Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3220
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RISPERDAL CONSTA (Kit)
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| dailymed-instance:dosage |
For patients who have never taken oral RISPERDAL,
it is recommended to establish tolerability with oral RISPERDAL prior
to initiating treatment with RISPERDAL CONSTA (risperidone). RISPERDAL CONSTA should be administered every 2 weeks by deep intramuscular
(IM) gluteal injection. Each injection should be administered by a health
care professional using the enclosed safety needle . Injections should
alternate between the two buttocks. Do not administer intravenously. The
recommended dose is 25 mg IM every 2 weeks. Although dose response for effectiveness
has not been established for RISPERDAL CONSTA,
some patients not responding to 25 mg may benefit from a higher dose of 37.5
mg or 50 mg. The maximum dose should not exceed 50 mg RISPERDAL CONSTA every
2 weeks. No additional benefit was observed with dosages greater than 50 mg
RISPERDAL CONSTA; however, a higher incidence
of adverse effects was observed. A lower initial dose
of 12.5 mg may be appropriate when clinical factors warrant dose adjustment,
such as in patients with hepatic or renal impairment, for certain drug interactions
that increase risperidone plasma concentrations ,
or in patients who have a history of poor tolerability to psychotropic medications.
The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Oral
RISPERDAL (or another antipsychotic medication) should be
given with the first injection of RISPERDAL CONSTA and
continued for 3 weeks (and then discontinued) to ensure that adequate therapeutic
plasma concentrations are maintained prior to the main release phase of risperidone
from the injection site (see CLINICAL
PHARMACOLOGY). Upward dosage adjustment
should not be made more frequently than every 4 weeks. The clinical effects
of this dose adjustment should not be anticipated earlier than 3 weeks
after the first injection with the higher dose. In
patients with clinical factors such as hepatic or renal impairment or certain
drug interactions that increase risperidone plasma concentrations , dose reduction as low as 12.5 mg may be appropriate. The efficacy
of the 12.5 mg dose has not been investigated in clinical trials. Do
not combine two different dosage strengths of RISPERDAL CONSTA in
a single administration.<br/>Pediatric Use: RISPERDAL CONSTA has not
been studied in children younger than 18 years old.<br/>Dosage in Special Populations: For elderly patients treated with RISPERDAL CONSTA,
the recommended dosage is 25 mg IM every 2 weeks. Oral RISPERDAL (or
another antipsychotic medication) should be given with the first injection
of RISPERDAL CONSTA and should be continued
for 3 weeks to ensure that adequate therapeutic plasma concentrations are
maintained prior to the main release phase of risperidone from the injection
site . 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 b.i.d.
during the first week, which can be increased to 1 mg b.i.d. or 2 mg
once daily during the second week. If a total daily dose of at least 2 mg
oral RISPERDAL is well tolerated, an injection of 25 mg RISPERDAL CONSTAcan
be administered every 2 weeks. Alternatively, a starting dose of RISPERDAL CONSTA of
12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been
investigated in clinical trials. Oral supplementation
should be continued for 3 weeks after the first injection until the main release
of risperidone from the injection site has begun. In some patients, slower
titration may be medically appropriate. Patients with
renal impairment may have less ability to eliminate risperidone than normal
adults. Patients with impaired hepatic function may have an increase in the
free fraction of the risperidone, possibly resulting in an enhanced effect
. Elderly patients and patients with a predisposition to hypotensive
reactions or for whom such reactions would posea 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
.<br/>Maintenance Therapy: Although no controlled studies have been conducted to answer
the question of how long patients should be treated with RISPERDAL CONSTA,
oral risperidone has been shown to be effective in delaying time to relapse
in longer-term use. It is recommended that responding patients be continued
on treatment with RISPERDAL CONSTA at the
lowest dose needed. Patients should be periodically reassessed to determine
the need for continued treatment.<br/>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.<br/>Switching from Other Antipsychotics: There are no systematically collected data to specifically
address switching schizophrenic patients from other antipsychotics to RISPERDAL CONSTA,
or concerning concomitant administration with other antipsychotics. Previous
antipsychotics should be continued for 3 weeks after the first injection of
RISPERDAL CONSTA to ensure that therapeutic
concentrations are maintained until the main release phase of risperidone
from the injection site has begun . For schizophrenic
patients who have never taken oral RISPERDAL, it is recommended
to establish tolerability with oral RISPERDAL prior to initiating
treatment with RISPERDAL CONSTA. As recommended
with other antipsychotic medications, the need for continuing existing EPS
medication should be re-evaluated periodically.<br/>Co-Administration of RISPERDAL CONSTA with
Certain Other Medications: Co-administration of carbamazepine and other CYP 3A4 enzyme
inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would
be expected to cause decreases in the plasma concentrations of active moiety
(the sum of risperidone and 9-hydroxyrisperidone), which could lead to decreased
efficacy of RISPERDAL CONSTA treatment.
