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XENIDATE XL 18 MG PROLONGED-RELEASE TABLETS

Active substance(s): METHYLPHENIDATE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Xenidate XL 18 mg Prolonged-release Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 18 mg methylphenidate hydrochloride
(equivalent to 15.57 mg methylphenidate)
Excipient with known effect:
Each prolonged-release tablet contains a maximum of 12.3 mg sucrose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release tablet.
Yellowish to yellow, round, biconvex film-coated tablets of 6.3 mm.

4.

CLINICAL PARTICULARS

4.1. Therapeutic indications
Attention-Deficit/Hyperactivity Disorder (ADHD)
Xenidate XL is indicated as part of a comprehensive treatment programme for Attention
Deficit / Hyperactivity Disorder (ADHD) in children aged 6 years and over and adolescents
when remedial measures alone prove insufficient. Treatment must be under the supervision of
a specialist in childhood behavioural disorders. Diagnosis should be made according to DSM
criteria or the guidelines in ICD-10 and should be based on a complete history and evaluation
of the patient. Diagnosis cannot be made solely on the presence of one or more symptom.

The specific aetiology of this syndrome is unknown, and there is no single diagnostic test.
Adequate diagnosis requires the use of medical and specialised psychological, educational,
and social resources.
A comprehensive treatment programme typically includes psychological, educational and
social measures as well as pharmacotherapy and is aimed at stabilising children with a
behavioural syndrome characterised by symptoms which may include chronic history of short
attention span, distractibility, emotional lability, impulsivity, moderate to severe
hyperactivity, minor neurological signs and abnormal EEG. Learning may possibly be
impaired.
Methylphenidate treatment is not indicated in all children with ADHD and the decision to use
the medicinal product must be based on a very thorough assessment of the severity and
chronicity of the child's symptoms in relation to the child's age.
Appropriate educational placement is essential, and psychosocial intervention is generally
necessary. Where remedial measures alone prove insufficient, the decision to prescribe a
stimulant must be based on rigorous assessment of the severity of the child's symptoms.
Methylphenidate should always be used according to the licensed indication and according to
prescribing / diagnostic guidelines.

4.2

Posology and method of administration
Treatment must be initiated under the supervision of a specialist in childhood
and/or adolescent behavioural disorders.
Pre-treatment screening
Prior to prescribing, it is necessary to conduct a baseline evaluation of a patient’s
cardiovascular status including blood pressure and heart rate. A comprehensive
history should document concomitant medications, past and present co-morbid
medical and psychiatric disorders or symptoms, family history of sudden
cardiac/unexplained death and accurate recording of pre-treatment height and weight
on a growth chart (see sections 4.3 and 4.4).
Ongoing monitoring
Growth, psychiatric and cardiovascular status should be continuously monitored (see
section 4.4).
-

Blood pressure and pulse should be recorded on a centile chart at each
adjustment of dose and then at least every 6 months;

-

Height, weight and appetite should be recorded at least every 6 months with
maintenance of a growth chart;

-

Development of de novo or worsening of pre-existing psychiatric disorders
should be monitored at every adjustment of dose and then at least every 6
months and at every visit.

Patients should be monitored for the risk of diversion, misuse and abuse of
methylphenidate.

Posology
Xenidate XL is taken once daily in the morning.
Dose titration
Careful dose titration is necessary at the start of treatment with methylphenidate.
Dose titration should be started at the lowest possible dose.
Other strengths of this medicinal product and other methylphenidate-containing
products may be available.
Dosage may be adjusted in 18 mg increments. In general, dosage adjustment may
proceed at approximately weekly intervals.
The maximum daily dosage of methylphenidate is 54 mg.
Patients new to methylphenidate
Clinical experience with methylphenidate is limited in these patients (see section 5.1).
Methylphenidate may not be indicated in all children with ADHD syndrome. Lower
doses of short-acting methylphenidate formulations may be considered sufficient to
treat patients new to methylphenidate. Careful dose titration by the physician in
charge is required in order to avoid unnecessarily high doses of methylphenidate. The
recommended starting dose of methylphenidate for patients who are not currently
taking methylphenidate, or for patients who are on stimulants other than
methylphenidate, is 18 mg once daily.

Patients currently using methylphenidate
The recommended dose of Xenidate XL for patients who are currently taking
methylphenidate three times daily at doses of 15 to 45 mg/day is provided in Table 1.
Dosing recommendations are based on current dose regimen and clinical judgement.

