Methylphenidate hydrochloride is a mild central nervous system (CNS) stimulant, available for oral administration as tablets of 5 mg, 10 mg, and 20 mg and as extended-release tablets of 10 mg 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.
Methylin® tablets: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and talc.
Methylin® ER tablets: hydroxypropyl methylcellulose 2208, magnesium stearate, microcrystalline cellulose, and talc.
Methylin is a mild central nervous system stimulant.
The mode of action in man is not completely understood, but Methylin 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 Methylin 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 in the ER tablets is more slowly but as extensively absorbed as in the regular tablets. Bioavailability of Methylin ER 20 mg Extended-Release Tablets was compared to a sustained-release reference product and an immediate-release product. The extent of absorption for the three products was similar, and the rate of absorption of the two sustained-release products was not statistically different. Relative bioavailability of the extended-release tablet compared to the immediate-release tablet, measured by the urinary excretion of methylphenidate major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 4.7 hours (1.3 to 8.2 hours) for the extended-release tablets and 1.9 hours (0.3 to 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.
Based on rate of bioavailability (AUC0→∞, Tmax, and Cmax), no significant statistical difference was found following single dose administration, in fasting and fed adults, of two Methylin ER 10 mg Extended-Release Tablets, or one methylphenidate hydrochloride USP sustained-release 20 mg tablet. The administration of the extended-release methylphenidate HCl USP tablets with food, resulted in a greater Cmax and AUC0→∞ than when administered in a fasting condition.
Pharmacokinetic and statistical analyses for a multiple dose study demonstrated that 3 times daily administration of two Methylin ER 10 mg Extended-Release Tablets met the requirements for bioequivalence to one methylphenidate hydrochloride USP sustained-release 20 mg tablet when administered every eight hours. Pharmacokinetic parameters (i.e., AUC0→∞, Tmax, Cmax, Cmin, and Cav) demonstrated achievement of steady state following 3 times daily administration of two Methylin ER 10 mg Extended-Release Tablets was confirmed.
In a clinical study involving adult subjects who received extended-release tablets, plasma concentrations of methylphenidate's major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate plasma concentration in the same subjects.
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.
Methylin 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.
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 Methylin, since the drug may aggravate these symptoms. Methylin 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.
Methylin 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).
Methylin ER is contraindicated in patients with severe hypertension, angina pectoris, cardiac arrhythmias, heart failure, recent myocardial infarction, hyperthyroidism or thyrotoxicosis (seeWARNINGS).
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.
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Methylin should not be used in children under 6 years, since safety and efficacy in this age group have not been established.
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 Methylin 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 one or more of the behavioral characteristics.
When these symptoms are associated with acute stress reactions, treatment with Methylin is usually not indicated.
Long-term effects of Methylin in children have not been well established.
Methylin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Methylin 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.
Methylin ER may decrease the hypotensive effect of guanethidine. Use 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 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.
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.
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/m2 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/m2 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 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.
Methlyphenidate 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/m2 basis, respectively.
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Methylin is administered to a nursing woman.
Long-term effects of methylphenidate in children have not been well established. Methylin should not be used in children under six years of age (seeWARNINGS).
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/m2 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/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
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. 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: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; 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 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 uled above may also occur.
In addition to the adverse events uled above, the following have been reported in patients receiving methylphenidate worldwide. The ul is alphabetized: abnormal behavior, aggression, anxiety, cardiac arrest, depression, fixed drug eruption, hyperactivity, irritability, sudden death, suicidal behavior (including completed suicide), and thrombocytopenia. Data are insufficient to support an estimation of incidence or establish causation.
Dosage should be individualized according to the needs and responses of the patient.
Methylin 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 one-month period, the drug should be discontinued.
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.
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 spans may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting 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 Methylin overdosage has not been established.
Each Methylin® (methylphenidate HCl tablet USP) 5 mg is available as a round, white unscored tablet debossed with 5 on one side and a on the other side.
Each Methylin® (methylphenidate HCl tablet USP) 10 mg is available as a round, white scored tablet debossed with 10 on one side of the tablet and a M on the other side.
