Dexmethylphenidate Hydrochloride Extended Release Capsules
DEA Controlled Substance Schedule C-II
TABLE OF CONTENTS
Dexmethylphenidate hydrochloride is a central nervous system (CNS) stimulant. Dexmethylphenidate hydrochloride is the d-threo-enantiomer of racemic methylphenidate hydrochloride, which is a 50/50 mixture of the d-threo and l-threo-enantiomers. Dexmethylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, (R,R’)-(+)-. Its empirical formula is C14H19NO2•HCl. Its molecular weight is 269.77 and its structural formula is:
Dexmethylphenidate hydrochloride is a white to off white powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone.
Dexmethylphenidate hydrochloride extended-release (ER) capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of dexmethylphenidate and a second delayed release of dexmethylphenidate. Dexmethylphenidate hydrochloride ER is available as 5, 10, 15, 20, 30, and 40 mg extended-release capsules. Dexmethylphenidate hydrochloride ER 5, 10, 15, 20, 30, and 40 mg extended-release capsules provide in a single dose the same amount of dexmethylphenidate as dosages of 2.5, 5, 7.5, 10, 15 or 20 mg of immediate-release dexmethylphenidate given twice daily as tablets.
Inactive ingredients: ammonio methacrylate copolymer, FD&C Blue #2 (5 mg, 15 mg and 40 mg strengths), FDA/E172 yellow iron oxide (10 mg, 15 mg, 30 mg, and 40 mg strengths), gelatin, ink Tan SW-8010, methacrylic acid copolymer, polyethylene glycol, sugar spheres, talc, titanium dioxide, and triethyl citrate.
|2. INDICATIONS AND USAGE|
Dexmethylphenidate hydrochloride extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older.
The effectiveness of dexmethylphenidate ER in the treatment of ADHD in patients aged 6 years and older was established in two placebo-controlled studies in patients meeting DSM-IV criteria for ADHD.
A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause 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 Type requires both inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations
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.
Need for Comprehensive Treatment Program
Dexmethylphenidate hydrochloride tablets are 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. Stimulants are 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 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 patient’s symptoms.
The effectiveness of dexmethylphenidate hydrochloride tablets for long-term use, i.e., for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use dexmethylphenidate hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
|3. DOSAGE AND ADMINISTRATION|
Dexmethylphenidate hydrochloride extended-release capsule is for oral administration once daily in the morning.
Dexmethylphenidate ER may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce. Dexmethylphenidate ER 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 mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use.
Dosage should be individualized according to the needs and responses of the patients.
3.1 Patients New to Methylphenidate
The recommended starting dose of dexmethylphenidate ER for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg/day for pediatric patients and 10 mg/day for adult patients.
Dosage may be adjusted in 5 mg increments for pediatric patients and in 10 mg increments for adult patients. In general, dosage adjustments may proceed at approximately weekly intervals. The patient should be observed for a sufficient duration at a given dose to ensure that a maximal benefit has been achieved before a dose increase is considered. In dose-response (fixed-dose) studies (pediatric from 10 to 30 mg/day and adult from 20 to 40 mg/day), all doses were effective vs. placebo. There was no clear finding, however, of greater average benefits for the higher doses compared to the lower doses. Adverse events and discontinuations, however, were dose-related. Doses above 30 mg/day in pediatrics and 40 mg/day in adults have not been studied and are not recommended.
3.2 Patients Currently Using Methylphenidate
For patients currently using methylphenidate, the recommended starting dose of dexmethylphenidate ER is half the total daily dose of racemic methylphenidate. Patients currently using immediate-release dexmethylphenidate may be switched to the same daily dose of dexmethylphenidate ER. The maximum recommended dose is 20 mg/day for pediatric and adult patients.
3.3 Maintenance/Extended Treatment
There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with dexmethylphenidate ER. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use dexmethylphenidate ER for extended periods in patients with ADHD should periodically reevaluate the long-term usefulness of the drug for the individual patient with periods off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.
3.4 Dose Reduction and Discontinuation
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 1-month period, the drug should be discontinued.
Dexmethylphenidate hydrochloride extended-release capsule is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.
4.2 Hypersensitivity to Methylphenidate
Dexmethylphenidate ER is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of the product.
Dexmethylphenidate ER is contraindicated in patients with glaucoma.
Dexmethylphenidate ER is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. (See ADVERSE REACTIONS.)
4.5 Monoamine Oxidase Inhibitors
Dexmethylphenidate ER 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).
|5. MECHANISM OF ACTION|
Dexmethylphenidate hydrochloride, the active ingredient in dexmethylphenidate hydrochloride extended-release capsules, is a central nervous system stimulant. Dexmethylphenidate, the more pharmacologically active d-enantiomer of racemic 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. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies of Focalin in pregnant women. Dexmethylphenidate did not cause major malformations in rats or rabbits; however, it did cause delayed skeletal ossification and decreased postweaning weight gain in rats. Dexmethylphenidate ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In studies conducted in rats and rabbits, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of teratogenic activity was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, postweaning body weight gain was decreased in male offspring at the highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels (AUCs) of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with 20 mg/day.
