Shire Pharmaceuticals Group Plc

INTUNIV® (Guanfacine Hydrochloride Prolonged Release), a Non-stimulant for the Treatment of ADHD, Receives Approval in Japan

Zug, Switzerland (ots/PRNewswire) - A New Non-stimulant Clinical Option for Children and Adolescents From 6 to 17 Years old With ADHD

Shire plc (LSE: SHP, NASDAQ: SHPG) today announced that its partner in Japan, Shionogi & Co., Ltd, has received the approval of the Japanese Ministry of Health, Labor and Welfare to manufacture and market INTUNIV. INTUNIV is a new, once-daily non-stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD),[1] a common psychiatric disorder in children and adolescents.[2],[3]

ADHD causes inattention, hyperactivity or impulsivity, or a combination of these symptoms,[4],[5] and can have substantial impact on all major areas of life, including: schooling, work and employment, behaviour, social functioning, self-esteem and health.[6]-[9]

INTUNIV is a selective alpha-2A adrenergic receptor agonist.[1] With a unique mechanism of action, INTUNIV represents an additional treatment option in the management of ADHD.

"Shire is committed to ensuring that every person with ADHD is able to benefit from a treatment most suited to their needs," said Philip J Vickers, PhD, Global Head of Shire Research and Development. "The approval of INTUNIV marks a significant advance in the treatment of ADHD in children and adolescents in Japan, who may benefit from a new treatment option."

As part of the partnership, a Phase 3 placebo-controlled clinical study and long-term extension study evaluating the efficacy and safety of INTUNIV in 254 patients was conducted in Japan. In the trial, INTUNIV administered once daily, showed significant improvements over placebo, as measured by ADHD-RS-IV total score, in all core symptoms of ADHD: hyperactivity/impulsivity, and inattention. The most common adverse events were somnolence in 146 patients (57.5%), decreased blood pressure in 39 patients (15.4%), and headache in 31 patients (12.2%).[1]

ADHD is a complex condition and approaches to treatment typically include educational methods, psychotherapy and medication.[10] When required, either stimulants or non-stimulants are indicated as part of a comprehensive treatment programme for ADHD. Children and adolescents have a wide spectrum of individual needs as patients, so it is important that a range of treatment options are available. Non-stimulant medications are an important alternative to stimulants for some ADHD patients.[10]

About ADHD

Attention deficit hyperactivity disorder (ADHD) is recognised by the World Health Organization (WHO).[2] Worldwide prevalence of ADHD is estimated to vary between 5.9% and 7.1%.[3]

Whilst the exact origin of ADHD is not fully understood, the area of the brain known as the prefrontal cortex is known to control several cognitive functions including attention and social behaviours,[9],[ 11],[12] and has been associated with some structural and functional abnormalities in individuals with ADHD.[13]-[15]

About INTUNIV

INTUNIV (guanfacine hydrochloride prolonged release) is a once-daily non-stimulant indicated for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents from 6 to 17 years old.[1]

INTUNIV provides significantly improved ADHD symptom control vs. placebo[1],[16] and has a well-documented safety profile across the dose range.[1]

INTUNIV contains the active substance guanfacine, a selective alpha-2A adrenergic receptor agonist.[1] Studies suggest that guanfacine may exert physiological effects by selectively stimulating the alpha-2A adrenergic receptor in the prefrontal cortex.[17]-[18]

INTUNIV is currently approved by Shire in the US, Canada, and Europe. Please refer to the local label for the approved indication.

INTUNIV Safety Information for Japan[1]

Precautions on indication

1. The efficacy and safety of INTUNIV in children under 6 years of 
   age or adults over 18 years of age have not been established.
2. If INTUNIV is continued after age 18 in patients who started 
   pharmacological treatment with this drug before the age of 18 
   years, it should be administered with caution after the 
   therapeutic benefits are weighed against the possible risks. The 
   efficacy and safety of INTUNIV should regularly be evaluated, and 
   if INTUNIV is of no value, it should be considered for 
   discontinuation and must not be administered without purpose.
3. A diagnosis of ADHD must be made with caution, according to 
   standard, established diagnostic criteria, including DSM* 
   published by the American Psychiatric Association. INTUNIV must be
   used only in patients who meet such criteria. 

