDI.

Pediatrics

Health Canada has not authorized an indication for pediatric use (see 1 INDICATIONS, 1.1 Pediatrics).

Geriatrics

Clinical studies of OKEDI in the treatment of schizophrenia did not include patients older than 65 years (see 14 CLINICAL TRIALS). In general, dose selection for an elderly patient should be cautious. Starting dose in this population should be OKEDI 75 mg. (See 3 SERIOUS WARNING AND PRECAUTIONS BOX; 4.2 Recommended Dose and Dosage Adjustment, Dosage Recommendations for Patients with Renal or Hepatic Impairment; 4.2 Recommended Dose and Dosage Adjustment, Dosage Recommendations for Concomitant Use wit Strong CYP2D6 inhibitors and Strong CYP3A4 Inducers; 7 WARNINGS AND PRECAUTIONS, General, Fall; 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Orthostatic Hypotension and Syncope; 7.1.4 Geriatrics).

Patients with Renal or Hepatic Impairment

OKEDI has not been systematically studied in patients with renal or hepatic impairment, and therefore it should be used with caution in these special populations. Based on oral risperidone, patients with renal impairment have less ability to eliminate the active antipsychotic fraction than adults with normal renal function (see 7 WARNINGS AND PRECAUTIONS, General, Renal). Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone and this may result in an enhanced effect associated with a safety risk namely drowsiness, sedation, tachycardia, hypotension and extrapyramidal symptoms (7 WARNINGS AND PRECAUTIONS, General, Hepatic/Biliary/Pancreatic).

OKEDI should be used with caution in these groups of patients. A careful titration up to at least 3 mg daily with oral risperidone (halving starting doses and slowing titration) before initiating treatment with OKEDI at a dose of 75 mg is recommended, if considered appropriate.

Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers

• Co-administration with Strong CYP2D6 Inhibitors

When considering initiation of treatment with CYP2D6 inhibitors such as fluoxetine or paroxetine, patients treated with OKEDI 100 mg should be treated with the lowest dose (75 mg) of OKEDI for 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy with a CYP2D6 inhibitor, to adjust for the expected increase in plasma concentrations of risperidone (See 9 DRUG INTERACTIONS).

• Co-administration with Strong CYP3A4 Inducers

At the initiation of therapy with CYP3A4 inducers, such as carbamazepine or other known hepatic enzyme inducers, patients should be closely monitored during the first 4 to 8 weeks.

On discontinuation of carbamazepine or other strong CYP3A4 hepatic enzyme inducers, the dosage of OKEDI should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone (See 9 DRUG INTERACTIONS).

4.4 Administration

INSTRUCTIONS FOR USE

OKEDI

Risperidone for extended-release injectable suspension

75 mg, single use

For intramuscular injection only after reconstitution

Do not administer by any other route

Important Information

• To be administered by a healthcare professional only.
• To be administered immediately after reconstitution.
• To be administered intramuscularly only, in gluteal or deltoid muscle, do not inject by any other route.
• Two administration safety needles are included: one for deltoid injection (21G, 1 inch) and the other for gluteus injection (20G, 2 inch).
• Do not substitute any component of the drug kit.
• As a universal precaution always wear gloves.
• The drug kit should be stored at room temperature between 15ºC – 30ºC.
• Read carefully the complete directions before use.
• CHECK CONTENTS

Working on a clean surface, open the pouches and discard the desiccant pack.

Each carton of OKEDI contains (see Figure 1):

• One pouch with a OKEDI prefilled powder (P) syringe with a WHITE plunger rod and WHITE finger flange.
• One pouch with SOLVENT for reconstitution of OKEDI 75 mg prefilled liquid (L) syringe with a TRANSPARENT plunger rod and a RED finger flange. This is the syringe you will use to inject the patient.
• Two administration needles 21G, 1-inch for deltoid (green cap) and a 20G, 2-inch for gluteus (yellow cap).

Figure 1

Discard the kit if any component is damaged or if discoloration or foreign particles are observed.

1.1 Inspect Liquid syringe

ENSURE that LIQUID syringe content flows normally as a liquid. The solvent freezes at 19 °C (See Figure 2).

If the solvent is frozen or partially frozen, warm it at room temperature until it flows normally.

Figure 2

1.2 Dislodge powder syringe

TAP the OKEDI syringe to dislodge potential packed powder near the cap (See Figure 3).

Figure 3

1. 2. CONNECT THE SYRINGES

2.1 Uncap syringes in upright position

Hold both syringes in upright position to prevent loss of product (See Figure 4).

Figure 4

PULL the GREY cap off the Liquid syringe (See Figure 5).

Figure 5

TWIST and PULL the WHITE Powder syringe cap off (See Figure 6).

Make sure to keep the Powder syringe in the upright position to prevent loss of product (See Figure 6).

Figure 6

2.2 Connect the syringes

Pick the Liquid syringe that has the RED coloured finger flange and place it on TOP of the Powder syringe , or slightly tilt it vertically (See Figure 7).

Figure 7

TWIST the syringes together until you feel a slight resistance.

Make sure that Powder syringe is in the upright position to prevent loss of product.

1. 3. MIX THE CONTENTS

STOP AND READ THIS SECTION BEFORE STARTING OR THE MEDICINE MAY NOT CORRECTLY RECONSTITUTE.

• PUSH VIGOROUSLY the Liquid content towards the Powder syringe.
• DO NOT WAIT for powder wetting and QUICKLY start mixing contents by pushing the plungers FAST and alternately for 100 pushes (2 pushes within 1 second, approximately 1 minute).
• ENSURE medicine is passing between both syringes for a proper mixing: medicine is viscous and you will need to apply force when pressing on the plunger rods.

Mix for at least 100 pushes (or 50 cycles, 1 cycle = followed by ) by doing alternately followed by (See Figure 8).

Figure 8

Make sure medicine is passing between both syringes.

When medicine is correctly mixed, the appearance will be a uniform suspension, off white to yellowish in colour, and thick consistency (See Figure 9).

Figure 9

Proceed immediately to prepare the injection syringe for administration.

1. 4. PREPARE INJECTION SYRINGE

4.1 Transfer medicine

Place downward pressure on the plunger rod and transfer all the content into the syringe that has attached the RED coloured flange (See Figure 10).

