Risperdal
Consta
Generic Name: risperidone (injection) (ris PER i done)
Brand Names: Risperdal
Consta
WARNING: INCREASED
MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with
dementia-related psychosis treated with antipsychotic drugs are at an increased
risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a
risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of
death in placebo-treated patients. Over the course of a typical 10-week controlled
trial, the rate of death in drug-treated patients was about 4.5%, compared to a
rate of about 2.6% in the placebo group. Although the causes of death were
varied, most of the deaths appeared to be either cardiovascular (e.g., heart
failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational
studies suggest that, similar to atypical antipsychotic drugs, treatment with
conventional antipsychotic drugs may increase mortality. The extent to which
the findings of increased mortality in observational studies may be attributed
to the antipsychotic drug as opposed to some characteristic(s) of the patients
is not clear. Risperdal Consta® (risperidone)
is not approved for the treatment of patients with dementia-related
psychosis. [see Warnings
and Precautions (5.1)]
Indications
and Usage for Risperdal Consta
Schizophrenia
Risperdal Consta® (risperidone)
is indicated for the treatment of schizophrenia [see Clinical Studies (14.1)].
Bipolar
Disorder
Risperdal Consta® is
indicated as monotherapy or as adjunctive therapy to lithium or valproate for
the maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2, 14.3)].
Risperdal
Consta Dosage and Administration
For patients who have
never taken oral RISPERDAL®, it is recommended to establish tolerability with
oral RISPERDAL®prior to initiating treatment with Risperdal Consta®.
Risperdal Consta® should
be administered every 2 weeks by deep intramuscular (IM) deltoid or gluteal
injection. Each injection should be administered by a health care professional
using the appropriate enclosed safety needle [see Dosage and Administration (2.8)]. For deltoid administration, use the 1-inch needle
alternating injections between the two arms. For gluteal administration, use
the 2-inch needle alternating injections between the two buttocks. Do not
administer intravenously.
Schizophrenia
The recommended dose for
the treatment of schizophrenia is 25 mg IM every 2 weeks. Although dose
response for effectiveness has not been established for Risperdal Consta®,
some patients not responding to 25 mg may benefit from a higher dose of 37.5 mg
or 50 mg. The maximum dose should not exceed 50 mg Risperdal Consta® every
2 weeks. No additional benefit was observed with dosages greater than 50 mg
Risperdal Consta®; however, a higher incidence of adverse effects
was observed.
The efficacy of Risperdal
Consta® in the treatment of schizophrenia has not
been evaluated in controlled clinical trials for longer than 12 weeks. Although
controlled studies have not been conducted to answer the question of how long
patients with schizophrenia should be treated with Risperdal Consta®, oral
risperidone has been shown to be effective in delaying time to relapse in
longer-term use. It is recommended that responding patients be continued on
treatment with Risperdal Consta® at the lowest dose needed. The physician who
elects to use Risperdal Consta® for extended periods should periodically
re-evaluate the long-term risks and benefits of the drug for the individual
patient.
Bipolar
Disorder
The recommended dose for
monotherapy or adjunctive therapy to lithium or valproate for the maintenance
treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients may
benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not
been studied in this population. The physician who elects to use Risperdal
Consta® for extended periods should periodically
re-evaluate the long-term risks and benefits of the drug for the individual
patient.
General
Dosing Information
A lower initial dose of
12.5 mg may be appropriate when clinical factors warrant dose adjustment, such
as in patients with hepatic or renal impairment, for certain drug interactions
that increase risperidone plasma concentrations [see Drug Interactions (7.11)] or in patients who have a history of poor
tolerability to psychotropic medications. The efficacy of the 12.5 mg dose has
not been investigated in clinical trials.
Oral RISPERDAL® (or
another antipsychotic medication) should be given with the first injection of
Risperdal Consta® and continued for 3 weeks (and then
discontinued) to ensure that adequate therapeutic plasma concentrations are
maintained prior to the main release phase of risperidone from the injection
site [see Clinical Pharmacology (12.3)].
Upward dose adjustment
should not be made more frequently than every 4 weeks. The clinical effects of
this dose adjustment should not be anticipated earlier than 3 weeks after the
first injection with the higher dose.
In patients with clinical
factors such as hepatic or renal impairment or certain drug interactions that
increase risperidone plasma concentrations [see Drug Interactions (7.11)], dose reduction as low as 12.5 mg may be
appropriate. The efficacy of the 12.5 mg dose has not been investigated in
clinical trials.
Do not combine two
different dose strengths of Risperdal Consta® in a single
administration.
Dosage
in Special Populations
Elderly
For elderly patients
treated with Risperdal Consta®, the recommended dosage is 25 mg IM every 2 weeks.
Oral RISPERDAL® (or another antipsychotic medication) should
be given with the first injection of Risperdal Consta® and
should be continued for 3 weeks to ensure that adequate therapeutic plasma
concentrations are maintained prior to the main release phase of risperidone
from the injection site [see Clinical Pharmacology (12.3)].
Renal or Hepatic
Impairment
Patients with renal or
hepatic impairment should be treated with titrated doses of oral RISPERDAL®prior
to initiating treatment with Risperdal Consta®. The recommended starting
dose is 0.5 mg oral RISPERDAL® twice daily during the first week, which can
be increased to 1 mg twice daily or 2 mg once daily during the second week. If
a total daily dose of at least 2 mg oral RISPERDAL® is
well tolerated, an injection of 25 mg Risperdal Consta® can
be administered every 2 weeks. Oral supplementation should be continued for 3
weeks after the first injection until the main release of risperidone from the
injection site has begun. In some patients, slower titration may be medically
appropriate. Alternatively, a starting dose of Risperdal Consta® of
12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been
investigated in clinical trials.
Patients with renal
impairment may have less ability to eliminate risperidone than normal adults.
Patients with impaired hepatic function may have an increase in the free
fraction of the risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)]. Elderly patients and patients with a
predisposition to hypotensive reactions or for whom such reactions would pose a
particular risk should be instructed in nonpharmacologic interventions that
help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the
edge of the bed for several minutes before attempting to stand in the morning
and slowly rising from a seated position). These patients should avoid sodium
depletion or dehydration, and circumstances that accentuate hypotension
(alcohol intake, high ambient temperature, etc.). Monitoring of orthostatic
vital signs should be considered [see Warnings and Precautions (5.7)].
Reinitiation
of Treatment in Patients Previously Discontinued
There are no data to
specifically address reinitiation of treatment. When restarting patients who
have had an interval off treatment with Risperdal Consta®, supplementation
with oral RISPERDAL® (or another antipsychotic medication) should
be administered.
Switching
from Other Antipsychotics
There are no
systematically collected data to specifically address switching patients from
other antipsychotics to Risperdal Consta®, or concerning
concomitant administration with other antipsychotics. Previous antipsychotics
should be continued for 3 weeks after the first injection of Risperdal Consta® to
ensure that therapeutic concentrations are maintained until the main release
phase of risperidone from the injection site has begun [see Clinical Pharmacology (12.3)]. For patients who have never taken oral RISPERDAL®, it
is recommended to establish tolerability with oral RISPERDAL® prior
to initiating treatment with Risperdal Consta®. As recommended with
other antipsychotic medications, the need for continuing existing EPS
medication should be re-evaluated periodically.
Co-Administration
of Risperdal Consta® with Certain Other Medications
Co-administration of
carbamazepine and other CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin,
phenobarbital) with risperidone would be expected to cause decreases in the
plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone
combined, which could lead to decreased efficacy of Risperdal Consta® treatment.
The dose of risperidone needs to be titrated accordingly for patients receiving
these enzyme inducers, especially during initiation or discontinuation of
therapy with these inducers [see Drug Interactions (7.11)]. At the initiation of therapy with carbamazepine
or other known CYP 3A4 hepatic enzyme inducers, patients should be closely
monitored during the first 4–8 weeks, since the dose of Risperdal Consta® may
need to be adjusted. A dose increase, or additional oral RISPERDAL®, may
need to be considered. On discontinuation of carbamazepine or other CYP 3A4
hepatic enzyme inducers, the dosage of Risperdal Consta® should
be re-evaluated and, if necessary, decreased. Patients may be placed on a lower
dose of Risperdal Consta® between 2 to 4 weeks before the planned
discontinuation of carbamazepine or other CYP 3A4 inducers to adjust for the
expected increase in plasma concentrations of risperidone plus
9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg
Risperdal Consta® and discontinuing from carbamazepine or other
CYP3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg
dose unless clinical judgment necessitates lowering the Risperdal Consta® dose
to 12.5 mg or necessitates interruption of Risperdal Consta® treatment.
The efficacy of the 12.5 mg dose has not been investigated in clinical trials.
Fluoxetine and paroxetine,
CYP 2D6 inhibitors, have been shown to increase the plasma concentration of
risperidone 2.5–2.8 fold and 3–9 fold respectively. Fluoxetine did not affect
the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the
concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone
needs to be titrated accordingly when fluoxetine or paroxetine is
co-administered. When either concomitant fluoxetine or paroxetine is initiated
or discontinued, the physician should re-evaluate the dose of Risperdal Consta®.
When initiation of fluoxetine or paroxetine is considered, patients may be
placed on a lower dose of Risperdal Consta® between 2 to 4 weeks
before the planned start of fluoxetine or paroxetine therapy to adjust for the
expected increase in plasma concentrations of risperidone. When fluoxetine or
paroxetine is initiated in patients receiving the recommended dose of 25 mg
Risperdal Consta®, it is recommended to continue treatment with the
25 mg dose unless clinical judgment necessitates lowering the Risperdal Consta® dose
to 12.5 mg or necessitates interruption of Risperdal Consta® treatment.
When Risperdal Consta® is initiated in patients already receiving
fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The
efficacy of the 12.5 mg dose has not been investigated in clinical trials. The
effects of discontinuation of concomitant fluoxetine or paroxetine therapy on
the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been
studied. [see Drug Interactions (7.11)]
Instructions
for Use
For
deltoid or gluteal intramuscular injection only
IMPORTANT RESOURCES
For additional
information, visit www.risperdalconsta.com or call Janssen Pharmaceuticals,
Inc. at1-800-JANSSEN (1-800-526-7736).
Important
Information
Risperdal Consta® requires
close attention to these step-by-step Instructions for Use to help ensure
successful administration.
Use
components provided
The components in this
dose pack are specifically designed for use with Risperdal Consta®.
Risperdal Consta® must be reconstituted only in the diluent
supplied in the dose pack.
Do
not substitute ANY components of
the dose pack.
Do
not store suspension after reconstitution
Administer dose as soon as
possible after reconstitution to avoid settling.
Proper
dosing
The entire contents of the
vial must be administered to ensure intended dose of Risperdal Consta® is
delivered.
SINGLE-USE
DEVICE
Do not
reuse. Medical devices require
specific material characteristics to perform as intended. These characteristics
have been verified for single use only. Any attempt to re-process the device
for subsequent re-use may adversely affect the integrity of the device or lead
to deterioration in performance.
Dose
pack contents
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Step
1 Assemble components
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Take out dose
pack Connect vial adapter to
vial
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Wait 30 minutes
Remove dose pack from the refrigerator and allow to sit at room
temperature for at least 30 minutes before
reconstituting.
Do not warm any other way.
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Remove cap from vial
Flip off colored cap from vial.
Wipe top of the grey stopper with an alcohol
swab. Allow to air dry.
Do not remove grey rubber stopper.
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Prepare vial adapter
Hold sterile blister as shown. Peel back and remove paper backing.
Do not remove vial adapter from blister.
Do not touch spike tip at any time. This will result
in contamination.
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Connect vial adapter to vial
Place vial on a hard surface and hold by the base. Center vial adapter
over the grey rubber stopper. Push vial adapter straight down onto vial top
until it snaps securely into place.
Do not place vial adapter on at an angle or diluent
may leak upon transfer to the vial.
