Methylphenidate Hydrochloride (LA)

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Overview

What is Methylphenidate Hydrochloride (LA)?

Methylphenidate hydrochloride, USP is a central nervous system (CNS) stimulant.

Methylphenidate hydrochloride extended-release capsules (LA) are an extended-release formulation of methylphenidate with a bi-modal release profile. Each bead-filled methylphenidate hydrochloride extended-release capsule (LA) contains half the dose as immediate-release beads and half as enteric- coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Methylphenidate hydrochloride extended-release 10, 20, 30, 40, and 60 mg capsules (LA) provide in a single dose the same amount of methylphenidate as dosages of 5, 10, 15, or 20, or 30 mg of methylphenidate hydrochloride tablets given twice a day.

The active substance in methylphenidate hydrochloride extended-release capsules (LA) 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 (LA) look like?

What are the available doses of Methylphenidate Hydrochloride (LA)?

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What should I talk to my health care provider before I take Methylphenidate Hydrochloride (LA)?

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How should I use Methylphenidate Hydrochloride (LA)?

Methylphenidate hydrochloride extended-release capsules (LA) are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of methylphenidate hydrochloride extended-release capsules (LA) in the treatment of ADHD was established in 1 controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see ).

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 2 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 6 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 6 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.

Methylphenidate hydrochloride extended-release capsules (LA) are for oral administration once daily in the morning. Methylphenidate hydrochloride extended-release capsules (LA) 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). Methylphenidate hydrochloride extended- release capsules (LA) 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 applesauce should not be warm because it could affect the modified release properties of this formulation. 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. Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules (LA).

What interacts with Methylphenidate Hydrochloride (LA)?

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What are the warnings of Methylphenidate Hydrochloride (LA)?

Serious Cardiovascular Events

Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems

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 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 including methylphenidate. 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 double-blind placebo-controlled study of methylphenidate hydrochloride extended-release capsules (LA), the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving methylphenidate hydrochloride extended-release capsules (LA) (+0.1 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 methylphenidate hydrochloride extended-release capsules (LA), 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 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 hydrochloride extended-release capsules (LA) should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.

What are the precautions of Methylphenidate Hydrochloride (LA)?

Hematologic Monitoring

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

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 capsules (LA). 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.

Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended- release capsules (LA). Consumption of alcohol while taking methylphenidate hydrochloride extended- release capsules (LA) may result in a more rapid release of the dose of methylphenidate.

Priapism

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

Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release capsules (LA).

Drug Interactions

Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways.

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

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Because of possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents.

As an inhibitor of dopamine reuptake, methylphenidate may be associated with pharmacodynamic interactions when coadministered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) as well as dopamine antagonists (antipsychotics, e.g., haloperidol).

Case reports suggest a potential interaction of methylphenidate with coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine) but pharmacokinetic interactions were not confirmed when explored at higher sample sizes. 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.

Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the - and -enantiomers of methylphenidate did not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.

Methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

An interaction with the anticoagulant ethylbiscoumacetate in 4 subjects was not confirmed in a subsequent study with a higher sample size (n=12).

Other specific drug-drug interaction studies with methylphenidate have not been performed .

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 to 74 mg/kg/day of methylphenidate.

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

Pregnancy

In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m basis).

Adequate and well-controlled studies in pregnant women have not been conducted. Methylphenidate hydrochloride extended-release capsules (LA) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 methylphenidate hydrochloride extended-release capsules (LA) are administered to a nursing woman.

Pediatric Use

Long-term effects of methylphenidate in children have not been well established. Methylphenidate hydrochloride extended-release capsules (LA) should not be used in children under 6 years of age (see ).

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

What are the side effects of Methylphenidate Hydrochloride (LA)?

The clinical program for methylphenidate hydrochloride extended-release capsules (LA) consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received methylphenidate hydrochloride extended-release capsules (LA) in doses of 10 to 40 mg per day. Safety of methylphenidate hydrochloride extended-release capsules (LA) was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight.

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 in a Double-Blind, Placebo-Controlled, Clinical Trial with Methylphenidate Hydrochloride Extended-Release Capsules (LA)

A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of methylphenidate hydrochloride extended-release capsules (LA) in children with ADHD aged 6 to 12 years. All subjects received methylphenidate hydrochloride extended-release capsules (LA) for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the 2-week, double-blind treatment phase of this study, patients received either placebo or methylphenidate hydrochloride extended-release capsules (LA) at their individually-titrated dose (range 10 mg to 40 mg).