Table 1: Recommended Dose Conversion from other Methylphenidate
hydrochloride Regimens, where available, to Xenidate XL

Previous
Methylphenidate
hydrochloride

Recommended
Xenidate XL
Dose

Daily Dose
5 mg
methylphenidate
three times daily

18 mg once daily

10 mg
methylphenidate
three times daily

36 mg once daily

15 mg
methylphenidate
three times daily

54 mg once daily

If improvement is not observed after appropriate dosage adjustment over a one-month
period, the medicinal product should be discontinued.
Long-term (more than 12 months) use in children and adolescents
The safety and efficacy of long term use of methylphenidate has not been
systematically evaluated in controlled trials. Methylphenidate treatment should not
and need not be indefinite. Methylphenidate treatment is usually discontinued during
or after puberty. The physician who elects to use methylphenidate for extended
periods (over 12 months) in children and adolescents with ADHD should periodically
re-evaluate the long-term usefulness of the medicinal product for the individual
patient with trial periods off medication to assess the patient’s functioning without
pharmacotherapy. It is recommended that methylphenidate is discontinued at least
once yearly to assess the child’s condition (preferable during times of school
holidays). Improvement may be sustained when the medicinal product is either
temporarily or permanently discontinued.
Dose reduction and discontinuation
Treatment must be stopped if the symptoms do not improve after appropriate dosage
adjustment over a one-month period. If paradoxical aggravation of symptoms or other
serious adverse events occur, the dosage should be reduced, or the medicinal product
should be discontinued.
Adults
In adolescents whose symptoms persist into adulthood and who have shown clear
benefit from treatment, it may be appropriate to continue treatment into adulthood.
However, start of treatment with Xenidate XL in adults is not appropriate (see
sections 4.4 and 5.1).
Older people
Methylphenidate should not be used in the elderly. Safety and efficacy has not been
established in this age group.

Paediatric population under 6 years of age

Methylphenidate should not be used in children under the age of 6 years. Safety and
efficacy in this age group has not been established.
Method of administration
Xenidate XL 18 mg must be swallowed whole with sufficient liquid, and must not be
chewed, divided, or crushed (see section 4.4).
Xenidate XL may be administered with or without food (see section 5.2).

4.3. Contraindications













4.4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
Glaucoma
Phaeochromocytoma
During treatment with non-selective, irreversible monoamine oxidase (MAO) inhibitors,
or within a minimum of 14 days of discontinuing those medicinal products, due to the risk
of hypertensive crisis (see section 4.5)
Hyperthyroidism or thyrotoxicosis
Diagnosis or history of severe depression, anorexia nervosa/anorexic disorders, suicidal
tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia,
psychopathic/borderline personality disorder
Diagnosis or history of severe and episodic (type I) bipolar (affective) disorder (that is not
well-controlled)
Pre-existing cardiovascular disorders including severe hypertension, heart failure, arterial
occlusive disease, angina, haemodynamically significant congenital heart disease,
cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and
channelopathies (disorders caused by the dysfunction of ion channels)
Pre-existing cerebrovascular disorders e.g. cerebral aneurysm, vascular abnormalities
including vasculitis or stroke

Special warnings and precautions for use
Methylphenidate treatment is not indicated in all children with ADHD and the
decision to use the medicinal product must be based on a very thorough
assessment of the severity and chronicity of the child’s symptoms in relation
to the child’s age.
Long-term use (more than 12 months) in children and adolescents
The safety and efficacy of long-term use of methylphenidate has not been
systematically evaluated in controlled trials. Methylphenidate treatment should
not and need not be indefinite. Methylphenidate treatment is usually
discontinued during or after puberty. Patients on long-term therapy (i.e. over
12 months) must have careful ongoing monitoring according to the guidance
in sections 4.2 and 4.4 for cardiovascular status, growth, appetite, development

of de novo or worsening of pre-existing psychiatric disorders. Psychiatric
disorders to monitor for are described below, and include (but are not limited
to) motor or vocal tics, aggressive or hostile behaviour, agitation, anxiety,
depression, psychosis, mania, delusions, irritability, lack of spontaneity,
withdrawal and excessive perseveration.
The physician who elects to use methylphenidate for extended periods (over
12 months) in children and adolescents with ADHD should periodically reevaluate the long term usefulness of the medicinal product for the individual
patient with trial periods off medication to assess the patient’s functioning
without pharmacotherapy. It is recommended that methylphenidate is dechallenged at least once yearly to assess the child’s condition (preferably
during times of school holidays). Improvement may be sustained when the
medicinal product is either temporarily or permanently discontinued.
Use in adults
Safety and efficacy have not been established for the initiation of treatment in
adults or the routine continuation of treatment beyond 18 years of age. If
treatment withdrawal has not been successful when an adolescent has reached
18 years of age continued treatment into adulthood may be necessary. The
need for further treatment of these adults should be reviewed regularly and
undertaken annually.
Use in the elderly
Methylphenidate should not be used in the elderly. Safety and efficacy has not
been established in this age group.
Use in children under 6 years of age
Methylphenidate should not be used in children under the age of 6 years.
Safety and efficacy in this age group has not been established.
Cardiovascular status
Patients who are being considered for treatment with stimulant medications
should have a careful history (including assessment for a family history of
sudden cardiac or unexplained death or malignant arrhythmia) and physical
exam to assess for the presence of cardiac disease, and should receive further
specialist cardiac evaluation if initial findings suggest such history or disease.
Patients who develop symptoms such as palpitations, exertional chest pain,
unexplained syncope, dyspnoea or other symptoms suggestive of cardiac
disease during methylphenidate treatment should undergo a prompt specialist
cardiac evaluation.
Analyses of data from clinical trials of methylphenidate in children and
adolescents with ADHD showed that patients using methylphenidate may
commonly experience changes in diastolic and systolic blood pressure of over
10 mmHg relative to controls. The short- and long-term clinical consequences
of these cardiovascular effects in children and adolescents are not known, but
the possibility of clinical complications cannot be excluded as a result of the
effects observed in the clinical trial data especially when treatment during
childhood/adolescence is continued into adulthood.