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Connect prefilled syringe to vial adapter
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Remove sterile blister
Keep vial vertical to prevent leakage.
Hold base of vial and pull up on the sterile blister to remove.
Do not shake.
Do not touch exposed luer opening on vial adapter.
This will result in contamination.
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Use proper grip
Hold by white collar at the tip of the syringe.
Do not hold syringe by the glass barrel during
assembly.
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Remove cap
Holding the white collar, snap off the white cap.
Do not twist or cut off the white cap.
Do not touch syringe tip. This will result in
contamination.
The broken-off cap can be discarded.
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Connect syringe to vial adapter
Hold vial adapter by skirt to keep stationary.
Hold syringe by white collar then
insert tip into the luer opening of the vial adapter.
Do not hold the glass syringe barrel. This may cause
the white collar to loosen or detach.
Attach the syringe to the vial adapter with a firm clockwise
twisting motion until it feels snug.
Do not over-tighten. Over-tightening may cause the
syringe tip to break.
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Step
2 Reconstitute microspheres
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Inject diluent
Inject entire amount of diluent from syringe into the vial.
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Suspend microspheres in diluent
Continuing to hold down the plunger rod, shake vigorously for
at least 10 seconds, as shown.
Check the suspension. When
properly mixed, the suspension appears uniform, thick and milky in color.
Microspheres will be visible in the liquid.
Immediately proceed to the next step so suspension does not settle.
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Transfer suspension to syringe
Invert vial completely. Slowly pull plunger rod down to withdraw
entire contents from the vial into the syringe.
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Remove vial adapter
Hold white collar on the syringe and unscrew from vial adapter.
Tear section of the vial label at the perforation. Apply detached label to
the syringe for identification purposes.
Discard both vial and vial adapter appropriately.
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Step
3 Attach needle
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Select appropriate needle
Choose needle based on injection location (gluteal or deltoid).
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Attach needle
Peel blister pouch open part way and use to grasp the base of the
needle, as shown.
Holding the white collar on the syringe, attach syringe to needle luer
connection with a firm clockwise twisting motion until
snug.
Do not touch needle luer opening. This will result in
contamination.
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Resuspend microspheres
Fully remove the blister pouch.
Just before injection, shake syringe vigorously again, as some settling will
have occurred.
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Step
4 Inject dose
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Remove transparent needle protector
Move the needle safety device back towards the syringe, as shown. Then
hold white collar on syringe and carefully pull the transparent needle
protector straight off.
Do not twist transparent needle protector, as the
luer connection may loosen.
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Remove air bubbles
Hold needle upright and tap gently to make any air bubbles rise to the
top.
Slowly and carefully press plunger rod upward to remove air.
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Inject
Immediately inject entire contents of syringe intramuscularly (IM)
into the gluteal or deltoid muscle of the patient.
Gluteal injection should be made into the upper-outer quadrant of the gluteal
area.
Do not administer intravenously.
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Secure needle in safety device
Using one hand, place
needle safety device at a 45-degree angle on a hard, flat surface. Press down
with a firm, quick motion until needle is fully engaged in safety device.
Avoid needle stick injury:
Do not use two hands.
Do not intentionally disengage or mishandle the
needle safety device.
Do not attempt to straighten the needle or engage the
safety device if the needle is bent or damaged.
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Properly dispose of needles
Check to confirm needle safety device is fully engaged.
Discard in an approved sharps container.
Also discard the unused needle provided in the dose pack.
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Dosage
Forms and Strengths
Risperdal Consta® is
available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg
risperidone. It is provided as a dose pack, consisting of a vial containing the
risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for
Risperdal Consta®, a West-Medimop Vial Adapter®, and
two Terumo SurGuard® 3 Needles for intramuscular injection (a 21 G
UTW 1-inch needle with needle protection device for deltoid administration and
a 20 G TW 2-inch needle with needle protection device for gluteal
administration).
Contraindications
Risperdal Consta® is
contraindicated in patients with a known hypersensitivity to either risperidone
or paliperidone, or to any of the excipients in the Risperdal Consta® formulation.
Hypersensitivity reactions, including anaphylactic reactions and angioedema,
have been reported in patients treated with risperidone and in patients treated
with paliperidone. Paliperidone is a metabolite of risperidone.
Warnings
and Precautions
Increased
Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly
patients with dementia-related psychosis treated with antipsychotic drugs are
at an increased risk of death. Risperdal Consta® (risperidone) is not approved
for the treatment of dementia-related psychosis (see Boxed Warning).
Cerebrovascular
Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related
Psychosis
Cerebrovascular adverse
events (e.g., stroke, transient ischemic attack), including fatalities, were
reported in patients (mean age 85 years; range 73–97) in trials of oral
risperidone in elderly patients with dementia-related psychosis. In
placebo-controlled trials, there was a significantly higher incidence of
cerebrovascular adverse events in patients treated with oral risperidone
compared to patients treated with placebo. Risperdal Consta® is
not approved for the treatment of patients with dementia-related
psychosis. [see also Boxed Warning and Warnings and Precautions (5.1)]
Neuroleptic
Malignant Syndrome (NMS)
A potentially fatal
symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS)
has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status,
and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may
include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and
acute renal failure.
The diagnostic evaluation
of patients with this syndrome is complicated. In arriving at a diagnosis, it
is important to identify cases in which the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection, etc.) and
untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central
anticholinergic toxicity, heat stroke, drug fever, and primary central nervous
system pathology.
The management of NMS
should include: (1) immediate discontinuation of antipsychotic drugs and other
drugs not essential to concurrent therapy; (2) intensive symptomatic treatment
and medical monitoring; and (3) treatment of any concomitant serious medical
problems for which specific treatments are available. There is no general
agreement about specific pharmacological treatment regimens for uncomplicated
NMS.
If a patient requires antipsychotic
drug treatment after recovery from NMS, the potential reintroduction of drug
therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
Tardive
Dyskinesia
A syndrome of potentially
irreversible, involuntary, dyskinetic movements may develop in patients treated
with antipsychotic drugs. Although the prevalence of the syndrome appears to be
highest among the elderly, especially elderly women, it is impossible to rely
upon prevalence estimates to predict, at the inception of antipsychotic
treatment, which patients are likely to develop the syndrome. Whether
antipsychotic drug products differ in their potential to cause tardive
dyskinesia is unknown.
The risk of developing
tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase as the duration of treatment and the total cumulative dose
of antipsychotic drugs administered to the patient increase. However, the
syndrome can develop, although much less commonly, after relatively brief
treatment periods at low doses.
There is no known
treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress)
the signs and symptoms of the syndrome and thereby may possibly mask the
underlying process. The effect that symptomatic suppression has upon the
long-term course of the syndrome is unknown.
Given these
considerations, Risperdal Consta® should be prescribed in a manner that is most
likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic
illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom
alternative, equally effective, but potentially less harmful treatments are not
available or appropriate. In patients who do require chronic treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory
clinical response should be sought. The need for continued treatment should be
reassessed periodically.
If signs and symptoms of
tardive dyskinesia appear in a patient treated with Risperdal Consta®,
drug discontinuation should be considered. However, some patients may require
treatment with Risperdal Consta® despite the presence of the syndrome.
Metabolic
Changes
Atypical antipsychotic
drugs have been associated with metabolic changes that may increase
cardiovascular/cerebrovascular risk. These metabolic changes include
hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in
the class have been shown to produce some metabolic changes, each drug has its
own specific risk profile.
Hyperglycemia and Diabetes
Mellitus
Hyperglycemia and diabetes
mellitus, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, have been reported in patients treated with
atypical antipsychotics including RISPERDAL®. Assessment of the
relationship between atypical antipsychotic use and glucose abnormalities is
complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of
diabetes mellitus in the general population. Given these confounders, the
relationship between atypical antipsychotic use and hyperglycemia-related
adverse events is not completely understood. However, epidemiological studies
suggest an increased risk of treatment-emergent hyperglycemia-related adverse
events in patients treated with the atypical antipsychotics. Precise risk
estimates for hyperglycemia-related adverse events in patients treated with
atypical antipsychotics are not available.
Patients with an
established diagnosis of diabetes mellitus who are started on atypical
antipsychotics, including RISPERDAL®, should be monitored
regularly for worsening of glucose control. Patients with risk factors for
diabetes mellitus (e.g., obesity, family history of diabetes) who are starting
treatment with atypical antipsychotics, including RISPERDAL®,
should undergo fasting blood glucose testing at the beginning of treatment and
periodically during treatment. Any patient treated with atypical antipsychotics,
including RISPERDAL®, should be monitored for symptoms of hyperglycemia
including polydipsia, polyuria, polyphagia, and weakness. Patients who develop
symptoms of hyperglycemia during treatment with atypical antipsychotics,
including RISPERDAL®, should undergo fasting blood glucose testing. In
some cases, hyperglycemia has resolved when the atypical antipsychotic,
including RISPERDAL®, was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of RISPERDAL®.
Pooled data from 3
double-blind, placebo-controlled studies in subjects with schizophrenia and 4
double-blind, placebo-controlled monotherapy studies in subjects with bipolar
mania with oral risperidone are presented in Table 1.
Table 1. Change in Random Glucose From Seven
Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult
Subjects With Schizophrenia or Bipolar Mania With Oral Risperidone
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RISPERDAL®
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Placebo
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1–8
mg/day
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>8–16
mg/day
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Mean change from baseline (mg/dL)
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N=555
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N=748
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N=164
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Serum Glucose
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-1.4
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0.8
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0.6
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Proportion of patients with shifts
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Serum Glucose
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0.6%
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0.4%
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0%
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(<140 mg/dL to ≥200
mg/dL)
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(3/525)
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(3/702)
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(0/158)
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In longer-term, controlled
and uncontrolled studies in adult subjects, RISPERDAL® was
associated with a mean change in glucose of +2.8 mg/dL at Week 24 (N=151) and
+4.1 mg/dL at Week 48 (N=50).
Dyslipidemia
Undesirable alterations in
lipids have been observed in patients treated with atypical antipsychotics.
Pooled data from 7 placebo-controlled,
3- to 8- week, fixed- or flexible-dose studies in adult subjects with
schizophrenia or bipolar mania are presented in Table 2.
Table 2. Change in Random Lipids From Seven
Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult
Subjects With Schizophrenia or Bipolar Mania With Oral Risperidone
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RISPERDAL®
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Placebo
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1–8
mg/day
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>8–16
mg/day
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Mean change from baseline (mg/dL)
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Cholesterol
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N=559
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N=742
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N=156
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Change from baseline
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0.6
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6.9
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1.8
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Triglycerides
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N=183
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N=307
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N=123
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Change from baseline
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-17.4
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-4.9
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-8.3
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Proportion of patients With Shifts
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Cholesterol
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2.7%
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4.3%
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6.3%
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(<200 mg/dL to ≥240
mg/dL)
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(10/368)
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(22/516)
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(6/96)
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Triglycerides
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1.1%
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2.7%
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2.5%
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(<500 mg/dL to ≥500
mg/dL)
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(2/180)
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(8/301)
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(3/121)
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In longer-term, controlled
and uncontrolled studies, RISPERDAL® was associated with
a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (N=231)
and +5.5 mg/dL at Week 48 (N=86); and (b) non-fasting triglycerides of +19.9
mg/dL at Week 24 (N=52).
Weight Gain
Weight gain has been
observed with atypical antipsychotic use. Clinical monitoring of weight is
recommended.
Data from a
placebo-controlled, 12-week, fixed-dose study in adult subjects with
schizophrenia are presented in Table 3.
