Download RISPERDAL CONSTA - Dosing - Dosage and Administration

RISPERDAL CONSTA® (risperidone)
Dosing - Dosage and Administration
The following information is provided because of your specific unsolicited
request and is not intended as an endorsement of any usage not contained
in the Prescribing Information. For complete information, please refer to the
enclosed full Prescribing Information, including the following sections: BOXED
WARNING(S), INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION,
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE
REACTIONS.
SUMMARY
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Tolerability - For patients who have never taken oral RISPERDAL®, it is
recommended to establish tolerability with oral RISPERDAL prior to initiating
treatment with RISPERDAL CONSTA®.1
Oral RISPERDAL (or another antipsychotic medication) should be given with
the first injection of RISPERDAL CONSTA and continued for 3 weeks.1
The recommended dose of RISPERDAL CONSTA for the treatment of
schizophrenia and monotherapy or adjunctive therapy to lithium or valproate
for the maintenance treatment of Bipolar I Disorder is 25 mg intramuscular
injection every 2 weeks. Some patients not responding to 25 mg may benefit
from a higher dose of 37.5 mg or 50 mg every 2 weeks.1
A lower initial dose of RISPERDAL CONSTA 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.1
Needle Size - RISPERDAL CONSTA should be administered every 2 weeks
by deep intramuscular deltoid or gluteal injection. Each injection should be
administered by a health care professional using the appropriate enclosed
safety needle. For deltoid administration, use the 1-inch (21 gauge
UTW) needle alternating injections between the two arms. For gluteal
administration, use the 2-inch (20 gauge TW) needle alternating injections
between the two buttocks. Do not administer intravenously.1
Deltoid and gluteal intramuscular injections of RISPERDAL CONSTA at the
same doses are bioequivalent and, therefore, interchangeable.1
The maximum dose of RISPERDAL CONSTA is 50 mg every 2 weeks.1
Upward dosage adjustment should not be made more frequently than
every 4 weeks.1
Do not combine two different dosage strengths of RISPERDAL CONSTA in a
single administration.1
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Switching Antipsychotics - There are no systematically collected
data to specifically address switching patients with schizophrenia 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.1
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)
should be administered.1
RISPERDAL CONSTA requires close attention to the step-by-step ’Instructions
for Use’ to help avoid difficulties in the use of the kit. See section 2.8 of the
full Prescribing Information for complete details.
The RISPERDAL CONSTA dose pack should be removed from the refrigerator
and allowed to sit at controlled room temperature (59-77 degrees F°) for at
least 30 minutes prior to reconstitution to support patient comfort during
the injection.
Table of Contents
PRESCRIBING INFORMATION ........................................................................
LITERATURE SEARCH ...................................................................................
DOSING GUIDELINES ..................................................................................
Initiating risperidone long-acting injection for adult schizophrenia patients ....
Hypersensitivity challenge .......................................................................
Conversion to risperidone long-acting injection ..........................................
From an oral conventional or atypical antipsychotic ..................................
From a conventional depot antipsychotic ................................................
From multiple antipsychotics ................................................................
Managing missed doses ..........................................................................
Steady-state plasma concentration achieved ...........................................
Steady-state plasma concentration not achieved (<4 consecutive
injections) ..........................................................................................
Managing breakthrough symptoms ...........................................................
Changing the dose of risperidone long-acting injection ................................
DOSING IN PIVOTAL TRIALS .........................................................................
Schizophrenia Trial....................................................................................
Adjunctive Trial in the Maintenance Treatment of Bipolar I Disorder ................
Monotherapy Trial in the Maintenance Treatment of Bipolar I Disorder ..............
CASE REPORT ON ADMINISTRATION ..............................................................
SELECTED ADDITIONAL REFERENCES ............................................................
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PRESCRIBING INFORMATION
Please refer to the following section of the enclosed Full Prescribing Information that
is relevant to your inquiry: DOSAGE AND ADMINISTRATION.
Published Date: Mar 30, 2017 12:52:44 AM Page 2 of 8
LITERATURE SEARCH
A literature search of MEDLINE® and an internal database pertaining to RISPERDAL
CONSTA and dosage and administration was conducted through March 3, 2016.