The dose of risperidone needs to be titrated accordingly for patients receiving
these enzyme inducers, especially during initiation or discontinuation of
therapy with these inducers . 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 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. 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
havenot been studied.<br/>Instructions for Use: RISPERDAL CONSTA must be
suspended only in the diluent supplied
in the dose pack, and must be administered with the needle supplied in the
dose pack. All components are required for administration. Do not substitute
any components of the dose pack. To assure that the intended dose of risperidone
is delivered, the full contents from the vial must beadministered. Administration
of partial contents may not deliver the intended dose of risperidone. Remove the dose pack of RISPERDAL CONSTA from
the refrigerator and allow it to come to room temperature prior to reconstitution. Upon suspension in the diluent, it is recommended to use
RISPERDAL CONSTA immediately. RISPERDAL CONSTA must
be used within 6 hours of suspension. Resuspension of RISPERDAL CONSTA will
be necessary prior to administration, as settling will occur over time once
the product is in suspension. Keeping the vial upright, shake vigorously back
and forth for as long as it takes to resuspend the microspheres. Once in suspension,
the product should not be exposed to temperatures above 77��F (25��C). Parenteral
drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
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| dailymed-instance:descripti... |
RISPERDAL (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 CHFNOand
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, 25, 37.5, or 50 mg risperidone
per vial. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide
(PLG) at a concentration of 381 mg risperidone per gram of microspheres. The
diluent for parenteral use is a clear, colorless solution. Composition of
the diluent includes polysorbate 20, sodium carboxymethyl cellulose, disodium
hydrogen phosphate dihydrate, citric acid anhydrous, sodium chloride, sodium
hydroxide, and water for injection. The microspheres are suspended in the
diluent prior to injection. RISPERDALCONSTA is
provided as a dose pack, consisting of a vial containing the microspheres,
a pre-filled syringe containing the diluent, a SmartSite Needle-Free
Vial Access Device, and one Needle-Pro 20 G TW safety needle.
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| dailymed-instance:clinicalP... |
Pharmacodynamics: The mechanism of action of RISPERDAL (risperidone),
as with other drugs used to treat schizophrenia, is unknown. However, it has
been proposed that the drug's therapeutic activity in schizophrenia is
mediated through a combination of dopamine Type 2 (D) and serotonin
Type 2 (5HT) receptor antagonism. Antagonism at receptors other
than Dand 5HTmay explain some of the other effects
of RISPERDAL. RISPERDAL is
a selective monoaminergic antagonist with high affinity (Ki of 0.12 to
7.3 nM) for the serotonin Type 2 (5HT), dopamine Type 2 (D),��1 and��2 adrenergic, and Hhistaminergic 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 5HT, 5HT, and
5HTreceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine
Dand haloperidol-sensitive sigma site, and no affinity (when
tested at concentrations>10M) for cholinergic muscarinic or��1 and��2 adrenergic receptors.<br/>Pharmacokinetics:<br/>Absorption: After a single intramuscular (gluteal) injection of RISPERDAL CONSTA (risperidone),
there is a small initial release of the drug (<about 1% of the dose), followed
by a lag time of 3 weeks. The main release of the drug starts from 3 weeks
onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following
the intramuscular (IM) injection. Therefore, oral antipsychotic supplementation
should be given during the first 3 weeks of treatment with RISPERDAL CONSTA to
maintain therapeutic levels until the main release of risperidone from the
injection site has begun (see DOSAGE
AND ADMINISTRATION). 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 to 50 mg RISPERDAL CONSTA,
plasma concentrations of risperidone, 9-hydroxyrisperidone and risperidone
plus 9-hydroxyrisperidone were linear.<br/>Distribution: Once absorbed, risperidone is rapidly distributed. The volume
of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin
and��1-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.<br/>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 (i.e., the active
moiety) results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP
2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism
of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP
2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very
low percentage of Asians, have little or no activity and are���poor
metabolizers���) and to inhibition by a variety of substrates and some
non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert
risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers
convert it much more slowly. Although extensive metabolizers have lower risperidone
and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the
pharmacokinetics of the active moiety, after single and multiple doses, are
similar in extensive and poor metabolizers. The interactions
of RISPERDAL CONSTA and other drugs have
not been systematically evaluated in human subjects. Risperidone could be
subject to two kinds of drug-drug interactions .