Figure 10

Make sure all the content is transferred, failure to fully transfer the content to the Liquid syringe may result in incorrect dosage.

4.2 Detach syringes

Once the medicine is fully transferred, separate the two syringes by untwisting (See Figure 11).

Proceed immediately to prepare the injection syringe for administration.

The injection must be given within 15 minutes after reconstitution.

Figure 11

4.3 Prepare the intramuscular injection

OKEDI is to be injected intramuscularly in the deltoid or gluteal muscle (See 10.3 Pharmacokinetics, Absorption, Injection sites).

Choose an injection site that is free of skin conditions (e.g. nodules, lesions, excessive pigment).

Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way.

Clean the injection site well with an alcohol pad, and let dry.

TIP: To help minimize irritation, rotate injection sites between deltoid or gluteal muscles.

4.4 Attach the safety needle

Choose the proper needle (See Figure 12):

• Deltoid: 21G, 1-inch for deltoid (green cap).
• Gluteus: 20G, 2-inch for gluteus (yellow cap).

Attach it using a clockwise twisting motion. Do not over-tighten.

Figure 12

4.5 Remove exceeding air

• Hold the syringe upright for several second to allow any air bubbles to rise.
• Due to the viscosity of the medication, bubbles might not rise as quickly as those in an aqueous solution.
• Remove needle cover and push out the excess of air (only big bubbles) from the syringe barrel.
• If you see the medication appearing at the needle tip, pull slightly back on the plunger to prevent medication spillage (See Figure 13).

DO NOT expel any drops of medicine, as this may result in incorrect dosage.

Figure 13

1. 5. ADMINISTER AND DISPOSE

5.1 Inject medicine

Insert the needle fully into the muscle (See Figure 14). DO NOT INJECT BY ANY OTHER ROUTE.

Figure 14

WARNINGS

• THICK MEDICATION. MAKE SURE TO FULLY INJECT IT.
• The injection time is longer than usual due to the viscosity of the medicine.
• Wait a few seconds before removing the needle.
• Avoid inadvertent injection into a blood vessel.
• Do not rub or apply pressure to the injection site

5.2 Dispose medicine

• Lock the needle guard by pressing on it using a finger (See Figure 15 A) or by pressing it on a flat surface (See Figure 15 B)
• Dispose immediately in a secure “sharps” disposal container.

Figure 15 A Figure 15 B

OR

OKEDI

risperidone for extended-release injectable suspension

100 mg, single use

For intramuscular injection only after reconstitution

Do not administer by any other route

Important Information

• To be administered by a healthcare professional only.
• To be administered immediately after reconstitution.
• To be administered intramuscularly only, in gluteal or deltoid muscle, do not inject by any other route.
• Two administration safety needles are included: one for deltoid injection (21G, 1 inch) and the other for gluteus injection (20G, 2 inch).
• Do not substitute any component of the drug kit.
• As a universal precaution always wear gloves.
• The drug kit should be stored at room temperature between 15°C – 30°C.
• Read carefully the complete directions before use.

1.1 CHECK CONTENTS

Working on a clean surface, open the pouches and discard the desiccant pack.

Each carton of OKEDI contains (See Figure 1).

• One pouch with a OKEDI prefilled powder (P) syringe with a WHITE plunger rod and WHITE finger flange.
• One pouch with SOLVENT for reconstitution of OKEDI prefilled liquid (L) syringe with a TRANSPARENT plunger rod and a BLUE finger flange. This is the syringe you will use to inject the patient.
• Two administration needles 21G, 1-inch for deltoid (green cap) and a 20G, 2-inch for gluteus (yellow cap).

Figure 1

Discard the kit if any component is damaged or if discoloration or foreign particles are observed.

1.1 Inspect Liquid syringe

ENSURE that LIQUID syringe content flows normally as a liquid. The solvent freezes at 19 ^oC (See Figure 2).

If the solvent is frozen or partially frozen, warm it at room temperature until it flows normally.

Figure 2

1.2 Dislodge Powder syringe

TAP the OKEDI syringe to dislodge potential packed powder near the cap (See Figure 3).

Figure 3

1. 2. CONNECT THE SYRINGES

2.1 Uncap syringes in upright position

Hold both syringes in upright position to prevent loss of product (See Figure 4).

Figure 4

PULL the GREY cap off the Liquid syringe (See Figure 5).

Figure 5

TWIST and PULL the WHITE Powder syringe cap off (See Figure 6).

Make sure to keep the Powder syringe in the upright position to prevent loss of product (See Figure 6).

Figure 6

2.2 Connect the syringes

Pick the Liquid syringe that has the BLUE coloured finger flange and place it on TOP of the Powder syringe , or slightly tilt it vertically (See Figure 7).

Figure 7

TWIST the syringes together until you feel a slight resistance.

Make sure that Powder syringe is in the upright position to prevent loss of product.

1. 3. MIX THE CONTENTS

STOP AND READ THIS SECTION BEFORE STARTING OR THE MEDICINE MAY NOT CORRECTLY RECONSTITUTE.

• PUSH VIGOROUSLY the Liquid content towards the Powder syringe.
• DO NOT WAIT for powder wetting and QUICKLY start mixing contents by pushing the plungers FAST and alternately for 100 pushes (2 pushes within 1 second, approximately 1 minute).
• ENSURE medicine is passing between both syringes for a proper mixing: medicine is viscous and you will need to apply force when pressing on the plunger rods.

Mix for at least 100 pushes (or 50 cycles, 1 cycle = followed by ) by doing alternately followed by (See Figure 8).

Figure 8

Make sure medicine is passing between both syringes.

When medicine is correctly mixed, the appearance will be a uniform suspension, off white to yellowish in colour, and thick consistency (See Figure 9).

Figure 9

Proceed immediately to prepare the injection syringe for administration.

1. 4. PREPARE INJECTION SYRINGE

4.1 Transfer medicine

Place downward pressure on the plunger rod and transfer all the content into the syringe that has attached the BLUE coloured flange (See Figure 10).

Figure 10

Make sure all the content is transferred, failure to fully transfer the content to the Liquid syringe may result in incorrect dosage.

