Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3603
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Dexmethylphenidate Hydrochloride (Tablet)
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Dexmethylphenidate hydrochloride tablets are administered twice daily, at least 4 hours apart. Dexmethylphenidate hydrochloride tablets may be administered with or without food. Dosage should be individualized according to the needs and responses of the patient.<br/>Patients New to Methylphenidate: The recommended starting dose of dexmethylphenidate hydrochloride tablets for patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg/day (2.5 mg twice daily). Dosage may be adjusted in 2.5 to 5 mg increments to a maximum of 20 mg/day (10 mg twice daily). In general, dosage adjustments may proceed at approximately weekly intervals.<br/>Patients Currently Using Methylphenidate: For patients currently using methylphenidate, the recommended starting dose of dexmethylphenidate hydrochloride tablets is half the dose of racemic methylphenidate. The maximum recommended dose is 20 mg/day (10 mg twice daily).<br/>Maintenance/Extended Treatment: There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with dexmethylphenidate hydrochloride tablets. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use dexmethylphenidate hydrochloride tablets for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with periods off medication to assess the patient's functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.<br/>Dose Reduction and Discontinuation: If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a 1 month period, the drug should be discontinued.
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Dexmethylphenidate hydrochloride is the d-threo-enantiomer of racemic methylphenidate hydrochloride, which is a 50/50 mixture of the d-threo and l-threo-enantiomers. Dexmethylphenidate hydrochloride is a central nervous system (CNS) stimulant, available in three tablet strengths. Each tablet contains dexmethylphenidate hydrochloride 2.5, 5 or 10 mg for oral administration. Dexmethylphenidate hydrochloride is methyl��-phenyl-2-piperidineacetate hydrochloride, (R,R')-(+)-. Its structural formula is: CHNO���HCl M.W. 269.77 Note:= asymmetric carbon centers Dexmethylphenidate hydrochloride is a white to off-white 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. Dexmethylphenidate hydrochloride tablets also contain the following inert ingredients: lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate. Additionally, 5 mg tablets contain D&C Yellow #10 aluminum lake; 2.5 mg tablets contain FD&C Blue #2 lake; 5 mg and 10 mg tablets contain colloidal silicon dioxide.
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Pharmacodynamics: Dexmethylphenidate hydrochloride is a central nervous system stimulant. Dexmethylphenidate hydrochloride, the more pharmacologically active enantiomer of the d- and l-enantiomers, 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. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.<br/>Pharmacokinetics:<br/>Absorption: Dexmethylphenidate hydrochloride is readily absorbed following oral administration of dexmethylphenidate hydrochloride tablets. In patients with ADHD, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1��hours post-dose. No differences in the pharmacokinetics of dexmethylphenidate hydrochloride were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with ADHD. When given to children as capsules in single doses of 2.5 mg, 5 mg, and 10 mg, Cand AUCof dexmethylphenidate were proportional to dose. In the same study, plasma dexmethylphenidate levels were comparable to those achieved following single dl-threo-methylphenidate HCl doses given as capsules in twice the total mg amount (equimolar with respect to dexmethylphenidate hydrochloride).<br/>Food Effects: In a single dose study conducted in adults, coadministration of 2 x 10 mg dexmethylphenidate hydrochloride with a high fat breakfast resulted in a dexmethylphenidate tof 2.9 hours post-dose as compared to 1.5 hours post-dose when given in a fasting state. Cand AUCwere comparable in both the fasted and non-fasted states.<br/>Distribution: Plasma dexmethylphenidate concentrations in children decline exponentially following oral administration of dexmethylphenidate hydrochloride.