FDA Approves INTUNIV® (guanfacine) Extended-Release Tablets for Use as Adjunctive Therapy to Stimulants for the Treatment of ADHD in Children and Adolescents

PHILADELPHIA, Feb. 28, 2011 /PRNewswire/ -- Shire plc, (LSE: SHP, Nasdaq: SHPGY), the global specialty biopharmaceutical company, today announced that the US Food and Drug Administration (FDA) approved the use of once-daily INTUNIV® (guanfacine) Extended-Release Tablets as adjunctive therapy to stimulants for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents ages 6 to 17 as part of a total treatment program. The approval is based on results from a 9-week placebo-controlled study of INTUNIV when given in combination with a stimulant, in children and adolescents with ADHD.(1)

"This approval of INTUNIV for treating ADHD as adjunctive therapy to a stimulant offers physicians a new treatment option for children and adolescents with ADHD who are having a suboptimal response to their current stimulant therapy," said Robert Findling, MD, Director of Child & Adolescent Psychiatry at University Hospitals Case Medical Center and Professor of Psychiatry & Pediatrics at Case Western Reserve University School of Medicine, a lead investigator for the study. "In this study, the once-daily dosing of INTUNIV was effective when taken in the morning or the evening, giving physicians flexibility when it comes to treating their patients with ADHD."

INTUNIV is indicated for the treatment of ADHD as monotherapy and as adjunctive therapy to stimulant medications in children and adolescents ages 6 to 17. The effectiveness of INTUNIV for more than 9 weeks has not been systematically evaluated. The physician electing to use INTUNIV for extended periods should periodically reevaluate its long-term usefulness for the individual patient. INTUNIV is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social).(1)

INTUNIV is the only once-daily ADHD medication approved for administration as adjunctive therapy to stimulants. INTUNIV, a nonstimulant, is a selective alpha-2A agonist.(1)

During the 9-week, multicenter, double-blind, randomized, placebo-controlled study, patients (N=455) experiencing a suboptimal response to stimulant treatment for ADHD received a morning or evening dose of INTUNIV (1 mg, 2 mg, 3 mg, or 4 mg) or placebo in combination with their prescribed dose of a stimulant.(2)  Clinicians using the ADHD-RS-IV, which includes both hyperactive/impulsive and inattentive subscales, reported significant reductions in total scores from baseline at end point for patients receiving INTUNIV and stimulant when INTUNIV was dosed either in the morning or evening, compared with placebo and stimulant.(2)

Suboptimal response was defined as treatment with a stable dose of stimulant for at least four weeks with improvement, yet persistence of mild to moderate ADHD symptoms in the opinion of the investigator (defined as an ADHD-RS-IV total score of at least 24, Clinical Global Impressions-Severity of Illness scale score of at least three). Patients with no response to stimulants prior to study enrollment were excluded from participating in this study.(2)

The most commonly observed adverse reactions (incidence greater than or equal to 5 percent and at least twice the rate for placebo) in this adjunctive trial were: somnolence, fatigue, insomnia, dizziness, and abdominal pain.(1)  The majority of events were mild or moderate in severity and no unique events were observed with INTUNIV given with a stimulant compared with those reported historically for either treatment alone.(2)  Three percent of patients receiving INTUNIV plus stimulant discontinued from the study due to adverse events, compared to 1 percent in the placebo plus stimulant group.(1)

Four serious adverse events (SAEs) were reported in the study and included syncope, mixed disturbance of emotions (similar to behaviors prior to study start), poison ivy, and a nonintentional overdose in a sibling of a study participant. All SAEs were considered by the investigator to be unrelated to INTUNIV.(2)

"This approval marks a significant development in our ADHD portfolio -- one that may help to address symptoms that many children with ADHD may experience while on stimulant treatment," said Michael Yasick, Senior Vice President of Shire's ADHD Business Unit. "We understand that every child is unique, and it is our goal to offer treatment options for ADHD in a variety of situations, whether a child could benefit from treatment with a stimulant, nonstimulant, or both."

About INTUNIV

INTUNIV is available in four doses -- 1 mg, 2 mg, 3 mg, and 4 mg.(1)  INTUNIV should be taken once a day.(1)  The active ingredient in INTUNIV is guanfacine. INTUNIV is not a central nervous system (CNS) stimulant or a controlled substance.(1)  It is not likely to cause dependence or be abused.(1)

IMPORTANT SAFETY INFORMATION

INTUNIV should not be used in patients with a history of hypersensitivity to guanfacine or any of its inactive ingredients or by patients taking other products containing guanfacine (eg, TENEX®).

Hypotension, bradycardia, and syncope were observed in clinical trials. Use INTUNIV with caution in treating patients who have experienced hypotension, heart block, bradycardia, or syncope, or who may have a condition that predisposes them to syncope; are treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Heart rate and blood pressure should be measured prior to initiation of therapy, following dose increases, and periodically while on therapy. Advise patients to avoid becoming dehydrated or overheated.

Somnolence and sedation were commonly observed in clinical trials. The potential for additive sedative effects with CNS depressant drugs should be considered. Patients should be cautioned against operating heavy equipment or driving until they know how they respond to INTUNIV. Advise patients to avoid use with alcohol.

The most common adverse reactions (incidence greater than or equal to 5% and at least twice the rate for placebo) in the monotherapy trials with INTUNIV were somnolence, fatigue, nausea, lethargy, and hypotension, and in the adjunctive trial with INTUNIV were somnolence, fatigue, insomnia, dizziness, and abdominal pain.

Please see Full Prescribing Information.

Additional information about INTUNIV is available at intuniv.com.

About ADHD

Attention deficit hyperactivity disorder (ADHD) is a psychiatric behavioral 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.(3)

ADHD is one of the most common childhood psychiatric disorders.(4)   In the United States, the prevalence of ADHD is approximately three to seven percent in school-aged children according to the Centers for Disease Control and Prevention (CDC).(5)

The specific etiology of ADHD is unknown, and there is no single diagnostic test for this disorder.(4) 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 Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR®) or International Classification of Diseases, 10th revision (ICD-10).(3,4)

Although there is no cure for ADHD, there are accepted treatments that have been demonstrated to improve symptoms.(4)  Standard treatments include educational approaches, psychological therapies that may include behavioral modification, and/or medication.(4)

Notes to editors

SHIRE PLC

Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician.  Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions.  Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights.  Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

For further information on Shire, please visit the Company's website: www.shire.com.

"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995

Statements included herein that are not historical facts are forward-looking statements. Such 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, the Company's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company's Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company's products; the Company's ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company's products; the Company's ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company's ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission.

References:

1. INTUNIV [package insert], Wayne, PA: Shire US Inc.; 02/2011.
2. Wilens T, Bukstein OG, Cutler AJ, Findling RL, Youcha S, White C, Rubin J. A multicenter placebo controlled study of extended-release guanfacine coadministered with stimulants in the treatment of ADHD: Effects on overall, morning, and evening ADHD assessments. Paper presented at: American Academy of Child and Adolescent Psychiatry Annual Meeting; October 28, 2010; New York, NY.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text Revision (DSM-IV-TR ®). Washington, DC: American Psychiatric Association; 2000:85-93.
4. Pliszka S and the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.
5. Centers for Disease Control and Prevention. Increasing prevalence of parent reported attention deficit/hyperactivity disorder among children -- United States, 2004 and 2007. Morb Mortal Weekly Rep (MMWR). 2010;59(44):1439-1443.

SOURCE Shire plc

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