Racemic methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.
6.2 Labor and Delivery
Dexmethylphenidate ER has not been studied in labor and delivery.
6.3 Nursing Mothers
It is not known whether dexmethylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if dexmethylphenidate ER is administered to a nursing woman. Information from 4 published case reports on the use of racemic methylphenidate during breastfeeding suggest that at maternal doses of 35-80 mg/day, milk concentrations of methylphenidate range from undetectable to 15.4 ng/mL. Based on these limited data, the calculated infant daily dose for an exclusively breastfed infant would be about 0.4 – 2.9 μg/kg/day or about 0.2-0.7% of the maternal weight adjusted dose.
6.4 Pediatric Use
The safety and efficacy of dexmethylphenidate ER in children under 6 years old have not been established. Long-term effects of dexmethylphenidate in children have not been well established.
|7. WARNINGS AND PRECAUTIONS|
7.1 Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems
Children and Adolescents
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.
7.2 Hypertension and other Cardiovascular Conditions
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.
7.3 Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
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.
7.4 Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
7.5 Bipolar Illness
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.
7.6 Emergence of New Psychotic or Manic Symptoms
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 post marketing experience of some medications indicated for the treatment of ADHD. 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.
7.8 Long-Term Suppression of Growth
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 7-week double-blind placebo-controlled study of dexmethylphenidate hydrochloride extended-release capsules, the mean weight gain was greater for patients receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate ER (-0.5 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.
7.10 Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
7.11 Use in Children Under Six Years of Age
Dexmethylphenidate ER should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.
7.12 Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
|8. ADVERSE REACTIONS|
Dexmethylphenidate ER was administered to 46 children and 7 adolescents with ADHD for up to 7 weeks and 206 adults with ADHD in clinical studies. During the clinical studies, 101 adult patients were treated for at least 6 months.
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, MedDRA 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.
8.1 Adverse Events Associated with Discontinuation of Treatment in Acute Clinical Studies with Dexmethylphenidate ER - Children
Overall, 50 of 684 children treated with Focalin immediate-release formulation (7.3%) experienced an adverse event that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each). None of the 53 dexmethylphenidate ER-treated pediatric patients discontinued treatment due to adverse events in the 7-week placebo-controlled study.
8.2 Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate ER-Treated Patients-Children
Table 1 enumerates treatment-emergent adverse events for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate ER doses of 5-30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate ER and for which the incidence in patients treated with dexmethylphenidate ER was at least twice the incidence in placebo-treated patients. 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.
Table 1. Treatment-Emergent Adverse Events Occurring During Double-Blind Treatment–Pediatric Patients
Table 2 below enumerates the incidence of dose-related adverse events that occurred during a fixed-dose, double-blind, placebo controlled trial of dexmethylphenidate ER up to 30mg/day versus placebo in children and adolescents with ADHD.
Table 2: Dose-related Adverse Events from a Fixed-dose Study of Double-Blind Treatment in Pediatric Patients By Organ-System and Preferred Term
8.3 Adverse Events Associated with Discontinuation of Treatment in Clinical Studies with Dexmethylphenidate ER - Adults
In the adult placebo-controlled study, 10.7% of the dexmethylphenidate ER-treated patients and 7.5% of the placebo-treated patients discontinued for adverse events. Among dexmethylphenidate ER-treated patients, insomnia (1.8%, n=3), feeling jittery (1.8%, n=3), anorexia (1.2%, n=2), and anxiety (1.2%, n=2) were the reasons for discontinuation reported by more than 1 patient.
8.4 Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate ER-Treated Patients - Adults
Table 3 enumerates treatment-emergent adverse events for the placebo-controlled, parallel-group study in adults with ADHD at fixed dexmethylphenidate ER doses of 20, 30, and 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate ER dose group and for which the incidences in patients treated with dexmethylphenidate ER appeared to increase with dose. 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.
Table 3. Treatment-Emergent Adverse Events Occurring During Double-Blind Treatment–Adults
Two other adverse reactions occurring in clinical trials with dexmethylphenidate ER at a frequency greater than placebo, but which were not dose related were: Feeling jittery (12% and 2%, respectively) and Dizziness (6% and 2%, respectively).
Table 4 summarizes changes in vital signs and weight that were recorded in the adult study (N=218) of dexmethylphenidate ER in the treatment of ADHD.
Table 4. Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose during Double-Blind Treatment – Adults
8.5 Post-Marketing Experience
The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate ER. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis
8.6 Adverse Events with Other Methylphenidate HCl Products
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
Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura
Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis
Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion
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.
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 above may also occur.
|9. DRUG ABUSE AND DEPENDENCE|
9.1 Controlled Substance Class
Dexmethylphenidate hydrochloride extended-release capsules, like other methylphenidate products, is classified as a Schedule II controlled substance by Federal regulation.
