Methylphenidate Hydrochloride

Switching to UZEDY at four weeks after the last dose of once-monthly paliperidone palmitate provided the most comparable pharmacokinetic (PK) pro on the relevant PK modeling data Additional data include new Phase 3 RISE and SHINE analyses demonstrating no new or unexpected safety concerns in young adults with schizophrenia treated with UZEDY Global ADVANCE survey findings also reveal real-world experiences and perspectives on long-acting injectable (LAI) schizophrenia treatments from healthcare professionals, caregivers and patients TEL AVIV, Israel & PARSIPPANY, N.J.--(BUSINESS WIRE)-- Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), today announced the presentation of seven studies from its long-acting injectable (LAI) schizophrenia research program. Presentations include data informing clinical strategies for switching patients to UZEDY, an extended-release injectable suspension of risperidone for subcutaneous use every one or two months for the treatment of schizophrenia in adults, from a once-monthly intramuscular injection of Invega Sustenna. The results were presented at the Psych Congress Elevate 2024 Annual Meeting taking place from May 30 – June 2 in Las Vegas, Nevada. “UZEDY is a long-acting formulation of risperidone with an innovative delivery system that requires no loading dose or oral supplementation and can be dosed at one- or two-month intervals to help with prevention of relapse. It is administered subcutaneously under the skin instead of intramuscularly, which is an important feature to discuss with patients,” said Eric Hughes, MD, PhD, Executive Vice President of Global R&D and Chief Medical Officer at Teva. “We are proud to share these clinical insights that may help healthcare providers understand more about switching between long-acting options for their schizophrenia patients.” In a population pharmacokinetic (PopPK) analysis, simulations were performed to predict PK exposures when switching to UZEDY 4 - 6 weeks at steady state after the last injection of once-monthly paliperidone palmitate. Model simulations showed that switching to UZEDY at four weeks after the last dose of once-monthly paliperidone palmitate yielded generally higher PK parameters, both within the total active moiety range for oral risperidone. Comparable doses included UZEDY at 125 mg (once-monthly dosing) or 250 mg (once-every-two-months dosing) to 234 mg of once-monthly paliperidone palmitate. The analysis aims to address the knowledge gap as limited clinical data currently exist to inform strategies for switching between the various available LAI treatment options with differing PK properties.1 Any switching strategy should be determined by clinicians on an individual basis, considering factors such as patient preference, scheduling convenience and potential tolerability issues or risk of symptom breakthrough. “The treatment and management of schizophrenia is a journey and many patients may see their needs evolve over time due to challenges with symptom control or simply due to a change in dosing preference,” said Christoph Correll, MD, Professor of Psychiatry at the Zucker School of Medicine, Hempstead, NY. “Researchers and clinicians like myself rely on analyses like these to understand strategies for switching between long-acting injectable options and help ensure each of our patients is on the most appropriate treatment.” Additional key data being presented at Psych Congress Elevate 2024: New data from the RISE (Risperidone Subcutaneous Extended-Release Study) and SHINE (A Study to Test TV-46000 for Maintenance Treatment of Schizophrenia) Phase 3 pivotal studies that supported the FDA approval of UZEDY for adults. The updated analysis evaluated the safety of once or twice monthly UZEDY for young adults (aged 18-21) who participated in the RISE and SHINE studies. No unexpected safety concerns or clinically meaningful trends in adverse events were observed.1 Qualitative data from four ADVANCE (Attitudes Driving Regional Differences in LAI Antipsychotic Utilization for Schizophrenia Among Healthcare Professionals, Patients and Caregivers) surveys showing: Ten psychiatrists, who average 18 years of experience and spend 45% of their practice time in hospital-based outpatient clinics, were interviewed and expressed that treatment priorities for patients with schizophrenia may differ depending on the care setting, but all described the potential benefits of LAIs for both patients and clinicians. 1 Seven psychiatric nurses, who average 17 years of experience and spend 47% of their practice time in outpatient clinics, were interviewed and expressed positive views of LAIs but had a limited understanding of specific LAI molecules and prioritized the benefits of LAIs for nonadherent patients, highlighting potential unmet HCP educational needs. 1 In the patient and caregiver surveys, 20 patients and 19 caregivers completed a 60-minute interview regarding the use of LAIs in schizophrenia. Most patient-reported perceptions regarding advantages of LAIs were convenience (n=7) and fewer side effects compared with oral antipsychotics (n=3). Caregivers emphasized the importance of a patient’s quality of life along with symptom management and expressed advantages of LAIs, including convenience to both the person with schizophrenia and the caregiver (n=10 and n=7, respectively). 