Vyvanse® (lisdexamfetamine dimesylate) Capsules, (CII) Now Approved in the US for Maintenance Treatment in Children and Adolescents with ADHD

PHILADELPHIA, May 1, 2013 /PRNewswire/ --

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today announced that the US Food and Drug Administration (FDA) approved the prescription medication Vyvanse^® (lisdexamfetamine dimesylate) Capsules, (CII) as a maintenance treatment in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Vyvanse is currently approved as a maintenance treatment in adults with ADHD. With this new approval, Vyvanse becomes the only stimulant approved for maintenance treatment in children, adolescents, and adults (patients ages 6 and above) with ADHD.

The approval is based on results from a 32-week study: 26 weeks of open-label treatment with Vyvanse followed by a 6-week randomized withdrawal phase. The study was designed to evaluate the continued efficacy of Vyvanse in children and adolescents (aged 6 to 17 years). A significantly lower proportion of treatment failures occurred among Vyvanse patients (15.8%) compared to placebo (67.5%) at end point of the randomized withdrawal period, showing that significantly more patients treated with Vyvanse maintained ADHD symptom control compared with placebo.

"It's important to help establish and maintain effective control of symptoms in patients with ADHD," said Valerie Arnold, MD, an investigator in the randomized withdrawal study. "With this study, physicians now have clinical data in children and adolescents ages 6 and above showing the effectiveness of Vyvanse as a maintenance treatment for ADHD. This additional approval of Vyvanse is welcome because children and adolescents with ADHD may have a need for extended treatment, and could benefit from a treatment option proven to maintain efficacy."

Vyvanse is a Schedule II controlled substance. CNS Stimulants (amphetamines and methylphenidate-containing products) have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence.

To evaluate the efficacy of Vyvanse for maintenance treatment in children and adolescents with ADHD, Shire elected to conduct a double-blind, placebo-controlled, randomized withdrawal clinical trial. In this design, patients who respond to a treatment are randomized to continue receiving that treatment or placebo. Using the proportion of patients experiencing symptom relapse as a primary outcome, this type of study in patients with ADHD can be used to demonstrate long-term efficacy in lieu of conducting a long-term, placebo-controlled, parallel-group study. The utility of this design is that the period of placebo exposure, with the potential for worsening of ADHD symptoms, is relatively short.

The double-blind, placebo-controlled, randomized withdrawal study was conducted in 276 children and adolescents aged 6 to 17 with ADHD. Of these patients, 236 participated in a preceding study and 40 directly enrolled. The study consisted of 4 phases:

• 4-week, open-label, dose-optimization phase in which patients received Vyvanse 30 mg/day, 50 mg/day, or 70 mg/day. Eligible subjects started on Vyvanse 30 mg/day and could be titrated in weekly increments of 20 mg until an optimal dose was reached (up to a maximum of 70 mg/day)
• 20-week, open-label, maintenance phase
• 2-week, open-label, fixed-dose phase in which patients were discontinued if they required further dose adjustments, experienced unacceptable tolerability, or had an Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score >22 or Clinical Global Impression Severity (CGI-S) score ≥3. Patients who maintained treatment response entered the randomized withdrawal phase.
• 6-week, double-blind, randomized withdrawal phase in which patients either received ongoing treatment with the same dose of Vyvanse (N=78) or were switched to placebo (N=79).

The primary outcome measure was the proportion of patients who met criteria for relapse of ADHD symptoms (treatment failure) at end point during the double-blind, randomized withdrawal phase. The end point measurement was defined as the last post-randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were observed. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and a ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind, randomized withdrawal phase. On the primary end point, significantly fewer patients met criteria for symptom relapse with Vyvanse (15.8%) versus placebo (67.5%) (P<.001).

During the 26-week open-label phase, 12 patients (4.3%) reported serious adverse events (SAEs), and 45 patients (16.3%) reported treatment-emergent adverse events (TEAEs) that resulted in Vyvanse discontinuation. During the randomized withdrawal phase, no SAEs were reported in the Vyvanse group, no patients in the Vyvanse group discontinued due to a TEAE, and 1 patient in the placebo group discontinued due to a TEAE. In addition, 39.7% (31/78) of patients receiving Vyvanse and 25.3% (20/79) on placebo reported TEAEs. The most common TEAEs (≥2%) reported in the Vyvanse treatment group during the randomized withdrawal phase included nasopharyngitis, headache, abdominal pain upper, oropharyngeal pain, decreased appetite, vomiting, weight decrease, abdominal pain, accidental overdose, aggression, cough, nausea and rhinitis.

Patients receiving Vyvanse demonstrated a moderate increase in mean pulse rate (~5 beats per minute) and blood pressure (~2 mm Hg systolic and diastolic blood pressure) between baseline and end point of the randomized withdrawal period. Patients treated with Vyvanse experienced a mean decrease in body weight of about 2 kg during the 26-week open-label period. Mean weight tended to increase in patients who switched to placebo during the randomized withdrawal phase. There were no deaths reported during the trial. The safety profile seen in this study was consistent with that of other studies of Vyvanse, and no new clinically relevant safety signals were associated with abrupt discontinuation of Vyvanse.

"This study is evidence of Shire's commitment to conducting research in ADHD and contributing to the body of knowledge about treatment options," said Arnaud Partiot, M.D., Ph.D., senior vice president and head of Research and Development for Shire. "Vyvanse is now the only stimulant approved for maintenance treatment in patients ages 6 and above."

