METHYLPHENIDATE HYDROCHLORIDE- methylphenidate hydrochloride tablet, chewable
Novel Laboratories, Inc.
Methylphenidate hydrochloride is a mild central nervous system (CNS) stimulant, available as 2.5 mg, 5 mg and 10 mg chewable tablets for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is
Each Methylphenidate Hydrochloride Chewable Tablet, for oral administration, contains 2.5 mg, 5 mg or 10 mg of methylphenidate hydrochloride USP. In addition, Methylphenidate Hydrochloride Chewable Tablets also contain the following inactive ingredients: aspartame, maltose, microcrystalline cellulose, grape flavor, pregelatinized starch, phosphoric acid, and stearic acid.
Methylphenidate HCl is a central nervous system (CNS) stimulant.
The mode of therapeutic action in humans is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.
There is neither specific evidence which clearly establishes the mechanism whereby Methylphenidate Hydrochloride Chewable Tablets produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.
Methylphenidate Hydrochloride Chewable Tablets are readily absorbed. Following oral administration of Methylphenidate Hydrochloride Chewable Tablets, peak plasma methylphenidate concentrations are achieved at about 1 to 2 hours. Methylphenidate Hydrochloride Chewable Tablets have been shown to be bioequivalent to Ritalin® tablet. The mean Cmax following a 20 mg dose is approximately10 ng/mL.
In a study in adult volunteers investigating the effects of a high-fat meal on the bioavailability of Methylphenidate Hydrochloride Chewable Tablets at a dose of 20 mg, the presence of food delayed the peak concentrations by approximately 1 hour (1.5 hours, fasted and 2.4 hours, fed). Overall, a high-fat meal increased the AUC of Methylphenidate Hydrochloride Chewable Tablets by about 20%, on average. Through a cross-study comparison, the magnitude of food effect is found to be comparable between the Methylphenidate Hydrochloride Chewable Tablets and Ritalin, the immediate release tablet.
Metabolism and Excretion
In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenylpiperidine acetic acid (PPA, ritalinic acid). The metabolite has little or no pharmacologic activity.
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose.
The pharmacokinetics of the Methylphenidate Hydrochloride Chewable Tablets have been studied in healthy adult volunteers. The mean terminal half-life (t½) of methylphenidate following administration of 20 mg Methylphenidate Hydrochloride Chewable Tablets (t½ = 3 hours) is comparable to the mean terminal t½ following administration of Ritalin (methylphenidate hydrochloride immediate-release tablets) (t½ = 2.8 hours) in healthy adult volunteers.
Gender – The effect of gender on the pharmacokinetics of methylphenidate after Methylphenidate Hydrochloride Chewable Tablets administration has not been studied.
Race – The influence of race on the pharmacokinetics of methylphenidate after Methylphenidate Hydrochloride Chewable Tablets administration has not been studied.
Age – The pharmacokinetics of methylphenidate after Methylphenidate Hydrochloride Chewable Tablets administration have not been studied in pediatrics.
There is no experience with the use of Methylphenidate Hydrochloride Chewable Tablets in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of Methylphenidate Hydrochloride Chewable Tablets.
There is no experience with the use of Methylphenidate Hydrochloride Chewable Tablets in patients with hepatic insufficiency.
Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Methylphenidate Hydrochloride Chewable Tablets are 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 one 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.
Marked anxiety, tension, and agitation are contraindications to Methylphenidate Hydrochloride Chewable Tablets, since the drug may aggravate these symptoms. Methylphenidate Hydrochloride Chewable Tablets are 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 Hydrochloride Chewable Tablets are 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).
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 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 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.
Psychiatric Adverse Events
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 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 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.
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.
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 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 Chewable Tablets, 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 treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
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.
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
USE IN CHILDREN LESS THAN SIX YEARS OF AGE
Methylphenidate Hydrochloride Chewable Tablets should not be used in children under six years, since safety and efficacy in this age group have not been established.
Methylphenidate Hydrochloride Chewable Tablets should be given cautiously to emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase dosage on their own initiative.
Chronically abusive use can lead to marked tolerance and psychic dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during drug withdrawal, since severe depression as well as the effects of chronic overactivity can be unmasked. Long-term follow-up may be required because of the patient’s basic personality disturbances.
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