Table 3. Mean Change in Body Weight (kg) and
the Proportion of Subjects With ≥7% Gain in Body Weight From
a Placebo-Controlled, 12-Week, Fixed-Dose Study in Adult Subjects With
Schizophrenia
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Risperdal
Consta®
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Placebo
(N=83)
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25 mg
(N=90)
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50 mg
(N=87)
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Weight
(kg)
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Change from baseline
|
-1.4
|
0.5
|
1.2
|
|
Weight
Gain
|
|
|
|
|
≥7%
increase from baseline
|
6%
|
10%
|
8%
|
In an uncontrolled,
longer-term, open-label study, Risperdal Consta® was associated with
a mean change in weight of +2.1 kg at Week 24 (N=268) and +2.8 kg at Week 50
(N=199).
Hyperprolactinemia
As with other drugs that
antagonize dopamine D2 receptors, risperidone elevates prolactin
levels and the elevation persists during chronic administration. Risperidone is
associated with higher levels of prolactin elevation than other antipsychotic
agents.
Hyperprolactinemia may
suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin
secretion. This, in turn, may inhibit reproductive function by impairing
gonadal steroidogenesis in both female and male patients. Galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported in patients
receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when
associated with hypogonadism may lead to decreased bone density in both female and
male subjects.
Tissue culture experiments
indicate that approximately one-third of human breast cancers are prolactin
dependent in vitro, a factor of potential importance if the
prescription of these drugs is contemplated in a patient with previously detected
breast cancer. An increase in pituitary gland, mammary gland, and pancreatic
islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic
adenomas) was observed in the risperidone carcinogenicity studies conducted in
mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic
studies conducted to date have shown an association between chronic
administration of this class of drugs and tumorigenesis in humans; the
available evidence is considered too limited to be conclusive at this time.
Orthostatic
Hypotension
Risperdal Consta® may
induce orthostatic hypotension associated with dizziness, tachycardia, and in
some patients, syncope, especially during the initial dose-titration period
with oral risperidone, probably reflecting its alpha-adrenergic antagonistic
properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated
with Risperdal Consta® in multiple-dose studies. Patients should be
instructed in nonpharmacologic interventions that help to reduce the occurrence
of orthostatic hypotension (e.g., sitting on the edge of the bed for several
minutes before attempting to stand in the morning and slowly rising from a seated
position).
Risperdal Consta® should
be used with particular caution in (1) patients with known cardiovascular
disease (history of myocardial infarction or ischemia, heart failure, or
conduction abnormalities), cerebrovascular disease, and conditions which would
predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2)
in the elderly and patients with renal or hepatic impairment. Monitoring of
orthostatic vital signs should be considered in all such patients, and a dose
reduction should be considered if hypotension occurs. Clinically significant
hypotension has been observed with concomitant use of oral RISPERDAL® and
antihypertensive medication.
Falls
Somnolence,
postural hypotension, motor and sensory instability have been reported with the
use of antipsychotics, including Risperdal Consta®, 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.
Leukopenia,
Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing
experience, events of leukopenia/neutropenia have been reported temporally
related to antipsychotic agents, including Risperdal Consta®.
Agranulocytosis has also been reported.
Possible risk factors for
leukopenia/neutropenia include pre-existing low white blood cell count (WBC)
and a history of drug-induced leukopenia/neutropenia. Patients with a history
of a clinically significant low WBC or a drug-induced leukopenia/neutropenia
should have their complete blood count (CBC) monitored frequently during the
first few months of therapy and discontinuation of Risperdal Consta®should
be considered at the first sign of a clinically significant decline in WBC in
the absence of other causative factors.
Patients with clinically
significant neutropenia should be carefully monitored for fever or other
symptoms or signs of infection and treated promptly if such symptoms or signs
occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should
discontinue Risperdal Consta® and have their WBC followed until recovery.
Potential
for Cognitive and Motor Impairment
Somnolence was reported by
5% of patients treated with Risperdal Consta® in multiple-dose
trials. Since risperidone has the potential to impair judgment, thinking, or
motor skills, patients should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain that treatment with
Risperdal Consta® does not affect them adversely.
Seizures
During premarketing
testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with
Risperdal Consta®. Therefore, Risperdal Consta® should
be used cautiously in patients with a history of seizures.
Dysphagia
Esophageal dysmotility and
aspiration have been associated with antipsychotic drug use. Aspiration
pneumonia is a common cause of morbidity and mortality in patients with
advanced Alzheimer's dementia. Risperdal Consta® and other
antipsychotic drugs should be used cautiously in patients at risk for
aspiration pneumonia. [see also Boxed Warning and Warnings and Precautions (5.1)]
Priapism
Priapism has been reported
during postmarketing surveillance [see Adverse Reactions (6.8)]. Severe priapism may require surgical
intervention.
Thrombotic
Thrombocytopenic Purpura (TTP)
A single case of TTP was
reported in a 28 year-old female patient receiving oral RISPERDAL® in
a large, open premarketing experience (approximately 1300 patients). She
experienced jaundice, fever, and bruising, but eventually recovered after
receiving plasmapheresis. The relationship to RISPERDAL®therapy
is unknown.
Body
Temperature Regulation
Disruption of body
temperature regulation has been attributed to antipsychotic agents. Both
hyperthermia and hypothermia have been reported in association with oral
RISPERDAL® or Risperdal Consta® use.
Caution is advised when prescribing Risperdal Consta® for
patients who will be exposed to temperature extremes.
Administration
Risperdal Consta® should
be injected into the deltoid or gluteal muscle, and care must be taken to avoid
inadvertent injection into a blood vessel. [see Dosage and Administration (2) and Adverse Reactions (6.7)]
Antiemetic
Effect
Risperidone has an
antiemetic effect in animals; this effect may also occur in humans, and may
mask signs and symptoms of overdosage with certain drugs or of conditions such
as intestinal obstruction, Reye's syndrome, and brain tumor.
Suicide
There is an increased risk
of suicide attempt in patients with schizophrenia or bipolar disorder, and
close supervision of high-risk patients should accompany drug therapy.
Risperdal Consta® is to be administered by a health care
professional [see Dosage and Administration (2)]; therefore, suicide due to an overdose is
unlikely.
Use
in Patients with Concomitant Illness
Clinical experience with
Risperdal Consta® in patients with certain concomitant systemic
illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy
Bodies who receive antipsychotics, including Risperdal Consta®, are
reported to have an increased sensitivity to antipsychotic medications.
Manifestations of this increased sensitivity have been reported to include
confusion, obtundation, postural instability with frequent falls,
extrapyramidal symptoms, and clinical features consistent with the neuroleptic
malignant syndrome.
Caution is advisable when
using Risperdal Consta® in patients with diseases or conditions that
could affect metabolism or hemodynamic responses. Risperdal Consta® has
not been evaluated or used to any appreciable extent in patients with a recent
history of myocardial infarction or unstable heart disease. Patients with these
diagnoses were excluded from clinical studies during the product's premarket
testing.
Increased plasma
concentrations of risperidone and 9-hydroxyrisperidone occur in patients with
severe renal impairment (creatinine clearance <30 mL/min/1.73 m2)
treated with oral RISPERDAL®; an increase in the free fraction of risperidone
is also seen in patients with severe hepatic impairment. Patients with renal or
hepatic impairment should be carefully titrated on oral RISPERDAL® before
treatment with Risperdal Consta® is initiated at a dose of 25 mg. A lower
initial dose of 12.5 mg may be appropriate when clinical factors warrant dose
adjustment, such as in patients with renal or hepatic impairment [see Dosage and Administration (2.4)].
Osteodystrophy
and Tumors in Animals
Risperdal Consta® produced
osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year
carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.
Risperdal Consta® produced
renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary
pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg
administered IM every 2 weeks. In addition, Risperdal Consta® produced
an increase in a marker of cellular proliferation in renal tissue in males in
the 1-year toxicity study and in renal tumor-bearing males in the 2-year
carcinogenicity study at 40 mg/kg administered IM every 2 weeks. (Cellular
proliferation was not measured at the low dose or in females in either study.)
The effect dose for
osteodystrophy and the tumor findings is 8 times the IM maximum recommended
human dose (MRHD) (50 mg) on a mg/m2 basis and is
associated with a plasma exposure (AUC) 2 times the expected plasma exposure
(AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal
to the IM MRHD on a mg/m2 basis). Plasma exposure (AUC) at the
no-effect dose was one third the expected plasma exposure (AUC) at the IM MRHD.
Neither
the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally
administered risperidone. Osteodystrophy was
not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a
1-year toxicity study.
The renal tubular and
adrenomedullary tumors in male rats and other tumor findings are described in
more detail in Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of
Fertility).
The relevance of these
findings to human risk is unknown.
Monitoring:
Laboratory Tests
No specific laboratory
tests are recommended.
Adverse
Reactions
The following are
discussed in more detail in other sections of the labeling:
·Increased mortality in elderly patients with
dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
·Cerebrovascular adverse events, including stroke,
in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
·Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
·Tardive dyskinesia [see Warnings and Precautions (5.4)]
·Metabolic changes [see Warnings and Precautions (5.5)]
·Hyperprolactinemia [see Warnings and Precautions (5.6)]
·Orthostatic hypotension [see Warnings and Precautions (5.7)]
·Falls [see Warnings and Precautions (5.8)]
·Leukopenia/Neutropenia and Agranulocytosis [see Warnings and Precautions (5.9)]
·Potential for cognitive and motor impairment [see Warnings and Precautions (5.10)]
·Seizures [see Warnings and Precautions (5.11)]
·Dysphagia [see Warnings and Precautions (5.12)]
·Priapism [see Warnings and Precautions (5.13)]
·Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.14)]
·Disruption of body temperature regulation [see Warnings and Precautions (5.15)]
·Avoidance of inadvertent injection into a blood
vessel [see Warnings and Precautions (5.16)]
·Antiemetic effect [see Warnings and Precautions (5.17)]
·Suicide [see Warnings and Precautions (5.18)]
·Increased sensitivity in patients with Parkinson's
disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.19)]
·Diseases or conditions that could affect metabolism
or hemodynamic responses [see Warnings and Precautions (5.19)]
·Osteodystrophy and tumors in animals [see Warnings and Precautions (5.20)]
The most common adverse
reactions in clinical trials in patients with schizophrenia (≥ 5%) were:
headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia,
sedation, weight increased, pain in extremity, and dry mouth. The most common
adverse reactions in the double-blind, placebo-controlled periods of the
bipolar disorder trials were weight increased (5% in the monotherapy trial) and
tremor and parkinsonism (≥ 10% in the adjunctive treatment trial).
The most common adverse
reactions that were associated with discontinuation from the 12-week
double-blind, placebo-controlled trial in patients with schizophrenia (causing
discontinuation in ≥1% of patients) were agitation, depression, anxiety, and
akathisia. Adverse reactions that were associated with discontinuation from the
double-blind, placebo-controlled periods of the bipolar disorder trials were
hyperglycemia (one patient in the monotherapy trial) and hypokinesia and
tardive dyskinesia (one patient each in the adjunctive treatment trial).
The data described in this
section are derived from a clinical trial database consisting of 2392 patients
exposed to one or more doses of Risperdal Consta® for the treatment of
schizophrenia. Of these 2392 patients, 332 were patients who received Risperdal
Consta® while participating in a 12-week
double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were
schizophrenia patients who received 25 mg or 50 mg Risperdal Consta®. The
conditions and duration of treatment with Risperdal Consta® in
the other clinical trials varied greatly and included (in overlapping
categories) double-blind, fixed- and flexible-dose, placebo- or
active-controlled studies and open-label phases of studies, inpatients and
outpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years)
exposures. Safety was assessed by collecting adverse events and performing
physical examinations, vital signs, body weights, laboratory analyses, and
ECGs.