Caution is indicated in treating patients whose underlying medical
conditions might be compromised by increases in blood pressure or heart
rate. See section 4.3 for conditions in which methylphenidate treatment in
contraindicated.
Cardiovascular status should be carefully monitored. Blood pressure and
pulse should be recorded on a centile chart at each adjustment of dose
and when clinically necessary and then at least every 6 months.
The use of methylphenidate is contraindicated in certain pre-existing
cardiovascular disorders unless specialist paediatric cardiac advice has
been obtained (see section 4.3).
Sudden death and pre-existing cardiac structural abnormalities or other
serious cardiac disorders
Sudden death has been reported in association with the use of stimulants of the
central nervous system at usual doses in children, some of whom had cardiac
structural abnormalities or other serious heart problems. Although some
serious heart problems alone may carry an increased risk of sudden death,
stimulant products are not recommended in children or adolescents with
known cardiac structural abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or other serious cardiac problems that may place them at
increased vulnerability to the sympathomimetic effects of a stimulant
medicine.

Misuse and cardiovascular events
Misuse of stimulants of the central nervous system may be associated with
sudden death and other serious cardiovascular adverse events.
Cerebrovascular disorders
See section 4.3 for cerebrovascular conditions in which methylphenidate
treatment is contraindicated. Patients with additional risk factors (such as a
history of cardiovascular disease, concomitant medications that elevate blood
pressure) should be assessed at every visit for neurological signs and
symptoms after initiating treatment with methylphenidate.
Cerebral vasculitis appears to be a very rare idiosyncratic reaction to
methylphenidate exposure. There is little evidence to suggest that patients at
higher risk can be identified and the initial onset of symptoms may be the first
indication of an underlying clinical problem. Early diagnosis, based on a high
index of suspicion, may allow the prompt withdrawal of methylphenidate and
early treatment. The diagnosis should therefore be considered in any patient
who develops new neurological symptoms that are consistent with cerebral
ischemia during methylphenidate therapy. These symptoms could include
severe headache, numbness, weakness, paralysis, and impairment of
coordination, vision, speech, language or memory.
Treatment with methylphenidate is not contraindicated in patients with
hemiplegic cerebral palsy.

Psychiatric disorders
Co-morbidity of psychiatric disorders in ADHD is common and should be
taken into account when prescribing stimulant products. In the case of
emergent psychiatric symptoms or exacerbation of pre-existing psychiatric
disorders, methylphenidate should not be given unless the benefits outweigh
the risks to the patient.
Development or worsening of psychiatric disorders should be monitored
at every adjustment of dose, then at least every 6 months, and at every
visit; discontinuation of treatment may be appropriate.
Exacerbation of pre-existing psychotic or manic symptoms
In psychotic patients, administration of methylphenidate may exacerbate
symptoms of behavioural disturbance and thought disorder.
Emergence of new psychotic or manic symptoms
Treatment-emergent psychotic symptoms (visual/tactile/auditory
hallucinations and delusions) or mania in children and adolescents without
prior history of psychotic illness or mania can be caused by methylphenidate
at usual doses. If manic or psychotic symptoms occur, consideration should be
given to a possible causal role for methylphenidate, and discontinuation of
treatment may be appropriate.
Aggressive or hostile behaviour
The emergence or worsening of aggression or hostility can be caused by
treatment with stimulants. Patients treated with methylphenidate should be
closely monitored for the emergence or worsening of aggressive behaviour or
hostility at treatment initiation, at every dose adjustment and then at least
every 6 months and every visit. Physicians should evaluate the need for
adjustment of the treatment regimen in patients experiencing behaviour
changes bearing in mind that upwards or downwards titration may be
appropriate. Treatment interruption can be considered.
Suicidal tendency
Patients with emergent suicidal ideation or behaviour during treatment for
ADHD should be evaluated immediately by their physician. Consideration
should be given to the exacerbation of an underlying psychiatric condition and
to a possible causal role of methylphenidate treatment. Treatment of an
underlying psychiatric condition may be necessary and consideration should
be given to a possible discontinuation of methylphenidate.
Tics
Methylphenidate is associated with the onset or exacerbation of motor and
verbal tics. Worsening of Tourette’s syndrome has also been reported. Family
history should be assessed and clinical evaluation for tics or Tourette’s
syndrome in children should precede use of methylphenidate. Patients should
be regularly monitored for the emergence or worsening of tics during
treatment with methylphenidate. Monitoring should be at every adjustment
of dose and then at least every 6 months or every visit.

