Attention-Deficit/Hyperactivity Disorder (ADHD)
Quillivant XR is indicated as part of a comprehensive treatment programme for Attention
Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over and adults
when remedial measures alone prove insufficient.
Treatment must be initiated and supervised by a physician specialised in the treatment
of ADHD such as an expert paediatrician, a child and adolescent psychiatrist or an
adult psychiatrist.
Special Diagnostic Considerations for ADHD in children
Diagnosis should be made according to the current DSM criteria or ICD guidelines and
should be based on a complete history and evaluation of the patient. Third-party
corroboration is desirable and 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 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.
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.
Special Diagnostic Considerations for ADHD in adults
Diagnosis should be made according to the current DSM criteria or ICD guidelines, and
should be based on a complete history and evaluation of the patient.
The specific etiology of this syndrome is unknown, and there is no single diagnostic test.
Adults with ADHD have symptom patterns characterised by restlessness, impatience, and
inattentiveness. Symptoms such as hyperactivity tend to diminish with increasing age,
possibly due to adaptation, neurodevelopment and self-medication. Inattentive symptoms are
more prominent and have a greater impact on adults with ADHD. Diagnosis in adults should
include a structured patient interview to determine current symptoms. The preexistence of
childhood ADHD is required and has to be determined retrospectively (by patients' records or
if not available by appropriate and structured instruments/interviews). Third-party
corroboration is desirable and treatment should not be initiated when the verification of
childhood ADHD symptoms is uncertain. Diagnosis should not be made solely on the
presence of one or more symptoms. The decision to use a stimulant in adults must be based
on a very thorough assessment and diagnosis should include moderate or severe functional
impairment in at least 2 settings (for example, social, academic, and/or occupational
functioning), affecting several aspects of an individual's life.

Treatment must be initiated and supervised by a physician specialised in the treatment of ADHD such as an expert paediatrician, a child and adolescent psychiatrist or an
adult psychiatrist.
Pre-treatment screening
In adults new to Quillivant XR, and if required by national practice, cardiologist advice is
needed prior to treatment initiation in order to check the absence of cardiovascular
contraindications.

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 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 in children should be recorded at least 6 monthly with
maintenance of a growth chart;
• Weight should be recorded for adults regularly;
• 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
Quillivant XR is taken once daily.
Dose titration
Careful dose titration is necessary at the start of treatment with methylphenidate. Dose
titration should be started at the lowest possible dose.
The recommended starting dose of Quillivant XR for patients 6 years and above is 20 mg
once daily orally in the morning. The dose may be titrated up or down weekly in increments
of 10 mg, 15 mg or 20 mg. The 10 mg and 15 mg doses can each be achieved by breaking in
half the functionally scored 20 mg and 30 mg tablets, respectively. Daily doses above 60 mg
have not been studied and are not recommended. As with any CNS stimulant, during titration
of Quillivant XR, the prescribed dose should be adjusted, if necessary, until a well-tolerated,
therapeutic dose is achieved.
Posology
Children
Children New to Methylphenidate: Quillivant XR may not be indicated in all children with
ADHD syndrome. Lower doses of short-acting methylphenidate formulations may be
considered sufficient to treat children 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 Quillivant XR for children who are not currently taking
methylphenidate, or for children who are on stimulants other than methylphenidate, is 20 mg
once daily.
Adults
Adults New to Methylphenidate: Quillivant XR may not be indicated in all adults with ADHD
syndrome. Lower doses of short-acting methylphenidate formulations may be considered
sufficient to treat adults 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 Quillivant XR for adults who are not currently taking
methylphenidate, or for adults who are on stimulants other than methylphenidate, is 20 mg once daily.

