Quillivant xr (oral)

Overdose

Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: 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.

Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered.

When treating overdose, practitioners should bear in mind that there is a prolonged release of methylphenidate from Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules.

Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. 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. 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 hemodialysis for methylphenidate overdosage has not been established; also, dialysis is considered unlikely to be of benefit due to the large volume of distribution of methylphenidate.

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with methylphenidate. Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.

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.

Contraindications

Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

Quillivant XR (Oral) is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product.

Quillivant XR (Oral) is contraindicated in patients with glaucoma.

Quillivant XR (Oral) is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome. (See ADVERSE REACTIONS.)

Quillivant XR (Oral) is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).

QuilliChew ER is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of QuilliChew ER. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products.

QuilliChew ER is contraindicated during concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI), because of the risk of hypertensive crisis.

-

- 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

- 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

Incompatibilities

Not applicable.

Pharmaceutical form

Undesirable effects

The clinical program for Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules consisted of six studies: two controlled clinical studies conducted in children with ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received Quillivant XR (Oral) in doses of 10-40 mg per day. Safety of Quillivant XR (Oral) was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight.

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MEDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of Quillivant XR (Oral) in children with ADHD aged 6-12 years. All subjects received Quillivant XR (Oral) for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the two-week double-blind treatment phase of this study, patients received either placebo or Quillivant XR (Oral) at their individually-titrated dose (range 10 mg-40 mg).

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

Adverse events with an incidence > 5% during the initial four-week single-blind Quillivant XR (Oral) titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.

Treatment-emergent adverse events with an incidence > 2% among Quillivant XR (Oral)-treated subjects, during the two-week double-blind phase of the clinical study, were as follows:

In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only one Quillivant XR (Oral)-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression).

In the single-blind titration period of this study, subjects received Quillivant XR (Oral) for up to 4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy.

Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur.

Other reactions include:

Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia

Gastrointestinal: abdominal pain, nausea

Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura.

Metabolism/Nutrition: anorexia, weight loss during prolonged therapy

Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette's syndrome, toxic psychosis

Vascular: blood pressure increased or decreased; cerebrovascular vasculitis; cerebral occlusions; cerebral hemorrhages and cerebrovascular accidents

Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:

Blood/Lymphatic: leukopenia and/or anemia

Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma

Psychiatric: transient depressed mood, aggressive behavior

Skin/Subcutaneous: scalp hair loss

Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules, like other products containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.)

The following are discussed in more detail in other sections of the labeling:

• Known hypersensitivity to methylphenidate products or other ingredients of QuilliChew ER
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors
• Drug Dependence
• Serious Cardiovascular Reactions
• Blood Pressure and Heart Rate Increases
• Psychiatric Adverse Reactions
• Priapism
• Peripheral Vasculopathy, including Raynaud's phenomenon
• Long-Term Suppression of Growth
• Risks in Phenylketonuria

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly reported (≥ 2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.

There is limited experience with QuilliChew ER in controlled trials. The safety data in this section is based on data from a laboratory classroom study conducted in 90 pediatric subjects (ages 6 to 12 years) with ADHD. The study consisted of a 6-week dose optimization period, followed by a randomized, double-blind, parallel group treatment period with the individually optimized dose of QuilliChew ER or placebo.

The most common (≥ 2% in the QuilliChew ER group and greater than placebo) adverse reactions reported in the double-blind, randomized, placebo-controlled phase in patient optimized to doses of QuilliChew ER 20 to 60 mg/day are described in Table 1.

Table 1: Common Adverse Reactions Occurring in ≥ 2% of Subjects on QuilliChew ER and Greater than Placebo During the Double-Blind Period of the ADHD Laboratory Classroom Study

The following adverse reactions have been identified during post-approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

Eye Disorders: Diplopia, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

Hepatobiliary Disorders: Severe hepatocellular injury

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Libido changes, Mania

Urogenital System: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

The table below shows all adverse reactions observed during clinical trials of children, adolescents, and adults and post-market spontaneous reports with Concerta XL and those, which have been reported with other methylphenidate hydrochloride formulations. If the adverse reactions with Concerta XL and the methylphenidate formulation frequencies were different, the highest frequency of both databases was used.

Frequency estimate:

# Frequency derived from adult clinical trials and not on data from trials in children and adolescents; may also be relevant for children and adolescents.

†Frequency derived from clinical trials in children and adolescent and reported at a higher frequency in clinical trials in adult patients.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Therapeutic indications

Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of Quillivant XR (Oral) in the treatment of ADHD was established in one controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).

A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home.

The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can't wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met.

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics.

Quillivant XR (Oral) is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.

