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Comparator of the cardiovascular effects of ADHD
medication in Children / Adolescents
Category
Methylphenidate
Strattera
4.2
Pre-treatment screening:
Pre-treatment screening:
Ongoing monitoring:
Ongoing monitoring:
• Pre-existing cardiovascular disorders (refer to SPC
for listed conditions which are as for atomoxetine)
• Pre-existing cerebrovascular disorders cerebral
aneurysm, vascular abnormalities including
vasculitis or stroke
• Patients with severe cardiovascular or
cerebrovascular disorders whose condition
would be expected to deteriorate if they
experienced increases in blood pressure or
heart rate that could be clinically important
Cardiovascular Status:
Cardiovascular Effects:
Posology and
Method of
administration
• A comprehensive history should document family
history of sudden cardiac /unexplained death
• Conduct a baseline evaluation of a patient’s
cardiovascular status including BP/HR
• Record BP/HR on a centile chart at each adjustment
of dose and then at least every 6 months
4.3
Contraindications
4.4
Special Warnings
and Precautions
for Use
• Take careful history/cardiac exam
• Consult cardiac specialist if indicated
• Possibility of clinical complications especially when
treatment is continued into adulthood
• Patients may commonly experience changes
in BP>10 mmHg (consequences of which are
unknown)
• Caution is indicated in treating patients whose
underlying medical conditions might be
compromised by increases in BP/HR
• Stimulant misuse may be associated with sudden
death/other serious cardiovascular adverse events
• Same sudden death warning for all meds
Long-term Use:
• Careful ongoing monitoring including CV status is
required with long term use
4.8
Undesirable
effects
Common reports of:
• Changes in BP/HR (usually increased), arrhythmia,
tachycardia, palpitations, hypertension
Uncommon reports of:
• Chest pain, hot flushes, cardiac murmur
Rare reports of:
• Angina
• Take an appropriate medical history
• Conduct a baseline evaluation of
cardiovascular status including BP/HR
• Cardiovascular status should be regularly
monitored
• Record BP/HR on a centile chart after each
adjustment of dose and then at least every
6 months
• Patients should have a careful history/
physical exam
• Consult cardiac specialist if indicated
• Atomoxetine can affect BP/HR which for
most is modest increase/may not be clinically
important
• In some patients (approx 6-12%) it is
clinically relevant (HR ≥20bpm and BP≥15-20
mmHg). Some patients (approx.15-32%)
who experience clinically relevant changes
had sustained/progressive increases
• Use with caution in patients whose
underlying medical conditions could be
worsened by increases in BP/HR
• Use with caution in congenital/acquired and
family history of QT problems
• Same sudden death warning for all
medications
• Use with caution in any condition that
may predispose patients to hypotension or
conditions associated with abrupt HR/BP
changes
Very common reports of:
• Blood pressure and pulse increased
Uncommon reports of:
• Palpitations, sinus tachycardia
PMS reports of:
• QT interval prolongation, Raynaud’s
phenomenon
Very rare reports of:
• Cardiac arrest; myocardial infarction, cerebral
arteritis and/or occlusion, Peripheral coldness,
Raynaud’s phenomenon, sudden cardiac death
Frequency unknown:
• Supraventricular tachycardia, bradycardia,
ventricular extrasystoles; extrasystoles
Refer to full SPCs for complete information on both compounds. SPCs for Strattera, Concerta, Equasym, and Ritalin can be found at www.medicines.ie
STRATTERAВ® (ATOMOXETINE). ABBREVIATED PRESCRIBING INFORMATION
REPUBLIC OF IRELAND. Presentation Hard capsules: 10mg, 18mg, 25mg, 40mg,
60mg, 80mg, or 100mg atomoxetine. Uses Treatment of Attention-Deficit/
Hyperactivity Disorder (ADHD) in children 6 years of age and older, in adolescents,
and in adults as part of a comprehensive treatment programme. Treatment must be
initiated by a specialist in the treatment of ADHD. In adults, the presence of
symptoms of ADHD that were pre-existing in childhood should be confirmed. Third
party corroboration is desirable and Strattera should not be initiated when the
verification of childhood ADHD symptoms is uncertain. Based on clinical judgment,
patients should have ADHD of at least moderate severity, as indicated by at least
moderate functional impairment in 2 or more settings. Diagnosis should be made
according to current DSM criteria or the guidelines in ICD. Treatment with Strattera
need not be indefinite. Re-evaluation of the need for continued therapy beyond 1
year is recommended, particularly when the patient has reached a stable and
satisfactory response. Dosage and Administration For oral use, administered as a