1 Below is the full set of UZEDY and long-acting injectable data presented by Teva at Psych Congress Elevate 2024. UZEDY (risperidone): (De novo) Switching Patients With Schizophrenia From Intramuscular Paliperidone Palmitate Once Monthly to TV-46000, a Long-Acting Subcutaneous Antipsychotic: An Exploration of Population Pharmacokinetic-Based Strategies (De novo) Safety and Exposure of TV-46000, a Long-Acting Subcutaneous Antipsychotic (LASCA) Formulation of Risperidone, in Adolescent and Young Adult Patients With Schizophrenia: Results From the Phase 3 RISE and SHINE Studies (Encore) Switching Patients With Schizophrenia to TV-46000, a Long-Acting Subcutaneous Antipsychotic, From Risperidone Microspheres (R064766): An Exploration of Population Pharmacokinetic-Based Strategies LAI Real-World Insights: (De novo) Experience and Perceptions of Psychiatrists Treating Schizophrenia With Long-Acting Injectable Antipsychotics: Qualitative Results From the Multinational ADVANCE Study (De novo) Psychiatric Nurse Perceptions of Long-Acting Injectable Therapies for Treating Schizophrenia: Qualitative Results From the Multinational ADVANCE Study (De novo) Attitudes Driving Regional Differences in LAI Antipsychotic Utilization for Schizophrenia Among HCPs, Patients and Caregivers (ADVANCE) Study: Experiences and Perceptions of LAIs from Caregivers (De novo) Attitudes Driving Regional Differences in LAI Antipsychotic Utilization for Schizophrenia Among HCPs, Patients and Caregivers (ADVANCE) Study: Patients’ Perspectives on Initial and Current Treatments INDICATION AND USAGE UZEDY (risperidone) extended-release injectable suspension for subcutaneous use is indicated for the treatment of schizophrenia in adults. 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. See below for additional Important Safety Information. About Schizophrenia Schizophrenia is a chronic, progressive and severely debilitating mental disorder that affects how one thinks, feels and acts.2 Patients experience an array of symptoms, which may include delusions, hallucinations, disorganized speech or behavior and impaired cognitive ability.2,3,4 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.3,4 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.4 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.4 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.5,6,7 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.2,3,4,5,6,7 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.1,8 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.8 For full prescribing information, visit . IMPORTANT SAFETY INFORMATION CONTINUED 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 . 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) is a global pharmaceutical leader with a category-defying portfolio, harnessing our generics expertise and stepping up innovation to continue the momentum behind the discovery, delivery, and expanded development of modern medicine. For over 120 years, Teva’s commitment to bettering health has never wavered. Today, the company’s global network of capabilities enables its ~37,000 employees across 58 markets to push the boundaries of scientific innovation and deliver quality medicines to help improve health outcomes of millions of patients every day. To learn more about how Teva is all in for better health, visit . 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: our ability to successfully develop and commercialize UZEDY (risperidone) extended-release injectable suspension for the treatment schizophrenia; our ability to successfully compete in the marketplace, including our ability to develop and commercialize additional pharmaceutical products; our ability to successfully execute our 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 to sustain and focus our portfolio of generics medicines; and other factors discussed in our Quarterly Report on Form 10-Q for the first quarter of 2024 and in our Annual Report on Form 10-K for the year ended December 31, 2023, 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 Data on file. Parsippany, NJ: Teva Neuroscience, Inc. 2 Substance Abuse and Mental Health Services Administration. Schizophrenia. . Accessed November 2023. 3 Velligan DI, Rao S. The Epidemiology and Global Burden of Schizophrenia. J Clin Psychiatry. 2023;84(1):MS21078COM5. . 4 Wander C. (2020). Schizophrenia: Opportunities to Improve Outcomes and Reduce Economic Burden Through Managed Care. The Am J Manag Care. 26(3 Suppl), S62–S68. . 5 Emsley, R., & Kilian, S. (2018). Efficacy and safety pro paliperidone palmitate injections in the management of patients with schizophrenia: an evidence-based review. Neuropsychiatric Dis. Treat., 14, 205–223. 6 Emsley, R., Chiliza, B., Asmal, L. et al. (2013) The nature of relapse in schizophrenia. BMC Psychiatry 13, 50. 7 Andreasen, N. C., et al. (2013). Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. The Am J Psychiatry, 170(6), 609–615. 8 UZEDY® (risperidone) extended-release injectable suspension, for subcutaneous injection Current Prescribing Information. Parsippany, NJ. Teva Neuroscience, Inc. View source version on businesswire.com: Contacts PR Contacts Kelley Dougherty +1 (973) 832-2810 Eden Klein +972 (3) 906 2645 IR Contacts Yael Ashman +972 (3) 914 8262 Sanjeev Sharma +1 (973) 658 2700 Ran Meir +1 (267) 468-4475 Source: Teva Pharmaceutical Industries Limited View this news release online at:

Tris Pharma announced that the FDA has cleared Ondya XR (clonidine hydrochloride) for paediatric use in attention-deficit hyperactivity disorder (ADHD). The once-daily extended-release non-stimulant oral suspension, with night-time dosing, is indicated as monotherapy or adjunctive therapy to stimulants for ADHD patients as young as six years old. According to Tris, Ondya XR  is the first liquid non-stimulant ADHD product approved in the US. The drug is slated to hit US pharmacies in the second half.Non-stimulant formulations are crucial for patients who don't respond well to stimulants or experience adverse effects from them. “Securing FDA approval…is not just an important milestone, but a testament to our unwavering commitment to…improving outcomes for this patient population,” remarked Tris CEO Ketan Mehta.The company noted that Ondya XR’s approval was backed by data from well-controlled studies of clonidine hydrochloride extended-release tablets.Clonidine was introduced in clinical practice in 1966 as a centrally acting anti-hypertensive agent, and remains a widely-prescribed drug for multiple indications. The extended-release tablet of clonidine hydrochloride marketed as Kapvay by Shionogi was first approved in 2010 for the treatment of ADHD.Apart from Ondya XR, Tris’ current portfolio of oral extended-release ADHD medications includes Dynavel XR (amphetamine) and Quillivant XR/QuilliChew ER (methylphenidate hydrochloride), which have been developed using the company’s proprietary LiquiXR technology. Tris’ pipeline also has several candidates in development for ADHD, pain, addiction and other neurological disorders.