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EQUASYM XL 60 MG MODIFIED-RELEASE CAPSULES HARD

Active substance(s): METHYLPHENIDATE HYDROCHLORIDE / METHYLPHENIDATE HYDROCHLORIDE / METHYLPHENIDATE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Equasym XL 60 mg modified-release capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 60 mg methylphenidate hydrochloride corresponding to
51.89 mg methylphenidate.
Excipient: 270 mg sucrose/capsule for Equasym XL 60 mg
For the full list excipients, see Section 6.1

3

PHARMACEUTICAL FORM
Modified release capsule, hard.
Equasym XL 60 mg capsule: The capsule has a white opaque cap imprinted
with “S544” in black and a white opaque body imprinted with “60 mg” in
black.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Methylphenidate is indicated as part of a comprehensive treatment programme
for attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years of
age and over 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-IV criteria or the
guidelines in ICD-10 and should be based on a complete history or 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 or may not be impaired.
Methylphenidate treatment is not indicated in all children with this syndrome
and the decision to use the drug 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. The use of methylphenidate should always
be used in this way according to the licensed indication and according to
prescribing / diagnostic guidelines.

4.2

Posology and method of administration
Equasym XL consists of an immediate release component (30% of the dose)
and a modified release component (70% of the dose). Hence Equasym XL
40 mg yields an immediate-release dose of 12 mg and an extended release
dose of 28 mg methylphenidate hydrochloride. The extended-release portion
of each dose is designed to maintain a treatment response through the
afternoon without the need for a midday dose. It is designed to deliver
therapeutic plasma levels for a period of approximately 8 hours, which is
consistent with the school day rather than the whole day (see section 5.2
“Pharmacokinetic properties”). For example, 40 mg of Equasym XL is
intended to take the place of 20 mg at breakfast and 20 mg at lunchtime of
immediate release methylphenidate hydrochloride.
Children (aged 6 years and over) and adolescents:
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 pretreatment 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 also 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 6 monthly 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 least every 6
months and at every visit.
Patients should be monitored for the risk of diversion, misuse and abuse of
methylphenidate.
Dose titration:
Careful dose titration is necessary at the start of treatment with
methylphenidate. Dose titration should be started at the lowest possible dose.
This is normally achieved using an immediate release formulation taken in
divided doses. The recommended starting daily dose is 5 mg once daily or
twice daily (e.g. at breakfast and lunch), increasing if necessary by weekly
increments of 5-10 mg in the daily dose according to tolerability and degree of
efficacy observed. Equasym XL 10 mg once daily may be used in place of
immediate release methylphenidate hydrochloride 5 mg twice daily from the
beginning of treatment where the treating physician considers that twice daily
dosing is appropriate from the outset and twice daily treatment administration
is impracticable.
The maximum daily dose of methylphenidate hydrochloride is 60 mg.
For doses not realisable/practicable with this strength, other strengths of this
medicinal product and other methylphenidate containing products are
available.
Patients Currently Using Methylphenidate: Patients established on an
immediate release methylphenidate hydrochloride formulation may be
switched to the milligram equivalent daily dose of Equasym XL.
Equasym XL should not be taken too late in the morning as it may cause
disturbances in sleep. If the effect of the medicinal product wears off too early
in the late afternoon or evening, disturbed behaviour and/or inability to go to
sleep may recur. A small dose of an immediate-release methylphenidate
hydrochloride tablet late in the day may help to solve this problem. In that
case, it could be considered that adequate symptom control might be achieved
with a twice daily immediate release methylphenidate regimen. The pros and
cons of a small evening dose of immediate-release methylphenidate versus
disturbances in falling asleep should be considered. Treatment should not
continue with Equasym XL if an additional late dose of immediate-release
methylphenidate is required, unless it is known that the same extra dose was
also required for a conventional immediate-release regimen at equivalent
breakfast/lunchtime dose. The regimen that achieves satisfactory symptom
control with the lowest total daily dose should be employed.