4.2 Detach syringes

Once the medicine is fully transferred, separate the two syringes by untwisting (See Figure 11).

Proceed immediately to prepare the injection syringe for administration.

The injection must be given within 15 minutes after reconstitution.

Figure 11

4.3 Prepare the intramuscular injection

OKEDI is to be injected intramuscularly in the deltoid or gluteal muscle (See 10.3 Pharmacokinetics, Absorption, Injection sites).

Choose an injection site that is free of skin conditions (e.g. nodules, lesions, excessive pigment).

Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way.

Clean the injection site well with an alcohol pad, and let dry.

TIP: To help minimize irritation, rotate injection sites between deltoid or gluteal muscles.

4.4 Attach the safety needle

Choose the proper needle (See Figure 12):

• Deltoid: 21G, 1-inch for deltoid (green cap).
• Gluteus: 20G, 2-inch for gluteus (yellow cap).

Attach it using a clockwise twisting motion. Do not over-tighten.

Figure 12

4.5 Remove exceeding air

• Hold the syringe upright for several second to allow any air bubbles to rise.
• Due to the viscosity of the medication, bubbles might not rise as quickly as those in an aqueous solution.
• Remove needle cover and push out the excess of air (only big bubbles) from the syringe barrel.

• If you see the medication appearing at the needle tip, pull slightly back on the plunger to prevent medication spillage (See Figure 13).

  

DO NOT expel any drops of medicine, as this may result in incorrect dosage.

Figure 13

1. 5. ADMINISTER AND DISPOSE

5.1 Inject medicine

Insert the needle fully into the muscle (See Figure 14). DO NOT INJECT BY ANY OTHER ROUTE.

Figure 14

WARNINGS

• THICK MEDICATION. MAKE SURE TO FULLY INJECT IT.
• The injection time is longer than usual due to the viscosity of the medicine.
• Wait a few seconds before removing the needle.
• Avoid inadvertent injection into a blood vessel.
• Do not rub or apply pressure to the injection site.

5.2 Dispose medicine

• Lock the needle guard by pressing on it using a finger (See Figure 15 A) or by pressing it on or a flat surface (See Figure 15 B)
• Dispose immediately in a secure “sharps” disposal container.

Figure 15 A Figure 15 B

OR

4.5 Missed Dose

Missing doses of OKEDI should be avoided. A patient who misses a dose should receive the next dose as soon as possible; the following dose should be scheduled 4 weeks thereafter (See 4.2 Recommended Dose and Dosage Adjustment, Recommended Dose).

It is recommended to re-initiate with the same dose of OKEDI as administered previously. After injection of OKEDI, plasma values attain similar active moiety steady-state exposure. No oral risperidone supplementation is recommended.

5 OVERDOSAGE

Symptoms

No cases of overdose were reported in premarketing studies of OKEDI.

Cases of overdose have been reported with oral risperidone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. In overdose, hyponatremia, hypokalemia, convulsions, prolonged QT, and widened QRS 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 and ensure adequate oxygenation and ventilation. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.

There is no specific antidote to risperidone. Appropriate supportive measures should be instituted. 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.

Consider the extended-release characteristics of OKEDI when assessing treatment needs and recovery.

For management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844-POISON-X (1-844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Composition

The following Table 2 presents the delivered amounts of the raw materials and the approximate delivered volume for the two dosage strengths:

Table 2 – Quantitative description of each ingredient for the Dosage Strengths

Dosage Forms and Packaging

OKEDI is available as a sterile two-syringe mixing system; a solvent syringe prefilled with the solvent dimethyl sulfoxide, a transparent and colourless solution. The powder syringe is prefilled with white to white-yellowish risperidone and poly (lactide-co-glycolide) acid co-polymer. The product is supplied as a kit and contains the liquid pre-filled syringe, powder pre-filled syringe and 2 safety needles; a 21G, 1-

inch safety needle with a green cap for deltoid administration and a 20G, 2-inch safety needle with a yellow cap for gluteal administration.

After mixing, OKEDI is an extended-release injectable suspension, for intramuscular use, in the following strengths of risperidone: 75 mg and 100 mg.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX

General

Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be experiencing conditions which may contribute to an elevation or reduction in core temperature, e.g., exercising strenuously, exposure to extreme heat or cold, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Fall: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including OKEDI, 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

Please see 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

Orthostatic Hypotension and Syncope: Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. 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).

OKEDI should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and (3) patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.

QT Interval: Caution should be exercised when OKEDI is prescribed in patients with known cardiovascular disease, history of cardiac arrhythmias, in patients with congenital long QT syndrome, bradycardia, or electrolyte disturbances (hypokalemia, hypomagnesemia), and in concomitant use with medicines known to prolong the QT interval, as it may increase the risk of arrhythmogenic effects.

Driving and Operating Machinery

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with OKEDI (See 8.2 Clinical Trial Adverse Reactions). Antipsychotics, including OKEDI, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that risperidone therapy does not adversely affect them.

Endocrine and Metabolism

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

Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes have been reported in trial subjects treated with OKEDI.

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 in patients treated with atypical antipsychotics including risperidone. 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 hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics.

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

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels, and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic gonadotropin releasing hormone, GnRH, resulting in reduced pituitary gonadotropin secretion. This may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

OKEDI 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 OKEDI treatment in patients with pituitary tumours. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats (see 16 NON-CLINICAL TOXICOLOGY). 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: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Gastrointestinal

Antiemetic Effect: Consistent with its dopamine antagonistic effect, OKEDI may have an antiemetic effect. Such an effect may mask the signs of toxicity due to overdosage with other drugs, or may mask symptoms of disease such as intestinal obstruction, Reye's syndrome, and brain tumour.

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

Genitourinary

Priapism: Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with oral 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. Severe priapism may require surgical intervention.

Hematologic

Leukopenia, neutropenia, agranulocytosis: In clinical trials and/or post-marketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of OKEDI 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. Discontinue OKEDI in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC until recovery.

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

Hepatic/Biliary/Pancreatic

OKEDI was not systematically studied in patients with hepatic impairment. Based on oral risperidone, patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone and this may result in an enhanced effect.

