Generic Name: methylphenidate hydrochloride
Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION
Concerta® 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.
Indications and Usage for Concerta
Concerta® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65 [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 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 of medical and 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
Concerta® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social). Drug treatment may not be indicated for all patients with ADHD. Stimulants are not intended for use in patients who exhibit 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.
Concerta Dosage and Administration
General Dosing Information
Concerta® should be administered orally once daily in the morning with or without food.
Concerta® must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17)].
Patients New to Methylphenidate
The recommended starting dose of Concerta® for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1).
| Patient Age | Recommended Starting Dose | Dose Range |
|---|---|---|
| Children 6–12 years of age | 18 mg/day | 18 mg – 54 mg/day |
| Adolescents 13–17 years of age | 18 mg/day | 18 mg – 72 mg/day not to exceed 2 mg/kg/day |
| Adults 18–65 years of age | 18 or 36 mg/day | 18 mg – 72 mg/day |
Patients Currently Using Methylphenidate
The recommended dose of Concerta® for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2. Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily.
| Previous Methylphenidate Daily Dose | Recommended Concerta® Starting Dose |
|---|---|
| 5 mg Methylphenidate twice daily or three times daily | 18 mg every morning |
| 10 mg Methylphenidate twice daily or three times daily | 36 mg every morning |
| 15 mg Methylphenidate twice daily or three times daily | 54 mg every morning |
| 20 mg Methylphenidate twice daily or three times daily | 72 mg every morning |
Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.
Dose Titration
Doses may be increased in 18-mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose. Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. Daily dosages above 72 mg in adults are not recommended.
A 27-mg dosage strength is available for physicians who wish to prescribe between the 18-mg and 36-mg dosages.
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 Concerta®. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods.
The effectiveness of Concerta® for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Concerta® 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.
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 one-month period, the drug should be discontinued.
Dosage Forms and Strengths
Concerta® (methylphenidate HCl) Extended-Release Tablets are available in the following dosage strengths: 18-mg tablets are yellow and imprinted with "alza 18," 27-mg tablets are gray and imprinted with "alza 27," 36-mg tablets are white and imprinted with "alza 36," and 54-mg tablets are brownish-red and imprinted with "alza 54."
Contraindications
Hypersensitivity to Methylphenidate
Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with Concerta®. Therefore, Concerta® is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions (6.6)].
Agitation
Concerta® is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.
Glaucoma
Concerta® is contraindicated in patients with glaucoma.
Tics
Concerta® is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome [see Adverse Reactions (6.4)].
Monoamine Oxidase Inhibitors
Concerta® is contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) [see Drug Interactions (7.1)].
Warnings and Precautions
Serious Cardiovascular Events
Sudden Death and Preexisting 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 deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is 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 mm Hg) and average heart rate (about 3 to 6 bpm) [see Adverse Reactions (6.5)], 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 preexisting 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.
Psychiatric Adverse Events
Preexisting Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting 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 patients 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 3482 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 patients with ADHD, and has been reported in clinical trials and the postmarketing 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.
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.
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 nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-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. Published data are inadequate to determine whether chronic use of amphetamines may cause 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.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Potential for Gastrointestinal Obstruction
Because the Concerta® tablet is nondeformable and does not appreciably change in shape in the GI tract, Concerta® should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, Concerta® should be used only in patients who are able to swallow the tablet whole [see Patient Counseling Information (17)].
Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Adverse Reactions
The following are discussed in more detail in other sections of the labeling:
- Drug Dependence [see Box Warning]
- Hypersensitivity to Methylphenidate [see Contraindications (4.1)]
- Agitation [see Contraindications (4.2)]
- Glaucoma [see Contraindications (4.3)]
- Tics [see Contraindications (4.4)]
- Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1)]
- Serious Cardiovascular Events [see Warnings and Precautions (5.1)]
- Psychiatric Adverse Events [see Warnings and Precautions (5.2)]
- Seizures [see Warnings and Precautions (5.3)]
- Long-Term Suppression of Growth [see Warnings and Precautions (5.4)]
- Visual Disturbance [see Warnings and Precautions (5.5)]
- Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.6)]
- Hematologic Monitoring [see Warnings and Precautions (5.7)]
The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis [see Adverse Reactions (6.1)].