First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone.
This occurs with quinidine, giving essentially all recipients a risperidone
pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits
and adverse effects of risperidone in patients receiving quinidine have notbeen evaluated, but observations in a modest number (n���70) of poor
metabolizers given risperidone 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 risperidone cause a decrease in the combined plasma concentrations of
risperidone and 9-hydroxyrisperidone .
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. In a drug
interaction study in schizophrenic patients, 11 subjects received oral risperidone
titrated to 6 mg/day for 3 weeks, followed by concurrent administration of
carbamazepine for an additional 3 weeks. During co-administration, the plasma
concentrations of risperidone and its pharmacologically active metabolite,
9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of
carbamazepine did not appear to be affected. Co-administration of other known
enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone
may cause similar decreases in the combined plasma concentrations of risperidone
and 9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone
treatment (see PRECAUTIONS
- Drug Interactions and DOSAGE AND ADMINISTRATION - Co-Administration of RISPERDAL'
CONSTA' with Certain Other Medications). Fluoxetine
(20 mg QD) and paroxetine (20 mg QD) 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% (see PRECAUTIONS���Drug Interactions and DOSAGE
AND ADMINISTRATION - Co-Administration of RISPERDAL'CONSTA' with
Certain Other Medications). Repeated
oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or
peak plasma concentrations (C) of lithium (n=13) . Repeated oral doses of risperidone (4
mg QD) did not affect the pre-dose or average plasma concentrations and exposure
(AUC) of valproate (1000 mg/day in three divided doses) compared to placebo
(n=21). However, there was a 20% increase in valproate peak plasma concentration
(C) after concomitant administration of risperidone . There were no significant interactions
between oral risperidone (1 mg QD) and erythromycin (500 mg QID) . Cimetidine and ranitidine increased the
bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine
did not affect the AUC of the active moiety, whereas ranitidine increased
the AUC of the active moiety by 20%. Amitriptyline
did not affect the pharmacokinetics of risperidone or the active moiety. In
drug interaction studies, risperidone did not significantly affect the pharmacokinetics
of donepezil and galantamine, which are metabolized by CYP 2D6. RISPERDAL'
(0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics
of digoxin.<br/>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 ofC-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.<br/>Special Populations:<br/>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 PRECAUTIONS
- Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION - Dosage
in Special Populations).).<br/>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��-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 PRECAUTIONS
- Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION - Dosage
in Special Populations).<br/>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 .<br/>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.
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| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
RISPERDAL CONSTA (risperidone)
is contraindicated in patients with a known hypersensitivity to the product
or any of its components.
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| dailymed-instance:supply |
RISPERDAL CONSTA (risperidone)
is available in dosage strengths of 12.5, 25, 37.5, or 50 mg risperidone.
It is provided as a dose pack, consisting of a vial containing the risperidone
microspheres, a pre-filled syringe containing 2 mL of diluent for RISPERDAL CONSTA,
a SmartSite Needle-Free Vial Access Device, and one Needle-Pro safety
needle for intramuscular injection (20 G TW needle with needle protection
device). 12.5-mg vial/kit (NDC 50458-309-11): 12.5
mg of a white to off-white powder provided in a vial with a violet flip-off
cap (NDC 50458-309-01). 25-mg vial/kit (NDC 50458-306-11):
25 mg of a white to off-white powder provided in a vial with a pink flip-off
cap (NDC 50458-306-01). 37.5-mg vial/kit (NDC
50458-307-11): 37.5 mg of a white to off-white powder provided in a vial with
a green flip-off cap (NDC 50458-307-01). 50-mg
vial/kit (NDC 50458-308-11): 50 mg of a white to off-white powder provided
in a vial with a blue flip-off cap (NDC 50458-308-01).<br/>Storage and Handling: The entire dose pack should be stored in the refrigerator
(36��- 46��F; 2��- 8��C) and protected from light. If
refrigeration is unavailable, RISPERDAL CONSTA can
be stored at temperatures not exceeding 77��F (25��C) for no more
than 7 days prior to administration. Do not expose unrefrigerated product
to temperatures above 77��F (25��C). Keep out of reach of children. 7519509April
2007��Janssen 2003 Risperidone is manufactured
by:Janssen Pharmaceutical Ltd.Wallingstown, Little Island, County
Cork, Ireland Microspheres are manufactured by:Alkermes
Controlled Therapeutics IIWilmington, Ohio Diluent
is manufactured by:Vetter Pharma Fertigung GmbH&Co. KGRavensburg
or Largenargen, Germany or RISPERDAL CONSTA is distributed by:Janssen, L.P.Titusville,
NJ 08560
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| dailymed-instance:genericDr... | |
| dailymed-instance:boxedWarn... |
Increased Mortality
in Elderly Patients with Dementia���Related Psychosis Elderly patients with dementia-related psychosis treated
with atypical antipsychotic drugs are at an increased risk of death compared
to placebo. Analyses of seventeen placebo controlled trials (modal duration
of 10 weeks) in these patients revealed a risk of death in the drug-treated
patients of between 1.6 to 1.7 times that seen in placebo-treated patients.