Switching from other Methylphenidate Products
If switching from other methylphenidate products, discontinue that treatment, and titrate with
Quillivant XR using the above titration schedule.
Do not substitute for other methylphenidate products on a milligram-per-milligram basis,
because of different methylphenidate base compositions and differing pharmacokinetic
profiles
Long-term (more than 12 months) use
The safety and efficacy of long-term use of methylphenidate have not been systematically
evaluated in controlled trials. Methylphenidate treatment should not and need not, be
indefinite. In children and adolescents, methylphenidate treatment is usually discontinued
during or after puberty. The physician who elects to use methylphenidate for extended
periods (over 12 months) in patients with ADHD should periodically re-evaluate the longterm
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 de-challenged at least once yearly to assess the patient's condition
(for children, preferably 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 discontinued.
Special populations
Elderly
Methylphenidate should not be used in the elderly. Safety and efficacy have not been
established in this age group. Quillivant XR has not been studied in ADHD in patients older
than 65 years.
Hepatic impairment
Methylphenidate has not been studied in patients with hepatic impairment.
Renal impairment
Methylphenidate has not been studied in patients with renal impairment.
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.
Method of administration
Quillivant XR is for oral use once daily in the morning.
Quillivant XR may be administered with or without food (see section 5.2).

• Hypersensitivity to methylphenidate 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 drugs, 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, hemodynamically 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.

Methylphenidate treatment is not indicated in all patients with ADHD and the decision to use
the drug must be based on a very thorough assessment of the severity and chronicity of the
patient's symptoms. When treatment of children is considered, assessment of the severity and
chronicity of the child's symptoms should be related to the child's age (6-18 years).
Long term use (more than 12 months) in children and adolescents
The safety and efficacy of long-term use of methylphenidate have 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 behavior, 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 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 (preferably during times of school holidays). Improvement may be sustained when the drug is either temporarily or
permanently discontinued.
Use in the elderly
Methylphenidate should not be used in the elderly. Safety and efficacy has not been
established in this age group. Quillivant XR has not been studied in ADHD in patients older
than 65 years.
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 is
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. Methylphenidate should be discontinued in patients under treatment with
repeated measures of tachycardia, arrhythmia or increased systolic blood pressure
(>95th percentile) and referral to a cardiologist should be considered.
The use of methylphenidate is contraindicated in certain pre-existing cardiovascular
disorders unless specialist pediatric 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 structural cardiac 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.
Adults

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking
stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases
is unknown, adults have a greater likelihood than children of having serious structural cardiac
abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease,
or other serious cardiac problems. Adults with such abnormalities should also generally not
be treated with stimulant drugs.
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 and 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
behavioral 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 behavior

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 behavior 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 behavioral 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 behavior during treatment for ADHD should be
evaluated immediately by their physician. Consideration should be given to the exacerbation
of an underlying psychiatric condition and a possible causal role of methylphenidate
treatment. Treatment of an underlying psychiatric condition may be necessary, and
consideration should be given to the 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 the 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 the 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 1 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 co-morbid
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 longterm
use of methylphenidate in children. Weight decrease has been reported with
methylphenidate treatment in adults (see section 4.8).
The effects of methylphenidate on final height and final weight are currently unknown and
are being studied.

Growth should be monitored during methylphenidate treatment: height, weight, and
appetite should be recorded for at least 6 monthly with the 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 patients 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.
Priapism
Prolonged and painful erections have been reported in association with methylphenidate
products, mainly in association with a change in the methylphenidate treatment regimen.
Patients who develop abnormally sustained or frequent and painful erections should seek
immediate medical attention.
Use with serotonergic medicinal products.
Serotonin syndrome has been reported following the coadministration of methylphenidate
with serotonergic medicinal products. If concomitant use of methylphenidate with a
serotonergic medicinal product is warranted, prompt recognition of the symptoms of
serotonin syndrome is important. These symptoms may include mental-status changes (e.g.,
agitation, hallucinations, coma), autonomic instability, e.g., tachycardia, labile blood
pressure, hyperthermia), and neuromuscular abnormalities (e.g., hyperreflexia,
incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Methylphenidate must be discontinued as soon as possible if serotonin syndrome is
suspected.
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 behavior. Frank psychotic episodes can occur,
especially in response to parenteral abuse.
Patient age, the presence of risk factors for substance use disorder (such as co-morbid
oppositional-defiant or conduct disorder and bipolar disorder), and previous or current
substance abuse should 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 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 the 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. Athletes must be aware that this
medicinal product may cause a positive reaction to 'anti-doping' tests.
Renal or hepatic insufficiency
There is no experience with the use of methylphenidate in patients with renal or hepatic insufficiency.
Hematological 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 (see section 4.8).
Risks in Patients with Phenylketonuria:
Phenylalanine can be harmful to patients with phenylketonuria (PKU). Quillivant XR
extended-release chewable tablets contain phenylalanine, a component of aspartame. Each 20
mg, 30 mg, and 40 mg extended-release chewable tablet contains 3 mg, 4.5 mg, and 6 mg
phenylalanine, respectively. Before prescribing Quillivant XR in patients with PKU, consider
the combined daily amount of phenylalanine from all sources, including Quillivant XR.