Equasym XL should be given in the morning before breakfast.
The capsules may be swallowed whole with the aid of liquids, or alternatively,
the capsule may be opened and the capsule contents sprinkled onto a small
amount (tablespoon) of applesauce and given immediately, and not stored for
future use. Drinking some fluids, e.g. water, should follow the intake of the
sprinkles with applesauce. The capsules and the capsule contents must not be
crushed or chewed.
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 drug for the individual patient with trial periods off
medication to assess the patient’s functioning without pharmacotherapy. It is
recommended that methylphenidate is de-challenged at least once yearly to
assess the child’s condition (preferable during times of school holidays).
Improvement may be sustained when the drug 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 discontinued.
Adults
Methylphenidate is not licensed for use in adults in ADHD. Safety and
efficacy have not been established in this age group.
Elderly
Methylphenidate should not be used in the elderly. Safety and efficacy has not
been established in this age group.
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.

4.3

Contraindications
Equasym XL is contra-indicated in patients with:


Known sensitivity to methylphenidate or to any of the excipients












4.4

Glaucoma
Phaeochromocytoma
During treatment with non-selective, irreversible monoamine oxidase
inhibitors, or within a minimum of 14 days following discontinuing
those drugs, due to risk of hypertensive crises (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 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 drug 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 drug for the individual patient with
trial periods off medication to assess the patient’s functioning without
pharmacotherapy. It is recommended that methylphenidate is de-challenged at
least once yearly to assess the child’s condition (preferably during times of
school holidays). Improvement may be sustained when the drug is either
temporarily or permanently discontinued.

Use in adults
Methylphenidate is not licensed for use in adults with ADHD. Safety and
efficacy have not been established in this age group.
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. 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 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 ‘Contraindications’).
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 in 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-emergentpsychotic 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 month 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, then at least every 6 months and at 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 6 monthly 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 drug withdrawal, since this may unmask
depression as well as chronic over-activity. Some patients may require longterm 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.
Excipients: sucrose intolerance
This medicinal product contains sucrose: patients with rare hereditary
problems of fructose intolerance, glucose-galactose malabsorption or sucroseisomaltase insufficiency should not take this medicine.
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.

4.5

Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interaction
It is not known how methylphenidate may affect plasma concentrations of
concomitantly administered drugs. Therefore, caution is recommended at
combining methylphenidate with other drugs, 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 drugs

already being taken and establish drug plasma concentrations (or for coumarin,
coagulation times).
Pharmacodynamic interactions
Anti-hypertensive drugs
Methylphenidate may decrease the effectiveness of drugs used to treat
hypertension.
Use with drugs that elevate blood pressure
Caution is advised in patients being treated with methylphenidate with any
other drug that can also elevate blood pressure (see also sections on
cardiovascular and cerebrovascular conditions in Section 4.4 Warnings and
Precautions for use).
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 Contraindications).
Use with alcohol
Alcohol may exacerbate the CNS adverse reactions of psychoactive drugs,
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)
Serious adverse events, including sudden death, have been reported in
concomitant use with clonidine. The safety of using methylphenidate in
combination with clonidine or other centrally acting alpha-2 agonists has not
been systematically evaluated.
Use with dopaminergic drugs
Caution is recommended when administering methylphenidate with
dopaminergic drugs, 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 limited amount of data from the use of methylphenidate in pregnant
women.

Cases of neonatal cardiorespiratory toxicity, specifically fetal tachycardia and
respiratory distress have been reported in spontaneous case reports.
Studies in animals have only shown 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.

Lactation
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.

4.7 Effects on ability to drive and use machines
Methylphenidate may cause dizziness, drowsiness and visual disturbances including
difficulties with accommodations, 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:
o The medicine is likely to affect your ability to drive.
o Do not drive until you know how the medicine affects you.
o It is an offence to drive while under the influence of this medicine.
o However, you would not be committing an offence (called ‘statutory defence’) if:
o The medicine has been prescribed to treat a medical problem and
10

o You have taken it according to the instructions given by the prescriber and in the
information provided with the medicine and
o It was not affecting your ability to drive safely.

