- RISE data show UZEDY to be an effective long-acting
injectable (LAI) antipsychotic treatment option for adults with
schizophrenia, with a known safety profile consistent with other
formulations of risperidone1
- In the RISE study, UZEDY significantly prolonged time to
impending relapse by up to 5.0 times (once-monthly dosing) versus
placebo in patients with schizophrenia1
- The U.S. Food and Drug Administration (FDA) approved UZEDY
in April 2023 for the treatment of schizophrenia in adults as a
subcutaneous injection dosed every one or two months
Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical
Industries Ltd. (NYSE and TASE: TEVA), today announced the
publication of efficacy and safety findings from the phase 3
Risperidone Subcutaneous Extended-Release (RISE) study in The
Lancet Psychiatry. The data supported the FDA approval for UZEDY,
which was approved in April 2023 for the treatment of schizophrenia
in adults as a subcutaneous injection every one or two months using
a pre-filled syringe.
In RISE, UZEDY significantly prolonged time to impending relapse
by 5.0 times with once-monthly dosing (HR 0.200, 95% CI
0.109–0.367; log rank p<0.0001) and 2.7 times with
once-every-two-months dosing (0.375, 0.227–0.618; log rank
p<0.0001) versus placebo in patients with schizophrenia,
corresponding to a decreased risk of relapse by 80% and 62.5%,
respectively.1 Study findings also show UZEDY provided clinically
relevant plasma concentrations within 24 hours of administration
and maintained them over the flexible dosing intervals.1,2
Additionally, the observed safety profile of UZEDY was consistent
with other approved formulations of risperidone – reinforcing its
potential role as an effective LAI treatment option for adults
living with schizophrenia.1
“Relapse remains a significant and ongoing challenge for
patients with schizophrenia as well as their caregivers and
physicians, and these RISE study findings demonstrate UZEDY’s
long-acting dosing has the potential to effectively prolong time to
relapse,” said Eric Hughes, MD, PhD, Executive Vice President of
Global R&D and Chief Medical Officer at Teva. “Importantly, a
diverse patient population was enrolled in the study, reflecting
Teva’s commitment to health equity in research and development as
well as ensuring there are clinical insights into the role of UZEDY
for every community impacted by schizophrenia.”
In the RISE study, 544 patients were randomized to receive a
subcutaneous injection of UZEDY once-monthly (n=183),
once-every-two-months (n=180), or placebo (n=181).1 In this study
population, 59% were Black or African American (n=322), 38% White
(n=206), 22% were Hispanic or Latinx (n=117), 1% were Asian (n=7),
<1% were Native Hawaiian or other Pacific Islander (n=2), <1%
did not report a race (n=3), and <1% were considered other race
(n=4).1
“Helping prevent relapses in my patients who live with
schizophrenia is critical to protecting their health and goals,”
said Christoph Correll, MD, practicing physician and professor of
psychiatry at the Zucker School of Medicine at Hofstra/Northwell,
Hempstead, NY. “The RISE study demonstrates that a long-acting
treatment option of a proven antipsychotic molecule may mitigate
the risk of relapse, helping address the needs and preferences of
patients with schizophrenia.”
UZEDY utilizes SteadyTeq™, a copolymer technology proprietary to
MedinCell, that controls the rate and duration of risperidone
release.2 With this delivery system, therapeutic blood
concentrations are reached within 6-24 hours of a single dose.1,
2
To read more on the RISE study findings published online in The
Lancet Psychiatry today, click here.
About Schizophrenia
Schizophrenia is a chronic, progressive and severely
debilitating mental disorder that affects how one thinks, feels and
acts.3 Patients experience an array of symptoms, which may include
delusions, hallucinations, disorganized speech or behavior and
impaired cognitive ability.3-5 Approximately 1% of the world’s
population will develop schizophrenia in their lifetime, and 3.5
million people in the U.S. are currently diagnosed with the
condition.4,5 Although schizophrenia can occur at any age, the
average age of onset tends to be in the late teens to the early 20s
for men, and the late 20s to early 30s for women.3 The long-term
course of schizophrenia is marked by episodes of partial or full
remission broken by relapses that often occur in the context of
psychiatric emergency and require hospitalization.3 Approximately
80% of patients experience multiple relapses over the first five
years of treatment, and each relapse carries a biological risk of
loss of function, treatment refractoriness, and changes in brain
morphology.6-8 Patients are often unaware of their illness and its
consequences, contributing to treatment nonadherence, high
discontinuation rates, and ultimately, significant direct and
indirect healthcare costs from subsequent relapses and
hospitalizations.3-8
About the Risperidone Subcutaneous Extended-Release (RISE)
Study
The RISE study was a multicenter, randomized, double-blind,
placebo-controlled study to evaluate the efficacy of risperidone
extended-release injectable suspension for subcutaneous use as a
treatment in patients (ages 13-65 years) with schizophrenia.9 544
patients were randomized to receive a subcutaneous injection of
TV-46000 once-monthly (q1M), once-every-two-months (q2M), or
placebo in a 1:1:1 ratio.9 Additional information can be found at
https://clinicaltrials.gov/study/NCT03503318.