The effectiveness of Quillivant XR (Oral) for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Quillivant XR (Oral) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

QuilliChew ER is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

Attention-Deficit/Hyperactivity Disorder (ADHD)

Concerta XL 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 the current DSM criteria or ICD guidelines 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 or may not be impaired.

Concerta XL 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.

Pharmacotherapeutic group

Pharmacodynamic properties

Methylphenidate hydrochloride, the active ingredient in Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules, is a 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 norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d-and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer.

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. The mode of therapeutic action in ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

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

In the pivotal clinical studies, Concerta XL was assessed in 321 patients already stabilised with immediate release preparations (IR) of methylphenidate and in 95 patients not previously treated with IR preparations of methylphenidate.

Clinical studies showed that the effects of Concerta XL were maintained until 12 hours after dosing when the product was taken once daily in the morning.

Eight hundred ninety-nine (899) adults with ADHD aged 18 to 65 years were evaluated in three double-blind, placebo-controlled studies of 5 to 13 weeks duration. Some short-term efficacy has been demonstrated for Concerta XL in a dosage range of 18 to 72 mg/day, but this has not been consistently shown beyond 5 weeks. In one study, in which response was defined as at least a 30% reduction from baseline in Conners' Adult ADHD Rating Scales (CAARS) ADHD Symptoms total score at Week 5 (endpoint) and analysed assuming subjects with missing data at their final visit were non-responders, a significantly higher proportion of patients responded to treatment with Concerta XL at doses of 18, 36, or 72 mg/day compared to placebo. In the two other studies, when analysed assuming subjects with missing data at their final visit were non-responders, there were numerical advantages for Concerta XL compared to placebo but a statistically significant difference in the proportion of patients meeting predefined response criteria was not demonstrated between Concerta XL and placebo.

Pharmacokinetic properties

Quillivant XR (Oral) produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Quillivant XR (Oral) is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Quillivant XR (Oral) given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Quillivant XR (Oral).

Quillivant XR (Oral) given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1).

The relative bioavailability of Quillivant XR (Oral) given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults.

Figure 1: Mean plasma concentration time-profile of methylphenidate after a single dose of Quillivant XR (Oral)® 40 mg q.d. and Ritalin® 20 mg given in two doses four hours apart

Table 1: Mean ± SD and range of pharmacokinetic parameters of methylphenidate after a single dose of Quillivant XR (Oral)® and Ritalin® given in two doses 4 hours apart

After oral administration of Quillivant XR (Oral) 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2).

Binding to plasma proteins is low (10%-33%). The volume of distribution was 2.65±1.11 L/kg for dmethylphenidate and 1.80±0.91 L/kg for l-methylphenidate.

The absolute oral bioavailability of methylphenidate in children was 22±8% for d-methylphenidate and 5±3% for l-methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, deesterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound.

In studies with Quillivant XR (Oral) and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Quillivant XR (Oral). The half-life of ritalinic acid is about 3-4 hours.

The systemic clearance is 0.40±0.12 L/h/kg for d-methylphenidate and 0.73±0.28 L/h/kg for lmethylphenidate. After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities ( < 1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites.

Administration times relative to meals and meal composition may need to be individually titrated.

When Quillivant XR (Oral) was administered with a high fat breakfast to adults, Quillivant XR (Oral) had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined.

There were no differences in the pharmacokinetics of Quillivant XR (Oral) when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food.

For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION).

Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including Ritalin. It is therefore advisable for patients to abstain from alcohol during treatment. An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the Quillivant XR (Oral)® 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be representative of the other available capsule strengths.

Following a single oral dose of 40 mg QuilliChew ER 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 QuilliChew ER (Figure 2).

Figure 2: Mean Methylphenidate Plasma Concentration-Time Profiles After Administration of 40 mg QuilliChew ER or Methylphenidate Immediate-Release Chewable Tablets (IRCT, 2 Equal Doses of 20 mg, 6 Hours Apart) Under Fasted Conditions in Healthy Volunteers

Food Effect

High-fat meal had no effect on the time to peak concentration, and increased Cmax and systemic exposure (AUCinf) of methylphenidate by about 20% and 4%, respectively, after a single dose administration of 40 mg QuilliChew ER.

Plasma methylphenidate concentrations decline monophasically following oral administration of QuilliChew ER.

The mean plasma terminal elimination half-life of methylphenidate was about 5.2 hours in healthy volunteers following a single 40 mg dose administration.

Metabolism

In humans, methylphenidate is metabolized primarily via de-esterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

Excretion

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.

At 40% alcohol concentration, there was about 90% release methylphenidate from QuilliChew ER 40 mg tablet within half an hour. The results with the 40 mg chewable tablet strength are considered representative of the other available tablet strengths.