Anxiety, agitation or tension
Methylphenidate is associated with the worsening of pre-existing anxiety,
agitation or tension. Clinical evaluation for anxiety, agitation or tension should
precede use of methylphenidate and patients should be regularly monitored
for the emergence or worsening of these symptoms during treatment, at
every adjustment of dose and then at least every 6 months or every visit.
Forms of bipolar disorder
Particular care should be taken in using methylphenidate to treat ADHD in
patients with comorbid bipolar disorder (including untreated type I bipolar
disorder or other forms of bipolar disorder) because of concern for possible
precipitation of a mixed/manic episode in such patients. Prior to initiating
treatment with methylphenidate, patients with comorbid depressive symptoms
should be adequately screened to determine if they are at risk for bipolar
disorder; such screening should include a detailed psychiatric history,
including a family history of suicide, bipolar disorder, and depression.
Close ongoing monitoring is essential in these patients (see above
‘Psychiatric disorders’ and section 4.2). Patients should be monitored for
symptoms at every adjustment of dose and then at least every 6 months or
every visit.
Growth
Moderately reduced weight gain and growth retardation have been reported
with the long-term use of methylphenidate in children.
The effects of methylphenidate on final height and final weight are currently
unknown and being studied.
Growth should be monitored during methylphenidate treatment: height,
weight and appetite should be recorded at least every 6 months with
maintenance of a growth chart. Patients who are not growing or gaining
height or weight as expected may need to have their treatment interrupted.
Seizures
Methylphenidate should be used with caution in patients with epilepsy.
Methylphenidate may lower the convulsive threshold in patient with prior
history of seizures, in patients with prior EEG abnormalities in absence of
seizures, and rarely in patients without a history of convulsions and no EEG
abnormalities. If seizure frequency increases or new-onset seizures occur,
methylphenidate should be discontinued.

Abuse, misuse and diversion
Patients should be carefully monitored for the risk of diversion, misuse and
abuse of methylphenidate.
Methylphenidate should be used with caution in patients with known drug or
alcohol dependency because of a potential for abuse, misuse or diversion.

Chronic abuse of methylphenidate can lead to marked tolerance and
psychological dependence with varying degrees of abnormal behaviour. Frank
psychotic episodes can occur, especially in response to parenteral abuse.
Patient age, the presence of risk factors for substance use disorder (such as comorbid oppositional-defiant or conduct disorder and bipolar disorder),
previous or current substance abuse should all be taken into account when
deciding on a course of treatment for ADHD.
Caution is called for in emotionally unstable patients, such as those with a
history of drug or alcohol dependence, because such patients may increase the
dosage on their own initiative.
For some high-risk substance abuse patients, methylphenidate or other
stimulants may not be suitable and non-stimulant treatment should be
considered.
Withdrawal
Careful supervision is required during medicinal product withdrawal, since
this may unmask depression as well as chronic over-activity. Some patients
may require long-term follow up.
Careful supervision is required during withdrawal from abusive use since
severe depression may occur.
Fatigue
Methylphenidate should not be used for the prevention or treatment of normal
fatigue states.
Choice of methylphenidate formulation
The choice of formulation of methylphenidate-containing product will have to
be decided by the treating specialist on an individual basis and depends on the
intended duration of effect.
Drug screening
This product contains methylphenidate which may induce a false positive
laboratory test for amphetamines, particularly with immunoassay screen test.
Renal or hepatic insufficiency
There is no experience with the use of methylphenidate in patients with renal
or hepatic insufficiency.
Haematological effects
The long-term safety of treatment with methylphenidate is not fully known. In
the event of leukopenia, thrombocytopenia, anaemia or other alterations,
including those indicative of serious renal or hepatic disorders, discontinuation
of treatment should be considered.
Potential for gastrointestinal obstruction