About UZEDY
UZEDY (risperidone) extended-release injectable suspension, for
subcutaneous use, is indicated for the treatment of schizophrenia
in adults. In clinical trials, UZEDY significantly reduced the risk
of schizophrenia relapse.2, 10 UZEDY administers risperidone
through copolymer technology under license from MedinCell that
allows for absorption and sustained release after subcutaneous
injection. UZEDY is the only long-acting, subcutaneous formulation
of risperidone available in both one- and two-month dosing
intervals.2 For full prescribing information, visit
https://www.uzedy.com/globalassets/uzedy/prescribing-information.pdf.
INDICATION AND USAGE
UZEDY (risperidone) extended-release injectable suspension for
subcutaneous use is indicated for the treatment of schizophrenia in
adults.
IMPORTANT SAFETY INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. UZEDY is not
approved for use in patients with dementia-related psychosis and
has not been studied in this patient population.
CONTRAINDICATIONS: UZEDY is contraindicated in patients
with a known hypersensitivity to risperidone, its metabolite,
paliperidone, or to any of its components. Hypersensitivity
reactions, including anaphylactic reactions and angioedema, have
been reported in patients treated with risperidone or
paliperidone.
WARNINGS AND PRECAUTIONS
Cerebrovascular Adverse Reactions: In trials of elderly
patients with dementia-related psychosis, there was a significantly
higher incidence of cerebrovascular adverse events (e.g., stroke,
transient ischemic attack), including fatalities, in patients
treated with oral risperidone compared to placebo. UZEDY is not
approved for use in patients with dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): 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 UZEDY and provide symptomatic
treatment and monitoring.
Tardive Dyskinesia (TD): TD, 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 predict which
patients will develop the syndrome. Whether antipsychotic drug
products differ in their potential to cause TD is unknown.
The risk of developing TD and the likelihood that it will become
irreversible are believed to increase with the duration of
treatment and the cumulative dose. The syndrome can develop, after
relatively brief treatment periods, even at low doses. It may also
occur after discontinuation. TD 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, possibly masking the
underlying process. The effect that symptomatic suppression has
upon the long-term course of the syndrome is unknown.
If signs and symptoms of TD appear in a patient treated with
UZEDY, drug discontinuation should be considered. However, some
patients may require treatment with UZEDY despite the presence of
the syndrome. 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.
Metabolic Changes: Atypical antipsychotic drugs have been
associated with metabolic changes that may increase
cardiovascular/cerebrovascular risk. These metabolic changes
include hyperglycemia, dyslipidemia, and body weight gain. While
all of the drugs in the class have been shown to produce some
metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and diabetes mellitus (DM), in some cases
extreme and associated with ketoacidosis or hyperosmolar coma or
death, have been reported in patients treated with atypical
antipsychotics, including risperidone. Patients with an established
diagnosis of DM who are started on atypical antipsychotics,
including UZEDY, should be monitored regularly for worsening of
glucose control. Patients with risk factors for DM (e.g., obesity,
family history of diabetes) who are starting treatment with
atypical antipsychotics, including UZEDY, should undergo fasting
blood glucose (FBG) testing at the beginning of treatment and
periodically during treatment. Any patient treated with atypical
antipsychotics, including UZEDY, should be monitored for symptoms
of hyperglycemia including polydipsia, polyuria, polyphagia, and
weakness. Patients who develop symptoms of hyperglycemia during
treatment with atypical antipsychotics, including UZEDY, should
undergo FBG testing. In some cases, hyperglycemia has resolved when
the atypical antipsychotic, including risperidone, was
discontinued; however, some patients required continuation of
antidiabetic treatment despite discontinuation of risperidone.
Dyslipidemia has been observed in patients treated with
atypical antipsychotics.
Weight gain has been observed with atypical antipsychotic
use. Monitoring weight is recommended.
Hyperprolactinemia: As with other drugs that antagonize
dopamine D2 receptors, risperidone elevates prolactin levels and
the elevation persists during chronic administration. Risperidone
is associated with higher levels of prolactin elevation than other
antipsychotic agents.