Use OKEDI with caution in patients with hepatic impairment. Prior to initiating treatment, it is advisable to carefully titrate patients with at least 3 mg daily of oral risperidone (halving starting doses and slowing titration). If patients can tolerate 3 mg of oral risperidone and are psychiatrically stable, a 75 mg dose of OKEDI may be considered.

Immune

Hypersensitivity: 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 OKEDI (see 2 CONTRAINDICATIONS).

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. It is unknown how many of these patients previously tolerated oral risperidone or paliperidone. However, anaphylactic-type reactions have occurred after injection with risperidone 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 OKEDI 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 OKEDI (see 2 CONTRAINDICATIONS). Caution should also be exercised in patients who have had serious allergic reactions to other medications. Prior to initiating treatment with OKEDI, tolerability with oral risperidone should be established (See 4 DOSAGE AND ADMINISTRATION and 8.5 Post-Market Adverse Reactions). For a complete list of ingredients, see 6 DOSAGE FORMS, STRENGHTS, COMPOSITION AND PACKAGING.

Neurologic

Extrapyramidal Symptoms: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups (See 8.2 Clinical Trial Adverse Reactions, Extrapyramidal Symptoms).

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 9.2 Drug-Drug Interactions).

Neuroleptic malignant syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including risperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. Consideration should be given to the long-acting nature of OKEDI. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

Seizures: Seizures have been observed during pre-marketing studies of risperidone in adult patients with schizophrenia. OKEDI should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, OKEDI should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs; and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. The lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with OKEDI, drug discontinuation should be considered. However, some patients may require treatment with OKEDI 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 OKEDI, 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, and 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.

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: There is an increased risk of suicide or attempted suicide in patients with schizophrenia, and thus, close supervision and appropriate clinical management of high-risk patients should accompany drug therapy. OKEDI is to be administrated by a healthcare professional (see 4 DOSAGE AND ADMINISTRATION); therefore, suicide due to an overdose is unlikely.

Renal

Renal impairment: OKEDI was not systematically studied in patients with renal impairment. Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than normal adults.

Use OKEDI with caution in patients with renal impairment. Prior to initiating treatment, it is advisable that patients be carefully titrated up to at least 3 mg daily of oral risperidone. If patients can tolerate 3 mg of oral risperidone and are psychiatrically stable, a 75 mg dose of OKEDI may be considered.

Reproductive Health

• Fertility

  Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with OKEDI may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential (see 7.1.1 Pregnant Women).

• Risks

Teratogenic Effects: No developmental toxicity studies were conducted with OKEDI.

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1566 women exposed to risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Multiples studies were conducted with oral risperidone on pregnant mice and rats. Several teratogenic effects were observed including but not limited to cleft palate, developmental delay and offspring mortality. For more details see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology, Teratogenic effects.

Nonteratogenic Effects: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including OKEDI, during pregnancy.

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 during risperidone exposure. SCARs commonly present as a combination of the following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. Discontinue risperidone if severe cutaneous adverse reactions occur.

7.1 Special Populations

7.1.1 Pregnant Women

OKEDI should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including OKEDI, during pregnancy. Healthcare professionals are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/.

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 OKEDI and for at least 12 weeks after the last injection.

7.1.3 Pediatrics

Pediatrics (< 18 years): No data are available to Health Canda; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Clinical studies of OKEDI did not include subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be made with caution, with a lower starting dose being recommended, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Therefore, geriatric patients should be titrated first with oral risperidone, to ensure that OKEDI’s lowest dose is appropriate for them.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment who should be given reduced doses. Because elderly patients are more likely to have decreased renal function; monitor renal function and adjust dosage.

In patients with renal impairment, carefully titrate with oral risperidone (halving starting doses and slowing titration) before initiating treatment with OKEDI at a dose of 75 mg. OKEDI was not systematically studied in patients with renal impairment; however, such effect has been investigated with oral risperidone (See 4.2 Recommended Dose and Dosage Adjustment, Geriatrics).

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 (See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX).

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

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The same adverse events described for other risperidone or paliperidone containing products should be considered in treatment with OKEDI.

The very commonly reported adverse events (AEs) (reported by ≥ 10%) are blood prolactin increase, hyperprolactinemia, akathisia, headache, somnolence, weight increased, injection site pain, and dizziness. In addition, the frequency of reported injection site reactions was similar across treatment groups with both OKEDI and placebo; the common (≥ 5%) of which was injection site pain. The systemic safety profile for OKEDI, was consistent with the known safety profile of oral risperidone.

Discontinuations Due to Adverse Events

Schizophrenia was the unique adverse event leading to discontinuation that occurred at a rate of ≥ 1% in OKEDI-treated patients (2.1% in each group) but lower than placebo (5.4%) in the placebo-controlled, randomized, double-blind, 12-week study. In a 12-month long-term, open-label safety study the adverse events associated with discontinuation were schizophrenia (7 subjects, 3.3%), akathisia, hepatic steatosis, hepatocellular injury, weight increased, diabetes mellitus, akathisia, extrapyramidal disorder, libido decreased, suicidal ideation and gynecomastia (each 1 subject, 0.5%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, 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 may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The safety of OKEDI was evaluated in a total of 549 adult subjects with schizophrenia who received at least 1 dose of OKEDI of either the recommended dose of 75 mg or 100 mg, during the clinical development program. At total of 147 subjects with schizophrenia received placebo. From the 549 subjects with schizophrenia who received OKEDI, 163 were in clinical studies of the development program and 386 were included in the placebo-controlled, randomized, double-blind, 12-week study and/or its 1-year open-label extension (OLE). From this study, 290 received OKEDI during the DB + OLE phases, 55 subjects were subjects from the placebo arm of the DB phase continue in the OLE phase, and 41 were de novo subjects in the OLE phase. From these 386 subjects with schizophrenia from the DB+OLE study, 168 subjects received at least 13 doses of OKEDI during the DB and OLE phases, including 78 patients (20.2%) who received 13 doses, one patient (1.0%) who received 15 doses, and 89 patients (23.1%) who received 16 doses of OKEDI.

Treatment Emergent Adverse Events (TEAEs) with an incidence of 1% or more and greater than placebo are shown in Table 3.