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.

Adverse events with an incidence >5% during the initial 4-week, single-blind methylphenidate hydrochloride extended-release capsules (LA) titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.

Treatment-emergent adverse events with an incidence >2% among methylphenidate hydrochloride extended-release capsules (LA)-treated subjects, during the 2-week, double-blind phase of the clinical study, were as follows:

	Preferred term	Methylphenidate Hydrochloride Extended-Release Capsules (LA)	Placebo
	N = 65	N = 71
N (%) 2 (3.1)	N (%) 0 (0.0)
Insomnia	2 (3.1)	0 (0.0)

Adverse Events Associated with Discontinuation of Treatment

In the 2-week, double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only 1 methylphenidate hydrochloride extended-release capsules (LA)-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression).

In the single-blind titration period of this study, subjects received methylphenidate hydrochloride extended-release capsules (LA) for up to 4 weeks. During this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy.

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:

Gastrointestinal:

Immune:

Metabolism/Nutrition:

Nervous System:

Vascular:

Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:

Blood/Lymphatic:

Hepatobiliary:

Musculoskeletal:

Psychiatric:

Skin/Subcutaneous:

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.

What should I look out for while using Methylphenidate Hydrochloride (LA)?

What might happen if I take too much Methylphenidate Hydrochloride (LA)?

How should I store and handle Methylphenidate Hydrochloride (LA)?

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]Dispense in tight container (USP).Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]Dispense in tight container (USP).Methylphenidate Hydrochloride Extended-Release Capsules (LA) 10 mg: white/light green (imprinted 199 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 20 mg: white/white (imprinted 200 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 30 mg: white/light blue (imprinted 201 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 40 mg: white/dark blue (imprinted 202 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 60 mg: light yellow/dark yellow (imprinted A602 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 10 mg: white/light green (imprinted 199 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 20 mg: white/white (imprinted 200 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 30 mg: white/light blue (imprinted 201 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 40 mg: white/dark blue (imprinted 202 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 60 mg: light yellow/dark yellow (imprinted A602 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 10 mg: white/light green (imprinted 199 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 20 mg: white/white (imprinted 200 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 30 mg: white/light blue (imprinted 201 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 40 mg: white/dark blue (imprinted 202 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 60 mg: light yellow/dark yellow (imprinted A602 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 10 mg: white/light green (imprinted 199 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 20 mg: white/white (imprinted 200 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 30 mg: white/light blue (imprinted 201 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 40 mg: white/dark blue (imprinted 202 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 60 mg: light yellow/dark yellow (imprinted A602 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 10 mg: white/light green (imprinted 199 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 20 mg: white/white (imprinted 200 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 30 mg: white/light blue (imprinted 201 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 40 mg: white/dark blue (imprinted 202 on both the body and cap)Methylphenidate Hydrochloride Extended-Release Capsules (LA) 60 mg: light yellow/dark yellow (imprinted A602 on both the body and cap)

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Methylphenidate hydrochloride, USP, the active ingredient in methylphenidate hydrochloride extended- release capsules (LA), is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. 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. Methylphenidate is a racemic mixture comprised of the and enantiomers. The enantiomer is more pharmacologically active than the enantiomer.

Non-Clinical Toxicology

Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways.

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

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Because of possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents.

As an inhibitor of dopamine reuptake, methylphenidate may be associated with pharmacodynamic interactions when coadministered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) as well as dopamine antagonists (antipsychotics, e.g., haloperidol).

Case reports suggest a potential interaction of methylphenidate with coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine) but pharmacokinetic interactions were not confirmed when explored at higher sample sizes. 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.

Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the - and -enantiomers of methylphenidate did not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.

Methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

An interaction with the anticoagulant ethylbiscoumacetate in 4 subjects was not confirmed in a subsequent study with a higher sample size (n=12).

Other specific drug-drug interaction studies with methylphenidate have not been performed .

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

The clinical program for methylphenidate hydrochloride extended-release capsules (LA) consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received methylphenidate hydrochloride extended-release capsules (LA) in doses of 10 to 40 mg per day. Safety of methylphenidate hydrochloride extended-release capsules (LA) was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight.

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.

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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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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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