ZUG, Switzerland, March 30, 2017 /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
- The efficacy and safety of INTUNIV in children under 6 years of
age or adults over 18 years of age have not been established.
- 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.
- 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.)
- 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.]
- Patients with a current or previous history of hypertension
[Blood pressure may increase when administration of this drug is
abruptly discontinued.]
- 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.]
- 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.]
- 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.]
- Patients with severe hepatic function disorder [The blood
concentration of this drug may increase.]
- Patients with severe renal function disorder [The blood
concentration of this drug may increase.]
- 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
- 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.
- 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.
- 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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References
- INTUNIV Prescribing Information, Shionogi & Co., Ltd
2017.
- POLANCZYK, G. et al. (2007). The Worldwide Prevalence of ADHD:
A Systematic Review and Metaregression Analysis. Am J Psych.
164:942-948.
- WILLCUTT, EG. (2012). The Prevalence of DSM-IV
Attention-deficit/Hyperactivity Disorder: A Meta-analytic Review.
Neurotherapeutics. 9:490-499.
- International Classification of Diseases, 10th ed., (ICD-10).
World Health Organization 2007. Chapter 5,F90.
http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98.
Last accessed June 2014.
- American Psychiatric Association. (2013) Diagnostic and
statistical manual of mental disorders: DSM-5 (5th ed.).
Arlington, VA: American
Psychiatric Publishing.
- 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.
- 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.
- 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.
- MANES, F. et al. (2002). Decision-making processes following
damage to the prefrontal cortex. Brain. 125:624-639.
- TAYLOR, E. et al. (2004). European clinical guidelines for
hyperkinetic disorder - first upgrade. European Child and
Adolescent Psychiatry. 13 Suppl 1:i7-i30.
- WILKINS, AJ. et al. (1987). Frontal lesions and sustained
attention. Neuropsychologia. 25:359-365.
- ANDERSON, SW. et al. (1999). Impairment of social and moral
behavior related to early damage in human prefrontal
cortex.
Nature Neuroscience. 2:1032-1037.
- FARAONE S, et al. (2005) Molecular Genetics of Attention
Deficit Hyperactivity Disorder. BioPsych 57:1313-1323.
- 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.
- 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.
- 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.
- 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.
- WANG, M. et al. (2007). Alpha2A-adrenoceptors strengthen
working memory networks by inhibiting cAMP-HCN
channel signaling
in prefrontal cortex. Cell 129:397-410.
For further information please contact:
Media
Lauren Starr
lauren.starr@shire.com
+41-41-288-4443