Absorption

Methylphenidate is readily absorbed. Following oral administration of Concerta XL to adults the drug overcoat dissolves, providing an initial maximum drug concentration at about 1 to 2 hours. The methylphenidate contained in the two internal drug layers is gradually released over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours, after which plasma levels of methylphenidate gradually decrease. Concerta XL taken once daily minimises the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. The extent of absorption of Concerta XL once daily is generally comparable to conventional immediate release preparations.

Following the administration of Concerta XL 18 mg once daily in 36 adults, the mean pharmacokinetic parameters were: Cmax 3.7 ± 1.0 (ng/mL), Tmax 6.8 ± 1.8 (h), AUCinf 41.8 ± 13.9 (ng.h/mL), and t½ 3.5 ± 0.4 (h).

No differences in the pharmacokinetics of Concerta XL were noted following single and repeated once daily dosing, indicating no significant drug accumulation. The AUC and t1/2 following repeated once daily dosing are similar to those following the first dose of Concerta XL 18 mg.

Following administration of Concerta XL in single doses of 18, 36, and 54 mg/day to adults, Cmax and AUCinf 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 Concerta XL 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 litres/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 Concerta XL 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 Concerta XL is similar.

Elimination

The elimination half-life of methylphenidate in adults following administration of Concerta XL 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 radiolabelled 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 differences in either the pharmacokinetics or the pharmacodynamic performance of Concerta XL when administered after a high fat breakfast on an empty stomach.

Special Populations

Gender

In healthy adults, the mean dose-adjusted AUCinf values for Concerta XL 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 Concerta XL, dose-adjusted AUCinf was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.

Age

The pharmacokinetics of Concerta XL has not been studied in children younger than 6 years of age. In children 7-12 years of age, the pharmacokinetics of Concerta XL 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 Concerta XL in patients with renal insufficiency. After oral administration of radiolabelled 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 Concerta XL.

Hepatic Insufficiency

There is no experience with the use of Concerta XL in patients with hepatic insufficiency.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac 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 drug.

Sudden death, 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 also 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.

Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, 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.

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate.

In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.

Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD including methylphenidate. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In the double-blind placebo-controlled study of Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving Quillivant XR (Oral) (+0.1 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Quillivant XR (Oral) should not be used in children under six years of age, since safety and efficacy in this age group have not been established.

Quillivant XR (Oral) should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Quillivant XR (Oral). The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised to avoid alcohol while taking Quillivant XR (Oral). Consumption of alcohol while taking Quillivant XR (Oral) may result in a more rapid release of the dose of methylphenidate.

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose on a mg/kg and mg/m² basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m² basis, respectively.

In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m² basis, respectively.

In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m² basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m² basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m² basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m² basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m² basis).

Adequate and well-controlled studies in pregnant women have not been conducted. Quillivant XR (Oral) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Quillivant XR (Oral) is administered to a nursing woman.

Long-term effects of methylphenidate in children have not been well established. Quillivant XR (Oral) should not be used in children under six years of age (see WARNINGS).

In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 1314), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m² basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Included as part of the PRECAUTIONS section.

CNS stimulants, including QuilliChew ER, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy.

Stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in children and adolescents with structural cardiac abnormalities and other serious cardiac problems, and in adults taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment with QuilliChew ER.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing QuilliChew ER. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulanttreated patients, compared to 0 in placebo-treated patients.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including QuilliChew ER, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation of digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including QuilliChew ER. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). QuilliChew ER 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 QuilliChew ER in patients with PKU, consider the combined daily amount of phenylalanine from all sources, including QuilliChew ER.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Advise patients and their caregivers that QuilliChew ER is a federally controlled substance, and it can be abused and lead to dependence. Instruct patients that they should not give QuilliChew ER to anyone else. Advise patients to store QuilliChew ER in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired QuilliChew ER through a medicine take-back program if available.

Advise patients that QuilliChew ER should be taken by mouth once daily in the morning with or without food.

Advise patients, caregivers, and family members that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with QuilliChew ER use. Instruct patients to contact a health care provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease.

Advise patients that QuilliChew ER can elevate blood pressure and heart rate.

Advise patients that QuilliChew ER, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania.

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism.

• Instruct patients beginning treatment with QuilliChew ER about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.
• Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
• Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking QuilliChew ER.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Advise patients, families, and caregivers that QuilliChew ER can cause slowing of growth and weight loss.

Advise patients to avoid alcohol while taking QuilliChew ER extended-release chewable tablets. Consumption of alcohol while taking QuilliChew ER may result in a more rapid release of the dose of methylphenidate.