In addition to the studies
in patients with schizophrenia, safety data are presented from a trial
assessing the efficacy and safety of Risperdal Consta® when
administered as monotherapy for maintenance treatment in patients with bipolar
I disorder. The subjects in this multi-center, double-blind, placebo-controlled
study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I
and who were stable on risperidone (oral or long-acting injection), were stable
on other antipsychotics or mood stabilizers, or were experiencing an acute
episode. After a 3-week period of treatment with open-label oral risperidone
(N=440), subjects who demonstrated an initial response to oral risperidone in
this period and those who were stable on risperidone (oral or long-acting injection)
at study entry entered into a 26-week stabilization period of open-label
Risperdal Consta® (N=501). Subjects who demonstrated a
maintained response during this period were then randomized into a 24-month
double-blind, placebo-controlled period in which they received Risperdal Consta® (N=154)
or placebo (N=149) as monotherapy. Subjects who relapsed or who completed the
double-blind period could choose to enter an 8-week open-label Risperdal Consta® extension
period (N=160).
Safety data are also
presented from a trial assessing the efficacy and safety of Risperdal Consta® when
administered as adjunctive maintenance treatment in patients with bipolar
disorder. The subjects in this multi-center, double-blind, placebo-controlled study
were adult patients who met DSM-IV criteria for Bipolar Disorder Type I or Type
II and who experienced at least 4 episodes of mood disorder requiring
psychiatric/clinical intervention in the previous 12 months, including at least
2 episodes in the 6 months prior to the start of the study. At the start of
this study, all patients (N=275) entered into a 16-week open-label treatment
phase in which they received Risperdal Consta® in addition to
continuing their treatment as usual, which consisted of various mood
stabilizers (primarily lithium and valproate), antidepressants, and/or
anxiolytics. Patients who reached remission at the end of this 16-week
open-label treatment phase (N=139) were then randomized into a 52-week
double-blind, placebo-controlled phase in which they received Risperdal Consta® (N=72)
or placebo (n=67) as adjunctive treatment in addition to continuing their
treatment as usual. Patients who did not reach remission at the end of the
16-week open-label treatment phase could choose to continue to receive
Risperdal Consta® as adjunctive therapy in an open-label
manner, in addition to continuing their treatment as usual, for up to an
additional 36 weeks as clinically indicated for a total period of up to 52
weeks; these patients (N=70) were also included in the evaluation of safety.
Adverse events during
exposure to study treatment were obtained by general inquiry and recorded by
clinical investigators using their own terminology. Consequently, to provide a
meaningful estimate of the proportion of individuals experiencing adverse
events, events were grouped in standardized categories using MedDRA
terminology.
Throughout this section,
adverse reactions are reported. Adverse reactions are adverse events that were
considered to be reasonably associated with the use of Risperdal Consta® (adverse
drug reactions) based on the comprehensive assessment of the available adverse
event information. A causal association for Risperdal Consta® often
cannot be reliably established in individual cases. Further, because clinical
trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates observed
in clinical practice.
The majority of all
adverse reactions were mild to moderate in severity.
Commonly-Observed
Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials -
Schizophrenia
Table 4 lists the adverse reactions
reported in 2% or more of Risperdal Consta®-treated patients with
schizophrenia in one 12-week double-blind, placebo-controlled trial.
Table 4. Adverse Reactions in ≥2%
of Risperdal Consta®-Treated Patients
with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial
|
|
|
Percentage
of Patients Reporting Event
|
|
|
Risperdal
Consta®
|
Placebo
|
|
System/Organ Class
|
25 mg
|
50 mg
|
|
|
Adverse
Reaction
|
(N=99)
|
(N=103)
|
(N=98)
|
|
*
Fatigue
includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder,
musculoskeletal stiffness, muscle rigidity, and bradykinesia. Akathisia
includes akathisia and restlessness. Sedation includes sedation and somnolence.
|
|
Eye disorders
|
|
|
|
|
Vision
blurred
|
2
|
3
|
0
|
|
Gastrointestinal disorders
|
|
Constipation
|
5
|
7
|
1
|
|
Dry mouth
|
0
|
7
|
1
|
|
Dyspepsia
|
6
|
6
|
0
|
|
Nausea
|
3
|
4
|
5
|
|
Toothache
|
1
|
3
|
0
|
|
Salivary
hypersecretion
|
4
|
1
|
0
|
|
General disorders and administration site
conditions
|
|
Fatigue*
|
3
|
9
|
0
|
|
Edema
peripheral
|
2
|
3
|
1
|
|
Pain
|
4
|
1
|
0
|
|
Pyrexia
|
2
|
1
|
0
|
|
Infections and infestations
|
|
Upper
respiratory tract infection
|
2
|
0
|
1
|
|
Investigations
|
|
Weight
increased
|
5
|
4
|
2
|
|
Weight
decreased
|
4
|
1
|
1
|
|
Musculoskeletal and connective tissue
disorders
|
|
Pain in
extremity
|
6
|
2
|
1
|
|
Nervous system disorders
|
|
Headache
|
15
|
21
|
12
|
|
Parkinsonism*
|
8
|
15
|
9
|
|
Dizziness
|
7
|
11
|
6
|
|
Akathisia*
|
4
|
11
|
6
|
|
Sedation*
|
5
|
6
|
3
|
|
Tremor
|
0
|
3
|
0
|
|
Syncope
|
2
|
1
|
0
|
|
Hypoesthesia
|
2
|
0
|
0
|
|
Respiratory, thoracic and mediastinal
disorders
|
|
Cough
|
4
|
2
|
3
|
|
Sinus
congestion
|
2
|
0
|
0
|
|
Skin and subcutaneous tissue disorders
|
|
Acne
|
2
|
2
|
0
|
|
Dry skin
|
2
|
0
|
0
|
Commonly-Observed
Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar
Disorder
Table 5 lists the
treatment-emergent adverse reactions reported in 2% or more of Risperdal Consta®-treated
patients in the 24-month double-blind, placebo-controlled treatment period of
the trial assessing the efficacy and safety of Risperdal Consta® when
administered as monotherapy for maintenance treatment in patients with Bipolar
I Disorder.
Table 5. Adverse Reactions in ≥2%
of Patients with Bipolar I Disorder Treated with Risperdal Consta® as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial
|
|
|
Percentage
of Patients Reporting Event
|
|
System/Organ Class
Adverse Reaction
|
Risperdal
Consta®
(N=154)
|
Placebo
(N=149)
|
|
Investigations
|
|
Weight
increased
|
5
|
1
|
|
Nervous system disorders
|
|
Dizziness
|
3
|
1
|
|
Vascular disorders
|
|
Hypertension
|
3
|
1
|
Table 6 lists the
treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week
double-blind, placebo-controlled treatment phase of a trial assessing the
efficacy and safety of Risperdal Consta® when administered as
adjunctive maintenance treatment in patients with bipolar disorder.
Table 6. Adverse Reactions in ≥ 4%
of Patients with Bipolar Disorder Treated with Risperdal Consta® as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled
Trial
|
|
|
Percentage
of Patients Reporting Event
|
|
System/Organ Class
Adverse Reaction
|
Risperdal
Consta® +
Treatment as Usual*
(N=72)
|
Placebo +
Treatment as Usual*
(N=67)
|
|
*
Patients received double-blind Risperdal Consta® or placebo in addition to continuing their
treatment as usual, which included mood stabilizers, antidepressants, and/or
anxiolytics.
†
Parkinsonism includes muscle rigidity,
hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes muscle
twitching and dyskinesia.
‡
Sedation
includes sedation and somnolence.
|
|
General disorders and administration site
conditions
|
|
Gait
abnormal
|
4
|
0
|
|
Infections and infestations
|
|
Upper
respiratory tract infection
|
6
|
3
|
|
Investigations
|
|
Weight
increased
|
7
|
1
|
|
Metabolism and nutrition disorders
|
|
Decreased
appetite
|
6
|
1
|
|
Increased
appetite
|
4
|
0
|
|
Musculoskeletal and connective tissue
disorders
|
|
Arthralgia
|
4
|
3
|
|
Nervous system disorders
|
|
Tremor
|
24
|
16
|
|
Parkinsonism†
|
15
|
6
|
|
Dyskinesia†
|
6
|
3
|
|
Sedation‡
|
7
|
1
|
|
Disturbance
in attention
|
4
|
0
|
|
Reproductive system and breast disorders
|
|
Amenorrhea
|
4
|
1
|
|
Respiratory, thoracic and mediastinal
disorders
|
|
Cough
|
4
|
1
|
Other
Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone
The following additional
adverse reactions occurred in < 2% of the Risperdal Consta®-treated
patients in the above schizophrenia double-blind, placebo-controlled trial
dataset, in < 2% of the Risperdal Consta®-treated patients in the
above double-blind, placebo-controlled period of the monotherapy bipolar
disorder trial dataset, or in < 4% of the Risperdal Consta®-treated
patients in the above double-blind, placebo-controlled period of the adjunctive
treatment bipolar disorder trial dataset. The following also includes
additional adverse reactions reported at any frequency in Risperdal Consta®-treated
patients who participated in the open-label phases of the above bipolar
disorder studies and in other studies, including double-blind, active
controlled and open-label studies in schizophrenia and bipolar disorder.
Blood
and lymphatic system disorders:
anemia, neutropenia
Cardiac
disorders: tachycardia, atrioventricular block
first degree, palpitations, sinus bradycardia, bundle branch block left,
bradycardia, sinus tachycardia, bundle branch block right
Ear
and labyrinth disorders: ear pain, vertigo
Endocrine
disorders: hyperprolactinemia
Eye
disorders: conjunctivitis, visual acuity
reduced
Gastrointestinal
disorders: diarrhea, vomiting, abdominal pain
upper, abdominal pain, stomach discomfort, gastritis
General
disorders and administration site conditions: injection site pain, chest discomfort, chest
pain, influenza like illness, sluggishness, malaise, induration, injection site
induration, injection site swelling, injection site reaction, face edema
Immune
system disorders: hypersensitivity
Infections
and infestations: nasopharyngitis,
influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract
infection, ear infection, pneumonia, lower respiratory tract infection,
pharyngitis, sinusitis, viral infection, infection, localized infection,
cystitis, gastroenteritis, subcutaneous abscess
Injury
and poisoning: fall, procedural pain
Investigations: blood prolactin increased, alanine
aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl
transferase increased, blood glucose increased, hepatic enzyme increased,
aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose
urine present
Metabolism
and nutritional disorders: anorexia, hyperglycemia
Musculoskeletal,
connective tissue and bone disorders:
posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck
pain, musculoskeletal chest pain
Nervous
system disorders: coordination abnormal,
dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural,
convulsion, akinesia, hypokinesia, dysarthria
Psychiatric
disorders: insomnia, agitation, anxiety, sleep
disorder, depression, initial insomnia, libido decreased, nervousness
Renal
and urinary disorders: urinary incontinence
Reproductive
system and breast disorders: galactorrhea,
oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder,
gynecomastia, breast discomfort, menstruation irregular, menstruation delayed,
menstrual disorder, ejaculation delayed
Respiratory,
thoracic and mediastinal disorders:
nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea
Skin
and subcutaneous tissue disorders:
rash, eczema, pruritus generalized, pruritus
Vascular
disorders: hypotension, orthostatic
hypotension
Additional Adverse Reactions
Reported with Oral RISPERDAL®
The following is a list of
additional adverse reactions that have been reported during the clinical trial
evaluation of oral RISPERDAL®, regardless of frequency of occurrence:
Blood
and Lymphatic Disorders: granulocytopenia
Cardiac
Disorders: atrioventricular block
Ear
and Labyrinth Disorders: tinnitus
Eye
Disorders: ocular hyperemia, eye discharge,
eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye,
lacrimation increased, photophobia, glaucoma
Gastrointestinal
Disorders: abdominal pain upper, dysphagia,
fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis,
aptyalism
General
Disorders: thirst, feeling abnormal, gait
disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug
withdrawal syndrome, peripheral coldness
Immune
System Disorders: drug hypersensitivity
Infections
and Infestations: tonsillitis, eye
infection, cellulitis, otitis media, onychomycosis, acarodermatitis,
bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media
chronic
Investigations: body temperature increased, heart rate increased,
eosinophil count increased, white blood cell count decreased, hemoglobin
decreased, blood creatine phosphokinase increased, hematocrit decreased, body
temperature decreased, blood pressure decreased, transaminases increased
Metabolism
and Nutrition Disorders: polydipsia
Musculoskeletal,
Connective Tissue, and Bone Disorders:
joint swelling, joint stiffness, rhabdomyolysis, torticollis
Nervous
System Disorders: hypertonia, balance
disorder, dysarthria, unresponsive to stimuli, depressed level of
consciousness, movement disorder, hypokinesia, parkinsonian rest tremor,
transient ischemic attack, cerebrovascular accident, masked facies, speech
disorder, loss of consciousness, muscle contractions involuntary, akinesia,
cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome,
diabetic coma, head titubation
Psychiatric
Disorders: blunted affect,
confusional state, middle insomnia, listlessness, anorgasmia
Renal
and Urinary Disorders: enuresis, dysuria,
pollakiuria
Reproductive
System and Breast Disorders: vaginal discharge,
retrograde ejaculation, ejaculation disorder, ejaculation failure, breast
enlargement
Respiratory,
Thoracic, and Mediastinal Disorders: epistaxis,
wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary
congestion, respiratory tract congestion, rales, respiratory disorder,
hyperventilation, nasal edema
Skin
and Subcutaneous Tissue Disorders: erythema,
skin discoloration, skin lesion, skin disorder, rash erythematous, rash
papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized,
rash maculopapular
Vascular
Disorders: flushing
Discontinuations
Due to Adverse Reactions
Schizophrenia
Approximately 11% (22/202)
of Risperdal Consta®-treated patients in the 12-week double-blind,
placebo-controlled schizophrenia trial discontinued treatment due to an adverse
event, compared with 13% (13/98) who received placebo. The adverse reactions
associated with discontinuation in two or more Risperdal Consta®-treated
patients were: agitation (3%), depression (2%), anxiety (1%), and akathisia
(1%).
