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«Biphentin® (methylphenidate hydrochloride controlled release capsules) 10, 15, 20, 30, 40, 50, 60 and 80 mg Central Nervous System Stimulant Purdue ...»

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(methylphenidate hydrochloride controlled release capsules)

10, 15, 20, 30, 40, 50, 60 and 80 mg

Central Nervous System Stimulant

Purdue Pharma

575 Granite Court

Pickering, ON


June 10, 2016

Control No.: 179185

Biphentin® is a trademark of Purdue Pharma

Biphentin® (methylphenidate HCl CR capsules) Page 1 of 39


Biphentin® (methylphenidate hydrochloride controlled release capsules) 10, 15, 20, 30, 40, 50, 60 and 80 mg


Central Nervous System Stimulant


Methylphenidate is a central nervous system (CNS) stimulant. The mode of action of stimulants in Attention-Deficit Hyperactivity Disorder (ADHD) is not completely understood, but they are thought to act primarily through indirect mechanisms, such as release of dopamine and norepinephrine from neuronal pools, and inhibition of neurotransmitter reuptake.

There is some evidence suggesting that the mechanism whereby methylphenidate produces its mental and behavioural effects in children is related to a dose-dependent blockade of the dopamine transporter and an increase in extracellular dopamine. While the evidence regarding how these effects relate to the condition of the CNS is not conclusive, it is likely that an increase in dopamine transporter activity is part of the underlying mechanistic basis of ADHD.

Pharmacokinetics of Methylphenidate:

Methylphenidate is rapidly and extensively absorbed following oral administration - with peak blood levels obtained in 1 to 3 hours.

Methylphenidate is excreted almost entirely in the urine. The primary route of metabolism for methylphenidate is desterification to the inactive metabolite ritalinic acid (α-phenyl-2-piperidine acetic acid), which represents 60-81% of the administered dose, and 6-oxy-α-phenyl-2- piperidineacetic acid (9-12% of the administered dose). Unchanged drug accounts for less than 1% of the administered dose. First pass metabolism results in an absolute bioavailability of 30% with large inter-individual differences (11-52%).

Biphentin® (methylphenidate HCl CR capsules) Page 2 of 39 Methylphenidate is eliminated from plasma with a mean half-life of 2.4 hours in children and

2.1 hours in adults. The apparent systemic clearance, for a 0.3 mg/kg dose, is 10.2 and

10.5 L/h/kg in children and adults, respectively. These data indicate that the pharmacokinetic behavior of methylphenidate in hyperactive children is similar to that in normal adults. The apparent distribution volume of methylphenidate in children is approximately 20 L/kg, with substantial variability (11 to 33 L/kg).

Methylphenidate excretion into breast milk has been noted in two case reports, where the calculated relative infant dose was  0.2% of the weight adjusted maternal dose.

In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Methylphenidate and its metabolites exhibit low plasma protein binding (approximately 15%).

Pharmacokinetics and Pharmacodynamics of Biphentin:

In a single dose study in healthy adult volunteer subjects, Biphentin® (methylphenidate hydrochloride controlled release capsules, 20 mg) was fully bioavailable, relative to two separate 10 mg doses of an immediate-release reference formulation (Ritalin®), under both fasted and fed conditions (relative AUCt 96% and 107%, respectively). In a single dose study in young children (6 - 12 years) with ADHD, Biphentin, when given at a dose equal to the patient’s pre-study methylphenidate dose (mean dose 38.6 mg), following a child’s typical breakfast, was fully bioavailable relative to the same daily dose of immediate-release methylphenidate (Ritalin®) given as two separate doses (relative AUCt 101%).

Biphentin was designed to be an alternative to separate doses of immediate release methylphenidate by providing a biphasic plasma concentration time profile when given as a single dose. The rate of increase in plasma methylphenidate concentration with the controlled release formulation was similar to that with the immediate-release formulation. In adults the initial peak concentration occurred at 1.7 hours post-dose for Biphentin and at 1.8 hours post-dose for the immediate-release formulation, when given under fasting conditions, and at

2.0 hours post-dose and 2.5 hours post-dose, respectively, when given with food. The initial Biphentin® (methylphenidate HCl CR capsules) Page 3 of 39 maximum concentration (Cmax) achieved with the controlled release formulation was 76% (fasted) and 84% (fed) of that of immediate-release methylphenidate. In young children, being treated for ADHD with methylphenidate, the initial peak concentration occurred at 2.6 hours post-dose for Biphentin and at 2.1 hours post-dose for the immediate-release formulation, when given at doses equal to the children’s pre-study maintenance doses. The initial maximum concentration achieved with the controlled release formulation was 79% of that of immediaterelease methylphenidate.