Each Methylin® (methylphenidate HCl tablet USP) 20 mg is available as a round, white scored tablet debossed with 20 on one side of the tablet and a on the other side.
Protect from light. Dispense in tight, light-resistant container with child-resistant closure.
Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Each Methylin® ER (methylphenidate HCl extended-release tablet USP) 10 mg is available as a round, white to off-white tablet, debossed with 1423 on one side and a on the other side.
Each Methylin® ER (methylphenidate HCl extended-release tablet USP) 20 mg is available as a round, white to off-white tablet, debossed with 1451 on one side and a on the other side.
Note: Methylin® and Methylin® ER tablets are color-additive free.
Dispense in tight, light-resistant container with child-resistant closure.
Methylin® (methylphenidate HCl tablets USP)
Methylin® ER (methylphenidate HCl extended-release tablets USP)
Read the Medication Guide that comes with Methylin® and Methylin® ER before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child's treatment with Methylin® and Methylin® ER.
|What is the most important information I should know about Methylin® and Methylin® ER?|
The following have been reported with use of Methylin® and Methylin® ER and other stimulant medicines.
1. Heart-related problems:
Your doctor should check you or your child carefully for heart problems before starting Methylin® and Methylin® ER.
Your doctor should check your or your child's blood pressure and heart rate regularly during treatment with Methylin® and Methylin® ER.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking Methylin® and Methylin® ER.
2. Mental (Psychiatric) problems:
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking Methylin® and Methylin® ER, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.
What Is Methylin® and Methylin® ER?
Methylin® and Methylin® ER is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Methylin® and Methylin® ER may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.
Methylin® and Methylin® ER should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.
Methylin® and Methylin® ER is also used in the treatment of a sleep disorder called narcolepsy.
|Methylin® and Methylin® ER is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep Methylin® and Methylin® ER in a safe place to prevent misuse and abuse. Selling or giving away Methylin® and Methylin® ER may harm others, and is against the law.|
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.
Who should not take Methylin® and Methylin® ER?
Methylin® and Methylin® ER should not be taken if you or your child:
Methylin® and Methylin® ER should not be used in children less than 6 years old because it has not been studied in this age group.
Methylin® and Methylin® ER may not be right for you or your child. Before starting Methylin® and Methylin® ER tell your or your child's doctor about all health conditions (or a family history of) including:
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Can Methylin® and Methylin® ER be taken with other medicines?
Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. Methylin® and Methylin® ER and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking Methylin® and Methylin® ER.
Your doctor will decide whether Methylin® and Methylin® ER can be taken with other medicines.
Especially tell your doctor if you or your child takes:
Know the medicines that you or your child takes. Keep a ul of your medicines with you to show your doctor and pharmacist.
Do not start any new medicine while taking Methylin® and Methylin® ER without talking to your doctor first.
How should Methylin® and Methylin® ER be taken?
What are possible side effects of Methylin® and Methylin® ER?
See “What is the most important information I should know about Methylin® and Methylin® ER?” for information on reported heart and mental problems.
Other serious side effects include:
Common side effects include:
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete ul of possible side effects. Ask your doctor or pharmacist for more information.
How should I store Methylin® and Methylin® ER?
General information about Methylin® and Methylin® ER
Medicines are sometimes prescribed for purposes other than those uled in a Medication Guide. Do not use Methylin® and Methylin® ER for a condition for which it was not prescribed. Do not give Methylin® and Methylin® ER to other people, even if they have the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about Methylin® and Methylin® ER. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Methylin® and Methylin® ER that was written for healthcare professionals, or you can visit www.Mallinckrodt.com or call 1-888-744-1414, option 2, then 1 between the hours of 7am and 5pm CST.
What are the ingredients in Methylin® and Methylin® ER?
Active Ingredient: methylphenidate HCl
Methylin® tablets: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and talc.
Methylin® ER tablets: hydroxypropyl methylcellulose 2208, magnesium stearate, microcrystalline cellulose, and talc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
St. Louis, MO 63134 U.S.A.