Orthostatic Hypotension and Syncope: UZEDY may induce
orthostatic hypotension associated with dizziness, tachycardia, and
in some patients, syncope. UZEDY should be used with particular
caution in patients with known cardiovascular disease,
cerebrovascular disease, and conditions which would predispose
patients to hypotension and 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
risperidone and antihypertensive medication.
Falls: Antipsychotics, including UZEDY, may cause
somnolence, postural hypotension, motor and sensory instability,
which may lead to falls and, consequently, fractures or other
fall-related injuries. Somnolence, postural hypotension, motor and
sensory instability have been reported with the use of risperidone.
For patients, particularly the elderly, with diseases, conditions,
or medications that could exacerbate these effects, assess the risk
of falls when initiating antipsychotic treatment and recurrently
for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis have been
reported with antipsychotic agents, including risperidone. In
patients with a pre-existing history of a clinically significant
low white blood cell count (WBC) or absolute neutrophil count (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 UZEDY 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 UZEDY in patients with ANC < 1000/mm3) and
follow their WBC until recovery.
Potential for Cognitive and Motor Impairment: UZEDY, like
other antipsychotics, may cause somnolence and has the potential to
impair judgement, thinking, and motor skills. Somnolence was a
commonly reported adverse reaction associated with oral risperidone
treatment. Caution patients about operating hazardous machinery,
including motor vehicles, until they are reasonably certain that
treatment with UZEDY does not affect them adversely.
Seizures During premarketing studies of oral risperidone
in adult patients with schizophrenia, seizures occurred in 0.3% of
patients (9 out of 2,607 patients), two in association with
hyponatremia. Use UZEDY cautiously in patients with a history of
seizures or other conditions that potentially lower the seizure
threshold.
Dysphagia: Esophageal dysmotility and aspiration have
been associated with antipsychotic drug use. Antipsychotic drugs,
including UZEDY, should be used cautiously in patients at risk for
aspiration.
Priapism has been reported during postmarketing
surveillance for other risperidone products. A case of priapism was
reported in premarket studies of UZEDY. Severe priapism may require
surgical intervention.
Body temperature regulation. Disruption of the body’s
ability to reduce core body temperature has been attributed to
antipsychotic agents. Both hyperthermia and hypothermia have been
reported in association with oral risperidone use. Strenuous
exercise, exposure to extreme heat, dehydration, and
anticholinergic medications may contribute to an elevation in core
body temperature; use UZEDY with caution in patients who experience
these conditions.
ADVERSE REACTIONS
The most common adverse reactions with risperidone (≥5% and
greater than placebo) were parkinsonism, akathisia, dystonia,
tremor, sedation, dizziness, anxiety, blurred vision, nausea,
vomiting, upper abdominal pain, stomach discomfort, dyspepsia,
diarrhea, salivary hypersecretion, constipation, dry mouth,
increased appetite, increased weight, fatigue, rash, nasal
congestion, upper respiratory tract infection, nasopharyngitis, and
pharyngolaryngeal pain.
The most common injection site reactions with UZEDY (≥5% and
greater than placebo) were pruritus and nodule.
DRUG INTERACTIONS
- Carbamazepine and other strong CYP3A4 inducers decrease plasma
concentrations of risperidone.
- Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors
increase risperidone plasma concentration.
- Due to additive pharmacologic effects, the concomitant use of
centrally-acting drugs, including alcohol, may increase nervous
system disorders.
- UZEDY may enhance the hypotensive effects of other therapeutic
agents with this potential.
- UZEDY may antagonize the pharmacologic effects of dopamine
agonists.
- Concomitant use with methylphenidate, when there is change in
dosage of either medication, may increase the risk of
extrapyramidal symptoms (EPS)
USE IN SPECIFIC POPULATIONS
Pregnancy: May cause EPS and/or withdrawal symptoms in
neonates with third trimester exposure. There is a pregnancy
exposure registry that monitors pregnancy outcomes in women exposed
to atypical antipsychotics, including UZEDY, during pregnancy.
Healthcare providers are encouraged to register patients by
contacting the National Pregnancy Registry for Atypical
Antipsychotics at 1-866-961-2388 or online at
http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/.
Lactation: Infants exposed to risperidone through
breastmilk should be monitored for excess sedation, failure to
thrive, jitteriness, and EPS.
Fertility: UZEDY may cause a reversible reduction in
fertility in females.
Pediatric Use: Safety and effectiveness of UZEDY have not
been established in pediatric patients.
Renal or Hepatic Impairment: Carefully titrate on oral
risperidone up to at least 2 mg daily before initiating treatment
with UZEDY.
Patients with Parkinson’s disease or dementia with Lewy
bodies can experience increased sensitivity to UZEDY.
Manifestations and features are consistent with NMS.
Please see the full Prescribing Information for
UZEDY, including Boxed WARNING.
