NDC 0527-3313 Methylphenidate Hydrochloride

Methylphenidate Hydrochloride

NDC Product Code 0527-3313

NDC Code: 0527-3313

Proprietary Name: Methylphenidate Hydrochloride What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Methylphenidate Hydrochloride What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.


Product Characteristics
Color(s):
YELLOW (C48330 - YELLOW)
GRAY (C48324 - GRAY)
WHITE (C48325 - WHITE)
RED (C48326 - RED)
Shape: OVAL (C48345)
Size(s):
13 MM
Imprint(s):
A18
A27
A36
A54
Score: 1

Code Structure
  • 0527 - Lannett Company, Inc.
    • 0527-3313 - Methylphenidate Hydrochloride

NDC 0527-3313-37

Package Description: 100 TABLET, EXTENDED RELEASE in 1 BOTTLE

NDC Product Information

Methylphenidate Hydrochloride with NDC 0527-3313 is a a human prescription drug product labeled by Lannett Company, Inc.. The generic name of Methylphenidate Hydrochloride is methylphenidate hydrochloride. The product's dosage form is tablet, extended release and is administered via oral form.

Labeler Name: Lannett Company, Inc.

Dosage Form: Tablet, Extended Release - A solid dosage form containing a drug which allows at least a reduction in dosing frequency as compared to that drug presented in conventional dosage form.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

DEA Schedule: Schedule II (CII) Substances What is the Drug Enforcement Administration (DEA) CII Schedule?
The controlled substances in the CII schedule have a high abuse potential with severe psychological or physical dependence liability, but have accepted medical use in the United States. Schedule CII controlled substances include certain narcotic, stimulant, and depressant drugs.


Methylphenidate Hydrochloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • METHYLPHENIDATE HYDROCHLORIDE 54 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • ETHYLCELLULOSES (UNII: 7Z8S9VYZ4B)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • TALC (UNII: 7SEV7J4R1U)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • AMMONIA (UNII: 5138Q19F1X)
  • SHELLAC (UNII: 46N107B71O)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • ETHYLCELLULOSES (UNII: 7Z8S9VYZ4B)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • TALC (UNII: 7SEV7J4R1U)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • SHELLAC (UNII: 46N107B71O)
  • AMMONIA (UNII: 5138Q19F1X)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82)
  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • ETHYLCELLULOSES (UNII: 7Z8S9VYZ4B)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • AMMONIA (UNII: 5138Q19F1X)
  • SHELLAC (UNII: 46N107B71O)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • ETHYLCELLULOSES (UNII: 7Z8S9VYZ4B)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • AMMONIA (UNII: 5138Q19F1X)
  • SHELLAC (UNII: 46N107B71O)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Central Nervous System Stimulant - [EPC] (Established Pharmacologic Class)
  • Central Nervous System Stimulation - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Lannett Company, Inc.
Labeler Code: 0527
FDA Application Number: ANDA211918 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-24-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Methylphenidate Hydrochloride Product Label Images

Methylphenidate Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Drug Dependence

Methylphenidate hydrochloride extended-release 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 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.

1 Indications And Usage

Methylphenidate Hydrochloride Extended-Release Tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65 [see Clinical Studies (14)].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 two 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 six 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 six 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 Type requires both inattentive and hyperactive-impulsive criteria to be met.

1.1 Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use of medical and 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 patient and not solely on the presence of the required number of DSM-IV characteristics.

1.2 Need For Comprehensive Treatment Program

Methylphenidate Hydrochloride Extended-Release Tablets are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social). Drug treatment may not be indicated for all patients with ADHD. Stimulants are not intended for use in patients who exhibit 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 patient’s symptoms.

2.1 General Dosing Information

Methylphenidate hydrochloride extended-release tablets should be administered orally once daily in the morning with or without food.Methylphenidate hydrochloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17)].