Over the course of a typical 10 week controlled trial, the rate of death
in drug-treated patients was about 4.5%, compared to a rate of about 2.6%
in the placebo group. Although the causes of death were varied, most of the
deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)
or infectious (e.g., pneumonia) in nature. RISPERDALCONSTA(risperidone)
is not approved for the treatment of patients with Dementia-Related Psychosis.
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:possibleD... |
diseasome-diseases:1025,
diseasome-diseases:1032,
diseasome-diseases:1377,
diseasome-diseases:1460,
diseasome-diseases:1984,
diseasome-diseases:2216,
diseasome-diseases:261,
diseasome-diseases:3423,
diseasome-diseases:347,
diseasome-diseases:3734,
diseasome-diseases:3841,
diseasome-diseases:3852,
diseasome-diseases:54,
diseasome-diseases:852,
diseasome-diseases:94,
diseasome-diseases:989
|
| dailymed-instance:precautio... |
General:<br/>Administration: RISPERDAL CONSTA should
be injected into the gluteal muscle, and care must be taken to avoid inadvertent
injection into a blood vessel. (see DOSAGE AND ADMINISTRATION and ADVERSE
REACTIONS���Postintroduction Reports [retinal artery occlusion].)<br/>Orthostatic Hypotension: RISPERDAL CONSTA (risperidone)
may induce orthostatic hypotension associated with dizziness, tachycardia,
and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic
properties. Syncope was reported in 0.8% (12/1499 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.<br/>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.<br/>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, WARNINGS:
Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)<br/>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/mbasis 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/mbasis). 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
under PRECAUTIONS, Carcinogenicity, Mutagenesis, Impairment of Fertility. The
relevance of these findings to human risk is unknown.<br/>Hyperprolactinemia: As with other drugs that antagonize dopamine Dreceptors,
risperidone elevates prolactin levels and the elevation persists during chronic
administration. Risperdone 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 resperidone carcinogenicity
studies conducted in mice and rats (see PRECAUTIONS���Carcinogenesis, Mutagenesis, Impairment of
Fertility). 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.<br/>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.<br/>Priapism: No cases of priapism have been reported in patients treated
with RISPERDAL CONSTA. However, rare cases
of priapism have been reported in patients treated with oral RISPERDAL.
While the relationship of these events to oral RISPERDAL use
has not been established, other drugs with alpha-adrenergic blocking effects
have been reported to induce priapism, and it is possible that RISPERDAL may
share this capacity. Severe priapism may require surgical intervention.<br/>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.<br/>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.<br/>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 use. Caution is advised
when prescribing RISPERDAL CONSTA for patients
who will be exposed to temperature extremes.<br/>Suicide: The possibility of a suicide attempt is inherent in schizophrenia,
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); therefore, suicide due to an overdose
is unlikely.<br/>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
m) 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 - Dosage in Special Populations).<br/>Information for Patients: Physicians are advised to discuss the following issues with
patients for whom they prescribe RISPERDAL CONSTA.<br/>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).<br/>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.<br/>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.<br/>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.<br/>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.<br/>Alcohol: Patients should be advised to avoid alcohol during treatment
with RISPERDAL CONSTA.<br/>Laboratory Tests: No specific laboratory tests are recommended.<br/>Drug Interactions: The interactions of RISPERDAL CONSTA and
other drugs have not been systematically evaluated. 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. Because
of its potential for inducing hypotension, RISPERDAL CONSTA may
enhance the hypotensive effects of other therapeutic agents with this potential. RISPERDAL CONSTA may antagonize the effects of levodopa and dopamine agonists. Amytriptyline
did not affect the pharmacokinetics of risperidone or the active moiety. Cimetidine
and ranitidine increased the bioavailability of risperidone by 64% and 26%,
respectively. However, cimetidine did not affect the AUC of the active moiety,
whereas ranitidine increased the AUC of the active moiety by 20%. Chronic
administration of clozapine with risperidone may decrease the clearance of
risperidone.<br/>Carbamazepine and Other CYP 3A4 Enzyme Inducers: In a drug interaction study in schizophrenic patients, 11
subjects received oral risperidone titrated to 6 mg/day for 3 weeks, followed
by concurrent administration of carbamazepine for an additional 3 weeks. During
co-administration, the plasma concentrations of risperidone and its pharmacologically
active metabolite, 9-hydroxyrisperidone, were decreased by about 50%. Plasma
concentrations of carbamazepine did not appear to be affected. 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 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
CYP3A4 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.