Because the methylphenidate tablet is nondeformable and does not appreciably
change in shape in the gastrointestinal (GI) tract, it should not ordinarily be
administered to patients with pre-existing severe GI narrowing (pathologic or
iatrogenic) or in patients with dysphagia or significant difficulty in swallowing
tablets. There have been rare reports of obstructive symptoms in patients with
known strictures in association with the ingestion of drugs in nondeformable
prolonged-release formulations.
Due to the prolonged-release design of the tablet, Xenidate XL should only be
used in patients who are able to swallow the tablet whole. Patients should be
informed that Xenidate XL must be swallowed whole with sufficient liquid.
Tablets must not be chewed, divided, or crushed.
Doping
Athletes must be aware that this medicine may cause a positive reaction to
‘anti-doping’ tests.
Excipients:
This medicinal product contains sucrose. Patients with rare hereditary
problems of fructose intolerance, glucose-galactose malabsorption or sucraseisomaltase insufficiency should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions
It is not known how methylphenidate may effect plasma concentrations of
concomitantly administered medicinal products. Therefore, caution is
recommended at combining methylphenidate with other medicinal products,
especially those with a narrow therapeutic window.
Methylphenidate is not metabolised by cytochrome P450 to a clinically
relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to
have any relevant impact on methylphenidate pharmacokinetics. Conversely,
the d- and l- enantiomers of methylphenidate do not relevantly inhibit
cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.
However, there are reports indicating that methylphenidate may inhibit the
metabolism of coumarin anticoagulants, anticonvulsants (e.g. phenobarbital,
phenytoin, primidone) and some antidepressants (tricyclics and selective
serotonin reuptake inhibitors). When starting or stopping treatment with
methylphenidate, it may be necessary to adjust the dosage of these medicinal
products already being taken and establish their plasma concentrations (or for
coumarin, coagulation times).
Pharmacodynamic interactions
Antihypertensive medicinal products
Methylphenidate may decrease the effectiveness of medicinal products used to
treat hypertension.

Use with medicinal products that elevate blood pressure
Caution is advised in patients being treated with methylphenidate and any
other active substances that can also elevate blood pressure (see also sections
on cardiovascular and cerebrovascular conditions in section 4.4).
Because of possible hypertensive crisis, methylphenidate is contraindicated in
patients being treated (currently or within the preceding 2 weeks) with nonselective, irreversible MAO-inhibitors (see section 4.3).
Use with alcohol
Alcohol may exacerbate the adverse CNS effect of psychoactive medicinal
products, including methylphenidate. It is therefore advisable for patients to
abstain from alcohol during treatment.
Use with halogenated anaesthetics
There is a risk of sudden blood pressure increase during surgery. If surgery is
planned, methylphenidate treatment should not be used on the day of surgery.
Use with centrally acting alpha-2 agonists (e.g. clonidine)
The long-term safety of using methylphenidate in combination with clonidine
or other centrally acting alpha-2 agonists has not been systematically
evaluated.
Use with dopaminergic substances
Caution is recommended when administering methylphenidate with
dopaminergic substances, including antipsychotics.
Because a predominant action of methylphenidate is to increase extracellular
dopamine levels, methylphenidate may be associated with pharmacodynamic
interactions when co-administered with direct and indirect dopamine agonists
(including DOPA and tricyclic antidepressants) or with dopamine antagonists
(including antipsychotics).

4.6. Fertility, pregnancy and lactation
Pregnancy
There is a limited amount of data from the use of methylphenidate in pregnant women.
Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory
distress have been reported in spontaneous case reports.
Studies in animals have only shown evidence of reproductive toxicity at maternally toxic
doses (see section 5.3).
Methylphenidate is not recommended for use during pregnancy unless a clinical decision is
made that postponing treatment may pose a greater risk to the pregnancy.
Breast-feeding
Methylphenidate has been found in the breast-milk of a woman treated with methylphenidate.

There is one case report of an infant who experienced an unspecified decrease in weight
during the period of exposure but recovered and gained weight after the mother discontinued
treatment with methylphenidate. A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from
methylphenidate therapy taking into account the benefit of breast feeding for the child and the
benefit of therapy for the woman.
Fertility
There were no relevant effects observed in the non-clinical studies.