Bipolar Disorder
In the 24-month
double-blind, placebo-controlled treatment period of the trial assessing the
efficacy and safety of Risperdal Consta® when administered as
monotherapy for maintenance treatment in patients with bipolar I disorder, 1
(0.6%) of 154 Risperdal Consta®-treated patients discontinued due to an adverse
reaction (hyperglycemia).
In the 52-week
double-blind phase of the placebo-controlled trial in which Risperdal Consta® was
administered as adjunctive therapy to patients with bipolar disorder in
addition to continuing with their treatment as usual, approximately 4% (3/72)
of Risperdal Consta®-treated patients discontinued treatment due to an
adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse
reactions associated with discontinuation in Risperdal Consta®-treated
patients were: hypokinesia (one patient) and tardive dyskinesia (one patient).
Dose
Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms:
Two methods were used to
measure extrapyramidal symptoms (EPS) in the 12-week double-blind,
placebo-controlled trial comparing three doses of Risperdal Consta® (25
mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including:
(1) the incidence of spontaneous reports of EPS symptoms; and (2) the change
from baseline to endpoint on the total score (sum of the subscale scores for
parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating
Scale (ESRS).
As shown in Table 1, the
overall incidence of EPS-related adverse reactions (akathisia, dystonia,
parkinsonism, and tremor) in patients treated with 25 mg Risperdal Consta® was
comparable to that of patients treated with placebo; the incidence of
EPS-related adverse reactions was higher in patients treated with 50 mg
Risperdal Consta®.
The median change from
baseline to endpoint in total ESRS score showed no worsening in patients
treated with Risperdal Consta® compared with patients treated with placebo:
0 (placebo group); -1 (25-mg group, significantly less than the placebo group);
and 0 (50-mg group).
Dystonia
Class Effect: 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.
Changes
in ECG
The electrocardiograms of
202 schizophrenic patients treated with 25 mg or 50 mg Risperdal Consta®and
98 schizophrenic patients treated with placebo in the 12-week double-blind,
placebo-controlled trial were evaluated. Compared with placebo, there were no
statistically significant differences in QTc intervals (using Fridericia's and
linear correction factors) during treatment with Risperdal Consta®.
The electrocardiograms of
227 patients with Bipolar I Disorder were evaluated in the 24-month
double-blind, placebo-controlled period. There were no clinically relevant
differences in QTc intervals (using Fridericia's and linear correction factors)
during treatment with Risperdal Consta® compared to placebo.
The electrocardiograms of
85 patients with bipolar disorder were evaluated in the 52-week double-blind,
placebo-controlled trial. There were no statistically significant differences
in QTc intervals (using Fridericia's and linear correction factors) during
treatment with Risperdal Consta® 25 mg, 37.5 mg, or 50 mg when administered as
adjunctive treatment in addition to continuing treatment as usual compared to
placebo.
Pain
Assessment and Local Injection Site Reactions
The mean intensity of
injection pain reported by patients with schizophrenia using a visual analog
scale (0 = no pain to 100 = unbearably painful) decreased in all treatment
groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0
to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator
ratings indicated that 1% of patients treated with 25 mg or 50 mg Risperdal
Consta®experienced redness, swelling, or induration at the
injection site.
In a separate study to
observe local-site tolerability in which Risperdal Consta® was
administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no
patient discontinued treatment due to local injection site pain or reaction.
Clinician ratings indicated that only mild redness, swelling, or induration at
the injection site was observed in subjects treated with 37.5 mg or 50 mg
Risperdal Consta® at 2 hours after deltoid injection. All
ratings returned to baseline at the predose assessment of the next injection 2
weeks later. No moderate or severe reactions were observed in any subject.
Postmarketing
Experience
The following adverse
reactions have been identified during postapproval use of risperidone; because
these reactions are reported voluntarily from a population of uncertain size,
it is not possible to reliably estimate their frequency: agranulocytosis,
alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood
cholesterol increased, blood triglycerides increased, diabetes mellitus,
diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal
syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate
antidiuretic hormone secretion, intestinal obstruction, jaundice, mania,
pancreatitis, priapism, QT prolongation, sleep apnea syndrome,
thrombocytopenia, urinary retention, and water intoxication. In addition, the
following adverse reactions have been observed during postapproval use of
Risperdal Consta®: cerebrovascular disorders, including
cerebrovascular accidents, and diabetes mellitus aggravated.
Retinal artery occlusion
after injection of Risperdal Consta® has been reported
during postmarketing surveillance. This has been reported in the presence of
abnormal arteriovenous anastomosis.
Serious injection site
reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and
ulcer have been reported with Risperdal Consta® during postmarketing
surveillance. Isolated cases required surgical intervention.
Very rarely, cases of
anaphylactic reaction after injection with Risperdal Consta® have
been reported during postmarketing experience in patients who have previously
tolerated oral risperidone.
Drug
Interactions
The interactions of
Risperdal Consta® with coadministration of other drugs have not
been systematically evaluated. The drug interaction data provided in this
section is based on studies with oral RISPERDAL®.
Centrally-Acting
Drugs and Alcohol
Given the primary CNS
effects of risperidone, caution should be used when Risperdal Consta® is
administered in combination with other centrally-acting drugs or alcohol.
Drugs
with Hypotensive Effects
Because of its potential
for inducing hypotension, Risperdal Consta® may enhance the
hypotensive effects of other therapeutic agents with this potential.
Levodopa
and Dopamine Agonists
Risperdal Consta® may
antagonize the effects of levodopa and dopamine agonists.
Amitriptyline
Amitriptyline did not
affect the pharmacokinetics of risperidone or of risperidone and
9-hydroxyrisperidone combined following concomitant administration with oral
RISPERDAL®.
Cimetidine
and Ranitidine
Cimetidine and ranitidine
increased the bioavailability of oral risperidone by 64% and 26%, respectively.
However, cimetidine did not affect the AUC of risperidone and
9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of
risperidone and 9-hydroxyrisperidone combined by 20%.
Clozapine
Chronic administration of
clozapine with risperidone may decrease the clearance of risperidone.
Lithium
Repeated doses of oral
RISPERDAL® (3 mg twice daily) did not affect the
exposure (AUC) or peak plasma concentrations (Cmax) of lithium (N=13).
Valproate
Repeated doses of oral
RISPERDAL® (4 mg once daily) did not affect the pre-dose
or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day
in three divided doses) compared to placebo (N=21). However, there was a 20%
increase in valproate peak plasma concentration (Cmax) after concomitant
administration of oral RISPERDAL®.
Digoxin
Oral RISPERDAL® (0.25
mg twice daily) did not show a clinically relevant effect on the
pharmacokinetics of digoxin.
Topiramate
Oral RISPERDAL® administered
at doses from 1–6 mg/day concomitantly with topiramate 400 mg/day resulted in a
23% decrease in risperidone Cmax and a 33% decrease in risperidone AUC0–12 hour at
steady state. Minimal reductions in the exposure to risperidone and
9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were
observed. This interaction is unlikely to be of clinical significance. There
was no clinically relevant effect of oral RISPERDAL® on
the pharmacokinetics of topiramate.
Drugs
That Inhibit CYP 2D6 and Other CYP Isozymes
Risperidone is metabolized
to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the
population and that can be inhibited by a variety of psychotropic and other
drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of
risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of
risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of
clinical studies involving a modest number of poor metabolizers (n≅70 patients) does not
suggest that poor and extensive metabolizers have different rates of adverse
effects. No comparison of effectiveness in the two groups has been made.
In vitro studies showed that drugs metabolized by
other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak
inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once
daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown
to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold
respectively. Fluoxetine did not affect the plasma concentration of
9-hydroxyrisperidone. Paroxetine lowered the concentration of
9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate the
dose of Risperdal Consta®. When initiation of fluoxetine or paroxetine is
considered, patients may be placed on a lower dose of Risperdal Consta®between
2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to
adjust for the expected increase in plasma concentrations of risperidone. When
fluoxetine or paroxetine is initiated in patients receiving the recommended
dose of 25 mg Risperdal Consta®, it is recommended to continue treatment with the
25-mg dose unless clinical judgment necessitates lowering the Risperdal Consta®dose
to 12.5 mg or necessitates interruption of Risperdal Consta® treatment.
When Risperdal Consta®is initiated in patients already receiving
fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The
efficacy of the 12.5 mg dose has not been investigated in clinical
trials. [see also Dosage and Administration (2.5)]. The effects of discontinuation of concomitant
fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and
9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant
interactions between oral RISPERDAL® and erythromycin.
Carbamazepine
and Other CYP 3A4 Enzyme Inducers
Carbamazepine co-administration
with oral RISPERDAL® decreased the steady-state plasma
concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma
concentrations of carbamazepine did not appear to be affected.
Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin,
rifampin, and phenobarbital) with risperidone may cause similar decreases in
the combined plasma concentrations of risperidone and 9-hydroxyrisperidone,
which could lead to decreased efficacy of Risperdal Consta® treatment.
At the initiation of therapy with carbamazepine or other known hepatic enzyme
inducers, patients should be closely monitored during the first 4–8 weeks,
since the dose of Risperdal Consta® may need to be
adjusted. A dose increase, or additional oral RISPERDAL®, may
need to be considered. On discontinuation of carbamazepine or other CYP 3A4
hepatic enzyme inducers, the dosage of Risperdal Consta® should
be re-evaluated and, if necessary, decreased. Patients may be placed on a lower
dose of Risperdal Consta® between 2 to 4 weeks before the planned
discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for
the expected increase in plasma concentrations of risperidone plus
9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg
Risperdal Consta® and discontinuing from carbamazepine or other
CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg
dose unless clinical judgment necessitates lowering the Risperdal Consta® dose
to 12.5 mg or necessitates interruption of Risperdal Consta® treatment.