*Diagnostic and Statistical Manual of Mental Disorders

Contraindication (INTUNIV is contraindicated in the following patients.)

1. Patients with a history of hypersensitivity to any of the 
ingredients of this drug.

2. Pregnant women or women who may possibly be pregnant.

3. Patients with atrioventricular block second-degree and 
third-degree. [The condition may get worse because of the central 
bradycardia effect of this drug.] 

Precautions

1. Careful Administration (INTUNIV should be administered with care in the following patients.)

1. Patients with a current or previous history of hypotension, 
   orthostatic hypotension, bradycardia, or cardiovascular disease, 
   or patients treating with drugs which can reduce blood pressure or
   pulse rate [INTUNIV may decrease blood pressure and heart rate.]
2. Patients with a current or previous history of hypertension [Blood
   pressure may increase when administration of this drug is abruptly
   discontinued.]
3. Patients with a current or previous history of arrhythmia, 
   patients with congenital long QT syndrome or patients treating 
   with drugs that are known to cause QT prolongation [QT 
   prolongation may occur because of this drug.]
4. Patients with a current or previous history of ischaemic heart 
   disease such as angina pectoris and myocardial infarction [If the 
   acute reduction of blood pressure occurs, ischaemic heart disease 
   may get worse because of the decreased coronary flow.]
5. Patients with cerebrovascular disorder such as cerebral infarction
   etc. [If the acute reduction of blood pressure occurs, the 
   symptoms may be aggravated due to the decrease in cerebral blood 
   flow.]
6. Patients with severe hepatic function disorder [The blood 
   concentration of this drug may increase.]
7. Patients with severe renal function disorder [The blood 
   concentration of this drug may increase.]
8. Patients in depressed state [The symptom may get worse because of 
   the sedative effects of this drug.] 

2. Important precautions

1.  Before prescribing INTUNIV, the physician or healthcare 
professional should fully inform the patient and his/her parent or 
other appropriate representative of its therapeutic position and 
potential risks, including adverse reactions to the drug, and 
instruct the patient on the proper administration method.  

2.  During long-term use of INTUNIV, the value of ongoing treatment
should be periodically assessed and patients should not be 
administered without purpose. ~ 

3.  Since syncope may occur when advanced decreases in blood 
pressure or pulse rate are observed, blood pressure and pulse rate 
should be measured prior to initiation of treatment of INTUNIV and 
1-2 weeks after changing the dosage. Blood pressure and pulse rate 
should also be measured at intervals of once in 4 weeks after setting
an optimal dose. Also, dehydration along with the administration of 
INTUNIV should be fully cautioned. If any dehydration symptoms are 
observed, proper care such as fluid replacement should be taken.  

4.  Since the effects on cardiovascular system (advanced 
bradycardia, hypotension, QT prolongation etc.) may appear, the 
following points should be cautioned before and during treatment with
INTUNIV. 
i)  The presence or absence of abnormality in ECG should be 
confirmed before treatment with INTUNIV. If any abnormality in ECG is
observed, the initiation of administration should be carefully 
judged.

ii) When INTUNIV is administered to patients with cardiovascular
disease or with a medical history of cardiovascular disease, or any 
abnormality in ECG is observed before treatment with INTUNIV, 
patients' condition should be carefully observed by conducting 
routine ECG and so on.

iii) Patients' cardiovascular condition should be cautioned 
during treatment with INTUNIV. If any symptoms suggesting the effects
on cardiovascular system (bradycardia, syncope, dizziness, 
palpitations, etc.) appear, proper care should be taken by conducting
ECG and so on. 
5. Since suicidal ideation or behavior may occur, patient's 
condition should be carefully observed. Also, patients, the parents 
or other appropriate representative should be instructed to contact a
medical institution immediately, if any suicidal symptoms occur.