4.7

Effects on ability to drive and use machines
Methylphenidate can cause dizziness, drowsiness and visual disturbances including
difficulties with accommodation, diplopia and blurred vision. It may have a moderate
influence on the ability to drive and use machines. Patients should be warned of these
possible effects and advised that if affected, they should avoid potentially hazardous
activities such as driving or operating machinery.
This medicine can impair cognitive function and can affect a patient’s ability to drive
safely. This class of medicine is in the list of drugs included in regulations under 5a
of the Road Traffic Act 1988. When prescribing this medicine, patients should be
told:

4.8



The medicine is likely to affect your ability to drive



Do not drive until you know how the medicine affects you



It is an offence to drive while under the influence of this medicine



However, you would not be committing an offence (called ‘statutory
defence’) if:



The medicine has been prescribed to treat a medical or dental problem and



You have taken it according to the instructions given by the prescriber and in
the information provided with the medicine and



It was not affecting your ability to drive safely

Undesirable effects
The table below shows all adverse drug reactions (ADRs) observed during
clinical trials of children, adolescents and adults and post-market spontaneous
reports with methylphenidate and those, which have been reported with other
methylphenidate hydrochloride formulations. If the ADRs with
methylphenidate prolonged release tablets and the other methylphenidate
formulation frequencies were different, the highest frequency of both
databases was used.
The frequency of undesirable effects listed below is defined using the
following convention:

Very common:
≥1/10
Common:
≥1/100 to <1/10
Uncommon: ≥1/1,000 to <1/100
Rare:
≥1/10,000 to <1/1,000
Very rare:
<1/10,000
Not known: cannot be estimated from the available data
System
Organ
Class

Adverse Drug Reaction
Frequency
Very
common

Infections
and
infestations

Common

Uncommo
n

Very rare

Not
known

Anaemia†,
leucopenia
†,
Thrombocytopenia,
Thrombocytopenic
purpura

Pancytopenia

Nasopharyngitis
, Upper
respiratory
tract
infection# ,
Sinusitis#

Blood and
lymphatic
system
disorders

Immune
system
disorders

Metabolis
m and
nutrition
disorders*

Rare

Hypersensitivity
reactions
such as
Angioneurotic
oedema,
Anaphylactic
reactions,
Auricular
swelling,
Bullous
conditions
Decreased
appetite†,
Moderatel
y reduced
weight and

System
Organ
Class

Adverse Drug Reaction
Frequency
Very
common

Common

Uncommo
n

Rare

Very rare

Not
known

Psychotic
disorders*,
auditory,
visual
and tactile
hallucination*,
anger,
suicidal
ideation*,
mood
altered,
restlessness,
tearfulness,
worsening
of preexisting
tics of
tourette's
syndrome*,
Logorrhoe
a,hypervigilance,
sleep
disorder

Mania*†,
Disorientation,
Libido
disorder,
Confusion
al state†

Suicidal
attempt
(including
completed
suicide)*
†,Abnorma
l thinking,
Apathy†,
Repetitive
behaviours
, Overfocussing

Delusions*†
, Thought
disturbances*,
Dependenc
e. Cases of
abuse and
dependenc
e have
been
described,
more often
with
immediate
release
formulations

Convulsio
ns,
Choreoathetoid
movement
s,
Reversible
ischaemic
neurologic
al deficit,
Neurolepti
c

Cerebrovascular
disorders* †
(including
vasculitis,
cerebral
haemorrhages,
cerebrovascular
accidents,
cerebral

height gain
during
prolonged
use in
children*
Psychiatric
disorders*

Insomnia,
Nervousness

Anorexia,
Affectlability,
Aggression*,
Agitation*,
Anxiety*,
Depression*,
Irritability,
Abnormal
behaviour,
Mood
swings,
Tics*,
Initial
insomnia# ,
Depressed
mood#,
Libido
decreased#
Tension# ,
Bruxism#,
Panic
attack#

Nervous
system
disorders

Headache

Dizziness, Sedation,
Dyskinesia Tremor†,
, PsychoLethargy#
motor
hyperactivity,
Somnolence,
Paresthaesi
a#, Tension
headache#

System
Organ
Class

Adverse Drug Reaction
Frequency
Very
common

Common

Eye
disorders

Accommo
dation
disorder#

Ear and
labyrinth
disorders

Vertigo#

Cardiac
disorders*

Arrhythmi
a, Tachycardia,
Palpitation
s

Vascular
disorders*

Hypertension

Uncommo
n

Blurred
vision†,
Dry eye#

Chest pain

Rare

Very rare

Not
known

malignant
syndrome
(NMS;
Reports
were
poorly
documente
d and in
most cases,
patients
were also
receiving
other
medicinal
products,
so the role
of methylphenidate
is unclear).

occlusion),
Grand mal
convulsion
*
,
Migraine†

Difficulties
in visual
accommodation,
Visual
impairmen
t, Diplopia

Mydriasis

Angina
pectoris

Cardiac
arrest,
myocardial
infarction

Hot flush#

Cerebral
arteritis

Supraventricular
tachycardi
a, Bradycardia,
Ventricular
extrasystoles†,
Extrasystoles†

