5.3 Neuroleptic Malignant Syndrome
(NMS)
(Additions
and/or revisions underlined)
NMS, a potentially fatal
symptom complex, has been reported
in association with antipsychotic drugs. Clinical manifestations of NMS are
hyperpyrexia, muscle rigidity, altered mental status including delirium,
and 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.
If NMS is suspected, immediately discontinue PERSERIS
and provide symptomatic treatment and monitoring.
5.4 Tardive Dyskinesia
(Additions
and/or revisions underlined)
Tardive dyskinesia, a syndrome consisting 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
which patients will develop the syndrome. Whether antipsychotic drug
products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing
tardive dyskinesia and the likelihood that it will become irreversible are
believed to increase with the duration of treatment and the total cumulative dose. The syndrome
can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of
treatment.
Tardive dyskinesia may remit, partially or
completely, if antipsychotic treatment is discontinued. 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, PERSERIS 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: 1) who suffer from a chronic
illness that 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, use the lowest dose and the shortest duration
of treatment producing a satisfactory clinical response. Periodically
reassess the need for continued treatment.
If signs and symptoms of
tardive dyskinesia appear in a patient treated with PERSERIS, drug
discontinuation should be considered. However,
some patients may require treatment with PERSERIS
despite the presence of the syndrome.
5.5 Metabolic Changes
(Additions and/or revisions underlined)
…
Dyslipidemia
Undesirable alterations in
lipids have been observed in patients treated with atypical antipsychotics. Before or soon after
initiation of antipsychotic medications, obtain a fasting lipid
profile at baseline and monitor periodically during
treatment.
Data from an 8-week double-blind, placebo-controlled study with PERSERIS
in adult patients with schizophrenia are presented in Table 2.
5.7 Orthostatic Hypotension and Syncope
(Additions and/or revisions underlined)
Risperidone may induce
orthostatic hypotension associated with dizziness, tachycardia, and in some
patients, syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose, probably reflecting its
alpha-adrenergic antagonistic properties…
5.8 Leuukopenia, Neutropenia, and Agranulocytosis
(Additions and/or revisions underlined)
In clinical trial and/or
postmarketing experience, events of leukopenia/neutropenia have been reported
temporally related to antipsychotic agents,
including risperidone. Agranulocytosis has also been reported.
Possible risk factors for
leukopenia and neutropenia include pre-existing low white blood cell
count (WBC) or absolute neutrophil count (ANC) and a history of
drug-induced leukopenia or neutropenia. In patients with a pre-existing history of a
clinically significant low WBC or ANC or a history of drug-
induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few
months of therapy. In such patients,
consider discontinuation of
PERSERIS at the first sign
of a clinically significant decline
in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms
or signs of infection
and treat promptly if such symptoms or signs occur. Discontinue
PERSERIS in patients with absolute neutrophil count <1000/mm3
and follow their WBC until recovery.
5.10 Potential for Cognitive
and Motor Impairment
(Additions and/or revisions underlined)
PERSERIS, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills.
In an 8-week, double-blind, placebo-controlled study, somnolence/sedation was reported by 7.0% and 7.7% of patients treated with
PERSERIS 90 mg and 120 mg, respectively.
Patients should be cautioned
about operating hazardous machinery, including motor
vehicles, until they are reasonably certain that treatment
with PERSERIS does not affect them adversely.
5.11 Seizures
(Additions and/or revisions underlined)
Seizures were observed during premarketing studies of risperidone in adult patients
with schizophrenia. PERSERIS
should be used cautiously in patients with a history of seizures or other
conditions that potentially lower the seizure threshold.
5.12 Dysphagia
(Additions and/or revisions underlined)
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. Antipsychotic drugs,
including PERSERIS, should
be used cautiously in patients at risk for aspiration [see Warnings and
Precautions (5.1)].
5.14 Body Temperature Regulation
(Additions and/or revisions underlined)
Atypical antipsychotics may
disrupt the body’s ability to reduce core body temperature. Both hyperthermia and
hypothermia have been reported in association with oral risperidone use. Strenuous
exercise, exposure to extreme heat, dehydration,
and anticholinergic medications may
contribute to an elevation in core body temperature; use PERSERIS with
caution in patients who may experience these conditions.