Advise patients with phenylketonuria that QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame.

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose on a mg/m basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 5 times the maximum recommended human dose on a mg/m² basis.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.

Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 8-fold the maximum recommended human dose on a mg/m² basis.

There are limited published studies and small case series that report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. There are clinical considerations. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 2 and 11 times, respectively, the maximum recommended human dose (MRHD). However, spina bifida was observed in rabbits at a dose 40 times the MRHD.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Fetal/Neonatal Adverse Reactions

CNS stimulant medications, such as QuilliChew ER, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Animal Data

In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m² basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m² basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m² basis).

Limited published literature reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QuilliChew ER and any potential adverse effects on the breastfed infant from QuilliChew ER or from the underlying maternal condition.

Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of QuilliChew ER have been established in pediatric patients ages 6 to 17 years. Use of QuilliChew ER in these age groups is based on one adequate and well-controlled clinical study in pediatric patients 6 to 12 years old, pharmacokinetic data in adolescents and adults, and safety information from other methylphenidate-containing products. The long-term efficacy of methylphenidate in pediatric patients has not been established. Safety and efficacy in pediatric patients below the age of 6 years have not been established.

Growth should be monitored during treatment with CNS stimulants, including QuilliChew ER. Children who are not growing or gaining weight as expected may need to have their treatment interrupted.

Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13–14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m² basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (12 times the MRHD on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

QuilliChew ER has not been studied in patients over the age of 65 years.

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.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 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 de-challenged 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.

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.

Sudden death and pre-existing structural cardiac 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 structural cardiac 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

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. Aggression has been reported in patients treated with methylphenidate. 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

Anxiety, agitation and tension have been reported in patients treated with methylphenidate. Methylphenidate is also associated with the worsening of pre-existing anxiety, agitation or tension, and anxiety led to discontinuation of methylphenidate in some patients. 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.). 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 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.

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 co-morbid 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 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.

Excipients: galactose intolerance

This medicinal product contains lactose: patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption 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.

Potential for gastrointestinal obstruction

Because the Concerta XL 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, Concerta XL should only be used in patients who are able to swallow the tablet whole. Patients should be informed that Concerta XL must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

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. 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.

Dosage (Posology) and method of administration

Quillivant XR (Oral)® (methylphenidate hydrochloride) extended-release capsules is for oral administration once daily in the morning. Quillivant XR (Oral) may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Quillivant XR (Oral) and/or their contents should not be crushed, chewed, or divided.

The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Patients should be advised to avoid alcohol while taking Quillivant XR (Oral).

Dosage should be individualized according to the needs and responses of the patients.

The recommended starting dose of Quillivant XR (Oral) is 20 mg once daily. Dosage may be adjusted in weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not recommended. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with Quillivant XR (Oral) 10 mg.

The recommended dose of Quillivant XR (Oral) for patients currently taking methylphenidate b.i.d. or sustained release (SR) is provided below.

For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose. Quillivant XR (Oral) dosage may be adjusted at weekly intervals in 10 mg increments.

Daily dosage above 60 mg is not recommended.

There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Quillivant XR (Oral). It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Quillivant XR (Oral) for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient's functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Prior to treating children, adolescents, and adults with CNS stimulants including QuilliChew ER, assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam).

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for QuilliChew ER use.

The recommended starting dose of QuilliChew ER 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 QuilliChew ER, the prescribed dose should be adjusted, if necessary, until a welltolerated, therapeutic dose is achieved.

Pharmacological treatment of ADHD may be needed for extended periods. Health care providers should periodically re-evaluate the long-term use of QuilliChew ER, and adjust dosage as needed.

QuilliChew ER should be orally administered once daily in the morning with or without food.

If switching from other methylphenidate products, discontinue that treatment, and titrate with QuilliChew ER 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.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. QuilliChew ER should be periodically discontinued to assess the child's condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

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.

Ongoing monitoring

- 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 at least every 6 months and at every visit.

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

Posology

Dose titration

Careful dose titration is necessary at the start of treatment with Concerta XL. Dose titration should be started at the lowest possible dose. A 27 mg dosage strength is available for those who wish to prescribe between the 18 mg and 36 mg dosages.

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 Concerta XL is 54 mg.

Patients New to Methylphenidate: Clinical experience with Concerta XL is limited in these patients. Concerta XL 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 Concerta XL 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 Concerta 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 Concerta XL

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug 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 de-challenged 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 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 Concerta XL in adults is not appropriate.

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.

Method of administration

Concerta XL must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

Concerta XL may be administered with or without food.

Concerta XL is taken once daily in the morning.

Special precautions for disposal and other handling

No special requirements.