single daily dose in the morning, with or without food. Some patients may benefit
from taking it twice daily in divided doses. Can be discontinued without dose
tapering. Dosing of children/adolescents up to 70 kg body weight: Initiate at a total
daily dose of approximately 0.5mg/kg and maintain for a minimum of 7 days prior to
upward dose titration according to clinical response and tolerability. The
recommended maintenance dose is approximately 1.2mg/kg/day. The safety of
single doses over 1.8mg/kg/day and total daily doses above 1.8mg/kg have not
been systematically evaluated. Dosing of children/adolescents over 70 kg body
weight: Initiate at a total daily dose of 40mg and maintain for a minimum of 7 days
prior to upward dose titration according to clinical response and tolerability. The
recommended maintenance dose is 80mg. Dosing of adults: Strattera should be
initiated at a total daily dose of 40mg. The initial dose should be maintained for a
minimum of 7 days prior to upward dose titration according to clinical response and
tolerability. The recommended maintenance daily dose is 80mg to 100mg. The
maximum recommended total daily dose is 100mg. The maximum recommended
total daily dose in children and adolescents over 70 kg and adults is 100mg. The
safety of single doses over 120mg and total daily doses above 150mg have not
been systematically evaluated. Prior to prescribing it is necessary to take an
appropriate medical history and conduct a baseline evaluation of a patient’s
cardiovascular status, including blood pressure and heart rate. This should be
recorded after each dose adjustment and then at least every 6 months. Special
Populations Doses may need to be modified in patients with hepatic insufficiency or
renal disease. For patients with a known poor metaboliser genotype (CYP2D6 poor
metabolisers), a lower starting dose and slower up titration of the dose may be
considered. Atomoxetine should not be used in children under 6 years of age. The
use of atomoxetine in elderly patients over 65 years of age has not been
systematically evaluated. Contra-indications Hypersensitivity to the active
substance or any of the excipients. Should not be used in patients with narrow
angle glaucoma. Should not be used in patients with phaeochromocytoma or a
history of the condition. Should not be used in combination with monoamine
oxidase inhibitors (MAOIs) and should not be used within 2 weeks of discontinuing
therapy with a MAOI. Treatment with a MAOI should not be initiated within 2 weeks
of discontinuing atomoxetine. Should not be used in patients with severe
cardiovascular or cerebrovascular disorders. Warnings and Special Precautions
Suicide-related behaviour (suicide attempts and suicidal ideation) has been reported
in patients treated with atomoxetine. In double-blind clinical trials, suicide-related
behaviours were uncommon but occurred more frequently in atomoxetine treated
patients, with no events in the placebo group. In adult double-blind clinical trials
there was no difference in frequency of suicide-related behaviour between
atomoxetine and placebo. Sudden death has been reported in patients with
structural cardiac abnormalities who were taking atomoxetine at usual doses.
Although some serious structural cardiac abnormalities alone carry an increased
risk of sudden death, use only with caution in patients with known serious structural
cardiac abnormalities and in consultation with a cardiac specialist. Atomoxetine can
affect heart rate and blood pressure. Most patients experience a modest increase
that may not be clinically important. However, as some patients do experience
clinically relevant changes in BP and HR (eg, 15 to 20mmHg/20 beats per minute),
use with caution in patients with hypertension, tachycardia, cerebrovascular or
other cardiovascular disease, or conditions that predispose to hypertension or
abrupt changes in heart rate or blood pressure. In some cases changes are
progressive or sustained. Pulse and blood pressure should be measured and
recorded before treatment is started and, during treatment, after each adjustment of
dose and then at least every 6 months. Patients who develop symptoms suggestive
of cardiac disease during treatment should undergo prompt specialist cardiac
evaluation. Long-term sustained changes in blood pressure may potentially
contribute to clinical consequences such as myocardial hypertrophy. Use with
caution in patients with congenital or acquired long QT or a family history of QT
prolongation. Patients with risk factors for cerebrovascular conditions should be
assessed at every visit for neurological signs and symptoms. Very rare cases of
severe liver injury, including acute liver failure, have been reported. Discontinue in
patients with jaundice or laboratory evidence of liver injury, and do not restart.