A double-blind, placebo-controlled, crossover comparison of the pharmacodynamics of Biphentin and immediate-release methylphenidate in children (age 6 to 17 years) with ADHD demonstrated equivalent improvements on the same daily dose, with a similar time-course, on both behavioural and cognitive parameters, relative to placebo. Biphentin was given as a single morning dose while immediate-release methylphenidate was given at the same daily dose, in equally divided doses in the morning and at lunchtime. Improvements relative to placebo were noted within 1 hour on Biphentin and persisted into the early evening.

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Biphentin® (methylphenidate hydrochloride controlled release capsules) is indicated for

treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in:

• Children (6-11 years of age)

• Adolescents (12-18 years of age)

• Adults ( 18 years of age) Children (6 years of age) Biphentin should not be used in children under 6 years, since safety and efficacy in this age group have not been established.

Geriatrics (65 years of age) No data available.

Biphentin® (methylphenidate HCl CR capsules) Page 4 of 39 A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and that were present before age 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g. in social, academic, or occupational functioning, and must 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 6 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 6 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. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met.

Special Diagnostic Considerations The specific etiology of ADHD 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 patient and not solely on the presence of the required number of DSM-IV characteristics.

Need for Comprehensive Treatment Program Biphentin 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 patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment

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Long-Term Use The effectiveness of Biphentin for long-term use, i.e. for more than 4 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use Biphentin for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

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• Anxiety, tension, agitation, thyrotoxicosis, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension or glaucoma.

• Patients who are hypersensitive to methylphenidate hydrochloride or to any other ingredient in the formulation or component of the container. For a complete listing of excipients, see the PHARMACEUTICAL INFORMATION, Non-medicinal Ingredients (all strengths) section of this product monograph.

• Patients with motor tics or with a family history or diagnosis of Tourette’s syndrome (verbal tics) (see ADVERSE REACTIONS).

• During treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result) (see PRECAUTIONS; Drug Interactions).

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General Biphentin® (methylphenidate hydrochloride controlled release capsules) has not been compared to other controlled release methylphenidate preparations on the Canadian market, and therefore is not interchangeable.

Children: Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who: a) are involved in strenuous exercise or activities, b) use other stimulants, or c) have a family history of sudden/cardiac death.

Prior to the initiation of treatment, a personal and family history (including assessment for a family history sudden death or ventricular arrhythmia) and physical exam should be obtained to assess for the presence of cardiac disease. In patients with relevant risk factors and based on the clinician’s judgement, further cardiovascular evaluation may be considered (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during ADHD treatment should undergo a prompt cardiac evaluation.

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Children and Adolescents: Sudden death has been reported in association with stimulant drugs used for ADHD treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious cardiac problems. Although some serious heart problems alone carry an increased risk of sudden death, Biphentin 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.

Adults: 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.

Pre-existing Cardiovascular and Cerebral Vascular Conditions CNS stimulants should be used with caution in patients with a condition of the cardiovascular or cerebrovascular system, taking into account risk predictors for these conditions. Patients should be screened for pre-existing or underlying cardiovascular or cerebrovascular conditions before initiation of treatment with stimulants and monitored for new conditions of the heart or brain during the course of treatment.

Hypertension Hypertension may occur during methylphenidate treatment in some patients. Caution is particularly 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 hyperthyroidism.

Biphentin® (methylphenidate HCl CR capsules) Page 8 of 39 Blood pressure should be monitored at appropriate intervals in patients receiving stimulants, especially in patients with pre-existing conditions that may result in hypertension.

Drug Dependence/Tolerance Biphentin should be given cautiously to emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase dosage on their own initiative.

Chronic abuse can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes can occur, especially with parenteral abuse.

Careful supervision is required during drug withdrawal, since severe depression and underlying hyperactivity can be unmasked. Long-term follow-up may be required because of the patient’s basic personality disturbances.

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