DOSING GUIDELINES
Marder et al (2003)2 published guidelines for dosing and initiating treatment
of risperidone long-acting injection (RLAI) in patients with or without current
antipsychotic treatment.
Initiating risperidone long-acting injection for adult schizophrenia
patients
In general, the initial dose of RLAI should be 25 mg every 2 weeks. Patients who
were previously on an oral antipsychotic or who had been taking no antipsychotic
should receive oral antipsychotic coverage during the first 3 weeks of RLAI
treatment. This 3 week oral antipsychotic coverage is needed because the main
release of risperidone after a single injection starts from 3 weeks onward, is
maintained from 4-6 weeks, and subsides by 7 weeks. Steady-state concentrations
are achieved after 4 consecutive RLAIs given every 2 weeks. First-episode patients
should begin with 25 mg and should be monitored closely for side effects.2
A higher dose of RLAI (37.5 mg or 50 mg) may be considered as the starting dose if
a patient has a history of refractory schizophrenia requiring high antipsychotic doses
(e.g., high doses of conventional depot). If a higher dose is needed, clinicians may
consider 37.5 mg every 2 weeks. If symptoms persist after steady state plasma
concentrations are reached (after at least 4 injections), the dose may be increased
to 50 mg every 2 weeks. Some clinicians in other countries have started a few
severely ill patients at 50 mg every 2 weeks.2
Hypersensitivity challenge
If a patient is oral risperidone naïve, a hypersensitivity challenge with a test dose
of 1-2 mg/day of oral risperidone for 2 consecutive days is recommended before
the first injection of risperidone long-acting. Patients who take a test dose should
continue taking their current antipsychotic treatment. If a patient has taken oral
risperidone in the past, a test dose is not necessary. The short duration of the
hypersensitivity challenge may only indicate an immediate hypersensitivity to
risperidone and is unlikely to reveal a delayed allergic reaction (e.g., allergic skin
reactions).2
Conversion to risperidone long-acting injection
From an oral conventional or atypical antipsychotic
Patients converting from an oral antipsychotic should continue to take the current
dose of the oral antipsychotic for 3 weeks following the first injection of risperidone
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long-acting 25 mg, until the first dose of RLAI reaches therapeutic levels. After 3
weeks, clinicians may begin to decrease the dose of the oral antipsychotic. The
length of the taper will depend on the stability of the patient. For most patients,
a short taper (e.g., 3-4 days) will be adequate, but more symptomatic patients
may benefit from a more gradual taper.2
From a conventional depot antipsychotic
Generally, physicians should initiate RLAI instead of the conventional depot
antipsychotic at the next scheduled injection date. Patients who have been regularly
receiving effective doses of a conventional depot antipsychotic (e.g., fluphenazine
and haloperidol decanoate) for about 6 months or longer will generally maintain
an adequate plasma drug concentration for at least 1 or 2 months after their last
injection. Therefore, patients should not require a dose of the conventional depot
antipsychotic when they receive their first injection of risperidone long-acting. No
coverage with oral risperidone or another oral antipsychotic is needed.2
From multiple antipsychotics
If a switch from multiple antipsychotics to RLAI is appropriate, the transition
should be made slowly. When possible, each of the current antipsychotics should
be gradually discontinued until the patient is only taking RLAI. Clinician judgment
should dictate the starting dose of RLAI.2
Managing missed doses
The appropriate strategy for patients who have missed a dose or doses of RLAI will
depend on whether a steady-state plasma concentration of RLAI has been reached.
Generally, steady-state plasma concentrations are achieved after 4 injections.2
Steady-state plasma concentration achieved
The next dose of RLAI should be given as soon as possible if steady-state
concentrations of RLAI have been achieved and only 3-6 weeks have passed since
the last injection. Clinicians should monitor for symptom recurrence. If more than
6 weeks have elapsed since the last injection, risperidone long-acting should be
initiated as soon as possible and 3 weeks of coverage with an oral antipsychotic
should be given.2
Steady-state plasma concentration not achieved (<4 consecutive
injections)
RLAI should be reinitiated as soon as possible and oral antipsychotic coverage for 3
weeks should be given.2
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Managing breakthrough symptoms
Clinicians should determine what type of breakthrough symptoms the patient
is experiencing (e.g., psychotic, depressive, or anxiety symptoms) and devise
a strategy accordingly.