The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Adverse Reactions (6.3)].
The development program for Concerta® included exposures in a total of 3906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses.
| Patient Population | N | Dose Range |
|---|---|---|
| Children | 2216 | 18 to 54 mg once daily |
| Adolescents | 502 | 18 to 72 mg once daily |
| Adults | 1188 | 18 to 108 mg once daily |
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
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.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of Concerta® based on the comprehensive assessment of the available adverse event information. A causal association for Concerta® often cannot be reliably established in individual cases. Further, 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 clinical trials of another drug and may not reflect the rates observed in clinical practice.
The majority of adverse reactions were mild to moderate in severity.
Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials
Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.
Children and Adolescents
Table 4 lists the adverse reactions reported in 1% or more of Concerta®-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.
| System/Organ Class Adverse Reaction | Concerta® (n=321) % | Placebo (n=318) % |
|---|---|---|
| ||
| Gastrointestinal Disorders | ||
| Abdominal pain upper | 6.2 | 3.8 |
| Vomiting | 2.8 | 1.6 |
| General Disorders and Administration Site Conditions | ||
| Pyrexia | 2.2 | 0.9 |
| Infections and Infestations | ||
| Nasopharyngitis | 2.8 | 2.2 |
| Nervous System Disorders | ||
| Dizziness | 1.9 | 0 |
| Psychiatric Disorders | ||
| Insomnia* | 2.8 | 0.3 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Cough | 1.9 | 0.9 |
| Oropharyngeal pain | 1.2 | 0.9 |
The majority of adverse reactions were mild to moderate in severity.
Adults
Table 5 lists the adverse reactions reported in 1% or more of Concerta®-treated adults in 2 placebo-controlled, double-blind clinical trials.
| System/Organ Class Adverse Reaction | Concerta® (n=415) % | Placebo (n=212) % |
|---|---|---|
| ||
| Cardiac Disorders | ||
| Tachycardia | 4.8 | 0 |
| Palpitations | 3.1 | 0.9 |
| Ear and Labyrinth Disorders | ||
| Vertigo | 1.7 | 0 |
| Eye Disorders | ||
| Vision blurred | 1.7 | 0.5 |
| Gastrointestinal Disorders | ||
| Dry mouth | 14.0 | 3.8 |
| Nausea | 12.8 | 3.3 |
| Dyspepsia | 2.2 | 0.9 |
| Vomiting | 1.7 | 0.5 |
| Constipation | 1.4 | 0.9 |
| General Disorders and Administration Site Conditions | ||
| Irritability | 5.8 | 1.4 |
| Infections and Infestations | ||
| Upper respiratory tract infection | 2.2 | 0.9 |
| Investigations | ||
| Weight decreased | 6.5 | 3.3 |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 25.3 | 6.6 |
| Anorexia | 1.7 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Muscle tightness | 1.9 | 0 |
| Nervous System Disorders | ||
| Headache | 22.2 | 15.6 |
| Dizziness | 6.7 | 5.2 |
| Tremor | 2.7 | 0.5 |
| Paresthesia | 1.2 | 0 |
| Sedation | 1.2 | 0 |
| Tension headache | 1.2 | 0.5 |
| Psychiatric Disorders | ||
| Insomnia | 12.3 | 6.1 |
| Anxiety | 8.2 | 2.4 |
| Initial insomnia | 4.3 | 2.8 |
| Depressed mood | 3.9 | 1.4 |
| Nervousness | 3.1 | 0.5 |
| Restlessness | 3.1 | 0 |
| Agitation | 2.2 | 0.5 |
| Aggression | 1.7 | 0.5 |
| Bruxism | 1.7 | 0.5 |
| Depression | 1.7 | 0.9 |
| Libido decreased | 1.7 | 0.5 |
| Affect lability | 1.4 | 0.9 |
| Confusional state | 1.2 | 0.5 |
| Tension | 1.2 | 0.5 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Oropharyngeal pain | 1.7 | 1.4 |
| Skin and Subcutaneous Tissue Disorders | ||
| Hyperhidrosis | 5.1 | 0.9 |
The majority of ADRs were mild to moderate in severity.