Treatment emergent psychotic or manic reactions, eg, hallucinations, delusional
thinking, mania, and agitation, can be caused by atomoxetine at usual doses. If
such symptoms occur, consideration should be given to a possible causal role of
atomoxetine, and discontinuation of treatment should be considered. Hostility and
emotional lability were more frequently observed in clinical trials among children
and adolescents treated with atomoxetine compared to those treated with placebo.
Patients who are being treated for ADHD should be carefully monitored for the
appearance or worsening of suicide-related behaviour, aggressive behaviour,
hostility, or emotional lability. Uncommonly, allergic reactions, including anaphylaxis,
have been reported. Introduce with caution in patients with a history of seizure.
Discontinuation of atomoxetine should be considered in any patient developing a
seizure or if there is an increase in seizure frequency where no other cause is
identified. Growth and development should be monitored in children and
adolescents during treatment with atomoxetine. Consideration should be given to
dose reduction or interrupting therapy in children and adolescents who are not
growing or gaining weight satisfactorily. Patients requiring long-term therapy should
be carefully monitored. Patients being treated for ADHD should be monitored for the
appearance or worsening of anxiety symptoms, depressed mood and depression,
or tics. Interactions Atomoxetine should not be used with MAOIs. Dose adjustment
and slower titration of atomoxetine may be necessary in those patients who are also
taking CYP2D6 inhibitor drugs (eg, SSRIs, quinidine, terbinafine). Caution is advised
when combining atomoxetine with potent inhibitors of cytochrome P450 enzymes
other than CYP2D6 in patients who are poor CYP2D6 metabolisers. Atomoxetine
should be administered with caution to patients being treated with high dose
nebulised or systemically administered (oral or intravenous) salbutamol (or other
beta2 agonists) because the action of salbutamol on the cardiovascular system can
be potentiated. Attention should be paid to monitoring heart rate and blood
pressure, and dose adjustments may be justified for either atomoxetine or
salbutamol (or other beta2 agonists) in the event of significant increases in heart rate
and blood pressure during co-administration of these drugs. There is the potential
for an increased risk of QT interval prolongation when atomoxetine is administered
with other QT prolonging drugs (such as neuroleptics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic
antidepressants, lithium, or cisapride), drugs that cause electrolyte imbalance (such
as thiazide diuretics), and drugs that inhibit CYP2D6. Caution is advised with
concomitant use of medicinal drugs which are known to lower the seizure threshold
(such as antidepressants or SSRIs, neuroleptics, phenothiazines or butyrophenone,
mefloquine, chloroquine, bupropion or tramadol). Atomoxetine should be used
cautiously with antihypertensive drugs, pressor agents, and drugs that affect
noradrenaline. Review of therapy may be justified in the case of significant change
in blood pressure. Pregnancy and Lactation Should not be used during pregnancy
unless the potential benefit justifies the potential risk to the foetus. Due to lack of
data, atomoxetine should be avoided during breast-feeding. Driving, etc Use
caution when driving or operating hazardous machinery. Undesirable Effects
(Clinical Trial Reporting) Children and Adolescents Headache, abdominal pain,
and decreased appetite are the most common adverse events but seldom lead to
drug discontinuation; abdominal pain and decreased appetite are usually transient.