4.8

Undesirable effects
The table below shows all adverse drug reactions (ADRs) observed during
clinical trials and post-market spontaneous reports with Equasym XL and
those, which have been reported with other methylphenidate hydrochloride

formulations. If the ADRs with Equasym XL and the methylphenidate
formulation frequencies were different, the highest frequency of both
databases was used.
Frequency estimate: very common (≥ 1/10); common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare
(<1/10000), not known (cannot be estimated from the available data).
System Organ Class
Adverse Drug Reaction
Infections and infestations
Common:
nasopharyngitis
Blood and lymphatic system disorders
Very rare:
anaemia, leucopenia, thrombocytopenia,
thrombocytopenic purpura
Not known:
pancytopenia
Immune System Disorders
Uncommon:
hypersensitivity reactions such as angioneurotic
oedema, anaphylactic reactions, auricular swelling,
bullous conditions, exfoliative conditions, urticarias,
pruritis, rashes and eruptions
Metabolism and nutrition disorders*
Common:
anorexia, decreased appetite, moderately reduced
weight and height gain during prolonged use in
children*
Psychiatric disorders*
insomnia, nervousness
Very common:
Common:

anorexia, affect lability, aggression*, agitation*,
anxiety*, depression*, irritability, abnormal
behaviour, bruxism

Uncommon:
psychotic disorders*, auditory, visual, and tactile
hallucinations*, anger, suicidal ideation*, mood
altered, mood swings, restlessness, tearfulness, tics*,
worsening of pre-existing tics or Tourette’s
syndrome*, hypervigilance, sleep disorder
Rare:
mania*, disorientation, libido disorder
Very rare:
suicidal attempt (including completed suicide)*,
transient depressed mood*, abnormal thinking,
apathy, repetitive behaviours, over-focussing
Not known:
delusions*, thought disturbances*, confusional state,
dependence
Cases of abuse and dependence have been described, more often with immediate
release formulations (frequency not known)
Nervous system disorders
Very common:
headache
dizziness, dyskinesia, psychomotor hyperactivity,

Common:
Uncommon:
Very rare:

Not known:
Eye disorders
Uncommon:
Rare:
Cardiac disorders
Common:
Uncommon:
Rare:
Very rare:
Not known:

somnolence
sedation, tremor
convulsions, choreo-athetoid movements, reversible
ischaemic neurological deficit Neuroleptic malignant
syndrome (NMS; Reports were poorly documented
and in most cases, patients were also receiving other
drugs, so the role of methylphenidate is unclear)
cerebrovascular disorders* (including vasculitis,
cerebral haemorrhages, cerebrovascular accidents,
cerebral arteritis, cerebral occlusion), grand mal
convulsions*, migraine
diplopia, blurred vision
difficulties in visual accommodation, mydriasis,
visual disturbance
arrhythmia, tachycardia, palpitations
chest pain
angina pectoris
cardiac arrest, myocardial infarction
supraventricular tachycardia, bradycardia, ventricular
extrasystoles, extrasystoles

Vascular disorders*
Common:
Very rare:

hypertension
cerebral arteritis and/or occlusion, peripheral
coldness, Raynaud’s phenomenon
Respiratory, thoracic and mediastinal disorders
Common:
cough, pharyngolaryngeal pain
Uncommon:
dyspnoea
Gastrointestinal disorders
Common:
abdominal pain, diarrhea, nausea, stomach
discomfort and vomiting, dry mouth
Uncommon:
constipation
Hepatobiliary disorders
Uncommon:
hepatic enzyme elevations
Very rare:
abnormal liver function, including hepatic coma
Skin and subcutaneous tissue disorders
Common:
alopecia, pruritus, rash, urticaria
angioneurotic oedema, bullous conditions,
Uncommon:
exfoliative conditions
hyperhidrosis, macular rash, erythema
Rare:
erythema multiforme, exfoliative dermatitis, fixed
drug eruption
Very rare:
Musculoskeletal and connective tissue disorders
Common:
arthralgia
Uncommon:
myalgia, muscle twitching
Very rare:
muscle cramps