(See also DOSAGE AND
ADMINISTRATION). Theefficacy of the 12.5 mg dose has
not been investigated in clinical trials.<br/>Fluoxetine and Paroxetine: Fluoxetine (20 mg QD) and paroxetine (20 mg QD), CYP 2D6
inhibitors, have been shown to increase the plasma concentration of risperidone
2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the
plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration
of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or
paroxetine is initiated or discontinued, the physician should re-evaluate
the dose of RISPERDAL CONSTA. When initiation
of fluoxetine or paroxetine is considered, patients may be placed on a lower
dose of RISPERDAL CONSTA between2 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).The effects of discontinuation of
concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone
and 9-hydroxyrisperidone have not been studied.<br/>Lithium: Repeated oral doses of risperidone (3 mg BID) did not affect
the exposure (AUC) or peak plasma concentrations (C) of lithium
(n=13).<br/>Valproate: Repeated oral doses of risperidone (4 mg QD) did not affect
the pre-dose or average plasma concentrations and exposure (AUC) of valproate
(1000 mg/day in three divided doses) compared to placebo (n=21). However,
there was a 20% increase in valproate peak plasma concentration (C)
after concomitant administration of risperidone.<br/>Digoxin: RISPERDAL (0.25 mg BID) did not show a clinically
relevant effect on the pharmacokinetics of digoxin.<br/>Drugs that Inhibit CYP 2D6 and Other CYP Isozymes: Risperidone is metabolized to 9-hydroxyrisperidone by CYP
2D6, an enzyme that is polymorphic in the population and that can be inhibited
by a variety of psychotropic and other drugs . Drug interactions
that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase
the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone.
Analysis of clinical studies involving a modest number of poor metabolizers
(n���70 patients) does not suggest that poor and extensive metabolizers
have different rates of adverse effects. No comparison of effectiveness in
the two groups has been made. In
vitro studies showed that drugs metabolized by other CYP isozymes,
including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone
metabolism. There were no significant interactions
between risperidone and erythromycin .<br/>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 risperidone did
not significantly affect the pharmacokinetics of donepezil and galantamine,
which are metabolized by CYP 2D6.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>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/mbasis. 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/mbasis.
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/mbasis. 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/mbasis),
in female rats at all doses tested (0.4, 1.5, and 6 times the oral MRHD on
a mg/mbasis), and in male rats at a dose 6 times the oral MRHD
on a mg/mbasis.<br/>Carcinogenesis - IM: RISPERDAL CONSTA was evaluated
in a 24-month carcinogenicity study in which SPF Wistar rats were treated
every 2 weeks with IM injections of either 5 mg/kg or 40 mg/kg of
risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/mbasis.
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/mbasis. 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/mbasis).
A significant increase in renal tubular tumors (adenoma, adenocarcinomas)
was observed in male rats at 8 times the IM MRHD on a mg/mbasis.
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
Dreceptor 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 PRECAUTIONS
- Hyperprolactinemia).<br/>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 Ames reverse mutation test for RISPERDAL CONSTA.<br/>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/mbasis.
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/mbasis.
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.<br/>Pregnancy:<br/>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/mbasis) 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/mbasis). 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/mbasis. 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/mbasis.