The efficacy of the 12.5 mg dose has not been investigated in clinical
trials. [see also Dosage and Administration (2.5)]
Drugs
Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a
relatively weak inhibitor of CYP 2D6. Therefore, Risperdal Consta® is
not expected to substantially inhibit the clearance of drugs that are
metabolized by this enzymatic pathway. In drug interaction studies, oral
RISPERDAL® did not significantly affect the
pharmacokinetics of donepezil and galantamine, which are metabolized by CYP
2D6.
USE
IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C.
The teratogenic potential
of oral risperidone was studied in three embryofetal development studies in
Sprague-Dawley and Wistar rats (0.63–10 mg/kg or 0.4 to 6 times the oral
maximum recommended human dose [MRHD] on a mg/m2 basis) and in one
embryofetal development study in New Zealand rabbits (0.31–5 mg/kg or 0.4 to 6
times the oral MRHD on a mg/m2 basis). The incidence of malformations was
not increased compared to control in offspring of rats or rabbits given 0.4 to
6 times the oral MRHD on a mg/m2 basis. In three reproductive studies in rats
(two peri/post-natal development studies and a multigenerational study), there
was an increase in pup deaths during the first 4 days of lactation at doses of
0.16–5 mg/kg or 0.1 to 3 times the oral MRHD on a mg/m2 basis.
It is not known whether these deaths were due to a direct effect on the fetuses
or pups or to effects on the dams.
There was no no-effect
dose for increased rat pup mortality. In one peri/post-natal development study,
there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times
the oral MRHD on a mg/m2 basis. In a cross-fostering study in Wistar
rats, toxic effects on the fetus or pups, as evidenced by a decrease in the
number of live pups and an increase in the number of dead pups at birth (Day
0), and a decrease in birth weight in pups of drug-treated dams were observed.
In addition, there was an increase in deaths by Day 1 among pups of
drug-treated dams, regardless of whether or not the pups were cross-fostered.
Risperidone also appeared to impair maternal behavior in that pup body weight
gain and survival (from Days 1 to 4 of lactation) were reduced in pups born to
control but reared by drug-treated dams. These effects were all noted at the
one dose of risperidone tested, i.e., 5 mg/kg or 3 times the oral MRHD on a
mg/m2 basis.
No studies were conducted
with Risperdal Consta®.
Placental transfer of
risperidone occurs in rat pups. There are no adequate and well-controlled
studies in pregnant women. However, there was one report of a case of agenesis
of the corpus callosum in an infant exposed to risperidone in
utero. The causal relationship to oral
RISPERDAL® therapy is unknown.
Non-Teratogenic Effects
Neonates exposed to
antipsychotic drugs (including RISPERDAL®) during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal
symptoms following delivery. There have been reports of agitation, hypertonia,
hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in
these neonates. These complications have varied in severity; while in some
cases symptoms have been self-limited, in other cases neonates have required
intensive care unit support and prolonged hospitalization.
Risperdal Consta® should
be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Labor
and Delivery
The effect of Risperdal
Consta® on labor and delivery in humans is unknown.
Nursing
Mothers
Risperidone and
9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women
should not breast-feed during treatment with Risperdal Consta® and
for at least 12 weeks after the last injection.
Pediatric
Use
Risperdal Consta® has
not been studied in children younger than 18 years old. However, juvenile
animal toxicology studies have been conducted with oral risperidone.
Juvenile dogs were treated
for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day.
Decreased bone length and density were seen, with a no-effect dose of 0.31
mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its
active metabolite paliperidone (9-hydroxy-risperidone) which were similar to
those in children and adolescents receiving the maximum recommended human dose
(MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen at all
doses in both males and females. The above effects showed little or no
reversibility in females after a 12 week drug-free recovery period.
In a study in which
juvenile rats were treated with oral risperidone from days 12 to 50 of age, a
reversible impairment of performance in a test of learning and memory was seen,
in females only, with a no-effect dose of 0.63 mg/kg/day. This dose produced
plasma levels (AUC) of risperidone plus paliperidone about half those observed
in humans at the MRHD. No other consistent effects on neurobehavioral or
reproductive development were seen up to the highest testable dose (1.25
mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus
paliperidone which were about two thirds of those observed in humans at the
MRHD.
The long-term effects of
risperidone on growth and sexual maturation have not been fully evaluated in
children and adolescents.
Geriatric
Use
In an open-label study, 57
clinically stable, elderly patients (≥ 65 years old) with schizophrenia or
schizoaffective disorder received Risperdal Consta® every
2 weeks for up to 12 months. In general, no differences in the tolerability of
Risperdal Consta® were observed between otherwise healthy
elderly and nonelderly patients. Therefore, dosing recommendations for
otherwise healthy elderly patients are the same as for nonelderly patients.
Because elderly patients exhibit a greater tendency to orthostatic hypotension
than nonelderly patients, elderly patients should be instructed in
nonpharmacologic interventions that help to reduce the occurrence of
orthostatic hypotension (e.g., sitting on the edge of the bed for several
minutes before attempting to stand in the morning and slowly rising from a
seated position). In addition, monitoring of orthostatic vital signs should be
considered in elderly patients for whom orthostatic hypotension is of
concern [see Warnings and Precautions (5.7)].
Concomitant use with
Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four
placebo-controlled trials in elderly patients with dementia-related psychosis,
a higher incidence of mortality was observed in patients treated with
furosemide plus oral risperidone when compared to patients treated with oral
risperidone alone or with oral placebo plus furosemide. No pathological
mechanism has been identified to explain this finding, and no consistent
pattern for cause of death was observed. An increase of mortality in elderly
patients with dementia-related psychosis was seen with the use of oral
risperidone regardless of concomitant use with furosemide. Risperdal Consta®is
not approved for the treatment of patients with dementia-related
psychosis. [see Boxed Warning and Warnings and Precautions (5.1)]
Drug
Abuse and Dependence
Controlled
Substance
Risperdal Consta® (risperidone)
is not a controlled substance.
Abuse
Risperdal Consta® has
not been systematically studied in animals or humans for its potential for
abuse. Because Risperdal Consta® is to be administered by health care
professionals, the potential for misuse or abuse by patients is low.
Dependence
Risperdal Consta® has
not been systematically studied in animals or humans for its potential for
tolerance or physical dependence.
Overdosage
Human
Experience
No cases of overdose were
reported in premarketing studies with Risperdal Consta®.
Because Risperdal Consta® is to be administered by health care
professionals, the potential for overdosage by patients is low.
In premarketing experience
with oral RISPERDAL®, there were eight reports of acute RISPERDAL®overdosage,
with estimated doses ranging from 20 to 300 mg and no fatalities. In general,
reported signs and symptoms were those resulting from an exaggeration of the
drug's known pharmacological effects, i.e., drowsiness and sedation,
tachycardia and hypotension, and extrapyramidal symptoms. One case, involving
an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia,
prolonged QT, and widened QRS. Another case, involving an estimated overdose of
36 mg, was associated with a seizure.
Postmarketing experience
with oral RISPERDAL® includes reports of acute overdose, with
estimated doses of up to 360 mg. In general, the most frequently reported signs
and symptoms are those resulting from an exaggeration of the drug's known
pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension,
and extrapyramidal symptoms. Other adverse reactions reported since market
introduction related to oral RISPERDAL® overdose include
prolonged QT interval and convulsions. Torsade de pointes has been reported in
association with combined overdose of oral RISPERDAL® and
paroxetine.
Management
of Overdosage
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. Therefore, appropriate supportive measures should be
instituted. The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate
measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine
and dopamine should not be used, since beta stimulation may worsen hypotension
in the setting of risperidone-induced alpha blockade). In cases of severe
extrapyramidal symptoms, anticholinergic medication should be administered.
Close medical supervision and monitoring should continue until the patient
recovers.
Risperdal
Consta Description
Risperidone is a
psychotropic agent belonging to the chemical class of benzisoxazole
derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The
structural formula is:
Risperidone is practically
insoluble in water, freely soluble in methylene chloride, and soluble in
methanol and 0.1 N HCl.
Risperdal Consta® (risperidone)
Long-Acting Injection is a combination of extended-release microspheres for
injection and diluent for parenteral use.
The extended-release
microspheres formulation is a white to off-white, free-flowing powder that is
available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg risperidone
per vial. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide
(PLG) at a concentration of 381 mg risperidone per gram of microspheres.
The diluent for parenteral
use is a clear, colorless solution. Composition of the diluent includes citric
acid anhydrous, disodium hydrogen phosphate dihydrate, polysorbate 20, sodium
carboxymethyl cellulose, sodium chloride, sodium hydroxide, and water for
injection. The microspheres are suspended in the diluent prior to injection.
Risperdal Consta® is
provided as a dose pack, consisting of a vial containing the microspheres, a
pre-filled syringe containing the diluent, a West-Medimop Vial Adapter®, and
two Terumo SurGuard® 3 Needles (a 21 G UTW 1-inch needle with
needle protection device for deltoid administration and a 20 G TW 2-inch needle
with needle protection device for gluteal administration).
Risperdal
Consta - Clinical Pharmacology
Mechanism
of Action
The mechanism of action of
Risperdal Consta®, as with other drugs used to treat schizophrenia,
is unknown. However, it has been proposed that the drug's therapeutic activity
in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2
(5HT2)
receptor antagonism.
RISPERDAL® is
a selective 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. RISPERDAL® acts
as an antagonist at other receptors, but with lower potency. RISPERDAL® has
low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A 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.
Pharmacodynamics
The clinical effect from
Risperdal Consta® results from the combined concentrations of
risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the other effects of
Risperdal Consta®.
Pharmacokinetics
Absorption
After a single
intramuscular (gluteal) injection of Risperdal Consta®,
there is a small initial release of the drug (< 1% of the dose), followed by
a lag time of 3 weeks. The main release of the drug starts from 3 weeks onward,
is maintained from 4 to 6 weeks, and subsides by 7 weeks following the
intramuscular (IM) injection. Therefore, oral antipsychotic supplementation
should be given during the first 3 weeks of treatment with Risperdal Consta® to
maintain therapeutic levels until the main release of risperidone from the
injection site has begun [see Dosage and Administration (2)]. Following single doses of Risperdal Consta®, the
pharmacokinetics of risperidone, 9-hydroxyrisperidone (the major metabolite),
and risperidone plus 9-hydroxyrisperidone were linear in the dosing range of
12.5 mg to 50 mg.
The combination of the
release profile and the dosage regimen (IM injections every 2 weeks) of
Risperdal Consta® results in sustained therapeutic
concentrations. Steady-state plasma concentrations are reached after 4
injections and are maintained for 4 to 6 weeks after the last injection.
Following multiple doses of 25 mg and 50 mg Risperdal Consta®,
plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone
plus 9-hydroxyrisperidone were linear.
Deltoid and gluteal
intramuscular injections at the same doses are bioequivalent and, therefore,
interchangeable.
Distribution
Once absorbed, risperidone
is rapidly distributed. The volume of distribution is 1–2 L/kg. Inplasma, risperidone is bound to albumin and α1-acid
glycoprotein. The plasma protein binding of risperidone is approximately 90%,
and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither
risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic
concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and
carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of
risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of
unknown clinical significance.
Metabolism and Drug
Interactions
Risperidone is extensively
metabolized in the liver. The main metabolic pathway is through hydroxylation
of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor
metabolic pathway is through N-dealkylation. The main metabolite,
9-hydroxyrisperidone, has similar pharmacological activity as risperidone.
Consequently, the clinical effect of the drug results from the combined
concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called
debrisoquin hydroxylase, is the enzyme responsible for metabolism of many
neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is
subject to genetic polymorphism (about 6%–8% of Caucasians, and a very low
percentage of Asians, have little or no activity and are "poor
metabolizers") and to inhibition by a variety of substrates and some
non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert
risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6
metabolizers convert it much more slowly. Although extensive metabolizers have
lower risperidone and higher 9-hydroxyrisperidone concentrations than poor
metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined,
after single and multiple doses, are similar in extensive and poor
metabolizers.