(Additions and/or revisions underlined)
The following are discussed in more detail
in previous sections
of the labeling:
Increased Mortality in Elderly Patients
with Dementia-Related Psychosis
[see Boxed Warning and Warnings and Precautions
(5.1)]
Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients
with Dementia- Related
Psychosis [see Warnings and Precautions (5.2)]
Neuroleptic Malignant Syndrome
(NMS) [see Warnings
and Precautions (5.3)]
Tardive Dyskinesia [see
Warnings and Precautions (5.4)]
Metabolic Changes [see
Warnings and Precautions (5.5)]
Hyperprolactinemia [see Warnings
and Precautions (5.6)]
- Orthostatic Hypotension and
Syncope [see Warnings
and Precautions (5.7)]
…
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Because clinical
trials are conducted
under widely varying
conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The safety of PERSERIS
was evaluated in a total of 837 adult patients with schizophrenia who received
at least 1 dose of PERSERIS during the clinical development program. A total of
322 patients were exposed to PERSERIS for at least 6 months, of which
234 patients were exposed to PERSERIS for at least 12 months; 281 and
176 of these, respectively, received the 120 mg dose.
Adverse drug reactions in
adult patients with schizophrenia (greater than or equal to 5% in
any PERSERIS-treated group and greater than placebo) during the 8-week
double-blind, placebo-controlled study) were weight increased, constipation,
sedation/somnolence, pain in extremity, back pain, akathisia, anxiety, and
musculoskeletal pain. In addition, the frequency of reported injection site
reactions was similar across treatment groups with both PERSERIS and placebo;
the most common (greater than or equal to 5%) of which were injection
site pain, and erythema. The systemic
safety profile for PERSERIS was consistent with the known
safety profile of oral
risperidone.
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
The following adverse reactions have
been identified during post approval use of oral risperidone. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia,
anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia,
diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia,
ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania,
pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism,
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN),
sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.
Postmarketing cases of extrapyramidal
symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking
methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation
of either or both medications.
8.1 Pregnancy
(Additions and/or revisions underlined)
…
Subcutaneous
administration of the delivery system to pregnant rats and rabbits during the
period of organogenesis caused developmental toxicity that included
post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations (external, skeletal, and visceral), at doses that are
52 (rat) and 43 (rabbit)
times the delivery
system amount present
in 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area. These effects
could be attributed to N-methyl-2-
pyrrolidone (NMP) an excipient in the
delivery system based on information in the published literature (see Data).
Subcutaneous administration of the delivery system to pregnant and lactating
rats had no effect on embryofetal and postnatal development at doses up
to 17 times the delivery system amount present in 120 mg risperidone
subcutaneous injectable suspension based on mg/m2 body surface area.
…
Subcutaneous administration
of the delivery system to pregnant rats and rabbits during the period of
organogenesis caused maternal toxicity (decreased body weight, weight gain and
food intake), post- implantation loss, decrease in number of live fetuses and
decrease in fetal weight at doses that are 52 (rat), and 43 (rabbit) times the delivery
system amount present in monthly 120 mg risperidone subcutaneous injectable
suspension based on mg/m2
body surface area. Developmental toxicity in both rat and rabbit included
skeletal and visceral malformations at doses 35 (rat), and 43 (rabbit) times
the delivery system amount
present in monthly
120 mg risperidone subcutaneous injectable suspension based on
mg/m2 body surface area. The NOAEL dose for these effects in both
species is 17 times the delivery system amount present in monthly 120 mg risperidone
subcutaneous injectable suspension based on mg/m2 body surface area.
These effects could be related to N-methyl-2-pyrrolidone (NMP), an excipient present in the delivery system. In published
animal developmental toxicity studies, NMP administered orally daily to
pregnant rats during organogenesis produced developmental toxicity below
maternally toxic levels and resulted in dose-dependent decrease in fetal body
weights, increased incidence of post- implantation loss, incomplete
ossification and increased incidence of external, visceral and skeletal
malformations. These toxicities occurred at doses that are ~3- to 12 -times the
NMP amount present in monthly 120 mg risperidone subcutaneous injectable
suspension based on mg/m2 body surface area.
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions underlined)
Infertility
Females
Based on the pharmacologic action of
risperidone (D2 receptor antagonism), treatment with PERSERIS may result in an increase
in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and
Precautions (5.6) and Nonclinical Toxicology (13.1)].
8.8 Patients with Parkinson’s Disease
or Dementia with Lewy Bodies
(Newly added subsection)
Patients with Parkinson’s disease or dementia
with Lewy bodies
can experience increased sensitivity to
risperidone. Manifestations can include confusion, obtundation, postural
instability with frequent falls, extrapyramidal symptoms, and clinical features
consistent with neuroleptic malignant syndrome.
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