Some patients experienced growth retardation early in therapy in terms of both
weight and height gain. With continued long-term treatment both height and weight
normalised to baseline. In adult and paediatric clinical trials, patients experienced
increases in heart rate and blood pressure. The following is based on adverse event
reporting and laboratory investigations from clinical trials and post-marketing
spontaneous reports in children and adolescents: Very common (≥10%): Headache,
somnolence, appetite decreased, abdominal pain, vomiting, nausea, blood pressure
and heart rate increased (based on measured vital signs). Common (≥1-<10%):
Anorexia, insomnia, irritability, mood swings, agitation, anxiety, depression and
depressed mood, tics, dizziness, mydriasis, constipation, dyspepsia, dermatitis,
pruritus, rash, fatigue, lethargy, weight decreased. Uncommon (≥0.1-<1%): Suiciderelated events, aggression, hostility, emotional lability, psychosis (including
hallucinations), syncope, tremor, migraine, paraesthesia, hypoaesthesia, seizure,
palpitations, sinus tachycardia, QT interval prolongation, blood bilirubin increased,
hyperhidrosis, allergic reactions, asthenia. Rare (≥1-<0.1%): Raynaud’s
phenomenon, abnormal/increased liver function tests, jaundice, hepatitis, liver
injury, acute hepatic failure, urinary hesitation, urinary retention, priapism, male
genital pain. In trials lasting up to ten weeks, weight loss was more pronounced in
poor metabolisers. Adults In adult ADHD clinical trials, the following system organ
classes had the highest frequency of adverse events during treatment with
atomoxetine: gastro-intestinal, nervous system, and psychiatric disorders. The
most common adverse events (≥5%) reported were appetite decreased (14.9%),
insomnia (11.3%), headache (16.3%), dry mouth (18.4%), and nausea (26.7%). The
majority of these events were mild or moderate in severity and the events most
frequently reported as severe were nausea, insomnia, fatigue, and headache. A
complaint of urinary retention or urinary hesitancy in adults should be considered
potentially related to atomoxetine. The following is based on adverse event reporting
and laboratory investigations from clinical trials and post-marketing spontaneous
reports in adults: Very common (≥10%): Appetite decreased, insomnia, headache,
dry mouth, nausea, blood pressure and heart rate increased (based on measured
vital signs). Common (≥1-<10%): Agitation, libido decreased, sleep disorder,
depression and depressed mood, anxiety, dizziness, dysgeusia, paraesthesia,
somnolence (including sedation), tremor, palpitations, tachycardia, flushing, hot
flush, abdominal pain, constipation, dyspepsia, flatulence, vomiting, dermatitis,
hyperhidrosis, rash, dysuria, pollakiuria, urinary hesitation, urinary retention,
dysmenorrhoea, ejaculation disorder, erectile disturbance, prostatitis, male genital
pain, asthenia, fatigue, lethargy, chills, feeling jittery, irritability, thirst, weight
decreased. Uncommon (≥ 0.1-<1%): Suicide-related events, aggression, hostility
and emotional lability, restlessness, tics, syncope, migraine, hypoaesthesia, QT
interval prolongation, peripheral coldness, allergic reactions, pruritus, urticaria,
muscle spasms, micturition urgency, ejaculation failure, menstruation irregular,
orgasm abnormal, feeling cold. Rare (≥1-<0.1%): Psychosis (including
hallucinations), seizure, Raynaud’s phenomenon, abnormal/increased liver function
tests, jaundice, hepatitis, liver injury, acute hepatic failure, blood bilirubin increased,
priapism. For full details of these and other side-effects, please see the Summary of
Product Characteristics, which is available at http://www.medicines.ie/. Legal
Category POM. Marketing Authorisation Numbers and Holder Strattera 10mg
hard capsules: PA 47/95/2, Strattera 18mg hard capsules: PA 47/95/3, Strattera
25mg hard capsules: PA 47/95/4, Strattera 40mg hard capsules: PA 47/95/5,
Strattera 60mg hard capsules: PA 47/95/6, Strattera 80mg hard capsules: PA
47/95/7, Strattera 100mg hard capsules: PA 47/95/8. Eli Lilly and Company Limited,
Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL, United Kingdom.
Date of Preparation or Last Review July 2013. Full Prescribing Information is
Available From Eli Lilly and Company Limited, Lilly House, Priestley Road,
Basingstoke, Hampshire, RG24 9NL. Telephone: Basingstoke (01256) 315 000.
E-mail: [email protected] or Eli Lilly and Company (Ireland) Limited, Hyde House,
65 Adelaide Road, Dublin 2, Republic of Ireland. Telephone: Dublin (01) 661 4377.
E-mail: [email protected] STRATTERAВ® (atomoxetine) is a registered trademark
of Eli Lilly and Company.
Adverse events and product complaints should be reported. To report
an adverse event or a product complaint about a Lilly medicine, please
call Lilly on: 01 664 0446. Adverse events and product complaints may
also be reported to the Irish Medicines Board. Reporting forms and
information can be found at www.imb.ie then click “Online Reporting”.
Date of Preparation: September 2013
IESTR00120b
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