The interactions of
Risperdal Consta® with coadministration of other drugs have not
been systematically evaluated in human subjects. Drug interactions are based
primarily on experience with oral RISPERDAL®. Risperidone could be
subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6
interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.11)]. This occurs with quinidine, giving essentially
all recipients a risperidone pharmacokinetic profile typical of poor
metabolizers. The therapeutic benefits and adverse effects of RISPERDAL® in
patients receiving quinidine have not been evaluated, but observations in a
modest number (n≅70) of poor metabolizers given oral RISPERDAL® do
not suggest important differences between poor and extensive metabolizers.
Second, co-administration of carbamazepine and other known enzyme inducers
(e.g., phenytoin, rifampin, and phenobarbital) with oral RISPERDAL® cause
a decrease in the combined plasma concentrations of risperidone and
9-hydroxyrisperidone [see Drug Interactions (7.12)]. It would also be possible for risperidone to
interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively
weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions (7.11)].
Excretion
Risperidone and its
metabolites are eliminated via the urine and, to a much lesser extent, via the
feces. As illustrated by a mass balance study of a single 1 mg oral dose
of 14C-risperidone administered as solution to three
healthy male volunteers, total recovery of radioactivity at 1 week was 84%,
including 70% in the urine and 14% in the feces.
The apparent half-life of
risperidone plus 9-hydroxyrisperidone following Risperdal Consta®administration
is 3 to 6 days, and is associated with a monoexponential decline in plasma
concentrations. This half-life of 3–6 days is related to the erosion of the
microspheres and subsequent absorption of risperidone. The clearance of
risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h
in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6
metabolizers, respectively. No accumulation of risperidone was observed during
long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or
50 mg Risperdal Consta®. The elimination phase is complete approximately 7
to 8 weeks after the last injection.
Renal Impairment
In patients with moderate
to severe renal disease treated with oral RISPERDAL®,
clearance of the sum of risperidone and its active metabolite decreased by 60%
compared with young healthy subjects. Although patients with renal impairment
were not studied with Risperdal Consta®, it is recommended that
patients with renal impairment be carefully titrated on oral RISPERDAL® before
treatment with Risperdal Consta® is initiated at a dose of 25 mg. A lower
initial dose of 12.5 mg may be appropriate when clinical factors warrant dose
adjustment, such as in patients with renal impairment [see Dosage and Administration (2.4)].
Hepatic Impairment
While the pharmacokinetics
of oral RISPERDAL® in subjects with
liver disease were comparable to those in young healthy subjects, the mean free
fraction of risperidone in plasma was increased by about 35% because of the
diminished concentration of both albumin and α1-acid glycoprotein. Although
patients with hepatic impairment were not
studied with Risperdal Consta®, it is recommended that patients with hepatic
impairment be carefully titrated on oral RISPERDAL® before
treatment with Risperdal Consta®is initiated at a dose of 25 mg. A lower initial
dose of 12.5 mg may be appropriate when clinical factors warrant dose
adjustment, such as in patients with hepatic impairment [see Dosage and Administration (2.4)].
Elderly
In an open-label trial,
steady-state concentrations of risperidone plus 9-hydroxyrisperidone in
otherwise healthy elderly patients (≥ 65 years old) treated with Risperdal
Consta® for up to 12 months fell within the range of
values observed in otherwise healthy nonelderly patients. Dosing
recommendations are the same for otherwise healthy elderly patients and
nonelderly patients [see Dosage and Administration (2)].
Race and Gender Effects
No specific
pharmacokinetic study was conducted to investigate race and gender effects, but
a population pharmacokinetic analysis did not identify important differences in
the disposition of risperidone due to gender (whether or not corrected for body
weight) or race.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Carcinogenesis - Oral
Carcinogenicity studies
were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to
mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and
37.5 times the oral maximum recommended human dose (MRHD) for schizophrenia (16
mg/day) on a mg/kg basis, or 0.2, 0.75, and 3 times the oral MRHD (mice) or
0.4, 1.5, and 6 times the oral MRHD (rats) on a mg/m2 basis.
A maximum tolerated dose was not achieved in male mice. There was a significant
increase in pituitary gland adenomas in female mice at doses 0.75 and 3 times
the oral MRHD on a mg/m2 basis. There was a significant increase in
endocrine pancreatic adenomas in male rats at doses 1.5 and 6 times the oral
MRHD on a mg/m2 basis. Mammary gland adenocarcinomas were
significantly increased in female mice at all doses tested (0.2, 0.75, and 3
times the oral MRHD on a mg/m2 basis), in female rats at all doses tested
(0.4, 1.5, and 6 times the oral MRHD on a mg/m2 basis), and in male
rats at a dose 6 times the oral MRHD on a mg/m2basis.
Carcinogenesis -
Intramuscular
Risperdal Consta® was
evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were
treated every 2 weeks with intramuscular (IM) injections of either 5 mg/kg or
40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a
mg/m2 basis. A control group received injections of
0.9% NaCl, and a vehicle control group was injected with placebo microspheres.
There was a significant increase in pituitary gland adenomas, endocrine
pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD
on a mg/m2 basis. The incidence of mammary gland
adenocarcinomas was significantly increased in female rats at both doses (1 and
8 times the IM MRHD on a mg/m2 basis). A significant increase in renal
tubular tumors (adenoma, adenocarcinomas) was observed in male rats at 8 times
the IM MRHD on a mg/m2 basis. Plasma exposures (AUC) in rats were
0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure
(AUC) at the IM MRHD.
Dopamine D2 receptor antagonists
have been shown to chronically elevate prolactin levels in rodents. Serum prolactin
levels were not measured during the carcinogenicity studies of oral
risperidone; however, measurements taken during subchronic toxicity studies
showed that oral risperidone elevated serum prolactin levels 5- to 6-fold in
mice and rats at the same doses used in the oral carcinogenicity studies. Serum
prolactin levels increased in a dose-dependent manner up to 6- and 1.5-fold in
male and female rats, respectively, at the end of the 24-month treatment with
Risperdal Consta® every 2 weeks. Increases in the incidence of
pituitary gland, endocrine pancreas, and mammary gland neoplasms have been
found in rodents after chronic administration of other antipsychotic drugs and
may be prolactin-mediated.
The relevance for human
risk of the findings of prolactin-mediated endocrine tumors in rodents is
unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic
potential for oral risperidone was found in the in
vitro Ames reverse mutation
test, in vitro mouse
lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in
vivo oral micronucleus test in mice,
the sex-linked recessive lethal test in Drosophila, or the in
vitro chromosomal aberration test in
human lymphocytes or in Chinese hamster cells.
In addition, no evidence
of mutagenic potential was found in the in
vitro Amesreverse mutation test for Risperdal
Consta®.
Impairment of Fertility
Oral risperidone (0.16 to
5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three
reproductive studies (two mating and fertility studies and a multigenerational
study) at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD)
(16 mg/day) on a mg/m2 basis. The effect appeared to be in females,
since impaired mating behavior was not noted in the mating and fertility study
in which males only were treated. In a subchronic study in Beagle dogs in which
oral risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility
and concentration were decreased at doses 0.6 to 10 times the oral MRHD on a
mg/m2 basis. Dose-related decreases were also noted
in serum testosterone at the same doses. Serum testosterone and sperm values
partially recovered, but remained decreased after treatment was discontinued.
No no-effect doses were noted in either rat or dog.
No mating and fertility
studies were conducted with Risperdal Consta®.
Clinical
Studies
Schizophrenia
The effectiveness of
Risperdal Consta® in the treatment of schizophrenia was
established, in part, on the basis of extrapolation from the established
effectiveness of the oral formulation of risperidone. In addition, the
effectiveness of Risperdal Consta® in the treatment of schizophrenia was
established in a 12-week, placebo-controlled trial in adult psychotic
inpatients and outpatients who met the DSM-IV criteria for schizophrenia.
Efficacy data were
obtained from 400 patients with schizophrenia who were randomized to receive
injections of 25 mg, 50 mg, or 75 mg Risperdal Consta® or
placebo every 2 weeks. During a 1-week run-in period, patients were
discontinued from other antipsychotics and were titrated to a dose of 4 mg oral
RISPERDAL®. Patients who received Risperdal Consta® were
given doses of oral RISPERDAL® (2 mg for patients in the 25-mg group, 4 mg
for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for
the 3 weeks after the first injection to provide therapeutic plasma
concentrations until the main release phase of risperidone from the injection
site had begun. Patients who received placebo injections were given placebo
tablets.
Efficacy was evaluated
using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item
inventory, composed of five subscales to evaluate positive symptoms, negative
symptoms, disorganized thoughts, uncontrolled hostility/excitement, and
anxiety/depression.
The primary efficacy
variable in this trial was change from baseline to endpoint in the total PANSS
score. The mean total PANSS score at baseline for schizophrenic patients in
this study was 81.5.
Total PANSS scores showed
significant improvement in the change from baseline to endpoint in
schizophrenic patients treated with each dose of Risperdal Consta® (25
mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there
were no statistically significant differences between the treatment effects for
the three dose groups, the effect size for the 75 mg dose group was actually
numerically less than that observed for the 50 mg dose group.
Subgroup analyses did not
indicate any differences in treatment outcome as a function of age, race, or
gender.
Bipolar
Disorder - Monotherapy
The effectiveness of
Risperdal Consta® for the maintenance treatment of Bipolar I
Disorder was established in a multicenter, double-blind, placebo-controlled
study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I,
who were stable on medications or experiencing an acute manic or mixed episode.
A total of 501 patients
were treated during a 26-week open-label period with Risperdal Consta®(starting
dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50
mg; in patients not tolerating the 25 mg dose, the dose could be reduced to
12.5 mg). In the open-label phase, 303 (60%) patients were judged to be stable
and were randomized to double-blind treatment with either the same dose of
Risperdal Consta® or placebo and monitored for relapse. The
primary endpoint was time to relapse to any mood episode (depression, mania,
hypomania, or mixed).
Time to relapse was
delayed in patients receiving Risperdal Consta® monotherapy as
compared to placebo. The majority of relapses were due to manic rather than
depressive symptoms. Based on their bipolar disorder history, subjects entering
this study had had, on average, more manic episodes than depressive episodes.
Bipolar
Disorder - Adjunctive Therapy
The effectiveness of
Risperdal Consta® as an adjunct to treatment with lithium or
valproate for the maintenance treatment of Bipolar Disorder was established in
a multi-center, randomized, double-blind, placebo-controlled study of adult
patients who met DSM-IV criteria for Bipolar Disorder Type I and who
experienced at least 4 episodes of mood disorder requiring psychiatric/clinical
intervention in the previous 12 months, including at least 2 episodes in the 6
months prior to the start of the study.
A total of 240 patients
were treated during a 16-week open-label period with Risperdal Consta®(starting
dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50
mg), as adjunctive therapy in addition to continuing their treatment as usual
for their bipolar disorder, which consisted of mood stabilizers (primarily
lithium and valproate), antidepressants, and/or anxiolytics. All oral
antipsychotics were discontinued after the first three weeks of the initial
Risperdal Consta® injection. In the open-label phase, 124
(51.7%) were judged to be stable for at least the last 4 weeks and were
randomized to double-blind treatment with either the same dose of Risperdal
Consta® or placebo in addition to continuing their
treatment as usual and monitored for relapse during a 52-week period. The
primary endpoint was time to relapse to any new mood episode (depression,
mania, hypomania, or mixed).
Time to relapse was
delayed in patients receiving adjunctive therapy with Risperdal Consta® as
compared to placebo. The relapse types were about half depressive and half
manic or mixed episodes.