ABOUT VYVANSE (lisdexamfetamine dimesylate)

Vyvanse, which was introduced in the United States in July 2007 for the treatment of ADHD in children ages 6 to 12 years, approved in April 2008 to treat ADHD in adults, approved in November 2010 to treat ADHD in adolescents ages 13 to 17, approved in January 2012 for maintenance treatment in adults, and approved in April 2013 for maintenance treatment in children and adolescents, is currently available in six once-daily dosage strengths of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg.

Vyvanse may be used as part of a total treatment program that may include counseling or other therapies.

Additional information about Vyvanse is available at http://www.vyvanse.com.

INDICATION

Vyvanse is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of Vyvanse in the treatment of ADHD was established on the basis of three short-term controlled trials in children ages 6 to 12 years, one short-term controlled trial in adolescents ages 13 to 17 years, one short-term trial in children and adolescents ages 6-17 years, one maintenance trial in children and adolescents ages 6-17 years, two short-term controlled trials in adults, and one maintenance trial in adults.

IMPORTANT SAFETY INFORMATION

• Contraindications:
  • Known hypersensitivity to amphetamines or other ingredients in Vyvanse. Anaphylactic reactions, Stevens - Johnson syndrome, angioedema, and urticaria have been observed in postmarketing reports.
  • Concurrent administration of monoamine oxidase inhibitors (MAOI) or administration of Vyvanse within 14 days of the last MAOI dose. Hypertensive crisis can occur.

• Educate patients about abuse and periodically re-evaluate the need for Vyvanse.
• Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in children and adolescents with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Prior to treatment assess for the presence of cardiac disease. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Vyvanse treatment.
• CNS stimulants cause an increase in blood pressure (mean increase about 2-4 mm Hg) and heart rate (mean increase about 3-6 bpm). Monitor all patients for tachycardia and hypertension.
• Use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with preexisting psychosis. Clinical evaluation for bipolar disorder is recommended prior to stimulant use.
• CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Monitor weight and height in children during treatment with Vyvanse. Treatment may need to be interrupted in children not growing as expected.
• The most common adverse reactions (≥5% and at least twice the rate of placebo) reported in clinical trials were:    
  • Children aged 6 to 12: decreased appetite, insomnia, upper abdominal pain, irritability, vomiting, decreased weight, nausea, dry mouth and dizziness;
  • Adolescents aged 13 to 17: decreased appetite, insomnia, and decreased weight;
  • Adults: decreased appetite, insomnia, dry mouth, diarrhea, nausea, anxiety and anorexia.

Please click here for Full Prescribing Information.

ABOUT ADHD

Attention-Deficit/Hyperactivity Disorder is a neurobehavioral disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development.

ADHD is one of the most common childhood psychiatric disorders. Although many people tend to think of ADHD as a childhood problem, 60% to 85% of children with ADHD may continue to meet the criteria for the disorder during their teenage years. Nearly 50% of children with ADHD may continue to meet the criteria for the disorder into adulthood, based on parent-report. The disorder is estimated to affect 4.4 percent of US adults aged 18 to 44 based on results from the National Comorbidity Survey Replication. When this percentage is extrapolated to the full US population aged 18 and over, approximately 10 million adults are estimated to have ADHD. Drug treatment may not be appropriate for all patients.

The specific etiology of ADHD is unknown, and there is no single diagnostic test for this disorder. Adequate diagnosis requires the use of medical and special psychological, educational, and social resources, utilizing diagnostic criteria specified in the Diagnostic and Statistical Manual of MentalDisorders, 4th Edition, Text Revision (DSM-IV-TR®) or International Classification of Diseases, 10^th revision (ICD-10).

Although there is no cure for ADHD, there are accepted treatments that have been demonstrated to improve symptoms. Standard treatments include educational approaches, psychological therapies which may include behavioral modification, and/or medication. Ongoing assessment and treatment may be necessary.

NOTES TO EDITORS

Shire enables people with life-altering conditions to lead better lives.

Through our deep understanding of patients' needs, we develop and provide healthcare in the areas of:

• Behavioral Health and Gastrointestinal conditions
• Rare Diseases
• Regenerative Medicine

as well as other symptomatic conditions treated by specialist physicians.

We aspire to imagine and lead the future of healthcare, creating value for patients, physicians, policymakers, payors and our shareholders.

http://www.shire.com

FORWARD - LOOKING STATEMENTS - "SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995

Statements included in this announcement that are not historical facts are forward-looking statements. Forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, that:

• Shire's products may not be a commercial success;
• revenues from ADDERALL XR are subject to generic erosion;
• the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payors in a timely manner for Shire's products may impact future revenues and earnings;
• Shire relies on a single source for manufacture of certain of its products and a disruption to the supply chain for those products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis;
• Shire uses third party manufacturers to manufacture many of its products and is reliant upon third party contractors for certain goods and services, and any inability of these third party manufacturers to manufacture products, or any failure of these third party contractors to provide these goods and services, in each case in accordance with its respective contractual obligations, could adversely affect Shire's ability to manage its manufacturing processes or to operate its business;
• the development, approval and manufacturing of Shire's products is subject to extensive oversight by various regulatory agencies and regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• the actions of certain customers could affect Shire 's ability to sell or market products profitably and fluctuations in buying or distribution patterns by such customers could adversely impact Shire's revenues, financial conditions or results of operations;
• investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire's activities in the highly regulated markets in which it operates may result in the distraction of senior management, significant legal costs and the payment of substantial compensation or fines;
• adverse outcomes in legal matters and other disputes, including Shire's ability to obtain, maintain, enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on Shire's revenues, financial condition or results of operations;
• and other risks and uncertainties detailed from time to time in Shire's filings with the U.S. Securities and Exchange Commission, including its most recent Annual Report on Form 10-K.

VYV-05105 04/13

Vyvanse® is a registered trademark of Shire LLC.

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SOURCE Shire plc