2.2 Patients New To Methylphenidate

The recommended starting dose of methylphenidate hydrochloride extended-release tablets for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1).Table 1. Methylphenidate Hydrochloride Extended-Release Tablets Recommended Starting Doses and Dose Ranges Patient Age Recommended Starting Dose Dose RangeChildren 6-12 years of age18 mg/day18 mg – 54 mg/dayAdolescents 13-17 years of age18 mg/day18 mg – 72 mg/daynot to exceed 2 mg/kg/dayAdults 18-65 years of age18 or 36 mg/day18 mg – 72 mg/day

2.3 Patients Currently Using Methylphenidate

The recommended dose of methylphenidate hydrochloride extended-release tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2. Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily.Table 2. Recommended Dose Conversion from Methylphenidate Regimens to Methylphenidate Hydrochloride Extended-Release Tablets Previous Methylphenidate Daily Dose Recommended Methylphenidate Hydrochloride Extended-Release Tablets Starting Dose5 mg Methylphenidate twice daily or three times daily18 mg every morning10 mg Methylphenidate twice daily or three times daily36 mg every morning15 mg Methylphenidate twice daily or three times daily54 mg every morning20 mg Methylphenidate twice daily or three times daily72 mg every morningOther methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.

2.4 Dose Titration

Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose. Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. Daily dosages above 72 mg in adults are not recommended.A 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages.

2.5 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 tablets. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods.The effectiveness of methylphenidate hydrochloride extended-release tablets for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use methylphenidate hydrochloride extended-release tablets 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.

2.6 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 one-month period, the drug should be discontinued.

3 Dosage Forms And Strengths

Methylphenidate hydrochloride extended-release tablets, USP are available in the following dosage strengths: 18 mg tablets are yellow, capsule shaped film coated tablets, and imprinted with “A18” on one side and plain on the other side, 27 mg tablets are gray, capsule shaped film coated tablets, and imprinted with “A27” on one side and plain on the other side, 36 mg tablets are white, capsule shaped film tablets, and imprinted with “A36” on one side and plain on the other side, and 54 mg tablets are red, capsule shaped film coated tablets, and imprinted with “A54” on one side and plain on the other side.

4.1 Hypersensitivity To Methylphenidate

Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with Methylphenidate Hydrochloride Extended-Release Tablets. Therefore, Methylphenidate Hydrochloride Extended-Release Tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions (6.6)].

4.2 Agitation

Methylphenidate Hydrochloride Extended-Release Tablets are contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

4.3 Glaucoma

Methylphenidate Hydrochloride Extended-Release Tablets are contraindicated in patients with glaucoma.

4.4 Tics

Methylphenidate Hydrochloride Extended-Release Tablets are contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome [see Adverse Reactions (6.4)].

4.5 Monoamine Oxidase Inhibitors

Methylphenidate Hydrochloride Extended-Release Tablets are contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) [see Drug Interactions (7.1)].

5.3 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.

5.4 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, including methylphenidate hydrochloride extended-release tablets, in both pediatric and adult patients [see Adverse Reactions (6.6)]. 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.

5.5 Peripheral Vasculopathy, Including Raynaud's Phenomenon

Stimulants, including methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.6 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 nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause 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.

5.7 Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

5.8 Potential For Gastrointestinal Obstruction

Because the methylphenidate hydrochloride extended-release tablet is nondeformable and does not appreciably change in shape in the GI tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the tablet whole [see Patient Counseling Information (17)].

5.9 Hematologic Monitoring

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

6 Adverse Reactions

  • The following are discussed in more detail in other sections of the labeling:Drug Dependence [see Box Warning]Hypersensitivity to Methylphenidate [see Contraindications (4.1)]Agitation [see Contraindications (4.2)]Glaucoma [see Contraindications (4.3)]Tics [see Contraindications (4.4)]Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1)]Serious Cardiovascular Events [see Warnings and Precautions (5.1)]Psychiatric Adverse Events [see Warnings and Precautions (5.2)]Seizures [see Warnings and Precautions (5.3)]Priapism [see Warnings and Precautions (5.4)]Long-Term Suppression of Growth [see Warnings and Precautions (5.6)]Visual Disturbance [see Warnings and Precautions (5.7)]Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8)]Hematologic Monitoring [see Warnings and Precautions (5.9)]The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis [see Adverse Reactions (6.1)].The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Adverse Reactions (6.3)].The development program for methylphenidate hydrochloride extended-release tablets included exposures in a total of 3,906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses.Table 3. Methylphenidate Hydrochloride Extended-Release Tablets Exposure in Double-Blind and Open-Label Clinical Studies Patient Population N Dose RangeChildren2,21618 to 54 mg once dailyAdolescents50218 to 72 mg once dailyAdults1,18818 to 108 mg once dailyAdverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.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.Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of methylphenidate hydrochloride extended-release tablets based on the comprehensive assessment of the available adverse event information. A causal association for methylphenidate hydrochloride extended-release tablets often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.The majority of adverse reactions were mild to moderate in severity.