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/mbasis. 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/mbasis. 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. Reversible extrapyramidal symptoms in the neonate were observed
following postmarketing use of risperidone during the last trimester of pregnancy. RISPERDAL CONSTA should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.<br/>Labor and Delivery: The effect of RISPERDAL CONSTA on
labor and delivery in humans is unknown.<br/>Nursing Mothers: In animal studies, risperidone and 9-hydroxyrisperidone are
excreted in milk. 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.<br/>Pediatric Use: RISPERDAL CONSTA has not
been studied in children younger than 18 years old.<br/>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 aseated position). In addition, monitoring of orthostatic vital signs should
be considered in elderly patients for whom orthostatic hypotension is of concern
(see CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE
AND ADMINISTRATION).<br/>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 also Boxed Warning, WARNINGS: Increased
Mortality in Elderly Patients with Dementia-Related Psychosis.)
|
| dailymed-instance:overdosag... |
Human Experience: No cases of overdose were reported in premarketing studies
with RISPERDAL CONSTA (risperidone). 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 (risperidone),
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 estimatedoverdose 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 events reported since market introduction
which were temporally (but not necessarily causally) related to oral RISPERDAL overdose
include torsades de pointes, prolonged QT interval, convulsions, cardiopulmonary
arrest, and rare fatality associated with multiple drug overdose.<br/>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 oral RISPERDAL. 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.
|
| dailymed-instance:genericMe... |
risperidone
|
| dailymed-instance:fullName |
RISPERDAL CONSTA (Kit)
|
| dailymed-instance:adverseRe... |
Adverse findings were assessed by spontaneous reports of
adverse events, laboratory tests, vital signs, body weight, and ECGs. Adverse
events were classified using the World Health Organization preferred terms.
Treatment-emergent adverse events were defined as those events with an onset
between the first dose and 49 days after the last dose. The
prescriber should be aware that these figures cannot be used to predict the
incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those which prevailed in this
clinical trial. Similarly, the cited frequencies cannot be compared with figures
obtained from other clinical investigations involving different treatments,
uses, and investigators. The cited figures, however, do provide the prescribing
physician with some basis for estimating the relative contribution of drug
and nondrug factors to the side effect incidence rate in the population studied.<br/>Associated with Discontinuation of Treatment: In the 12-week, placebo-controlled trial, the incidence of
schizophrenic patients who discontinued treatment due to an adverse event
was lower with RISPERDAL CONSTA (11%; 22/202 patients)
than with placebo (13%; 13/98 patients).<br/>Incidence in Controlled Trials: The incidence of adverse reactions in the placebo-controlled
trial was based on 202 schizophrenic patients treated with 25 or 50 mg
RISPERDAL CONSTA and 98 schizophrenic
patients treated with placebo for up to 12 weeks.<br/>Commonly Observed Adverse Events in Controlled Clinical Trials: Spontaneously reported, treatment-emergent adverse events
with an incidence of 5% or greater in at least one of the RISPERDAL CONSTA groups
(25 mg or 50 mg) and at least twice that of placebo were: somnolence, akathisia,
parkinsonism, dyspepsia, constipation, dry mouth, fatigue, weight increase.<br/>Adverse Events Occurring at an Incidence of 2% or More in Patients
Treated with RISPERDAL CONSTA:: Table
1 enumerates adverse events that occurred at an incidence
of 2% or more, and were at least as frequent among patients treated with 25
mg or 50 mg RISPERDAL CONSTA���as patients treated
with placebo in the 12-week, placebo-controlled trial. This table shows the
percentage of patients in each dose group who spontaneously reported at least
one episode of an event at some time during double-blind treatment. All patients
were titrated to a dose of 4 mg oral RISPERDAL during a 1-week
run-in period. Patients who received RISPERDAL CONSTA were
given doses of oral RISPERDAL (2 mg for patients in the 25-mg
group, and 4 mg for patients in the 50-mg group) during the 3 weeks
after the first injection to provide therapeutic levels until the main release
phase of risperidone from the injection site had begun. Patients who received
placebo injections were given placebo tablets.<br/>Dose Dependency of Adverse Events:<br/>Vital Sign Changes:: RISPERDAL is associated with orthostatic
hypotension and tachycardia . In the placebo-controlled trial,
orthostatic hypotension was observed in 2% of patients treated with 25 mg
or 50 mg RISPERDAL CONSTA .<br/>Weight Changes:: In the 12-week, placebo-controlled trial, 9% of patients
treated with RISPERDAL CONSTA, compared
with 6% of patients treated with placebo, experienced a weight gain of>7% of
body weight at endpoint.<br/>Laboratory Changes:: The percentage of patients treated with RISPERDAL CONSTA who
experienced potentially important changes in routine serum chemistry, hematology,
or urinalysis parameters was similar to or less than that of placebo patients.
