Shire Pharmaceuticals Group Plc

Shire Receives European Approval for INTUNIV®? (Guanfacine Hydrochloride Prolonged Release Tablets) as a Non-stimulant ADHD Treatment for Children and Adolescents

Zug, Switzerland (ots/PRNewswire) - The first selective alpha-2A adrenergic receptor agonist licensed for the treatment of ADHD in the EU   

Shire today announced that the European Commission granted Marketing Authorisation for once-daily, non-stimulant INTUNIV(R) (guanfacine hydrochloride prolonged release tablets) for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective.[1] INTUNIV must be used as a part of a comprehensive ADHD treatment programme, typically including psychological, educational and social measures.[1]

"The approval of INTUNIV marks a significant advance in the treatment of ADHD in children and adolescents in Europe. Previously, physicians had only one licensed non-stimulant option for these patients," said Perry Sternberg, Senior Vice President, Neuroscience Business Unit, Shire. "The importance of simply providing physicians with the ability to choose the non-stimulant option that may best suit the needs of their patients should not be overlooked, considering the complexities and different manifestations of the disorder in children and adolescents."

The European Commission decision to grant approval is based on data from three pivotal Phase 3 studies investigating the short- and long-term safety and efficacy of INTUNIV in children and adolescents with ADHD.[2]-[4]

The European Commission decision to grant Marketing Authorisation follows a positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in July 2015 and applies to all 28 EU member states and Iceland, Liechtenstein and Norway.

About ADHD in children and adolescents 

ADHD is a common psychiatric disorder in children and adolescents[5]-[7] and is recognised by the World Health Organization (WHO).[8] The core symptoms are inattention, hyperactivity and impulsivity.[7] Worldwide, prevalence of ADHD is estimated to be between 5.29% and 7.1%, and just under 5% for children and adolescents (<18 years).[5],[6] While the exact origin of ADHD is unknown, it is recognised that the disorder may be caused by the interplay between genetic and environmental factors.[9]-[11]

About INTUNIV 

INTUNIV is indicated in the EU, Iceland, Liechtenstein and Norway as a non-stimulant for the treatment of ADHD in children and adolescents aged 6 to 17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective.[1]

INTUNIV must be used as a part of a comprehensive ADHD treatment programme, typically including psychological, educational and social measures.[1]

Guanfacine is a selective alpha-2A adrenergic receptor agonist in that it has 15-20 times higher affinity for this receptor subtype than for the alpha-2B or alpha-2C subtypes.[1] Guanfacine is a non-stimulant. The mode of action of guanfacine in ADHD is not fully established. Preclinical research suggests guanfacine modulates signalling in the prefrontal cortex and basal ganglia through direct modification of synaptic noradrenalin transmission at the alpha 2- adrenergic receptors.[1]

The effects of guanfacine in the treatment of ADHD have been examined in children and adolescents (6 to 17 years). Guanfacine showed significantly greater efficacy than placebo on symptoms of ADHD based upon investigator ratings on the ADHD Rating Scale (ADHD-RS).[1]

INTUNIV is also licensed in the US and Canada. For more information on the product labelling in these markets, refer to the US Prescribing Information and the Canadian Product Monograph, respectively. In the US, generic versions of Intuniv for the treatment of ADHD are available.

INTUNIV safety information[1]

Guidance for Use 

Pre-treatment screening: A baseline evaluation needs to be conducted to identify patients at increased risk of somnolence and sedation, hypotension and bradycardia, QT-prolongation arrhythmia and weight increase/risk of obesity.

Monitoring: During dose titration, weekly monitoring for signs and symptoms of somnolence and sedation, hypotension and bradycardia should be performed. During the first year of treatment, the patient should be assessed at least every 3 months for signs and symptoms as during dose titration and for weight increase/risk of obesity.

The physician who elects to use Intuniv for extended periods (over 12 months) should re-evaluate the usefulness of Intuniv every 3 months for the first year and then at least yearly, and consider trial periods off medication to assess the patient's functioning without pharmacotherapy, preferably during times of school holidays.