For breakthrough psychotic symptoms, an oral antipsychotic should be added
to quickly control symptoms. The oral antipsychotic can be discontinued if the
breakthrough episode is successfully treated. Consider increasing the dose of RLAI if
the symptoms are severe and persist with an adequate dose of oral antipsychotic
supplementation or return when the oral antipsychotic is discontinued. A dose
increase of RLAI will not have an immediate effect on breakthrough psychotic
symptoms since the effect from the dose increase will take 3 weeks to begin to
elevate the patient’s plasma drug level.2
Changing the dose of risperidone long-acting injection
Clinicians should wait until the drug has achieved steady-state plasma concentration
at the present dose before deciding whether the dose should be increased or
decreased. If warranted, the dose can be increased or decreased in 12.5 mg
increments within the dose range of 25 to 50 mg.2
DOSING IN PIVOTAL TRIALS
Schizophrenia Trial
Kane et al (2003)3 published the results from a 12-week, double-blind,
placebo-controlled multicenter, randomized trial to evaluate the efficacy and
tolerability of RLAI in 400 patients with schizophrenia (n=370 ITT population). Prior
to the 12-week double-blind period, patients were screened for one week followed
by a run-in phase of one week when previous treatments were discontinued and oral
risperidone was initiated at 2 mg/day and then titrated up to 4 mg/day for at least
three days. Patients then entered the double-blind period and were randomized to
receive six injections of placebo, RLAI 25 mg, 50 mg, or 75 mg every two weeks.
Oral risperidone supplementation was given to patients randomized to RLAI during
the first 3 weeks of the double-blind phase. Patients randomized to receive RLAI
25 mg, 50 mg, and 75 mg were given oral risperidone 2 mg, 4 mg, and 6 mg,
respectively. Patients randomized to receive placebo injections were given oral
placebo supplementation. No oral supplementation was permitted during weeks
4-12 of the double-blind phase. There were significant improvements from baseline
on the PANSS total score as well as the positive and negative subscale scores in the
three RLAI groups compared to placebo (p<0.05).
RLAI (25 mg, 50 mg, and 75 mg) was more effective than placebo in treating
patients with schizophrenia for up to 12 weeks as assessed by the total PANSS
score and the positive and negative subscales, with no apparent added benefit of
a dose above 50 mg. RLAI was generally well tolerated with a similar incidence of
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EPS in the placebo and 25-mg groups. In addition, little pain or discomfort was
experienced at the injection site.
Adjunctive Trial in the Maintenance Treatment of Bipolar I Disorder
Macfadden et al (2009)4 presented the results from a double-blind, prospective,
randomized, placebo-controlled study in adult patients (18-70 years of age)
with Bipolar I Disorder who relapse frequently. The two-phase study included
an open-label stabilization phase (16 weeks; n=240) and a double-blind
relapse-prevention phase (up to 52 weeks; n=124). Patients maintaining a stable
dose and treatment response during the last 4 weeks of the open-label stabilization
entered the double-blind phase. During the open-label phase, patients received
RLAI 25 to 50 mg in addition to TAU (treatment as usual). TAU was defined as any
medication used to treat bipolar disorder including mood stabilizers, antidepressants,
and anxiolytics. All oral antipsychotics were tapered off after the first three weeks.
During the double-blind phase, patients were randomized to receive either RLAI plus
TAU or placebo plus TAU. Patients received the same dose of RLAI as they were
receiving at the end of the open-label phase. Doses of TAU medications and RLAI
could not change during the double-blind treatment. Modal RLAI doses in patients
during the double-blind phase were 25 mg in 67.7%, 37.5 mg in 27.7%, and 50
mg in 4.6%. A Kaplan-Meier survival analysis indicated that time to relapse was
significantly longer in patients assigned to RLAI plus TAU than in those assigned to
placebo plus TAU (p=0.010). The most common adverse events (≥10%) were
tremor, insomnia, muscle rigidity, and mania.