Renal and urinary disorders
Uncommon:
haematuria
Reproductive system and breast disorders
Rare:
gynaecomastia
General disorders and administration site conditions
Common:
pyrexia, growth retardation during prolonged use in
children*
Uncommon:

chest pain, fatigue

Very rare:

sudden cardiac death*

Not known:
Investigations
Common:

chest discomfort, hyperpryrexia

Uncommon:

changes in blood pressure and heart rate (usually an
increase) *, weight decreased
cardiac murmur*, hepatic enzyme increased

Very rare:

blood alkaline phosphatase increased, blood bilirubin
increased, platelet count decreased, white blood
count abnormal
*
See Section 4.4 ‘Special Warnings and precautions for use’

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, psychosis, sweating, flushing, headache,
hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension,
mydriasis and dryness of mucous membranes.
Treatment
There is no specific antidote to methylphenidate overdosage.
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 gut 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 and agents
used for ADHD and nootropics, Centrally acting Sympathomimetics, ATC
code: N06BA04
Mechanism of action: Equasym XL is a mild CNS stimulant with more
prominent effects on mental than on motor activities. Its mode of action in
man is not completely understood but its effects are thought to be due to
cortical stimulation and possibly to stimulation of the reticular activating
system.
In a pivotal study 318 subjects aged between 6 and 12 years received at least
one dose of study medication out of 327 subjects randomized. Scores for the
IOWA Conner’s rating, the primary efficacy endpoint assessed by teachers
during the school day, showed the following results for the per protocol
population (279 patients treated for 21 days):

Placebo
(N=39)a

Immediate Release
Methylphenidate

Equasym XL
(N=120)

(N=120)b
Baseline Mean (SD)

6.0 (3.64)

6.1 (3.74)

5.8 (3.59)

LS Mean (SE)

7.7 (0.50)

4.3 (0.29)

4.5 (0.29)

95% CI

6.69, 8.66

3.71, 4.84

3.98, 5.10

Difference from Placebo

-

-3.4

-3.1

95% CI for the difference

-

-4.53, -2.26

-4.26, -2.00

-

<0.001

<0.001

Difference from MIR

-

-

-0.3

97.5% lower CI bound for
the difference

-

-

-1.06

Day 21/Withdrawal

P-value

c

a

N=38 at Day 7; b N=118 at Day 7; c Treatment groups have been compared using ANCOVA,
with effects for treatment and baseline as covariates

In contrast to these results for the primary efficacy measure, differences
between the Equasym XL and immediate release methylphenidate groups were
observed for the Parent IOWA Conner’s secondary efficacy variable. This was
based on assessments later in the evening, suggesting that there is some loss of
efficacy of Equasym XL late in the day relative to twice daily immediate
release methylphenidate. See also section 5.2. (Pharmacokinetic properties)
and section 4.2 (Posology and method of administration).
The mechanism by which Equasym XL exerts its mental and behavioural
effects in children is not clearly established, nor is there conclusive evidence
showing how these effects relate to the condition of the central nervous
system. It is thought to block the re-uptake of noradrenaline and dopamine into
the presynaptic neurone and increase the release of these monoamines into the
extraneuronal space. Equasym XL is a racemic mixture of the d- and l-threo
enantiomers of methylphenidate. The d-enantiomer is more pharmacologically
active than the l-enantiomer.