Table 3 –Treatment Emergent Adverse Events in 1% or More of OKEDI-Treated Subjects (and Greater than Placebo) in a 12-Week Double-Blind, Placebo-Controlled, Fixed-Dose Schizophrenia Trial.

Selected Adverse Events

Changes in Body Weight: Data from a 12-week double-blind (DB), placebo-controlled trial indicate a dose-dependant increase in the weight gain ≥ 7% increase from baseline to postdose assessments in OKEDI 75 mg and 100 mg groups compared to placebo.

Data from the 12-week DB, placebo-controlled study with OKEDI in adults subjects with schizophrenia are presented in Table 4.

Table 4– Change in Body Weight from Baseline to End of Study and ≥ 7% increase from baseline in a 12-week double-blind, placebo-controlled study in adult participants with schizophrenia

*The “n” in the Weight Mean Change row are the number of participants with data at baseline and end of study visits.

**Data shown as number of subjects with at least one postbaseline value as denominator and number of participants satisfying the predefined criterion as numerator.

In a 12-month long-term open-label extension (OLE) safety study, for all subjects receiving OKEDI including placebo subjects transferred to OKEDI from the DB trial, roll-over OKEDI patients and de novo patients already stabilized on risperidone before enrolling to the OLE, the mean increase in weight from baseline was 0.9 ± 5.14 kg and 1.2 ± 3.09 kg after treatment with OKEDI 75 mg and 100 mg, respectively.

Extrapyramidal Symptoms (EPS): Several methods were used to measure EPS, including: (1) the Barnes Akathisia Rating Scale (BARS) global clinical rating score which evaluates akathisia, (2) the Abnormal Involuntary Movement Scale (AIMS) score which evaluates dyskinesia, (3) the Simpson-Angus Scale (SAS) global score which broadly evaluates parkinsonism, and (4) the incidence of spontaneous reports of EPS-related adverse reactions.

In the 12-week double-blind, placebo-controlled study, the mean changes from baseline in BARS, AIMS, and SAS total scores were comparable between OKEDI- and placebo-treated patients. At all postbaseline assessments, mean changes from baseline were between 0.0 and 0.1 (inclusive) for the BARS, between -0.1 and 0.1 (inclusive) for the AIMS and between 0.048 and 0.145 (inclusive) for the SAS.

The rates of TEAEs associated with EPS were similar across treatment groups. There was a higher incidence of akathisia in the OKEDI 100 mg (7.5%) group compared with the OKEDI 75 mg (4.2%) and placebo group (2.0%); reports of extrapyramidal disorders were higher in the OKEDI 100 mg group (0.7%) compared with the OKEDI 75 mg (0%) and placebo (0%) groups.

Reports of dystonia were higher in the OKEDI 75 mg (2.8%) compared with the OKEDI 100 mg (2.1%) and placebo groups (0.7%).

Pain Assessment and Local Injection Site Reactions: The observed adverse events related to the injection site and their frequency were similar between deltoid and gluteal injection site.

• Reported Adverse Events: The most commonly reported injection site related adverse reaction was pain with 3.4%, 5.6% and 2.7% for placebo, OKEDI 75 mg and OKEDI 100 mg, respectively. Amongst the injection site related adverse reactions, pain and swelling were common with overall frequency of 3.9% and 1.1%; discomfort and erythema were uncommon with overall frequency of 0.2% and 0.7%, respectively. No adverse event of induration was recorded. The majority of these reactions were reported to be of mild to moderate severity and were resolved within the first week after administration.
• Injection Site Evaluation and Pain Score: In addition to the observed adverse events during the 12-week, double-blind, placebo-controlled study, injection site pain was assessed by participants using a visual analog scale (VAS) (0= no pain to 10= unbearably painful) after each dose and injection sites were evaluated for redness, swelling and induration by designated personnel after each injection. The mean subject-reported injection site pain VAS scores were similar for all treatment groups following any of the injections. Mean overall VAS score was 2.4 ± 2.56, 2.3 ± 2.31 and 2.5 ± 2.38 for placebo, OKEDI 75 mg and OKEDI 100 mg, respectively. Amongst the injection site reactions evaluated by designated study site personnel redness and swelling were common with overall frequencies of 6.2 % and 1.8 %, respectively. Induration was uncommon with an overall frequency of 0.7 %.

8.3 Less Common Clinical Trial Adverse Reactions

Other Adverse Reactions Observed During the Clinical Trial Evaluations of OKEDI

The following list of less common adverse reactions (less than 1%) in Phase 3 studies does not include reactions: (1) already listed in previous tables or elsewhere in labeling, (2) which are part of the disease state, (3) for which a drug cause was remote, (4) which were so general as to be uninformative, or (5) which were not considered to have significant clinical implications.

Gastrointestinal Disorders: nausea

General Disorders and Administration Site conditions: fatigue, injection site reaction (including injection site erythema and discomfort)

Nervous System Disorders: drooling, extrapyramidal disorder, sedation

Psychiatric Disorders: anxiety

Reproductive System and Breast Disorders: amenorrhoea, erectile dysfunction

Vascular Disorders: hypotension

Other Adverse Reactions Reported in Clinical Trials with Oral Risperidone and Paliperidone

The following is a list of additional ADRs that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence:

Blood and Lymphatic System Disorders: anemia, eosinophil count increased, granulocytopenia, hematocrit decreased, neutropenia, white blood cell count decreased

Cardiac Disorders: atrioventricular block, atrioventricular block first degree, bundle branch block left, bundle branch block right, еlectrocardiogram abnormal, electrocardiogram QT prolonged, palpitations, postural orthostatic tachycardia syndrome, sinus arrhythmia, sinus bradycardia, sinus tachycardia, tachycardia

Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo

Eye Disorders: conjunctivitis, dry eye, eye discharge, eye movement disorder, eye infection, eye rolling, eye swelling, eyelid edema, eyelid margin crusting, glaucoma, lacrimation increased, ocular hyperemia, oculogyration, photophobia, visual acuity reduced, vision blurred

