Dexmethylphenidate Hydrochloride Extended-Release Capsules: Indications, Dosage, Precautions, Adverse Effects
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Dexmethylphenidate Hydrochloride Extended-Release Capsules – Product Information

Manufacture: Actavis
Country: United States
Condition: ADHD (Attention Deficit Hyperactivity Disorder)
Class: CNS stimulants
Form: Capsules
Ingredients: Dexmethylphenidate Hydrochloride, Acetyltributyl Citrate, Ethylcellulose, Gelatin, Hypromellose, Hypromellose Acetate Succinate, Sugar Spheres (which Contains Sucrose And Starch), Talc, And Titanium Dioxide, D And C Red #28 And Fd And C Blue #1. Black Printing Ink Sw-9008/sw-9009 Contains Black Iron Oxide, Potassium Hydroxide, Propylene Glycol, Shellac

Warning:drug dependence

Dexmethylphenidate hydrochloride extended-release 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, s ince severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up

Indications and usage

Dexmethylphenidate hydrochloride extended-release is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older.

The effectiveness of dexmethylphenidate hydrochloride extended-release 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 [see Clinical Studies (14)].

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.

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 extended-release 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.

Long-Term Use

The effectiveness of dexmethylphenidate hydrochloride extended-release for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use dexmethylphenidate hydrochloride extended-release for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].

Dosage and administration

Dexmethylphenidate hydrochloride extended-release is for oral administration once daily in the morning.

Dexmethylphenidate hydrochloride extended-release 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). Dexmethylphenidate hydrochloride extended-release 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 patient.

Patients New to Methylphenidate

The recommended starting dose of dexmethylphenidate hydrochloride extended-release 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.

Patients Currently Using Methylphenidate

For patients currently using methylphenidate, the recommended starting dose of dexmethylphenidate hydrochloride extended-release is half the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate hydrochloride may be switched to the same daily dose of dexmethylphenidate hydrochloride extended-release.

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 hydrochloride extended-release. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use dexmethylphenidate hydrochloride extended-release 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.

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.

Dosage forms and strengths

15 mg extended-release capsules

30 mg extended-release capsules

Contraindications

Agitation

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

Hypersensitivity to Methylphenidate

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of the product. Hypersensitivity reactions, including angioedema and anaphylactic reactions, have been observed in patients treated with methylphenidate [see Adverse Reactions (6.5 and 6.6)].

Glaucoma

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with glaucoma.

Tics

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome [see Adverse Reactions (6.1)].

Monoamine Oxidase Inhibitors

Dexmethylphenidate hydrochloride extended-release 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).

Warnings and precautions

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.

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.

Hypertension and other Cardiovascular Conditions

Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 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.

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.

Pre-Existing Psychosis

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

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.

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.

Aggression

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.

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, the mean weight gain was greater for patients receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended- release (-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.

Seizures

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.

Priapism

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.

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

Stimulants, including dexmethylphenidate hydrochloride extended-release, 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 post-marketing 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 for digital changes is necessary during treating with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Visual Disturbance

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

Use in Children Under Six Years of Age

Dexmethylphenidate hydrochloride extended-release should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.

Hematologic Monitoring

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

Adverse reactions

Dexmethylphenidate hydrochloride extended-release 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.

Adverse Events Associated with Discontinuation of Treatment in Acute Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release – Children

Overall, 50 of 684 children treated with dexmethylphenidate hydrochloride 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 hydrochloride extended- release-treated pediatric patients discontinued treatment due to adverse events in the 7-week placebo- controlled study.

Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release-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 hydrochloride extended-release doses of 5 to 30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release 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 Events1 Occurring During Double-Blind Treatment– Pediatric Patients

Dexmethylphenidate Hydrochloride Extended-Release N=53 Placebo N=47
No. of Patients with AEs
Total 76%57%
Primary System Organ Class / Adverse Event Preferred Term
Gastrointestinal Disorders 38% 19%
Dyspepsia 8% 4%
Metabolism and Nutrition Disorders 34% 11%
Decreased Appetite30%9%
Nervous System Disorders30%13%
Headache25%11%
Psychiatric Disorders26%15%
Anxiety6%0%
1Events, regardless of causality, for which the incidence for patients treated with dexmethylphenidate hydrochloride extended-release was at least 5% and twice the incidence among placebo-treated patients. Incidence has been rounded to the nearest whole number.

Table 2 below enumerates the incidence of dose-related adverse events that occurred during a fixed- dose, double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride extended-release 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

ADVERSE EVENT Dexmethylphenidate Hydrochloride Extended-Release 10 mg/d N=64 Dexmethylphenidate Hydrochloride Extended-Release 20 mg/d N=60 Dexmethylphenidate Hydrochloride Extended-Release 30 mg/d N=58 Placebo N=63
Gastrointestinal disorders22%23%29%24%
Vomiting2%8%9%0%
Metabolism and nutritional disorders16%17%22%5%
Anorexia5%5%7%0
Psychiatric Disorders19%20%38%8%
Insomnia5%8%17%3%
Depression003%0
Mood swings003%2%
Other Adverse events
Irritability02%5%0
Nasal Congestion005%0
Pruritus003%0

Adverse Events Associated with Discontinuation of Treatment in Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release – Adults

In the adult placebo-controlled study, 10.7% of the dexmethylphenidate hydrochloride extended- release-treated patients and 7.5% of the placebo-treated patients discontinued for adverse events. Among dexmethylphenidate hydrochloride extended-release-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.

Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release-Treated Patients-Adults

Table 3 enumerates treatment-emergent adverse events for the placebo-controlled, parallel-group study in adults with ADHD at fixed dexmethylphenidate hydrochloride extended-release 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 hydrochloride extended-release dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release 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 Events1 Occurring During Double-Blind Treatment– Adults

Dexmethylphenidate Hydrochloride Extended-Release 20 mg/d N=57 Dexmethylphenidate Hydrochloride Extended-Release 30 mg/d N=54 Dexmethylphenidate Hydrochloride Extended-Release 40 mg/d N=54 Placebo N=53
No. of Patients with AEs
Total84%94%85%68%
Primary System Organ Class /Adverse Event
Preferred Term
Gastrointestinal Disorders28%32%44%19%
Dry Mouth7%20%20%4%
Dyspepsia5%9%9%2%
Nervous System Disorders37%39%50%28%
Headache26%30%39%19%
Psychiatric Disorders40%43%46%30%
Anxiety5%11%11%2%
Respiratory, Thoracic and Mediastinal Disorders16%9%15%8%
Pharyngolaryngeal Pain4%4%7%2%
1 Events, regardless of causality, for which the incidence was at least 5% in a dexmethylphenidate hydrochloride extended-release group and which appeared to increase with randomized dose.

Incidence has been rounded to the nearest whole number.

Two other adverse reactions occurring in clinical trials with dexmethylphenidate hydrochloride extended-release 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 hydrochloride extended-release in the treatment of ADHD.

Table 4. Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double- Blind Treatment – Adults

Dexmethylphenidate Hydrochloride Extended-Release 20 mg/d N=57 Dexmethylphenidate Hydrochloride Extended-Release 30 mg/d N=54 Dexmethylphenidate Hydrochloride Extended-Release 40 mg/d N=54 Placebo N=53
Pulse (bpm)3.1 ± 11.14.3 ± 11.76.0 ± 10.1-1.4 ± 9.3
Diastolic BP (mmHg)-0.2 ± 8.21.2 ± 8.92.1 ± 8.00.3 ± 7.8
Weight (kg)-1.4 ± 2.0-1.2 ± 1.9-1.7 ± 2.3-0.1 ± 3.9

Post-Marketing Experience

The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate hydrochloride extended-release. 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

Adverse Events with Other Methylphenidate HCl Dosage Forms

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, 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, libido changes

Skin/Subcutaneous: scalp hair loss

Urogenital: priapism

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.

Drug interactions

Dexmethylphenidate hydrochloride extended-release should not be used in patients being treated (currently or within the preceding two weeks) with MAO Inhibitors [see Contraindications (4.5)].

Because of possible effects on blood pressure, dexmethylphenidate hydrochloride extended-release 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.

The effects of gastrointestinal pH alterations on the absorption of dexmethylphenidate from dexmethylphenidate hydrochloride extended-release have not been studied. Since the modified release characteristics of dexmethylphenidate hydrochloride extended-release are pH dependent, the coadministration of antacids or acid suppressants could alter the release of dexmethylphenidate.

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.

Use in specific populations

Pregnancy

Teratogenic Effects: Pregnancy Category C:

There are no adequate and well controlled studies of dexmethylphenidate hydrochloride 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 hydrochloride extended-release 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.

Labor and Delivery

Dexmethylphenidate hydrochloride extended-release has not been studied in labor and delivery.

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 hydrochloride extended-release 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 to 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 to 2.9 mcg/kg/day or about 0.2 to 0.7% of the maternal weight adjusted dose.

Pediatric Use

The safety and efficacy of dexmethylphenidate hydrochloride extended-release in children under 6 years old have not been established. Long-term effects of dexmethylphenidate hydrochloride in children have not been well established [see Warnings and Precautions (5.13)].

In a study conducted in young rats, racemic 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] of racemic methylphenidate 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 racemic MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the racemic MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Geriatric Use

Dexmethylphenidate hydrochloride extended-release has not been studied in the geriatric population.

Drug abuse and dependence

Controlled Substance Class

Dexmethylphenidate hydrochloride extended-release, like other methylphenidate products, is classified as a Schedule II controlled substance by Federal regulation.

Abuse, Dependence, Tolerance

See complete boxed warning for drug abuse and dependence information at the beginning of Full Prescribing Information.

Overdosage

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.

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.

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.

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 hydrochloride overdosage has not been established.

How supplied/storage and handling

Dexmethylphenidate hydrochloride extended-release capsules contain white to off-white pellets and are available as follows:

15 mg - Size 2 capsule with white opaque body and light pink opaque cap printed with and 806 in black inkon both cap and body. Capsules are supplied in bottles of 100 (NDC 45963-806-11).

30 mg - Size 00 capsule with white opaque cap and body printed with and 833 in black ink on both cap and body. Capsules are supplied in bottles of 100 (NDC 45963-833-11).

Store at 25°C (77°F), excursions permitted 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

Patient counseling information

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dexmethylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for dexmethylphenidate hydrochloride extended-release. 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.

Priapism

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 [seeWarnings and Precautions (5.10)].

Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]

  • Instruct patients beginning treatment with dexmethylphenidate hydrochloride extended-release capsules 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 s igns of unexplained wounds appearing on fingers or toes while taking dexmethylphenidate hydrochloride extended-release capsules.
  • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.