9.2 Abuse, Dependence, Tolerance
See complete boxed warning for drug abuse and dependence information at the beginning of Full Prescribing Information.
10.1 Signs and Symptoms
Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS 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.
10.2 Recommended Treatment
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 dexmethylphenidate from dexmethylphenidate 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 for dexmethylphenidate overdosage has not been established.
10.3 Poison Control Center
The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate.
|11. DRUG INTERACTIONS|
MAO Inhibitors: Dexmethylphenidate ER should not be used in patients being treated (currently or within the preceding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).
Pressor agents: Because of possible effects on blood pressure, dexmethylphenidate ER should be used cautiously with pressor agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Dexmethylphenidate is metabolized primarily to d-ritalinic acid by de-esterification and not through oxidative pathways.
Antacids: The effects of gastrointestinal pH alterations on the absorption of dexmethylphenidate from dexmethylphenidate ER have not been studied. Since the modified release characteristics of dexmethylphenidate ER are pH dependent, the coadministration of antacids or acid suppressants could alter the release of dexmethylphenidate.
Coumarin anticoagulants, anticonvulsants, tricyclic drugs: Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate.
Clonidine: Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally-acting alpha-2-agonists has not been systematically evaluated.
Dexmethylphenidate ER produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately 4 hours apart) when orally administered to healthy adults. The initial rate of absorption for dexmethylphenidate ER is similar to that of dexmethylphenidate tablets as shown by the similar rate parameters between the two formulations, i.e., first peak concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1 ½ hours (typical range 1-4 hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) is slightly longer for dexmethylphenidate ER given once daily (about 6.5 hours, range 4.5-7 hours) compared to dexmethylphenidate tablets given in two doses 4 hours apart, although the ranges observed are greater for dexmethylphenidate ER.
Dexmethylphenidate ER given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than dexmethylphenidate 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.
The AUC (exposure) after administration of dexmethylphenidate ER given once daily is equivalent to the same total dose of dexmethylphenidate tablets given in two doses 4 hours apart. The variability in Cmax, Cmin, and AUC is similar between dexmethylphenidate ER and dexmethylphenidate IR with approximately a three-fold range in each.
Radiolabeled racemic methylphenidate is well absorbed after oral administration with approximately 90% of the radioactivity recovered in urine. However, due to first pass metabolism the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22-25%.
Administration times relative to meals and meal composition may need to be individually titrated.
No food effect study was performed with dexmethylphenidate ER. However, the effect of food has been studied in adults with racemic methylphenidate in the same type of extended-release formulation. The findings of that study are considered applicable to dexmethylphenidate ER. After a high fat breakfast, there was 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 is no evidence of dose dumping in the presence or absence of food. There were no differences in the plasma concentration-time profile, when administered with applesauce, compared to administration in the fasting condition. The results are expected not to differ for dexmethylphenidate ER.
The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12-15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65±1.11 L/kg. Plasma dexmethylphenidate concentrations decline monophasically following oral administration of dexmethylphenidate ER.
Metabolism and Excretion
In humans, dexmethylphenidate is metabolized primarily to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo-enantiomer, based on a finding of no levels of l-threo-methylphenidate being detectable after administration of up to 40 mg dexmethylphenidate in adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic (d,l-) methylphenidate was d,l-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.
In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes at concentrations observed after therapeutic doses.
Intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40±0.12 L/kg.h-1 corresponding to 0.56±0.18 L/min. The mean terminal elimination halflife of dexmethylphenidate was just over 3 hours in healthy adults and typically varied between 2 and 4.5 hours with an occasional subject exhibiting a terminal half-life between 5 and 7 hours. Children tend to have slightly shorter half-lives with means of 2–3 hours.
|13. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: Focalin XR, by NOVARTIS.
b) Generic drugs: None.
2) How Supplied:
5 mg Extended-Release Capsules (NDC 0078-0430-05) light-blue, (imprinted NVR D5) supplied in bottles of 100
10 mg Extended-Release Capsules (NDC 0078-0431-05) light caramel (imprinted NVR D10) supplied in bottles of 100
15 mg Extended-Release Capsules (NDC 0078-0493-05) green (imprinted NVR D15) supplied in bottles of 100
20 mg Extended-Release Capsules (NDC 0078-0432-05) white (imprinted NVR D20) supplied in bottles of 100
25 mg Extended-Release Capsules (NDC 0078-0608-05) light-blue and white (imprinted NVR D25) supplied in bottles of 100
30 mg Extended-Release Capsules (NDC 0078-0433-05) light caramel and white (imprinted NVR D30) supplied in bottles of 100
35 mg Extended-Release Capsules (NDC 0078-0609-05) light-blue and light caramel (imprinted NVR D35) supplied in bottles of 100
40 mg Extended-Release Capsules (NDC 0078-0434-05) green and white (imprinted NVR D40) supplied in bottles of 100
3) Storage: Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F). Dispense in tight container.