Gastrointestinal Disorders: aptyalism, cheilitis, dysphagia, fecaloma, fecal incontinence, flatulence, gastroenteritis, gastritis, intestinal obstruction, lip swelling, swollen tongue, toothache

General Disorders: chest pain, chills, discomfort, drug withdrawal syndrome, edema, face edema, edema peripheral, feeling abnormal, gait disturbance, generalized edema, influenza-like illness, malaise, peripheral coldness, pitting edema, sluggishness, thirst

Hepatobiliary disorders: gamma-glutamyltransferase increased, hepatic enzyme increased, transaminases increased

Immune System Disorders: anaphylactic reaction, drug hypersensitivity

Infections and Infestations: acarodermatitis, bronchitis, bronchopneumonia, cellulitis, cystitis, ear infection, eye infection, influenza viral infection, localized infection, nasopharyngitis, onychomycosis, otitis media, otitis media chronic, pharyngitis, pneumonia, rhinitis, respiratory tract infection, sinusitis, tonsillitis, tracheobronchitis, upper respiratory tract infection, urinary tract infection, viral infection

Injury, poisoning and procedural complications: fall

Investigations: alanine aminotransferase increased, blood creatine phosphokinase increased, blood insulin increased, blood pressure decreased, body temperature decreased, body temperature increased, electrogram QT corrected interval prolonged, electrocardiogram T wave abnormal, electrogram T wave inversion, eosinophil count increased, heart rate increased, hematocrit decreased, hemoglobin decreased, insulin C-peptide increased, transaminases increased, white blood cell count decreased

Metabolism and Nutrition Disorders: anorexia, blood cholesterol increased, blood triglycerides increased, decreased appetite, hyperglycemia, hyperinsulinemia, polydipsia, weight decreased

Musculoskeletal, Connective Tissue, and Bone Disorders: arthralgia, back pain, blood creatine phosphokinase increased, joint stiffness, joint swelling, muscle contracture, muscle rigidity, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, posture abnormal, rhabdomyolysis, shoulder pain, torticollis, trismus

Nervous System Disorders: akinesia, balance disorder, bradykinesia, cerebral ischemia, cerebrovascular accident, cerebrovascular disorder, coordination abnormal, cogwheel rigidity, diabetic coma, depressed level of consciousness, disturbance in attention, dizziness postural, dyskinesia (includes athetosis, chorea, choreoathetosis, movement disorder, muscle twitching, myoclonus), grand mal convulsion, head titubation, hypoesthesia, hypokinesia, loss of consciousness, masked facies, movement disorder, muscle contractions involuntary, neuroleptic malignant syndrome, paresthesia, parkinsonian gait, Parkinson’s disease, psychomotor hyperactivity, speech disorder, syncope, tongue paralysis, tardive dyskinesia, transient ischemic attack, unresponsive to stimuli

Psychiatric Disorders: aggression, agitation, anorgasmia, blunted affect, confusional state, listlessness, libido decreased, middle insomnia, nervousness, sleep disorder

Renal and Urinary Disorders: dysuria, enuresis, pollakiuria, urinary incontinence

Reproductive System and Breast Disorders: breast discharge, breast discomfort, breast engorgement, breast enlargement, breast pain, breast swelling, breast tenderness, ejaculation disorder, erectile dysfunction, gynecomastia, menstruation delayed, menstrual disorder, retrograde ejaculation, sexual dysfunction, vaginal discharge

Respiratory, Thoracic, and Mediastinal Disorders: cough, dysphonia, dyspnea, epistaxis, hyperventilation, nasal congestion, nasal edema, pharyngolaryngeal pain, pneumonia aspiration, productive cough, pulmonary congestion, rales, respiratory disorder, respiratory tract congestion, sinus congestion, wheezing

Skin and Subcutaneous Tissue Disorders: acne, drug eruption, dry skin, eczema, erythema, hyperkeratosis, pruritus, skin discoloration, skin disorder, skin lesion, rash, rash erythematous, rash generalized, rash maculopapular, rash papular, seborrheic dermatitis, urticaria

Vascular Disorders: flushing, hypotension, ischemia

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

Clinical Trial Findings

Increased Prolactin

In the 12-week double-blind, placebo-controlled study, there was a typical increase in mean prolactin levels in fasting blood samples from baseline to the post-dose assessments in both the OKEDI 75 mg and

100 mg groups, while mean prolactin for the placebo group decreased during the study. Changes in mean prolactin were dose-dependent and the change in mean at end of treatment from baseline was approximately 2.8-fold higher.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been identified during post approval use of oral risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic Disorders: thrombocytopenia, thrombotic thrombocytopenic purpura

Cardiac Disorders: atrial fibrillation, cardiopulmonary arrest

Endocrine Disorders: inappropriate antidiuretic hormone secretion, precocious puberty

Eye Disorders: floppy iris syndrome (intraoperative)

Gastrointestinal Disorders: pancreatitis, ileus, intestinal obstruction

General Disorders: hypothermia, drug withdrawal syndrome neonatal, sudden death

Hepatobiliary disorders: jaundice

Immune System Disorders: anaphylactic reaction

Investigations: QT prolongation

Metabolism and Nutrition Disorders: diabetes mellitus, diabetic ketoacidosis (in patients with impaired glucose metabolism), hyperinsulinemia, hypoglycemia, water intoxication

Neoplasms benign, malignant and unspecified (incl cysts and polyps): pituitary adenoma

Nervous System Disorders: dysgeusia

Psychiatric Disorders: catatonia, mania

Reproductive System and Breast Disorders: priapism

Renal and Urinary Disorders: urinary retention

Respiratory, Thoracic, and Mediastinal Disorders: pulmonary embolism, sleep apnea syndrome

Skin and Subcutaneous Tissue Disorders: alopecia, angioedema

Vascular Disorders: deep vein thrombosis

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.

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

Adverse events reported since market introduction of risperidone, which were temporally related include the following: angioedema, skin manifestations of allergy including cases of Stevens-Johnson syndrome, toxic epidermal necrolysis (TENS), Drug Reaction with Eosinophilia and System Symptoms (DRESS), systemic manifestations of allergy including a case of anaphylactic shock, neuroleptic malignant syndrome, body temperature dysregulation, apnea, atrial fibrillation, benign pituitary adenomas, intestinal obstruction, Parkinson’s disease aggravated, and cerebrovascular adverse events, such as strokes (cerebrovascular accident), and transient ischemic attacks, including some fatalities.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Drugs known to prolong the QT interval

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

Centrally acting drugs and alcohol

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

Levodopa and Dopamine agonists

OKEDI may antagonize the effects of levodopa and dopamine agonists.