System
Organ
Class

Adverse Drug Reaction
Frequency
Very
common

Common

Uncommo
n

Rare

Very rare
and/or
occlusion,
Peripheral
coldness†,
Raynaud's
phenomenon

Respirator
y, thoracic
and
mediastinal
disorders

Cough,
Oropharyngeal
pain

Dyspnoea†

Gastrointestinal
disorders

Abdominal Constipain upper, pation
Diarrhoea,
Nausea, †
Abdominal
discomfort,
Vomiting,
Dry
mouth†,
Dyspepsia#

Hepatobiliary
disorders

Abnormal
liver
function,
including
hepatic
encephalop
athy

Skin and
subcutaneous tissue
disorders

Alopecia,
Pruritis,
Rash,
Urticaria

Exfoliative
conditions

Musculoskeletal
and
connective

Arthralgia,
Muscle
tightness#,
Muscle

Myalgia†,
Muscle
twitching

Hyperhidrosis†,
Macular
Rash;
Erythema

Erythema
multiforme
,
Exfoliative
dermatitis,
Fixed drug
eruption
Muscle
cramps

Not
known

System
Organ
Class

Adverse Drug Reaction
Frequency
Very
common

tissue
disorders

Common

Uncommo
n

Rare

Very rare

Not
known

Chest
discomfort,
hyperpyrexia

spasms#

Renal and
urinary
disorders

Haematuri
a,Pollakiuri
a

Reproductive
system and
breast
disorders

Gynaecomastia

General
disorders
and
administration site
conditions

Pyrexia,
Growth
retardation
during
prolonged
use in
children*,
Fatigue†,
Irritability#
, Feeling
jittery#,
Asthenia#,
Thirst#

Chest pain

Sudden
cardiac
death*

Investigations

Changes in
blood
pressure
and heart
rate
(usually an
increase)*,
Weight
decreased*,
Alanine
aminotrans
ferase
increased#

Cardiac
murmur*,
Hepatic
enzyme
increased

Blood
alkaline
phosphatas
e
increased,
Blood
bilirubin
increased,
Platelet
count
decreased,
White
blood cell
count
abnormal

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard

4.9

Overdose
When treating patients with overdose, allowances must be made for the delayed
release of methylphenidate from formulations with extended durations of action.
Signs and symptoms:
Acute overdose, mainly due to overstimulation of the central and sympathetic nervous
systems, may result in vomiting, agitation, tremors, hyperreflexia, muscle twitching,
convulsions (may be followed by coma), euphoria, confusion, hallucinations,
delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations,
cardiac arrhythmias, hypertension, mydriasis and dryness of mucous membranes.
Management:
There is no specific antidote to methylphenidate overdose.
Treatment consists of appropriate supportive measures.
The patient must be protected against self-injury and against external stimuli that
would aggravate overstimulation already present. If the signs and symptoms are not
too severe and the patient is conscious, gastric contents may be evacuated by
induction of vomiting or gastric lavage. Before performing gastric lavage, control
agitation and seizures if present and protect the airway. Other measures to detoxify
the intestine include administration of activated charcoal and a cathartic. In the
presence of severe intoxication, a carefully titrated dose of a benzodiazepine should
be given before performing gastric lavage.
Intensive care must be provided to maintain adequate circulation and respiratory
exchange; external cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal haemodialysis for overdose of
methylphenidate has not been established.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics; Psychostimulants, agents used for
ADHD and nootropics; centrally acting sympathomimetics, ATC code: N06BA04
Mechanism of action
Methylphenidate is a mild central nervous system (CNS) stimulant. The mode of
therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Methylphenidate is thought to block the reuptake of noradrenaline and dopamine into
the presynaptic neurone and increase the release of these monoamines into the
extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and lisomers. The d-isomer is more pharmacologically active than the l-isomer.

5.2

Pharmacokinetic properties
Absorption
Methylphenidate is readily absorbed. Following oral single dose
administration the prolonged release multiple unit formulation (consisting of
an IR and a PR fraction) shows a biphasic methylphenidate release profile.
The immediate release component provides an initial maximum plasma
concentration after 1.35 h and the prolonged release fraction provides a second
peak plasma concentration after approx. 5.30 h. Methylphenidate taken once
daily minimises the fluctuations between peak and trough concentrations
associated with immediate-release methylphenidate three times daily. The
extent of absorption of methylphenidate once daily is generally comparable to
conventional immediate release preparations administered three times daily.
Based on the submitted bioequivalence study Methylphenidate HCl 54 mg PR
Tablets is considered bioequivalent to the originator, Concerta® 54 mg
Retardtabletten. This conclusion can be extrapolated to the other strengths of
the product series.
Following the administration of methylphenidate 54 mg once daily in 52
adults under fasted conditions, the relevant mean pharmacokinetic parameters
were: AUC(0-2.5 h) 12.95 ng/ml*h and AUC(2.5-24 h) 97.583 ng/ml*h , Cmax(0-2.5 h)
6.6 ng/ml and Cmax(2.5-24 h) 11.2 ng/ml, tmax(0-2.5 h) 1.4 h and tmax(2.5-24 h) 5.3 h.
Following administration of a prolonged release methylphenidate formulation
in single doses of 18, 36, and 54 mg/day to adults, Cmax and AUC(0-inf) of
methylphenidate were proportional to dose.
Distribution
Plasma methylphenidate concentrations in adults decline biexponentially
following oral administration. The half-life of methylphenidate in adults
following oral administration of methylphenidate was approximately 3.5 h.

