METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE

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Overview

What is METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

Methylphenidate hydrochloride USP is a mild central nervous system (CNS) stimulant, available for oral administration as extended-release tablets of 10 and 20 mg. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is

Methylphenidate hydrochloride USP is a white, odorless, fine crystalline 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. Its molecular weight is 269.77.

Inactive Ingredients.

What does METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE look like?

What are the available doses of METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

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What should I talk to my health care provider before I take METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

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How should I use METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

Attention Deficit Disorders, Narcolepsy

Attention Deficit Disorders

Methylphenidate hydrochloride is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.

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.

Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. 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 1 or more of these characteristics.

Drug treatment is not 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 primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. 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.

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

Adults

Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

Children (6 years and over)

Methylphenidate hydrochloride should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended.

If improvement is not observed after appropriate dosage adjustment over a 1-month period, the drug should be discontinued.

Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug.

Methylphenidate hydrochloride should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.

What interacts with METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

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What are the warnings of METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

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What should I look out for while using METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

Marked anxiety, tension, and agitation are contraindications to methylphenidate hydrochloride, since the drug may aggravate these symptoms. Methylphenidate is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome.

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

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 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 2-4 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 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 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 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.

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. 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 methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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 Raynauds phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment 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

Methylphenidate should not be used in children under 6 years, since safety and efficacy in this age group have not been established.

What might happen if I take too much METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Rabdomyolysis has also been reporte in overdose.

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

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. In the presence of severe intoxication, use a carefully titrated dosage of a barbiturate before performing gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic.

Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.

Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Methylphenidate hydrochloride overdosage has not been established.

How should I store and handle METHYLPHENIDATE HYDROCHLORIDE EXTENDED RELEASE?

Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17Methylphenidate Hydrochloride Extended-Release Tablets are available as follows:Tablets 10 mg-Bottles of 60 NDC 10702-0075-06Bottles of 100 NDC 10702-0075-01Tablets 20 mg-Bottles of 60 NDC 10702-0076-06Bottles of 100 NDC 10702-0076-01Note:Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.Manufactured by:KVK-Tech, Inc.110 Terry DriveNewtown, PA 18940Item ID #: 006236/04 Rev:07/17

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Pharmacodynamics

Methylphenidate is a mild central nervous system stimulant.

The mode of action in man is not completely understood, but Methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect.

There is neither specific evidence which clearly establishes the mechanism whereby Methylphenidate produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.

Effects on QT Interval

The effect of Focalin XR (dexmethylphenidate, the pharmacologically active enantiomer of Methylphenidate) on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled study following single doses of Focalin XR 40 mg in 75 healthy volunteers. ECGs were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.

Pharmacokinetics

Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the methylphenidate hydrochloride tablet, measured by the urinary excretion of methylphenidate hydrochloride major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the extended-release tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults.

In a clinical study involving adult subjects who received extended-release tablets, plasma concentrations of methylphenidate hydrochloride’s major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate hydrochloride plasma concentration in the same subjects.

Non-Clinical Toxicology

Marked anxiety, tension, and agitation are contraindications to methylphenidate hydrochloride, since the drug may aggravate these symptoms. Methylphenidate is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome.

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

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 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 2-4 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 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 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 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.

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. 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 methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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 Raynauds phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment 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

Methylphenidate should not be used in children under 6 years, since safety and efficacy in this age group have not been established.

The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.

Butalbital, acetaminophen and caffeine may enhance the effects of: other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

Patients with an element of agitation may react adversely; discontinue therapy if necessary.

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

Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methylphenidate hydrochloride should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of 1 or more of the behavioral characteristics.

When these symptoms are associated with acute stress reactions, treatment with methylphenidate hydrochloride is usually not indicated.

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 methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for methylphenidate hydrochloride extended-release tablets. 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

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

Drug Interactions

Methylphenidate should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see ). Because of possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents.

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways.

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 case of coumarin, coagulation times), when initiating or discontinuing methylphenidate.

Carcinogenesis/Mutagenesis/Impairment of Fertility

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

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

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

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

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

Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy; libido changes. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: serotonin syndrome in combination with serotonergic drugs, rhabdomyolysis, instances of abnormal liver function, ranging from transaminase elevation to severe hepatic injury; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of 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 10-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.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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