Drugs with hypotensive effect

Because of its potential to induce hypotension, OKEDI 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.

9.3 Drug-Behavioural Interactions

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

9.4 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.

The interactions of OKEDI with co-administration of other drugs have not been systematically evaluated. The drug interaction data provided in this section is based on studies with oral risperidone (See Table 5).

Table 5 – Clinically Important Drug Interactions with OKEDI

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

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 7 WARNINGS AND PRECAUTIONS, General, Neurologic).

Concomitant use with Furosemide: See 7.1.4 Geriatrics, Concomitant Use with Furosemide regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide plus risperidone.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The mechanism of action of risperidone, in schizophrenia, is unclear. The drug’s therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxy-risperidone (paliperidone). Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.

Risperidone also binds to α1-adrenergic receptors, 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 Pharmacodynamics

Non-clinical pharmacodynamic studies have not been conducted with OKEDI. Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT₂), dopamine Type 2 (D₂), α1 and α2 adrenergic, and H₁ histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT_1C, 5HT_1D, and 5HT_1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.

10.3 Pharmacokinetics

The PK profile of OKEDI has been evaluated in a single dose clinical study in healthy volunteers and in three clinical studies in patients with stable schizophrenia: after a single dose and multiple dose studies. Additionally, a comparative bioavailability study (to evaluate the steady-state comparative bioavailability of IM OKEDI and oral risperidone), and one multiple dose study of acute treatment (to explore PK characteristics of OKEDI and associations with efficacy and safety) were also performed.

Following single doses of OKEDI, plasma exposure (AUC and C_max) of risperidone, 9-hydroxyrisperidone, and total active moiety increased in an approximately dose proportional manner at doses of 75 and 100 mg.

Plasma exposures at steady state were compared between oral risperidone and OKEDI. Steady state exposure for active moiety after OKEDI 100 mg compared to 4 mg oral risperidone was 25% higher for AUC, 17% higher for C_max, and 8% higher for C_min. Simulations based on population pharmacokinetic modelling show that OKEDI 75 mg exposure was similar to 3 mg oral risperidone at steady state.

Total active moiety concentrations reached clinically relevant levels within the first hours after the first injection without use of a loading dose or any supplemental oral risperidone.

Figure 1. Median and 90% prediction interval active moiety plasma concentration time curve after gluteal administration of 4 consecutive doses of OKEDI 75 mg (upper panel) and OKEDI 100 mg (lower panel). Simulations based on post-hoc parameters and covariates of PRISMA-3 patients.

Absorption

OKEDI contains risperidone in a suspension delivery system that shows a combined absorption process. Following intramuscular injection, a small amount of the drug is immediately released at the moment of the injection that provides immediate plasma levels. After a first peak concentration, reached within 48 hours, mean plasma concentrations decrease sustainedly through Day 14 and then increased again to reach a second peak between approximately Day 21 and Day 24. Following the second peak, plasma concentration decreases gradually over time. The suspension forms a depot that provides sustained therapeutic plasma concentrations that are maintained over the 4 week interval.

After a single intramuscular injection of OKEDI 75 (ROV-RISP-2011-01 study) and 100 mg (ROV-RISP-2020-02 study), mean active moiety concentrations of 13.42 ± 8.6 and 29.25 ± 12.5 ng/mL were achieved, respectively, two hours after administration. Active moiety plasma concentrations were 17.32 ± 8.4 and 20.75 ± 17.3 ng/mL respectively one month after administration, and in most of the patients the drug was completely eliminated 60 days after administration, with active moiety values lower than 1 ng/mL.

The mean trough plasma concentrations (C_trough) and mean maximum peak plasma concentrations (C_max) of active moiety following repeated intramuscular injections with OKEDI are shown in Table 6.

Table 6 - C_trough, C_max and AUCss of active moiety (risperidone + 9-OH-risperidone) following repeated IM injections with OKEDI

Steady state concentrations were attained after the first dose (Figure 1).

Injection site: The average C_max, C_trough and AUC of the total active moiety were similar for both injection sites.

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein. The plasma protein binding of risperidone is 88%, that of 9-hydroxy-risperidone 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 (paliperidone) by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

Elimination

Following a single injection of OKEDI, the mean terminal elimination half-life (T1/2) for OKEDI 75 mg, and OKEDI 100 mg was 8.68 and 8.07 days for the active moiety. This prolonged half-life is related to the slow release of risperidone from the implant depot and subsequent absorption of risperidone into the systemic circulation. In most patients, the drug is completely eliminated 60 days after administration, with median active moiety values lower than 1 ng/mL (See Figure 1).

Risperidone is mainly excreted in the urine and to a lesser extent, in the feces.

Special Populations and Conditions

• Pediatrics: Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
• Geriatrics: No available data
• Age: No specific pharmacokinetic study was conducted to investigate age effects. Based on population pharmacokinetic analyses, for the age range between 18 to 64 years, age do not have a clinical meaningful effect on the pharmacokinetics of OKEDI.

• Sex: No specific pharmacokinetic study was conducted to investigate sex effects. Based on

  • population pharmacokinetic analyses, despite that male patients had 20% lower AUC compared to females, sex do not have a clinical meaningful effect on the pharmacokinetics of OKEDI.
• Genetic Polymorphism: CYP2D6, is the enzyme responsible for the metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Plasma exposure to total active moiety was similar in CYP2D6 extensive, intermediate and poor metabolizers following intramuscular injection with OKEDI, supporting no need for dose adjustment based on genotype of CYP2D6.
• Ethnic origin: No specific pharmacokinetic study was conducted to investigate ethnic origin effects. Based on population pharmacokinetic analyses, only Caucasian (52.6%) and African American (42.1%) were fairly represented, and without any clinical meaningful effect of ethnic origin on the pharmacokinetics of OKEDI.
• Hepatic Insufficiency: The effect of hepatic impairment on the pharmacokinetics of OKEDI has not been studied. The effect of hepatic impairment on the pharmacokinetics of oral risperidone has been evaluated in a dedicated phase I study. While the pharmacokinetics of 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.
• Renal Insufficiency: OKEDI was not studied in patients with renal impairment, however, such effect has been investigated with oral risperidone. In patients with moderate to severe renal disease treated with oral risperidone, the apparent clearance (CL/F) of total active moiety was decreased by 60% in patients with moderate to severe renal disease compared with young healthy subjects.