Pharmacokinetic interactions
It is not known how methylphenidate may affect the 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 metabolized 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 (tricyclic and selective serotonin reuptake inhibitors). When starting
and 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).

Pharmacodynamics 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 other drugs 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 (ongoing treatment or received during the last 14 days) with non-selective,
irreversible MAO-inhibitors (see section 4.3).
Use with alcohol
Alcohol may exacerbate the adverse CNS effect of psychoactive medicinal products,
including methylphenidate. In-vitro data suggest that alcohol concentrations higher than 10%
increase the cumulative release of MPH from Quillivant XR tablets. The clinical relevance of
this finding on the MPH exposure after oral ingestion of Quillivant XR in combination with
alcohol is not known. It is therefore advisable for patients to abstain from alcohol during
treatment.
Use with serotonergic medicinal products.
There have been reports of serotonin syndrome following the coadministration of
methylphenidate with serotonergic medicinal products. If concomitant use of
methylphenidate with a serotonergic medicinal product is warranted, prompt recognition of
the symptoms of serotonin syndrome is important (see section 4.4). Methylphenidate must be
discontinued as soon as possible if serotonin syndrome is suspected.
Use with halogenated anesthetics.
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 of
methylphenidate and 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 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.

Pregnancy
Data from a cohort study of in total approximately 3,400 pregnancies exposed in the first
trimester do not suggest an increased risk of overall birth defects. There was a small
increased occurrence of cardiac malformations (pooled adjusted relative risk, 1.3; 95 % CI,
1.0-1.6), corresponding to 3 additional infants born with congenital cardiac malformations for
every 1000 women who receive methylphenidate during the first trimester of pregnancy,
compared with non-exposed pregnancies.
Cases of neonatal cardiorespiratory toxicity, specifically fetal 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 is excreted in human milk. Based on reports of breast milk sampling from
five mothers, methylphenidate concentrations in human milk resulted in infant doses of
0.16% to 0.7% of the maternal weight-adjusted dosage and a milk to maternal plasma ratio
ranging between 1.1 and 2.7.
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 breastfeeding or to discontinue/abstain from
methylphenidate therapy, taking into account the benefit of breastfeeding for the child and the
benefit of therapy for the woman.
Fertility
No human data on the effect of methylphenidate on fertility are available. There were no
relevant effects observed in the non-clinical studies.

Methylphenidate may 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.
When prescribing this medicine, patients should be told:
• 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.