Additionally, no patients discontinued treatment due to changes in serum chemistry,
hematology, or urinalysis parameters.<br/>ECG Changes:: The electrocardiograms of 202 schizophrenic patients
treated with 25 mg or 50 mg RISPERDAL CONSTA and
98 schizophrenic patients treated with placebo in a 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. Between-group
comparisons for pooled placebo-controlled trials with oral RISPERDAL revealed
no statistically significant differences between risperidone and placebo in
mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals,
and heart rate. When all oral RISPERDAL doses were pooled
from randomized controlled trials in several indications, there was a mean
increase in heart rate of 1 beat per minute compared to no change for placebo
patients. In short-term schizophrenia trials, higher doses of oral risperidone
(8-16 mg/day) were associated with a higher mean increase in heart rate compared
to placebo (4-6 beats per minute).<br/>Pain Assessment and Local Injection Site Reactions:: The mean intensity of injection pain reported by patients
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.<br/>Other Events Observed During the Premarketing Evaluation of RISPERDAL CONSTA���: During its premarketing assessment, RISPERDAL CONSTA was
administered to 1499 patients in multiple-dose studies. The conditions
and duration of exposure to RISPERDAL CONSTA varied
greatly, and included (in overlapping categories) open-label and double-blind
studies, uncontrolled and controlled studies, inpatient and outpatient studies,
fixed-dose and titration studies, and short-term and long-termexposure studies.
In all studies, untoward events associated with this exposure were obtained
by spontaneous report and were recorded by clinical investigators using terminology
of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without
first grouping similar types of untoward events into a smaller number of standardized
event categories. In the listings that follow, spontaneously
reported adverse events were classified using World Health Organization (WHO)
preferred terms. The frequencies presented, therefore, represent the proportion
of the 1499 patients exposed to multiple doses of RISPERDAL CONSTA who
experienced an event of the type cited on at least one occasion while receiving
RISPERDAL CONSTA. All reported events are
included except those already listed in Table 1, those events for which a drug cause
was remote, those event terms which were so general as to be uninformative,
and those events reported only once which did not have a substantial probability
of being acutely life-threatening. It is important to emphasize that, although
the reported events occurred during treatment with RISPERDAL CONSTA,
they were not necessarily caused by it. Events are
further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those
occurring in at least 1/100 patients (only those not already listed in the
tabulated results from the placebo-controlled trial appear in this listing);
infrequent adverse events are those occurring in 1/100 to 1/1000 patients;
and rare events are those occurring in fewer than 1/1000 patients. Psychiatric
Disorders Frequent: anxiety,
psychosis, depression, agitation, nervousness, paranoid reaction, delusion,
apathy. Infrequent: anorexia,
impaired concentration, impotence, emotional lability, manic reaction, decreased
libido, increased appetite, amnesia, confusion, euphoria, depersonalization,
paroniria, delirium, psychotic depression. Central
and Peripheral Nervous System Disorders Frequent: hypertonia, dystonia. Infrequent: dyskinesia, vertigo, leg cramps, tardive dyskinesia,
involuntary muscle contractions, paraesthesia, abnormal gait, bradykinesia,
convulsions, hypokinesia, ataxia, fecal incontinence, oculogyric crisis, tetany,
apraxia, dementia, migraine. Rare: neuroleptic
malignant syndrome. In the integrated
database of multiple-dose studies (1499 patients with schizophrenia or schizoaffective
disorder), 9 patients (0.6%) treated with RISPERDAL CONSTA (all
dosages combined) experienced an adverse event of tardive dyskinesia. Body
as a Whole/General Disorders Frequent: back pain, chest pain, asthenia. Infrequent: malaise, choking. Gastrointestinal Disorders Frequent: nausea, vomiting, abdominal pain. Infrequent: gastritis, gastroesophageal reflux,
flatulence, hemorrhoids, melena, dysphagia, rectal hemorrhage, stomatitis,
colitis, gastric ulcer, gingivitis, irritable bowel syndrome, ulcerative stomatitis. Respiratory
System Disorders Frequent: dyspnea. Infrequent: pneumonia,
stridor, hemoptysis. Rare: pulmonary
edema. Skin and Appendage Disorders Frequent: rash. Infrequent: eczema, pruritus, erythematous rash, dermatitis, alopecia, seborrhea,
photosensitivity reaction, increased sweating. Metabolic
and Nutritional Disorders Infrequent: hyperuricemia, hyperglycemia, hyperlipemia, hypokalemia, glycosuria,
hypercholesterolemia, obesity, dehydration, diabetes mellitus, hyponatremia. Musculo-Skeletal