11 STORAGE, STABILITY AND DISPOSAL

OKEDI may be stored in its unopened original package at room temperature 15°C to 30°.

OKEDI should be used immediately after reconstitution.

For disposal instructions, see more detailed safe disposal instructions under 4.2 Recommended Dose and Dosage Adjustment.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Risperidone

Chemical name: 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one.

Molecular formula and molecular mass: C₂₃H₂₇FN₄O₂, molecular weight 410.5 g/mol

Structural formula:

Physicochemical properties: Risperidone is a white or almost white powder. It is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in dichloromethane, and dissolves in dilute acid solutions 0.1N HCl.

Ionization Constant: pK_a = 8.07 ± 0.10

Partition Coefficient: log P = 2.678 ± 0.406

Melting Point: 170 ^oC

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

The efficacy of OKEDI (75 mg and 100 mg) in the treatment of schizophrenia in adults was established in one Phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel groups study. The study admitted patients with a current diagnosis of schizophrenia, according to the DSM-5 criteria who were experiencing an acute exacerbation or relapse, who had a Positive and Negative Syndrome Scale (PANSS) score at the baseline period between 80 and 120, inclusive. At the screening visit, all risperidone naïve patients received 2 mg/day oral risperidone for 3 days to ensure a lack of any clinically significant hypersensitivity reactions before the trial. Patients with previous history of being treated with risperidone did not receive oral risperidone at the screening and started directly with OKEDI (75 mg or 100 mg) or placebo after randomization. Four hundred and thirty-eight (438) patients were randomised to receive either injection of OKEDI (75 mg or 100 mg) or placebo in the gluteal or deltoid muscle every 4 weeks for a total of 3 doses. In total, patients received 717 injections of OKEDI: 75.5% in the gluteal muscle and 24.5% in deltoid muscle. The mean age of patients was 42.0 (SD: 11.02) years. Two-thirds of patients were male (67.0%) and one-third female (33.0%). Approximately half of patients were White (48.5%) and half were Black or African American (49.9%). Mean BMI of patients was 28.22 (SD: 5.247) kg/m². Demographics and baseline characteristics are presented in Table 7. Demographic and other baseline characteristics were similar in each treatment group. No supplemental oral risperidone was permitted during the study.

Table 7 - Summary of patient demographics for clinical trials in Schizophrenia

14.2 Study Results

The primary endpoint was the change in PANSS total score from baseline to end of study (Day 85). Both OKEDI 75 and 100 mg doses demonstrated a statistically significant improvement compared with placebo based on the primary endpoint (Table 8). Other secondary endpoints were generally supportive of the primary endpoint.

Table 8 - Mean change in PANSS and CGI-S total score from baseline to the end of study (day 85) (mITT Population)

The key secondary efficacy endpoint was defined as the mean change from baseline at Day 85 on the Clinical Global Impression – Severity (CGI-S) score. Both OKEDI treatment groups demonstrated statistically significantly better CGI-S scores versus placebo from day 8 onwards.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

OKEDI was administered for 2 or 12 cycles in rabbits and dogs at doses ranging from 2.5 to 15 mg/kg. The observations in these studies were consistent with the pharmacology of the risperidone active moiety and/or the route of administration of OKEDI.

Results from the OKEDI toxicology studies were consistent with the nonclinical toxicology data known for risperidone and included miosis, as well as enlargement or swelling of the mammary glands. At the site of injection, nodule formation, swelling and inflammation were reported, with higher severity and incidence in the high dose groups of rabbits (15 mg/kg) and dogs (7.5 mg/kg). Reversibility was observed after 4 weeks without administration.

Based on the 12-cycle repeat-dose studies, the safety margins for risperidone were 4.3 (rabbit) and 2 (dog) times the expected exposure achieved at the maximum recommended human dose.

Genotoxicity:

No evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for OKEDI.

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

In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for OKEDI.

Carcinogenicity:

No carcinogenicity studies were conducted with OKEDI.

Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18-months to mice and for 25-months to rats. These doses are equivalent to approximately 0.2-, 0.75-, and 3-times (mice) and 0.4-, 1.5-, and 6-times (rats) the MHRD of 16 mg/day, based on a mg/m² body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m² (mg/kg) basis at which these tumors occurred.

Table 9 - Summary of Tumor Occurrence at the Multiples of the Human Dose on a mg/m² (mg/kg) Basis with Oral Risperidone Dosing

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the oral risperidone carcinogenicity studies; however, measurements during sub chronic 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 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 IM risperidone microspheres every 2 weeks. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear (see 7 WARNINGS AND PRECAUTIONS, General, Endocrine and Metabolism).

Reproductive and Developmental Toxicology:

No mating and fertility studies were conducted with OKEDI.

Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1-to 3-times the maximum recommended human dose (MRHD), of 16 mg/day based on mg/m² body surface area. The effect appeared to be in females since impaired mating behavior was not noted in the male fertility study. In a sub chronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6-to 10-times the MRHD based on mg/m² body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

Teratogenic effects: Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3- times the maximum recommended human dose (MRHD) of 16 mg/day based on mg/m² body surface area; maternal toxicity occurred at 4-times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are doses up to 6-times the MRHD of 16 mg/day risperidone based on mg/m² body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6-times the MRHD, and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2- times the MRHD based on mg/m² body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1-to 3-times the MRHD of 16 mg/day based on mg/m² body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5-times the MRHD based on mg/m² body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered.

Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3-times the MRHD based on mg/m², and the only dose tested in the study (See 7 WARNINGS AND PRECAUTIONS, Reproductive Health, Risks, Teratogenic effects).