The table below shows all adverse reactions observed during clinical trials of children,
adolescents, and adults and post-market spontaneous reports with Quillivant XR and those
which have been reported with other methylphenidate hydrochloride formulations. If the
adverse reactions with Quillivant XR 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 (≥ 1/1 000 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 Reaction
	Frequency
	Very common	Common	Uncommon	Rare	Very rare	Not known
Infections and infestations		Nasopharyn gitis, Upper respiratory tract infection#, Sinusitis#
Blood and lymphatic system disorders					Anaemia†, Leucopenia† , Thrombocytopenia, Thrombocytopenic purpura	Pancytopenia
Immune system disorders			Hypersensitivity reactions such as Angioneurotic oedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus, Rashes, and Eruptions
Metabolism and nutritional disorders*		Anorexia, Decreased appetite†, Moderately reduced weight and height gain during prolonged use in children*
Psychiatric disorders*	Insomnia, Nervous ness	Affect lability, Aggression* , Agitation*, Anxiety*†, Depression* #, Irritability, Abnormal behaviour, Mood swings, Tics*, Initial insomnia#, Depressed mood#, Libido decreased#, Tension#, Bruxism^, Panic attack#	Psychotic disorders*, Auditory, visual and tactile hallucinatio n*, Anger, Suicidal ideation*, Mood altered, Restlessnes s†, Tearfulness, Worsening of preexisting tics of Tourette's syndrome*, Logorrhoea, Hypervigila nce, Sleep disorder	Mania*†, Disorientati on, Libido disorder, Confusional state†	Suicidal attempt (including completed suicide)* †, Transient depressed mood*, Abnormal thinking, Apathy†, Repetitive behaviours, Overfocussing	Delusions*†, Thought disturbances*, dependence. Cases of abuse and dependence have been described, more often with immediate release formulations
Nervous system disorders	Headache	Dizziness, Dyskinesia, Psychomotor hyperactivity, Somnolence, Paresthaesia #, Tension headache#	Sedation, Tremor†, Lethargy#		Convulsion, Choreoathetoid 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 methylpheni date is unclear).	Cerebrovascular disorders*† (incl uding vasculitis, cerebral haemorrhages, cerebrovascular accidents, cerebral arteritis, cerebralocclusion), Grand malconvulsion*, Migraine†, Dysphemia
Eye disorders		Accommodation disorder#	Blurred vision†, Dry eye#	Difficulties in visual accommoda tion, Visual impairment, Diplopia		Mydriasis
Ear and labyrinth disorders		Vertigo#
Cardiac disorders*		Arrhythmia, Tachycardia, Palpitations	Chest pain	Angina pectoris	Cardiac arrest; Myocardial infarction	Supraventricular tachycardia, Bradycardia, Ventricular extrasystoles†,Extrasystoles†
Vascular disorders*		Hypertension	Hot flush#		Cerebral arteritis and/or occlusion, Peripheral coldness†, Raynaud's phenomenon
Respiratory, thoracic and mediastinai disorders		Cough, Oropharyngeal pain	Dyspnoea†
Gastrointestinal disorders		Abdominal pain upper, Diarrhoea, Nausea†, Abdominal discomfort, Vomiting, Dry mouth†, Dyspepsia#	Constipation†
Hepatobiliary disorders		Alanine aminotransferase increased#	Hepatic enzyme increased		Abnormal liver function, including acute hepatic failure and hepatic coma, Blood alkaline phosphatase increased, Blood bilirubin increased†
Skin and subcutane ous tissue disorders		Alopecia, Pruritis, Rash, Urticaria, Hyperhidrosis†	Angioneurotic oedema,Bullous conditions, Exfoliative conditions	Macular rash; Erythema	Erythema multiforme, Exfoliative dermatitis, Fixed drug eruption
Musculoskeletal and connective tissue disorders		Arthralgia, Muscle tightness#, Muscle spasms#	Myalgia†,Muscle twitching		Muscle cramps	Trismus^
Renal and urinary disorders			Haematuria, pollakiuria			Incontinence
Reproductive system and breast disorders		Erectile dysfunction#		Gynaecomastia		Priapism*,Erection increased* and Prolonged erection*
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*	Chest discomfort†, Hyperpyrexia
Investigations		Changes in blood pressure and heart rate (usually an increase)*, Weight decreased*	Cardiac murmur*		Platelet count decreased, White blood cell count abnormal
* See section 4.4 # Frequency derived from adult clinical trials and not on data from trials in children and adolescents; may also be relevant for children and adolescents. † Adverse drug reaction from clinical trials in adult patients that were reported with a higher frequency than in children and adolescents. ^ Based on the frequency calculated in adult ADHD studies (no cases were reported in the paediatric studies).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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:

To report any side effect(s):
- The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa

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.
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. The efficacy of activated charcoal has not been established.
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.