5.2

Pharmacokinetic properties
Absorption: Equasym XL has a plasma profile showing two phases of active
substance release, with a sharp, initial, upward slope similar to a
methylphenidate immediate-release tablet, and a second rising portion
approximately three hours later, followed by a gradual decline.
Peak plasma concentrations of approximately 40 nmol/litre (11 ng/ml) are
attained, on average, 1-2 hours after administration of 0.30 mg/kg. The peak
plasma concentrations, however, show considerable intersubject variability.

The range of concentrations at 1.5 hours was 3.2 – 13.3 ng/ml with a mean of
7.7 ng/ml. The second phase of release resulted in a second maximum
observed concentration in most subjects at 4.5 hours after dosing, with the
observed concentrations ranging from 4.9 – 15.5 ng/ml with a mean of
8.2 ng/ml. Administration of an extended release formulation at breakfast
instead of two immediate release formulation tablets (breakfast and lunch)
may reduce the pre-lunch trough and post lunch peak of methylphenidate, and
plasma levels may be lower after the end of the school day. Clinical trial data
suggest that the different pharmacokinetic profiles may result in a different
pattern of behaviour and symptom control during the day for some patients
compared with a conventional immediate release methylphenidate regimen. In
particular there may be some reduction of symptom control in the late
afternoon and early evening (see section 5.1 Pharmacodynamic properties).
These differences should be taken into consideration when assessing their
individual requirements.
The area under the plasma concentration curve (AUC), as well as the peak
plasma concentration, is proportional to the dose.
Food Effects: Ingestion together with food with a high fat content delays its
absorption (Tmax) by approximately one hour and increases the maximum
concentration (Cmax) by approximately 30% and the amount absorbed (AUC)
by approximately 17%.
Sprinkle Administration: The Cmax Tmax and AUC of the sprinkled contents of
the Equasym XL capsule are similar (bioequivalent) to the intact capsule.
Equasym XL may, therefore, be administered either as an intact capsule, or the
capsule may be opened and the contents swallowed, without chewing,
immediately after sprinkling onto applesauce or other similar soft food.
Age: the Pharmacokinetics of Equasym XL have not been studied in children
younger than 7 years of age.
Availability, systemic: Owing to extensive first-pass metabolism its systemic
availability amounts to approximately 30% (11-51%) of the dose.
Distribution: In the blood, methylphenidate and its metabolites become
distributed in the plasma (57%) and the erythrocytes (43%). Methylphenidate
and its metabolites have a low plasma protein-binding rate (10-33%). The
apparent distribution has been calculated as 13.1 litres/kg.
Elimination: Methylphenidate is eliminated from the plasma with a mean halflife 2 hours, and the calculated mean systemic clearance is 10 litres/h/kg.
Within 48-96 hours 78-97% of the dose administered is excreted in the urine
and 1-3% in the faeces in the form of metabolites.
The bulk of the dose is excreted in the urine as 2-phenyl-2-piperidyl acetic acid
(PPAA, 60-86%).

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/fetal development
Methylphenidate is not considered to be a teratogenic in rats and rabbits. Fetal
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
Capsule content
Sugar Spheres (Sucrose, Maize starch)
Povidone K29 to K32
Opadry Clear YS-1-7006 (hypromellose, macrogol 400 and macrogol 8000)
Ethylcellulose Aqueous Dispersion
Dibutyl Sebacate
Capsule shell
Gelatin
Titanium dioxide (E171)
Black printing ink:
Shellac glaze 45% (20% esterified) in ethanol
Propylene glycol
Ammonium hydroxide 28%
Iron oxide black (E172)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store below 25°C.

6.5

Nature and contents of container
Clear PVC/Aclar blister with aluminum foil backing and vinyl seal coating.
Pack sizes:

28 modified-release capsules, hard.

30 modified-release capsules, hard.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
Tel.-Nr.: 0800 055 6614
e-mail: Medinfoglobal@shire.com

8

MARKETING AUTHORISATION NUMBER(S)
PL 27303/0009

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
05/02/2013

10

DATE OF REVISION OF THE TEXT
14/05/2014

Expand Transcript

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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