About Teva
Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) has
been developing and producing medicines to improve people’s lives
for more than a century. We are a global leader in generic and
innovative medicines with a portfolio consisting of over 3,500
products in nearly every therapeutic area. Around 200 million
people around the world take a Teva medicine every day, and are
served by one of the largest and most complex supply chains in the
pharmaceutical industry. Along with our established presence in
generics, we have significant innovative research and operations
supporting our growing portfolio of innovative and
biopharmaceutical products. Learn more at www.tevapharm.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, which are based on management’s current beliefs and
expectations and are subject to substantial risks and
uncertainties, both known and unknown, that could cause our future
results, performance or achievements to differ significantly from
that expressed or implied by such forward-looking statements. You
can identify these forward-looking statements by the use of words
such as “should,” “expect,” “anticipate,” “estimate,” “target,”
“may,” “project,” “guidance,” “intend,” “plan,” “believe” and other
words and terms of similar meaning and expression in connection
with any discussion of future operating or financial performance.
Important factors that could cause or contribute to such
differences include risks relating to the development and
commercial success of UZEDY (risperidone) extended-release
injectable suspension for the treatment of schizophrenia in adults;
our ability to successfully compete in the marketplace, including
our ability to develop and commercialize competition for our
innovative medicines, our ability to achieve expected results from
investments in our product pipeline, our ability to develop and
commercialize additional pharmaceutical products, our ability to
successfully launch and execute our new Pivot to Growth strategy,
including to expand our innovative and biosimilar medicines
pipeline and profitably commercialize the innovative medicines and
biosimilar portfolio, whether organically or through business
development and the effectiveness of our patents and other measures
to protect our intellectual property rights; our substantial
indebtedness; our business and operations in general, including,
the impact of global economic conditions and other macroeconomic
developments and the governmental and societal responses thereto,
and costs and delays resulting from the extensive pharmaceutical
regulation to which we are subject; compliance, regulatory and
litigation matters, including failure to comply with complex legal
and regulatory environments; other financial and economic risks;
and other factors discussed in our Quarterly Report on Form 10-Q
for the second quarter of 2023 and in our Annual Report on Form
10-K for the year ended December 31, 2022, including in the section
captioned “Risk Factors.” Forward-looking statements speak only as
of the date on which they are made, and we assume no obligation to
update or revise any forward-looking statements or other
information contained herein, whether as a result of new
information, future events or otherwise. You are cautioned not to
put undue reliance on these forward-looking statements.
1 Kane J, Harary E, et al (2023). Efficacy and safety of
TV-46000, a long-acting, subcutaneous, injectable formulation of
risperidone, for schizophrenia: a randomised clinical trial in the
USA and Bulgaria. The Lancet Psychiatry, 10(12), 935-944.
https;//doi.org/10.1016/ S2215-0366(23)00288-2.
2 UZEDY™ (risperidone) extended-release injectable suspension,
for subcutaneous injection Current Prescribing Information.
Parsippany, NJ. Teva Neuroscience, Inc.
3 Substance Abuse and Mental Health Services Administration.
Schizophrenia. https://www.samhsa.gov/mental-health/schizophrenia.
Accessed November 2023.
4 Velligan DI, Rao S. The epidemiology and global burden of
schizophrenia. J Clin Psychiatry. 2023;84(1):MS21078COM5.
https://doi.org/10.4088/JCP.MS21078COM5.
5 Wander C. (2020). Schizophrenia: opportunities to improve
outcomes and reduce economic burden through managed care. The
American journal of managed care, 26(3 Suppl), S62–S68.
https://doi.org/10.37765/ajmc.2020.43013
6 Emsley, R., & Kilian, S. (2018). Efficacy and safety
profile of paliperidone palmitate injections in the management of
patients with schizophrenia: an evidence-based review.
Neuropsychiatric disease and treatment, 14, 205–223.
7 Emsley, R., Chiliza, B., Asmal, L. et al. (2013) The nature of
relapse in schizophrenia. BMC Psychiatry 13, 50.
8 Andreasen, N. C., et al. (2013). Relapse duration, treatment
intensity, and brain tissue loss in schizophrenia: a prospective
longitudinal MRI study. The American journal of psychiatry, 170(6),
609–615.
9 Clinicaltrials.gov. Study to Evaluate TV-46000 as Maintenance
Treatment in Adult and Adolescent Participants With Schizophrenia
(RISE). https://clinicaltrials.gov/study/NCT03503318. Accessed
November 2023.
10 Data on file. Parsippany, NJ: Teva Neuroscience, Inc.
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IR Contacts Ran Meir, +1 (267) 468-4475 Yael Ashman, +972
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Klein, +972 (3) 906 2645
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