Pharmacotherapeutic group: centrally acting sympathomimetics: ATC code: N06BA04.
Mechanism of action
Methylphenidate HCl 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 l-isomers. The d-isomer
is more pharmacologically active than the l-isomer.
Clinical efficacy and safety
Children
The efficacy of Quillivant XR was evaluated in a laboratory classroom study conducted in 90
pediatric subjects (ages 6 to 12 years) with ADHD. Patients in the trial met DSM-IV criteria
for ADHD. The study began with a 6-week open-label dose optimization period with an
initial Quillivant XR dose of 20 mg. Patients were instructed to chew each dose once daily in
the morning. The dose could be titrated weekly in increments of 10 to 20 mg until a
therapeutic dose or the maximum dose of 60 mg/day was reached.
Eighty-six of the 90 enrolled subjects then entered a 1-week randomized, double-blind,
parallel group treatment period with the individually optimized dose of Quillivant XR or
placebo. The intent-to-treat (ITT) population consisted of 85 randomized subjects who
received at least 1 dose of double-blind study drug and had at least 1 post-Baseline
assessment of the primary efficacy variable. At the end of the double-blind treatment period,
the laboratory classroom raters and teachers evaluated the attention and behavior of the
subjects, throughout the day using the Swanson, Kotkin, Agler, M-Flynn, and Pelham
(SKAMP) rating scale. The SKAMP rating scale is a validated 13-item teacher-rated scale
that assesses manifestations of ADHD in a classroom setting.

The SKAMP-Combined score, measured at 0.75, 2, 4, 8, 10, 12, and 13 hours post-dose
during the laboratory classroom day at the end of the double-blind treatment period, was used to assess the primary and the key secondary efficacy parameters. The primary efficacy
endpoint was the average of treatment effects across all the time points as specified above
during the classroom day. The key secondary efficacy parameters were onset and duration of
clinical effect. Quillivant XR was statistically significantly superior to placebo with respect to
the primary endpoint (Table 2). Quillivant XR also showed improvement over placebo at
0.75, 2, 4, and 8 hours post-dosing. Efficacy results at each time point are summarized in Figure 1.

Table 1: Primary Efficacy Result (ITT Population)

Primary Efficacy measure: Average of Treatment Effect Across All Time Points Based on SKAMP-Combined Score 

Study Number	Treatment Group	Primary Efficacy measure: Average of Treatment Effect Across All Time Points Based on SKAMP-Combined Score
		Mean Pre-Dose Score on ClassroomDay (SD)	LS Mean (SE) for the Classroom day	Placebo-subtracted Differencea (95% CI)
Study 1	Quillivant XR (N=42)	17.5 (11.6)	12.1 (1.4)	-7.0 (-10.9, -3.1)
	Placebo (N- 43)	13.8 (10.0)	19.1 (1.4)

 

N: number of patients; SD: standard deviation; SE: standard error; LS Mean: least-squares
mean; CI: confidence interval.
aLeast-Squares Mean Difference (drug minus placebo).
Figure 1: SKAMP-Combined Scores Over Time (LS Mean ±SE) by Treatment
Group (ITT Population)

ITT: intent-to-treat
LS means from post-dose time-points were obtained from a repeated measures mixed model
with terms for center, hour, treatment and treatment by hour interaction. For the pre-dose
time-point, arithmetic means and standard errors are displayed.

Methylphenidate tablets contain the racemate of methylphenidate, which consists of equal
parts of d-methylphenidate and l-methylphenidate. The solubility of the racemate in water is
>100 mg/mL.
Absorption
Following a single oral dose of 40 mg Quillivant XR under fasting conditions, plasma
methylphenidate reached maximal concentration (Cmax) at a median time of 5 hours after
dosing. Compared to an immediate-release formulation of methylphenidate chewable tablet
(40 mg in 2 equal doses of 20 mg, 6 hours apart), methylphenidate mean peak concentration
and exposure (AUCinf) was about 20% and 11% lower, respectively, after single-dose
administration of 40 mg Quillivant XR (Figure 2).
Figure 2 Mean Methylphenidate Plasma Concentration-Time Profiles After Administration of 40 mg Quillivant XR or Methylphenidate Immediate-
Release Chewable Tablets (IRCT, 2 Equal Doses of 20 mg, 6 Hours Apart) Under Fasted Conditions in Healthy Volunteers.

Distribution
The plasma concentration of -methylphenidate declines biexponentially after oral
administration. The plasma protein binding of -methylphenidate is approx.—15%. The
distribution volume at steady-state after an intravenous single dose is 2.23 L/kg (2.65 ±1.1
L/kg for d-methylphenidate and 1.80 ±0.91 L/kg for l-methylphenidate).