System Disorders Frequent: arthralgia, skeletal pain. Infrequent: torticollis, arthrosis, muscle weakness, tendinitis, arthritis,
arthropathy. Heart Rate and Rhythm Disorders Frequent: tachycardia. Infrequent: bradycardia, AV block, palpitation, bundle branch block. Rare: T-wave inversion. Cardiovascular
Disorders Frequent: hypotension. Infrequent: postural hypotension. Urinary
System Disorders Frequent: urinary incontinence. Infrequent: hematuria, micturition frequency, renal pain, urinary retention. Vision
Disorders Infrequent: conjunctivitis, eye pain, abnormal accommodation. Reproductive
Disorders, Female Frequent: amenorrhea. Infrequent: nonpuerperal
lactation, vaginitis, dysmenorrhea, breast pain, leukorrhea. Resistance
Mechanism Disorders Infrequent: abscess. Liver and Biliary System Disorders Frequent: increased hepatic enzymes. Infrequent: hepatomegaly, increased SGPT. Rare: bilirubinemia, increased GGT, hepatitis,
hepatocellular damage, jaundice, fatty liver, increased SGOT. Reproductive
Disorders, Male Infrequent: ejaculation failure. Application Site Disorders Frequent: injection site pain. Infrequent: injection site reaction. Hearing and Vestibular
Disorders Infrequent: earache, deafness, hearing decreased. Red
Blood Cell Disorders Frequent: anemia. White Cell and Resistance Disorders Infrequent: lymphadenopathy, leucopenia, cervical
lymphadenopathy. Rare: granulocytopenia,
leukocytosis, lymphopenia. Endocrine Disorders Infrequent: hyperprolactinemia, gynecomastia,
hypothyroidism. Platelet, Bleeding and Clotting Disorders Infrequent: purpura, epistaxis. Rare: pulmonary embolism, hematoma, thrombocytopenia. Myo-,
Endo-, and Pericardial and Valve Disorders Infrequent: myocardial ischemia, angina pectoris,
myocardial infarction. Vascular (Extracardiac) Disorders Infrequent: phlebitis. Rare: intermittent claudication, flushing, thrombophlebitis.<br/>Postintroduction Reports: Adverse events reported since market introduction which were
temporally (but not necessarily causally) related to oral RISPERDAL therapy
include the following: anaphylactic reaction, angioedema, apnea, atrial fibrillation,
cerebrovascular disorder, including cerebrovascular accident, diabetes mellitus
aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal obstruction,
jaundice, mania, pancreatitis, Parkinson's disease aggravated, pituitary
adenomas, pulmonary embolism, and QT prolongation. There have been rare reports
of sudden death and/or cardiopulmonary arrest in patients receiving oral RISPERDAL.
A causal relationship with oral RISPERDAL has not beenestablished.
It is important to note that sudden and unexpected death may occur in psychotic
patients whether they remain untreated or whether they are treated with other
antipsychotic drugs. 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.
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Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related
psychosis treated with atypical antipsychotic drugs are at an increased risk
of death compared to placebo. RISPERDALCONSTA(risperidone)
is not approved for the treatment of dementia-related psychosis (see Boxed Warning).<br/>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 foruncomplicated
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.<br/>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.<br/>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, WARNINGS: Increased
Mortality in Elderly Patients with Dementia-Related Psychosis.)<br/>Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with
ketoacidosis or hyperosmolar coma or death, has 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 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 should
undergofasting blood glucose testing at the beginning of treatment and periodically
during treatment. Any patient treated with atypical antipsychotics should
be monitored for symptoms of hyperglycemia including polydipsia, polyuria,
polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during
treatment with atypical antipsychotics should undergo fasting blood glucose
testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic
was discontinued; however, some patients required continuation of anti-diabetic
treatment despite discontinuation of the suspect drug.
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RISPERDAL CONSTA(risperidone)
is indicated for the treatment of schizophrenia. The
efficacy of RISPERDAL CONSTA is based in
part on a 12-week, placebo-controlled trial in schizophrenic inpatients or
outpatients, along with extrapolation from the established efficacy of oral
RISPERDAL in this population. The
effectiveness of RISPERDAL CONSTA in longer-term
use, that is, more than 12 weeks, has not been systematically evaluated
in controlled trials. However, oral risperidone has been shown to be effective
in delaying time to relapse in longer-term use. Patients should be periodically
reassessed to determine the need for continued treatment .
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RISPERDAL CONSTA
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