Discontinuation: Patients/caregivers should be instructed not to discontinue Intuniv without consulting their physician. Blood pressure and pulse may increase following discontinuation of Intuniv. Individuals may have larger increases than reflected by the mean changes. Blood pressure and pulse should be monitored in all patients during dose downward titration and following discontinuation of Intuniv. Tapering Intuniv dosing during withdrawal is recommended to minimise these potential withdrawal effects.

Contraindications 

Hypersensitivity to the active substance or to any of the excipients.

Special warnings and precautions for use 

Caution is advised when treating patients with Intuniv who have a history of hypotension, bradycardia, syncope or a condition that may predispose them to syncope such as hypotension, orthostatic hypotension, bradycardia or dehydration, heart block or cardiovascular disease. Caution is also advised when treating patients with Intuniv who are being treated concomitantly with antihypertensives or other medicinal products that can reduce blood pressure or heart rate or increase the risk of syncope. Patients should be advised to drink plenty of fluid.

Guanfacine should be prescribed with caution in patients with a known history of QT prolongation, risk factors for torsade de pointes or who are taking medicinal products known to prolong the QT interval.

Intuniv may cause somnolence and sedation predominantly at the start of treatment. Before Intuniv is used with any other centrally active depressants the potential for additive sedative effects should be considered. Patients should not drink alcohol whilst taking Intuniv. Patients are advised against operating heavy equipment, driving or cycling until they know how they respond to treatment with Intuniv.

Patients with emergent suicidal ideation or behavior during treatment for ADHD should be evaluated immediately by their physician.

Children and adolescents treated with Intuniv may show an increase in their BMI. Therefore, monitoring of height, weight and BMI should be done prior to initiation of therapy and then every 3 months for the first year, taking into consideration clinical judgement. 6 monthly monitoring should follow thereafter, with more frequent monitoring following any dose adjustment.

Patients with rare hereditary problems of galactose intolerance, the lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interactions 

When Intuniv is used concomitantly with CYP3A4/5 inhibitors (e.g. ketoconazole, grapefruit juice) and inducers, plasma concentrations of guanfacine may be elevated or lowered, potentially affecting the efficacy and safety of Intuniv.

Side effects 

          Very common
           (frequency
      greater than or
       equal to1/10):            Somnolence, headache, abdominal pain and fatigue.

                         Decreased appetite, depression, anxiety, affect lability,
                        insomnia, middle insomnia, nightmare, sedation, dizziness,
                                   lethargy, bradycardia, hypotension, orthostatic
               Common      hypotension, vomiting, diarrhoea, nausea, constipation,
     (greater than or     abdominal/stomach discomfort, dry mouth, rash, enuresis,
     equal to1/100 to            irritability, blood pressure decreased and weight
              <1/10):                                                    increased

                           Hypersensitivity, agitation, hallucination, convulsion,
                                syncope/loss of consciousness, dizziness postural,
                           atrioventricular block first degree, tachycardia, sinus
             Uncommon             arrhythmia, pallor, asthma, dyspepsia, pruritis,
     (greater than or            pollakiuria, asthenia, chest pain, blood pressure
    equal to1/1000 to                  increased, heart rate decreased and alanine
             <1/100):                                  aminotransferase increased.
 

Please consult the SPC for rare (greater than or equal to1/10000 to <1/1000) side effects with Intuniv.

NOTES TO EDITORS 

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

Our strategy is to focus on developing and marketing innovative specialty medicines to meet significant unmet patient needs.

We provide treatments in Rare Diseases, Neuroscience, Gastrointestinal and Internal Medicine and we are developing treatments for symptomatic conditions treated by specialist physicians in other targeted therapeutic areas, such as Ophthalmics.

http://www.shire.com

THE "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. 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, 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;
 
- product sales from ADDERALL XR(R) and INTUNIV(R) are subject to generic
  competition;
 
- the failure to obtain and maintain reimbursement, or an adequate level of
  reimbursement, by third-party payers in a timely manner for Shire's products may
  affect future revenues, financial condition and results of operations;
 
- Shire conducts its own manufacturing operations for certain of its products and is
  reliant on third party contract manufacturers to manufacture other products and to
  provide goods and services. Some of the Shire's products or ingredients are only
  available from a single approved source for manufacture. Any disruption to the supply
  chain for any of the Shire's 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 for some period of time;
 