<br/>Metabolism and Excretion: In humans, dexmethylphenidate is metabolized primarily to d-��-phenyl-piperidine acetic acid (also known as d-ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is little or no in vivo interconversion to the l-threo-enantiomer, based on a finding of minute levels of l-threo-methylphenidate being detectable in a few samples in only 2 of 58 children and adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accountable for approximately 80% of the dose. In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes. The mean plasma elimination half-life of dexmethylphenidate is approximately 2.2 hours.<br/>Special Populations:<br/>Gender: Pharmacokinetic parameters were similar for boys and girls (mean age 10 years). In a single dose study conducted in adults, the mean dexmethylphenidate AUCvalues (adjusted for body weight) following single 2 x 10 mg doses of dexmethylphenidate hydrochloride were 25% to 35% higher in adult female volunteers (n = 6) compared to male volunteers (n = 9). Both tand twere comparable for males and females.<br/>Race: There is insufficient experience with the use of dexmethylphenidate hydrochloride to detect ethnic variations in pharmacokinetics.<br/>Age: The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride administration have not been studied in children less than 6 years of age. When single doses of dexmethylphenidate hydrochloride were given to children between the ages of 6 to 12 years and healthy adult volunteers, Cof dexmethylphenidate was similar, however, children showed somewhat lower AUCs compared to the adults.<br/>Renal Insufficiency: There is no experience with the use of dexmethylphenidate hydrochloride in patients with renal insufficiency. After oral administration of radiolabeled racemic 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 very little unchanged drug isexcreted in the urine, renal insufficiency is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride.<br/>Hepatic Insufficiency: There is no experience with the use of dexmethylphenidate hydrochloride in patients with hepatic insufficiency. (For Drug Interactions, see PRECAUTIONS.)<br/>Clinical Studies: Dexmethylphenidate hydrochloride was evaluated in two double-blind, parallel-group, placebo-controlled trials in untreated or previously treated patients aged 6 to 17 years old with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD). Both studies included all three subtypes of ADHD, i.e., Combined Type, Predominantly Inattentive Type, or Predominantly Hyperactive-Impulsive Type. While both children and adolescents were included, the sample was predominantly children, thus, the findings are most pertinent to this age group. In both studies, the primary comparison of interest was dexmethylphenidate hydrochloride versus placebo. Dexmethylphenidate hydrochloride (5, 10, or 20 mg/day total dose), dl-threo-methylphenidate HCl (10, 20, or 40 mg/day total dose), and placebo were compared in a multicenter, 4 week, parallel group study in n = 132 patients. Patients took the study medication twice daily, 3.5 to 5.5 hours between doses. Treatment was initiated with the lowest dose, and doses could be doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. The change from baseline to week 4 of the averaged score (an average of two ratings during the week) of the teacher's version of the SNAP-ADHD Rating Scale,a scale for assessing ADHD symptoms, was the primary outcome. Patients treated with dexmethylphenidate hydrochloride showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. The other study, involving n = 75 patients, was a multicenter, placebo-controlled, double-blind, 2 week treatment withdrawal study in children who were responders during a 6 week, open label initial treatment period. Children took study medication twice a day separated by a 3.5 to 5.5 hour interval. The primary outcome was proportion of treatment failures at the end of the 2 week withdrawal phase, where treatment failure was defined as a rating of 6 (much worse) or 7 (very much worse) on the Investigator Clinical Global Impression - Improvement (CGI-I). Patients continued on dexmethylphenidate hydrochloride showed a statistically significant lower rate of failure over patients who received placebo.
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Agitation: Dexmethylphenidate hydrochloride tablets are contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.<br/>Hypersensitivity to Methylphenidate: Dexmethylphenidate hydrochloride tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product.<br/>Glaucoma: Dexmethylphenidate hydrochloride tablets are contraindicated in patients with glaucoma.<br/>Tics: Dexmethylphenidate hydrochloride tablets are contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome (see ADVERSE REACTIONS).<br/>Monoamine Oxidase Inhibitors: Dexmethylphenidate hydrochloride 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).