6. While hostility and aggression are frequently observed in AD/HD 
patients, occurrence of these events during treatment has been also 
reported. The occurrence or worsening of these events should be 
carefully monitored during treatment.

7.  Since INTUNIV may cause weight increase, body weight should be 
monitored regularly. If any symptom of obesity appears, proper care 
should be taken such as food therapy, movement therapy, etc.

8.  Since sleepiness, sedation, etc. may occur, patients should be 
cautioned not to engage in operating potentially hazardous machinery,
including automobiles during treatment. 

Drug interactions

This drug is primarily metabolized by the hepatic metabolizing enzymes CYP3A4 and CYP3A5.

Adverse reactions

Out of 254 patients evaluated for safety before NDA approval, adverse reactions (including abnormal changes in laboratory values) were observed in 190 patients (74.8%). Main adverse reactions were somnolence in 146 patients (57.5%), decreased blood pressure in 39 patients (15.4%), and headache in 31 patients (12.2%).

1. Clinically significant adverse reactions

1. Hypotension (?5%), bradycardia (?5%): Since advanced hypotension 
   or/and bradycardia may occur and lead to syncope, patients' 
   condition should be carefully monitored, measuring blood pressure 
   and pulse rate regularly. If any of these symptoms appears, proper
   care such as dose reduction, interruption, or discontinuation 
   should be taken.
2. Syncope (Incidence unknown[Note 1]): Since syncope may occur, 
   patients should be fully observed. If any abnormality is observed,
   proper care such as discontinuation of administration should be 
   taken.
3. Atrioventricular block (<0.5%): Since atrioventricular block may 
   occur, proper care such as dose reduction, interruption, or 
   discontinuation should be taken if any abnormality is observed. 

2. Other adverse reactions

If the following adverse reactions occur, appropriate measures such as dose reduction, interruption, or discontinuation should be taken as necessary.



greater than   <5%, greater
or equal        than or                     
Incidence
Type/ Incidence        to 5%    equal to 1%      <1%           
unknown[Note 1]


Hypersensitivity,
Hypersensitivity                                                 
rash, pruritus



Tachycardia, sinus

arrhythmia, pallor,
Orthostatic   Increased         
hypertensive
Cardiovascular                 hypotension   blood pressure    
encephalopathy

Nightmare,
affect
Somnolence,                  lability,
headache,                  agitation,        
Anxiety, depression,
insomnia,                  sedation,         
lethargy, convulsion,
Psychoneurologic    dizziness   Irritability   asthenia          
hypersomnia

Decreased
appetite,
nausea,
constipation,
diarrhea,
Abdominal      thirst,                       
Abdominal discomfort,
Gastrointestinal         pain     vomiting                       
dyspepsia

Enuresis,    Pollakiuria,
increased    increased ALT      
Asthma, chest pain,
Others               Malaise       weight     (GPT)              
dehydration 

Note 1: The incidence of adverse reactions on the basis of overseas clinical studies and spontaneous reports is unknown.

NOTES TO EDITORS

About Shire

Shire is the leading global biotechnology company focused on serving people with rare diseases and other highly specialized conditions. We strive to develop best-in-class products, many of which are available in more than 100 countries, across core therapeutic areas including Hematology, Immunology, Neuroscience, Ophthalmics, Lysosomal Storage Disorders, Gastrointestinal / Internal Medicine / Endocrine and Hereditary Angioedema; and a growing franchise in Oncology.