- the manufacture of Shire's products is subject to extensive oversight by various
  regulatory agencies. Regulatory approvals or interventions associated with changes to
  manufacturing sites, ingredients or manufacturing processes could lead to significant
  delays, an increase in operating costs, lost product sales, an interruption of
  research activities or the delay of new product launches;
 
- Shire has a portfolio of products in various stages of research and development.
  The successful development of these products is highly uncertain and requires
  significant expenditures and time, and there is no guarantee that these products will
  receive regulatory approval;
 
- the actions of certain customers could affect Shire's ability to sell or market
  products profitably. Fluctuations in buying or distribution patterns by such customers
  can adversely affect 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 significant legal costs and the payment of substantial
  compensation or fines;
 
- adverse outcomes in legal matters and other disputes, including Shire's ability to
  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;
 
- Shire faces intense competition for highly qualified personnel from other
  companies and organizations. Shire is undergoing a corporate reorganization and was
  the subject of an unsuccessful acquisition proposal and the consequent uncertainty
  could adversely affect Shire's ability to attract and/or retain the highly skilled
  personnel needed for Shire to meet its strategic objectives;
 
- failure to achieve Shire's strategic objectives with respect to the acquisition of
  NPS Pharmaceuticals, Inc. may adversely affect Shire's financial condition and results
  of operations;
 

and other risks and uncertainties detailed from time to time in Shire's filings with the US Securities and Exchange Commission, including its most recent Annual Report on Form 10-K.

REFERENCES: 

1) Intuniv Summary of Product Characteristics. Shire Pharmaceuticals Ireland Limited.
  2015.
2) HERVAS A, et al. (2014) Efficacy and safety of extended-release guanfacine
  hydrochloride in children and adolescents with attention-deficit/hyperactivity
  disorder: a randomized, controlled, phase III trial. Eur Neuropsychopharmacol.
  24:1861-72.
3) NEWCORN JH, et al. (2014) Long-term maintenance of efficacy of extended-release
  guanfacine hydrochloride (GXR) in children and adolescents with
  attention-deficit/hyperactivity disorder (ADHD): double-blind, placebo-controlled,
  multicentre, phase 3, randomized withdrawal study. Poster presented at the 22nd
  European Congress of Psychiatry; Munich, Germany.
4) WILENS TE, et al. (2014) A multicentre, placebo-controlled trial of guanfacine
  extended release in adolescents with attention-deficit/hyperactivity disorder. Poster
  presented at the 3rd EUNETHYDIS International Conference on ADHD; Istanbul, Turkey.
5) POLANCZYK G, et al. (2007) The worldwide prevalence of ADHD: a systematic review and
  metaregression analysis. Am J Psychiatry. 164:942-8.
6) WILLCUTT EG. (2012) The prevalence of DSM-IV attention-deficit/hyperactivity disorder:
  a meta-analytic review. Neurotherapeutics. 2012;9:490-9.
7) American Psychiatric Association. (2013) Diagnostic and statistical manual of mental
  disorders: DSM-5 (5th ed.). Arlington, VA: American Psychiatric Publishing.
8) International Classification of Diseases, 10th ed. (ICD-10). World Health Organization
  2007. Chapter 5, F90. Available at:
  http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98 Last accessed
  September 2015.
9) LANGLEY K, et al. (2007) Effects of Low Birth Weight, Maternal Smoking in Pregnancy
  and Social Class on the Phenotypic Manifestation of Attention Deficit Hyperactivity
  Disorder and Associated Antisocial Behaviour: Investigation in a Clinical Sample. BMC
  Psychiatry. 7:26.
  10) FARAONE S, et al. (2005) Molecular Genetics of Attention Deficit Hyperactivity
  Disorder. BioPsych 57:1313-1323.
  11) NIGG J, et al. (2010) Measured Gene-by-environment Interaction in Relation to
  Attention-deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry.
  49:863-873.
 
 
For further information, please contact: 
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Media 
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Gwen Fisher 
gfisher@shire.com 
+1-484-595-9836 
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Deborah Hibbett 
dhibbett@shire.com 
+41-41-288-4359

 
 
Investors 
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Sarah Elton-Farr 
seltonfarr@shire.com 
+44(0)1256 894157 
 

 

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