Data from FDA - Curated by Toby Galbraith - Last updated 23 May 2017

Indication(s)

INDICATIONS AND USAGE 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 CLINICAL PHARMACOLOGY). 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. 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. 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 the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Methylphenidate hydrochloride extended-release capsules (LA) are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be 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 other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. 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. Long-Term Use The effectiveness of methylphenidate hydrochloride extended-release capsules (LA) for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use methylphenidate hydrochloride extended-release capsules (LA) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

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Advisory information

contraindications
CONTRAINDICATIONS Agitation Methylphenidate hydrochloride extended-release capsules (LA) are contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Hypersensitivity to Methylphenidate Methylphenidate hydrochloride extended-release capsules (LA) are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product. Glaucoma Methylphenidate hydrochloride extended-release capsules (LA) are contraindicated in patients with glaucoma. Tics Methylphenidate hydrochloride extended-release capsules (LA) are contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome (see ADVERSE REACTIONS). Monoamine Oxidase Inhibitors Methylphenidate hydrochloride extended-release capsules (LA) are contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).
Special warnings and precautions
PRECAUTIONS 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 Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] Instruct patients beginning treatment with methylphenidate hydrochloride extended-release capsules (LA) about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. 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). Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 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 d- and l-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 in vivo. 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 2 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 2 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. 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 2 basis, respectively. Pregnancy Pregnancy Category C 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 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m 2 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 2 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 2 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 2 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 2 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 WARNINGS). 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 2 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 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
Adverse reactions
ADVERSE REACTIONS 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) Treatment-Emergent Adverse Events 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 (%) N = 71 N (%) Anorexia 2 (3.1) 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: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: abdominal pain, nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis Vascular: blood pressure increased or decreased; cerebrovascular vasculitis; cerebral occlusions; cerebral hemorrhages and cerebrovascular accidents 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 Musculoskeletal: rhabdomyolysis Psychiatric: transient depressed mood, aggressive behavior, libido changes 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 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.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Administration of Dose 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). Dosing Recommendations Dosage should be individualized according to the needs and responses of the patients. Initial Treatment The recommended starting dose of methylphenidate hydrochloride extended-release capsules (LA) is 20 mg once daily. Dosage may be adjusted in weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not recommended. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with methylphenidate hydrochloride extended-release capsules (LA) 10 mg. Patients Currently Receiving Methylphenidate The recommended dose of methylphenidate hydrochloride extended-release capsules (LA) for patients currently taking methylphenidate twice a day or sustained release (SR) is provided below. Previous Methylphenidate Dose Recommended Methylphenidate Hydrochloride Extended-Release Capsule (LA) Dose 5 mg methylphenidate twice a day 10 mg once a day 10 mg methylphenidate twice a day or 20 mg methylphenidate-SR 20 mg once a day 15 mg methylphenidate twice a day 30 mg once a day 20 mg methylphenidate twice a day or 40 mg of methylphenidate-SR 40 mg once a day 30 mg methylphenidate twice a day or 60 mg methylphenidate-SR 60 mg once a day For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose. Methylphenidate hydrochloride extended-release capsule (LA) dosage may be adjusted at weekly intervals in 10 mg increments. Daily dosage above 60 mg is not recommended. 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 methylphenidate hydrochloride extended-release capsules (LA). It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use methylphenidate hydrochloride extended-release capsules (LA) for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. 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.
Pregnancy and lactation
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.

Interactions

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 d- and l-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 in vivo.

More information

Category Value
Authorisation number ANDA078458
Agency product number 4B3SC438HI
Orphan designation No
Product NDC 60687-220
Date Last Revised 16-05-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder American Health Packaging

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