Biotransformation & Elimination
Following a single 60 mg oral dose of Quillivant XR in 28 healthy adult subjects under
fasting conditions, the mean plasma terminal elimination half-life of d-methylphenidate was
5.6 (± 0.8) hours.
In humans, methylphenidate is metabolized primarily via de-esterification to alpha-phenylpiperidine
acetic acid (PPAA). The metabolite has little or no pharmacologic activity.
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity
was recovered in urine. The main urinary metabolite was PPAA, accounting for
approximately 80% of the dose.
The effect of food intake
In a study in adult volunteers to investigate the effects of a high-fat meal on the
bioavailability of QUILLIVANT XR at a dose of 60mg, the presence of food reduced the
time to peak concentration by approximately 1 hour (fed: 4 hours vs. fasted: 5 hours).
Overall, a high-fat meal increased the average Cmax of QUILLIVANT XR by about 28%
and the AUC by about 19%. These changes are not considered clinically significant.

Special populations
Gender: There is no relevant difference in pharmacokinetic parameters between male and
female healthy volunteers or patients.
Ethnic background
The values for dose-adapted AUC for methylphenidate are the same for all ethnic groups.
There may be insufficient data to prove ethnic variations with regard to pharmacokinetic
properties.
Age
There is no demonstrable difference in pharmacokinetics between hyperactive children and
healthy volunteers. The pharmacokinetic properties of methylphenidate have not been studied
in children under the age of six years or for adults over the age of 65 years.
Renal impairment
There is no experience from treating patients with renal impairment. After oral administration
of methylphenidate to humans, the medicinal product undergoes extensive metabolization,
and renal clearance is not an important elimination route for methylphenidate. Renal
clearance is therefore expected to have little effect on the pharmacokinetic properties of
Ritalin.
Hepatic impairment
There is no experience of the treatment of patients with hepatic impairment.

Carcinogenicity
In lifetime rat and mouse carcinogenicity studies, increased numbers of malignant liver
tumors 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 teratogenic in rats and rabbits. Fetal toxicity (i.e.,
total litter loss) and maternal toxicity were noted in rats at maternally toxic doses.

Quillivant XR 20 mg Extended-Release Chewable Tablets
Sodium Polystyrene Sulfonate TP, Povidone Kollidon 30, Triacetin, Polyvinyl Acetate
Dispersion 30 Kollicoat SR 30D, Mannitol Pearlitol 100SD, Xanthan Gum Gumixan K,
Crospovidone Kollidon CL SF, Microcrystalline Cellulose and Guar Gum, Aspartame, Citric
Acid Anhydrous, N C Cherry Flavor Art 825 466, Talc, Dental Type Silica, Magnesium
Stearate, Opadry II Clear Art 86F190002.

Quillivant XR 30 mg Extended-Release Chewable Tablets
Sodium Polystyrene Sulfonate TP, Povidone Kollidon 30, Triacetin, Polyvinyl Acetate
Dispersion 30 Kollicoat SR 30D, Mannitol Pearlitol 100SD, Xanthan Gum Gumixan K,
Crospovidone Kollidon CL SF, Microcrystalline Cellulose and Guar Gum, Aspartame, Citric
Acid Anhydrous, N C Cherry Flavor Art 825 466, D and C Red No 30, Talc, Dental Type
Silica, Magnesium Stearate, Opadry II Clear Art 86F190002.

Quillivant XR 40 mg Extended-Release Chewable Tablets
Sodium Polystyrene Sulfonate TP, Povidone Kollidon 30, Triacetin, Polyvinyl Acetate
Dispersion 30 Kollicoat SR 30D, Mannitol Pearlitol 100SD, Xanthan Gum Gumixan K,
Crospovidone Kollidon CL SF, Microcrystalline Cellulose and Guar Gum, Aspartame, Citric
Acid Anhydrous, N C Cherry Flavor Art 825 466, D and C Red No 7, Talc, Dental Type
Silica, Magnesium Stearate, Opadry II Clear Art 86F190002.

Not applicable.

3 years/36 months.

Store at 20°C to 25ºC (68°F to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF).

Quillivant XR extended-release Chewable Tablets is available in bottles. Each bottle
contains 100 extended-release chewable tablets.

Comply with local laws and regulations on drug disposal of CNS stimulants.