How
Supplied/Storage and Handling
Risperdal Consta® (risperidone)
is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg
risperidone. It is provided as a dose pack, consisting of a vial containing the
risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for
Risperdal Consta®, a West-Medimop Vial Adapter®, and
two Terumo SurGuard® 3 Needles for intramuscular injection (a 21 G
UTW 1-inch needle with needle protection device for deltoid administration and
a 20 G TW 2-inch needle with needle protection device for gluteal
administration).
12.5-mg vial/kit (NDC
50458-309-11): 41 mg (equivalent to 12.5 mg of risperidone) of a white to
off-white powder provided in a vial with a violet flip-off cap (NDC
50458-309-01).
25-mg vial/kit (NDC
50458-306-11): 78 mg (equivalent to 25 mg of risperidone) of a white to
off-white powder provided in a vial with a pink flip-off cap (NDC
50458-306-01).
37.5-mg vial/kit (NDC
50458-307-11): 116 mg (equivalent to 37.5 mg of risperidone) of a white to
off-white powder provided in a vial with a green flip-off cap (NDC
50458-307-01).
50-mg vial/kit (NDC
50458-308-11): 152 mg (equivalent to 50 mg of risperidone) of a white to
off-white powder provided in a vial with a blue flip-off cap (NDC
50458-308-01).
Storage and Handling
The entire dose pack
should be stored in the refrigerator (36°–46°F; 2°–8°C) and protected from
light.
If refrigeration is
unavailable, Risperdal Consta® can be stored at temperatures not exceeding
77°F (25°C) for no more than 7 days prior to administration. Do not expose
unrefrigerated product to temperatures above 77°F (25°C).
Patient
Counseling Information
Physicians are advised to
discuss the following issues with patients for whom they prescribe Risperdal
Consta®.
Orthostatic
Hypotension
Patients should be advised
of the risk of orthostatic hypotension and 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) [see Warnings and Precautions (5.7)].
Interference
with Cognitive and Motor Performance
Because Risperdal Consta® has
the potential to impair judgment, thinking, or motor skills, patients should be
cautioned about operating hazardous machinery, including automobiles, until
they are reasonably certain that treatment with Risperdal Consta® does
not affect them adversely [see Warnings and Precautions (5.10)].
Pregnancy
Patients should be advised
to notify their physician if they become pregnant or intend to become pregnant
during therapy and for at least 12 weeks after the last injection of Risperdal
Consta® [see Use in Specific Populations (8.1)].
Nursing
Patients should be advised
not to breast-feed an infant during treatment and for at least 12 weeks after
the last injection of Risperdal Consta® [see Use in Specific Populations (8.3)].
Concomitant
Medication
Patients should be advised
to inform their physicians if they are taking, or plan to take, any
prescription or over-the-counter drugs, since there is a potential for
interactions [see Drug Interactions (7)].
Alcohol
Patients should be advised
to avoid alcohol during treatment with Risperdal Consta® [see Drug Interactions (7.1)].
Product ofIreland
Risperidone active
ingredient is manufactured by:
Janssen Pharmaceutical
Wallingstown, Little Island,County
Cork,Ireland
Microspheres are
manufactured by:
Alkermes, Inc.
Wilmington,Ohio
Diluent is manufactured
by:
Vetter Pharma Fertigung GmbH & Co. KG
Langenargen,Germany
or
Cilag AG
Schaffhausen,Switzerland
Risperdal Consta® is
manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville,NJ08560
© 2007 Janssen Pharmaceutical Companies
PRINCIPAL
DISPLAY PANEL - 12.5 mg Kit Carton
12.5
mg
Dose
Pack
Store
Package
in
Refrigerator
(see
bottom panel for
storage
conditions)
Rx
only
Single
use only
NDC 50458-309-11
RisperdalCONSTA®
risperiDONE Long-Acting Injection
DOSE
PACK CONTENTS:
One 12.5 mg vial of risperidone extended-release microspheres for
injectionOne pre-filled syringe containing 2 mL of diluentOne West-Medimop Vial Adapter®One 21-gauge UTW 1" Terumo SurGuard® 3 safety
needle for deltoid injectionOne 20-gauge TW 2" Terumo SurGuard® 3 safety
needle for gluteal injection
Do
not substitute any components of the dose pack.
For
deltoid or gluteal intramuscular injection only
Each
injection should be administered by a healthcare professional.
PLEASE
READ COMPLETE INSTRUCTIONS PRIOR TO USE.
PRINCIPAL
DISPLAY PANEL - 25 mg Kit Carton
25 mg
Dose
Pack
Store
Package
in
Refrigerator
(see
bottom panel for
storage
conditions)
Rx
only
Single
use only
NDC 50458-306-11
RisperdalCONSTA®
risperiDONE Long-Acting Injection
DOSE
PACK CONTENTS:
One 25 mg vial of risperidone extended-release microspheres for
injectionOne pre-filled syringe containing 2 mL of diluentOne West-Medimop Vial Adapter®One 21-gauge UTW 1" Terumo SurGuard® 3 safety
needle for deltoid injectionOne 20-gauge TW 2" Terumo SurGuard® 3 safety
needle for gluteal injection
Do
not substitute any components of the dose pack.
For
deltoid or gluteal intramuscular injection only
Each
injection should be administered by a healthcare professional.
PLEASE
READ COMPLETE INSTRUCTIONS PRIOR TO USE.
PRINCIPAL
DISPLAY PANEL - 37.5 mg Kit Carton
37.5
mg
Dose
Pack
Store
Package
in
Refrigerator
(see
bottom panel for
storage
conditions)
Rx
only
Single
use only
NDC 50458-307-11
RisperdalCONSTA®
risperiDONE Long-Acting Injection
DOSE
PACK CONTENTS:
One 37.5 mg vial of risperidone extended-release microspheres for
injectionOne pre-filled syringe containing 2 mL of diluentOne West-Medimop Vial Adapter®One 21-gauge UTW 1" Terumo SurGuard® 3 safety
needle for deltoid injectionOne 20-gauge TW 2" Terumo SurGuard® 3 safety
needle for gluteal injection
Do
not substitute any components of the dose pack.
For
deltoid or gluteal intramuscular injection only
Each
injection should be administered by a healthcare professional.
PLEASE
READ COMPLETE INSTRUCTIONS PRIOR TO USE.
PRINCIPAL
DISPLAY PANEL - 50 mg Kit Carton
50 mg
Dose
Pack
Store
Package
in
Refrigerator
(see
bottom panel for
storage
conditions)
Rx
only
Single
use only
NDC 50458-308-11
RisperdalCONSTA®
risperiDONE Long-Acting Injection
DOSE
PACK CONTENTS:
One 50 mg vial of risperidone extended-release microspheres for
injectionOne pre-filled syringe containing 2 mL of diluentOne West-Medimop Vial Adapter®One 21-gauge UTW 1" Terumo SurGuard® 3 safety
needle for deltoid injectionOne 20-gauge TW 2" Terumo SurGuard® 3 safety
needle for gluteal injection
Do
not substitute any components of the dose pack.
For
deltoid or gluteal intramuscular injection only
Each
injection should be administered by a healthcare professional.
PLEASE
READ COMPLETE INSTRUCTIONS PRIOR TO USE.
|
Risperdal Consta risperidone kit
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50458-309
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50458-309-11
|
1 KIT in 1 BOX
|
|
|
|
Quantity of Parts
|
|
Part #
|
Package Quantity
|
Total Product Quantity
|
|
|
|
Part 1
|
1 VIAL
|
2 mL
|
|
|
|
Part 2
|
1 SYRINGE
|
2 mL
|
|
|
|
|
Part 1 of 2
|
|
Risperdal Consta risperidone injection, powder, for suspension, extended release
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
risperidone (risperidone)
|
risperidone
|
12.5 mg in 2 mL
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 VIAL
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Part 2 of 2
|
|
DILUENT diluent
injection, solution
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
polysorbate
20
|
|
|
carboxymethylcellulose
sodium
|
|
|
sodium
phosphate, dibasic, heptahydrate
|
|
|
anhydrous
citric acid
|
|
|
sodium
chloride
|
|
|
sodium
hydroxide
|
|
|
water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 SYRINGE
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Risperdal Consta risperidone kit
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50458-306
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50458-306-11
|
1 KIT in 1 BOX
|
|
|
|
Quantity of Parts
|
|
Part #
|
Package Quantity
|
Total Product Quantity
|
|
|
|
Part 1
|
1 VIAL
|
2 mL
|
|
|
|
Part 2
|
1 SYRINGE
|
2 mL
|
|
|
|
|
Part 1 of 2
|
|
Risperdal Consta risperidone injection, powder, for suspension, extended release
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
risperidone (risperidone)
|
risperidone
|
25 mg in 2 mL
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 VIAL
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Part 2 of 2
|
|
DILUENT diluent
injection, solution
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
polysorbate
20
|
|
|
carboxymethylcellulose
sodium
|
|
|
sodium
phosphate, dibasic, heptahydrate
|
|
|
anhydrous
citric acid
|
|
|
sodium
chloride
|
|
|
sodium
hydroxide
|
|
|
water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 SYRINGE
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Risperdal Consta risperidone kit
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50458-307
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50458-307-11
|
1 KIT in 1 BOX
|
|
|
|
Quantity of Parts
|
|
Part #
|
Package Quantity
|
Total Product Quantity
|
|
|
|
Part 1
|
1 VIAL
|
2 mL
|
|
|
|
Part 2
|
1 SYRINGE
|
2 mL
|
|
|
|
|
Part 1 of 2
|
|
Risperdal Consta risperidone injection, powder, for suspension, extended release
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
risperidone (risperidone)
|
risperidone
|
37.5 mg in 2 mL
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 VIAL
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Part 2 of 2
|
|
DILUENT diluent
injection, solution
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
polysorbate
20
|
|
|
carboxymethylcellulose
sodium
|
|
|
sodium
phosphate, dibasic, heptahydrate
|
|
|
anhydrous
citric acid
|
|
|
sodium
chloride
|
|
|
sodium
hydroxide
|
|
|
water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 SYRINGE
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Risperdal Consta risperidone kit
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50458-308
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50458-308-11
|
1 KIT in 1 BOX
|
|
|
|
Quantity of Parts
|
|
Part #
|
Package Quantity
|
Total Product Quantity
|
|
|
|
Part 1
|
1 VIAL
|
2 mL
|
|
|
|
Part 2
|
1 SYRINGE
|
2 mL
|
|
|
|
|
Part 1 of 2
|
|
Risperdal Consta risperidone injection, powder, for suspension, extended release
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
risperidone (risperidone)
|
risperidone
|
50 mg in 2 mL
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 VIAL
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Part 2 of 2
|
|
DILUENT diluent
injection, solution
|
|
|
Product Information
|
|
|
|
|
|
|
Route of Administration
|
INTRAMUSCULAR
|
DEA Schedule
|
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
polysorbate
20
|
|
|
carboxymethylcellulose
sodium
|
|
|
sodium
phosphate, dibasic, heptahydrate
|
|
|
anhydrous
citric acid
|
|
|
sodium
chloride
|
|
|
sodium
hydroxide
|
|
|
water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
|
2 mL in 1 SYRINGE
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
|
|
Marketing
Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA021346
|
10/29/2003
|
|
|
|
Labeler - Janssen
Pharmaceuticals, Inc. (063137772)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Alkermes, Inc.
|
|
858582083
|
MANUFACTURE(50458-309, 50458-306, 50458-307,
50458-308)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Janssen Pharmaceutical
|
|
985042969
|
API MANUFACTURE(50458-309, 50458-306,
50458-307, 50458-308)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Cilag AG
|
|
483237103
|
MANUFACTURE(50458-309, 50458-306, 50458-307,
50458-308)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Vetter
|
|
344217323
|
MANUFACTURE(50458-309, 50458-306, 50458-307,
50458-308)
|
Revised: 03/2017
Janssen Pharmaceuticals, Inc.