Other Adverse Reactions Observed in Concerta® Clinical Trials
This section includes adverse reactions reported by Concerta®-treated subjects in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by Concerta®-treated subjects who participated in open-label and postmarketing clinical trials.
Blood and Lymphatic System Disorders: Leukopenia
Eye Disorders: Accommodation disorder, Dry eye
Vascular Disorders: Hot flush
Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea
General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst
Infections and Infestations: Sinusitis
Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased
Musculoskeletal and Connective Tissue Disorders: Muscle spasms
Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence
Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic
Reproductive System and Breast Disorders: Erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
Skin and Subcutaneous Tissue Disorders: Rash, Rash macular
Vascular Disorders: Hypertension
Discontinuation Due to Adverse Reactions
Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 Concerta® patients (0.6%) including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).
In the 2 placebo-controlled studies of adults, 25 Concerta® patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the Concerta® patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).
In the 11 open-label studies of children, adolescents, and adults, 266 Concerta® patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).
Tics
In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with Concerta®.
In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). The treatment period was up to 9 months with mean treatment duration of 7.2 months.
Blood Pressure and Heart Rate Increases
In the laboratory classroom clinical trials in children (Studies 1 and 2), both Concerta® once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with Concerta® and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for Concerta® and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with Concerta® at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for Concerta® and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for Concerta® and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for Concerta® and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.1]).
Postmarketing Experience
The following additional adverse reactions have been identified during postapproval use of Concerta®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:
Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura
Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles
Eye Disorders: Diplopia, Mydriasis, Visual impairment
General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased
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: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching
Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia
Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania
Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema
Vascular Disorders: Raynaud's phenomenon
Drug Interactions
MAO Inhibitors
Concerta® should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors [see Contraindications (4.5)].
Vasopressor Agents
Because of possible increases in blood pressure, Concerta® should be used cautiously with vasopressor agents [see Warnings and Precautions (5.1)].
Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors
Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of Concerta® on a mg/kg and mg/m2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1–2 times that seen in trials in volunteers and patients with the maximum recommended dose of Concerta® based on the AUC.
The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. Concerta® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of Concerta® on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Concerta® is administered to a nursing woman.
In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.
Pediatric Use
Concerta® should not be used in children under six years, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established.
Geriatric Use
Concerta® has not been studied in patients greater than 65 years of age.
Drug Abuse and Dependence
Controlled Substance
Methylphenidate is a Schedule II controlled substance under the Controlled Substances Act.
Abuse
As noted in the Box Warning, Concerta® 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.
In two placebo-controlled human abuse potential studies, single oral doses of Concerta® were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration.
In one study (n=40), both Concerta® (108 mg) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, Concerta® (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation – Euphoria) responses produced by 60 mg IR MPH.
In another study (n=49), both doses of Concerta® (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of Concerta® (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, Concerta® produced statistically significantly lower subjective responses on these two scales than IR MPH. Concerta® (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 22% of the total amount of methylphenidate in Concerta® tablets is available for immediate release from the drug overcoat [see System Components and Performance (11.1)].
Although these findings reveal a relatively lower response to Concerta® on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of Concerta® in the community is unknown.
Dependence
As noted in the Box Warning, 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.
Overdosage
Signs and Symptoms
Signs and symptoms of Concerta® overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, muscle twitching, convulsion, grand mal convulsion, confusional state, hallucinations (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmia, hypertension, mydriasis, and dry mouth.
Recommended Treatment
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 pyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Concerta® overdosage has not been established.
The prolonged release of methylphenidate from Concerta® should be considered when treating patients with overdose.
Poison Control Center
As with the management of all overdosage, the possibi
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