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Dexmethylphenidate hydrochloride tablets, 2.5 mg are blue, round-shaped, convex tablets debossed with���93���on one side and���5275���on the other side, available in bottles of 100. Dexmethylphenidate hydrochloride tablets, 5 mg are yellow, round-shaped, convex tablets debossed with���93���on one side and���5276���on the other side, available in bottles of 100. Dexmethylphenidate hydrochloride tablets, 10 mg are white to off-white, round-shaped, convex tablets, debossed with���93���on one side and���5277���on the other side, available in bottles of 100. Store at 20��to 25��C (68��to 77��F) [See USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
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DRUG DEPENDENCE: Dexmethylphenidate hydrochloride tablets 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 drug 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.
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Hematologic Monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dexmethylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for dexmethylphenidate hydrochloride 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 begiven 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.<br/>Drug Interactions: Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Because of possible effects on blood pressure, dexmethylphenidate hydrochloride should be used cautiously with pressor agents. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic 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. 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. Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day. In a 24 week study of racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate. Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma cell forward mutation assay, or the in vivo mouse bone marrow micronucleus test. Racemic methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay, and was negative in vivo in the mouse bone marrow micronucleus assay. However, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay of racemic methylphenidate in cultured Chinese Hamster Ovary (CHO) cells. Racemic 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 of up to 160 mg/kg/day.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether dexmethylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if dexmethylphenidate hydrochloride is administered to a nursing woman.<br/>Pediatric Use: The safety and efficacy of dexmethylphenidate hydrochloride in children under 6 years old have not been established. Long-term effects of dexmethylphenidate hydrochloride in children have not been well established (see WARNINGS). In a study conducted in young rats, racemic methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13 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] of racemic methylphenidate on a mg/mbasis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the racemic MRHD on a mg/mbasis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the racemic MRHD on a mg/mbasis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
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Signs and Symptoms: Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.<br/>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 hyperpyrexia. Efficacy of peritoneal dialysis for dexmethylphenidate hydrochloride overdosage has not been established.<br/>Poison Control Center: As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate.
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Dexmethylphenidate Hydrochloride
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Dexmethylphenidate Hydrochloride (Tablet)
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The pre-marketing development program for dexmethylphenidate hydrochloride included exposures in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). These participants received dexmethylphenidate hydrochloride 5, 10, or 20 mg/day. The 684 ADHD patients (ages 6 to 17 years) were evaluated in two controlled clinical studies, two clinical pharmacology studies, and two uncontrolled long-term safety studies. Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collectingadverse events, and results of physical examinations, vital sign and body weight measurements, and laboratory analyses. Adverse events during exposure were primarily obtained 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 tabulations that follow, standard COSTART dictionary 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.<br/>Adverse Findings in Clinical Trials with Dexmethylphenidate Hydrochloride:<br/>Adverse Events Associated with Discontinuation of Treatment: No dexmethylphenidate hydrochloride-treated patients discontinued due to adverse events in two placebo-controlled trials. Overall, 50 of 684 children treated with dexmethylphenidate hydrochloride (7.3%) experienced an adverse event that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each).<br/>Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride-Treated Patients: Table 1 enumerates treatment-emergent adverse events for two, placebo-controlled, parallel group trials in children with ADHD at dexmethylphenidate hydrochloride doses of 5, 10, and 20 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride where the incidence in patients treated with dexmethylphenidate hydrochloridewas at least twice the incidence in placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.<br/>Adverse Events with Other Methylphenidate HCl Products: 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.<br/>Other Reactions Include: Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette's syndrome, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/lymphatic: leukopenia and/or anemia Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma Psychiatric: transient depressed mood, aggressive behavior Skin/subcutaneous: 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 ten year old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine.It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. 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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Serious Cardiovascular Events:<br/>Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems:<br/>Psychiatric Adverse Events:<br/>DRUG DEPENDENCE: Dexmethylphenidate hydrochloride tablets 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 drug 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.
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Dexmethylphenidate Hydrochloride
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