The rate of protein binding of methylphenidate and of its metabolites is
approximately 15%. The apparent volume of distribution of methylphenidate
is approximately 13 l/kg.
Biotransformation
In humans, methylphenidate is metabolised primarily by de-esterification to
alpha-phenyl-piperidine acetic acid (PPA, approximately 50 fold the level of
the unchanged substance) which has little or no pharmacologic activity. In
adults the metabolism of methylphenidate once daily as evaluated by
metabolism to PPA is similar to that of methylphenidate three times daily. The
metabolism of single and repeated once daily doses of methylphenidate is
similar.
Elimination
The elimination half-life of methylphenidate in adults following administration
of methylphenidate was approximately 3.5 hours. After oral administration,
about 90% of the dose is excreted in urine and 1 to 3% in faeces, as
metabolites within 48 to 96 hours. Small quantities of unchanged methylphenidate are recovered in urine (less than 1%). The main urinary metabolite
is alpha-phenyl-piperidine acetic acid (60-90%).
After oral dosing of radio-labelled methylphenidate in humans, about 90% of
the radioactivity was recovered in urine. The main urinary metabolite was
PPA, accounting for approximately 80% of the dose.
Food Effects
In patients, there were no relevant differences in either the pharmacokinetics
or the pharmacodynamic performance of methylphenidate when administered
after a high fat breakfast or on an empty stomach.
Special Populations
Gender
In healthy adults, the mean dose-adjusted AUC(0-inf) values for
methylphenidate were 36.7 ng*h/ml in men and 37.1 ng*h/ml in women, with
no differences noted between the two groups.
Race
In healthy adults receiving methylphenidate, dose-adjusted AUC(0-inf) was
consistent across ethnic groups; however, the sample size may have been
insufficient to detect ethnic variations in pharmacokinetics.
Paediatric population
The pharmacokinetics of methylphenidate has not been studied in children
younger than 6 years of age. In children 7-12 years of age, the
pharmacokinetics of methylphenidate after 18, 36 and 54 mg were (mean ±
SD): Cmax 6.0 ± 1.3, 11.3 ± 2.6, and 15.0 ± 3.8 ng/ml, respectively, tmax 9.4 ±
0.02, 8.1 ± 1.1, 9.1 ± 2.5 h, respectively, and AUC0-11.5 50.4 ± 7.8, 87.7 ± 18.2,
121.5 ± 37.3 ng*h/ml, respectively.

Renal insufficiency
There is no experience with the use of methylphenidate in patients with renal
insufficiency. After oral administration of radio-labelled methylphenidate in
humans, methylphenidate was extensively metabolised and approximately
80% of the radioactivity was excreted in the urine in the form of PPA. Since
renal clearance is not an important route of methylphenidate clearance, renal
insufficiency is expected to have little effect on the pharmacokinetics of
methylphenidate.
Hepatic insufficiency
There is no experience with the use of methylphenidate in patients with
hepatic insufficiency.

5.3

Preclinical safety data
Carcinogenicity
In life-time rat and mouse carcinogenicity studies, increased numbers of
malignant liver tumours were noted in male mice only. The significance of this
finding to humans is unknown.
Methylphenidate did not affect reproductive performance or fertility at low
multiples of the clinical dose.
Pregnancy-embryonal/foetal development
Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal
toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at
maternally toxic doses.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Sugar spheres (sucrose, maize starch)
Hypromellose
Talc
Ethylcellulose
Hydroxypropylcellulose
Triethyl citrate
Hypromellose acetate succinate
Carmellose sodium
Cellulose, microcrystalline
Magnesium stearate
Silica, colloidal anhydrous
Hydrochloric acid (pH adjustment)
Tablet coating:

Hypromellose
Macrogol (6000)
Talc
Titanium dioxide (E171)
Iron oxide yellow (E172)
Hydrochloric acid (pH adjustment)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
HDPE bottles with child-resistant PP screw caps.
Pack sizes:
28 or 30 prolonged-release tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal

7

MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station close
Potters Bar
Hertfordshire
EN6 1TL

UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 04569/1417

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
13/06/2014

10

DATE OF REVISION OF THE TEXT
16/10/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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