Monotherapy Trial in the Maintenance Treatment of Bipolar I Disorder
Quiroz et al (2010)5 conducted a randomized, double-blind, placebo-controlled,
multicenter study evaluating the use of RLAI for the prevention of mood episodes in
adult patients (18-65 years of age) with Bipolar I Disorder. Patients were separated
into 3 groups based on mood and medication status: acute episode, stable on
risperidone for at least 4 weeks, or stable on another antipsychotic or mood stabilizer
for at least 4 weeks. Five hundred fifty-nine patients were initially enrolled. Patients
with an acute episode or patients taking another antipsychotic or mood stabilizer
before the study received 3-weeks of oral risperidone. Patients taking risperidone
before the study or those that achieved an initial response during the 3-week oral
risperidone phase were enrolled in a 26-week open-label RLAI stabilization phase
(n=501). Patients were either initiated on 25 mg RLAI every 2 weeks or continued
their dose of RLAI from screening if they were stable. The 12.5 mg dose was
available for those that were unable to tolerate 25 mg of RLAI. The maximum dose
was 50 mg of RLAI every 2 weeks. Doses could be titrated at 4 week intervals
based on patient response during the first 18 weeks of the stabilization period.
Patients maintaining a stable dose and treatment response during the last 8-weeks
of the open-label stabilization phase entered a double-blind treatment phase and
were randomized to either their current dose of RLAI (n=154) or placebo (n=149).
Patients continued in the double-blind phase until they either completed 24 months,
met relapse criteria, withdrew from the study, or the study was terminated. During
the double-blind phase, 77% of patients received 25 mg of RLAI (modal dose). There
was a significant delay in time to relapse of a mood episode for patients treated with
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RLAI compared to placebo (p<0.001). The most common adverse events (≥5%)
were insomnia, depression, mania, bipolar I disorder, agitation, and headache.
CASE REPORT ON ADMINISTRATION
Tang et al (2007)6 reported a case of a 39-year-old male patient with retinal
artery occlusion after receiving RLAI. The dose of the RLAI was not reported. Thirty
minutes after receiving the injection into his right gluteal muscle, the patient began
to experience a change in vision in his right eye. The patient presented to his
physician four days after the injection, when the blurred vision in his right eye
persisted. The patient had 20/20 visual acuity in both eyes. However, there was
a superior field deficit in the right eye. Intraocular pressures were 10 and 11 mm
Hg. Examination revealed a microsphere in the inferior branch retinal artery of the
right eye, which occluded the artery and resulted in poor perfusion to areas distal to
the occlusion. The physician hypothesized that the microsphere embolized from the
injection site, through the patent foramen ovale, and into the patient’s right fundus.
No changes in the left fundus were noted.
SELECTED ADDITIONAL REFERENCES
Additionally, a letter to the editor addressing dosing strategies7 and an article
describing a clinical audit of adherence to dosing recommendations for RLAI8 have
been included in the References section.
ENCLOSURES
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RISPERDAL CONSTA® (risperidone long-acting injection) [package insert].
Titusville, NJ: Janssen Pharmaceuticals, Inc.
REFERENCES
1. RISPERDAL CONSTA® (risperidone long-acting injection) [package insert].
Titusville, NJ: Janssen Pharmaceuticals, Inc.
2. Marder SR, Conley R, Ereshefsky L, et al. Dosing and switching strategies for
long-acting risperidone. J Clin Psychiatry 2003;64(supp 16):41-46.
3. Kane J, Eerdekens M, Lindenmayer JP. Long-acting injection injectable
risperidone: efficacy and safety of the first long-acting injection atypical
antipsychotic. Am J Psychiatry 2003;160(6):1125-1132.
4. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind,
placebo-controlled study of maintenance treatment with adjunctive risperidone
long-acting therapy in patients with bipolar I disorder who relapse frequently.
Bipolar Disord 2009;11:827-839.
5. Quiroz JA, Yatham LN, Palumbo JM, et al. Risperidone long-acting injectable
monotherapy in the maintenance treatment of Bipolar I Disorder. Biol
Psychiatry 2010;68:156-162.
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6. Tang J, Weiter JJ.Branch retinal artery occlusion after injection of a long-acting
risperidone preparation. Ann Intern Med 2007;147(4):283-284.
7. Viner MW, Matuszak JM, Knight LJ. Initial dosing strategies for long-acting
injectable risperidone. J Clin Psychiatry 2006;67(8):1310-1311.
8. Mangan B, Rogers C, Wilton K, Adherence to risperidone long-acting injection
dosing recommendations. Prog Neurol Psychiatry 2009;13(5):32-39.
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