Our employees come to work everyday with a shared mission: to develop and deliver breakthrough therapies for the hundreds of millions of people in the world affected by rare diseases and other high-need conditions, and who lack effective therapies to live their lives to the fullest.

http://www.shire.com

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A further list and description of risks, uncertainties and other matters can be found in Shire's most recent Annual Report on Form 10-K and in Shire's subsequent Quarterly Reports on Form 10-Q, in each case including those risks outlined in "ITEM 1A: Risk Factors", and in Shire's subsequent reports on Form 8-K and other Securities and Exchange Commission filings, all of which are available on Shire's website.

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References

 1. INTUNIV Prescribing Information, Shionogi & Co., Ltd 2017.
 2. POLANCZYK, G. et al. (2007). The Worldwide Prevalence of ADHD: A 
    Systematic Review and Metaregression Analysis. Am J Psych. 
    164:942-948.
 3. WILLCUTT, EG. (2012). The Prevalence of DSM-IV 
    Attention-deficit/Hyperactivity Disorder: A Meta-analytic Review.
    Neurotherapeutics. 9:490-499.
 4. International Classification of Diseases, 10th ed., (ICD-10). 
    World Health Organization 2007. Chapter 5,F90. http://apps.who.in
    t/classifications/icd10/browse/2010/en#/F90-F98. Last accessed 
    June 2014.
 5. American Psychiatric Association. (2013) Diagnostic and 
    statistical manual of mental disorders: DSM-5 (5th ed.). 
    Arlington, VA: American Psychiatric Publishing.
 6. DIAMANTOPOULOU S, et al. Impact of Executive Functioning and 
    Symptoms of Attention Deficit Hyperactivity Disorder on 
    Children's Peer Relations and School Performance. Dev 
    Neuropsychol 2007; 32(1):521-542.
 7. BIEDERMAN J, et al. Functional Impairments in Adults with 
    Self-reports of Diagnosed ADHD: A Controlled Study of 1001 Adults
    in the Community. J Clin Psychiatry 2006; 67:524-540.
 8. SHAW M, et al. A Systematic Review and Analysis of Long-term 
    Outcomes in Attention Deficit Hyperactivity Disorder: Effects of 
    Treatment and Non-treatment. BMC Medicine 2012; 10:99.
 9. MANES, F. et al. (2002). Decision-making processes following 
    damage to the prefrontal cortex. Brain. 125:624-639.
10. TAYLOR, E. et al. (2004). European clinical guidelines for 
    hyperkinetic disorder - first upgrade. European Child and 
    Adolescent Psychiatry. 13 Suppl 1:i7-i30.
11. WILKINS, AJ. et al. (1987). Frontal lesions and sustained 
    attention. Neuropsychologia. 25:359-365.
12. ANDERSON, SW. et al. (1999). Impairment of social and moral 
    behavior related to early damage in human prefrontal  cortex. 
    Nature Neuroscience. 2:1032-1037.
13. FARAONE S, et al. (2005) Molecular Genetics of Attention Deficit 
    Hyperactivity Disorder. BioPsych 57:1313-1323.
14. RUBIA, K. et al. (1999). Hypofrontality in attention deficit 
    hyperactivity disorder during higher-order motor control: a study
    with functional MRI. American Journal of Psychiatry. 156:891-896.
15. HOEKZEMA, E. et al. (2014). An independent components and 
    functional connectivity analysis of resting state FMRI data 
    points to neural network dysregulation in adult ADHD. Human Brain
    Mapping. 35:1261-1272.
16. 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. European Neuropsychopharmacology. 
    24:1861-1872.
17. REN, WW. et al. (2012). Stimulation of α(2A)-adrenoceptors 
    promotes the maturation of dendritic spines in cultured neurons 
    of the medial prefrontal cortex. Molecular and Cellular 
    Neuroscience. 49:205-216.
18. WANG, M. et al. (2007). Alpha2A-adrenoceptors strengthen working 
    memory networks by inhibiting cAMP-HCN  channel signaling in 
    prefrontal cortex. Cell 129:397-410. 

Contact:

please contact:
Media
Lauren Starr
lauren.starr@shire.com
+41-41-288-4443



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