6.1 Commonly Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials

Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.

6.2 Other Adverse Reactions Observed In Methylphenidate Hydrochloride Extended-Release Tablets Clinical Trials

This section includes adverse reactions reported by methylphenidate hydrochloride extended-release tablets-treated subjects in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by methylphenidate hydrochloride extended-release tablets-treated subjects who participated in open-label and postmarketing clinical trials.Blood and Lymphatic System Disorders: LeukopeniaEye Disorders: Accommodation disorder, Dry eyeVascular Disorders: Hot flushGastrointestinal Disorders: Abdominal discomfort, Abdominal pain, DiarrheaGeneral Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, ThirstInfections and Infestations: SinusitisInvestigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increasedMusculoskeletal and Connective Tissue Disorders: Muscle spasmsNervous System Disorders: Lethargy, Psychomotor hyperactivity, SomnolencePsychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, TicReproductive System and Breast Disorders: Erectile dysfunctionRespiratory, Thoracic and Mediastinal Disorders: DyspneaSkin and Subcutaneous Tissue Disorders: Rash, Rash macularVascular Disorders: Hypertension

6.3 Discontinuation Due To Adverse Reactions

Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 methylphenidate hydrochloride extended-release tablets patients (0.6%) including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).In the 2 placebo-controlled studies of adults, 25 methylphenidate hydrochloride extended-release tablets patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the methylphenidate hydrochloride extended-release tablets patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).In the 11 open-label studies of children, adolescents, and adults, 266 methylphenidate hydrochloride extended-release tablets patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

6.4 Tics

In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with methylphenidate hydrochloride extended-release tablets.In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). The treatment period was up to 9 months with mean treatment duration of 7.2 months.

6.5 Blood Pressure And Heart Rate Increases

In the laboratory classroom clinical trials in children (Studies 1 and 2), both methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind treatment (3.6 and -1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double-blind treatment for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were -1.2 and -0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.1)].

6.6 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of methylphenidate hydrochloride extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpuraCardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystolesEye Disorders: Diplopia, Mydriasis, Visual impairmentGeneral Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreasedHepatobiliary disorders: Hepatocellular injury, Acute hepatic failureImmune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NECInvestigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormalMusculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, RhabdomyolysisNervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugsPsychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changesReproductive System and Breast Disorders: PriapismSkin and Subcutaneous Tissue Disorders: Alopecia, ErythemaVascular Disorders: Raynaud's phenomenon

7.1 Mao Inhibitors

Methylphenidate hydrochloride extended-release tablets should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors [see Contraindications (4.5)].

7.2 Vasopressor Agents

Because of possible increases in blood pressure, methylphenidate hydrochloride extended-release tablets should be used cautiously with vasopressor agents [see Warnings and Precautions (5.1)].

7.3 Coumarin Anticoagulants, Antidepressants, And Selective Serotonin Reuptake Inhibitors

Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). 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.

8.2 Labor And Delivery

The effect of methylphenidate hydrochloride extended-release tablets on labor and delivery in humans is unknown.

8.3 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 tablets are administered to a nursing woman.In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.

8.4 Pediatric Use

Methylphenidate hydrochloride extended-release tablets should not be used in children under six years, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established.

8.5 Geriatric Use

Methylphenidate hydrochloride extended-release tablets have not been studied in patients greater than 65 years of age.

9.1 Controlled Substance

Methylphenidate is a Schedule II controlled substance under the Controlled Substances Act.

9.2 Abuse

As noted in the Box Warning, methylphenidate hydrochloride extended-release 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.In two placebo-controlled human abuse potential studies, single oral doses of methylphenidate hydrochloride extended-release tablets were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration.In one study (n=40), both methylphenidate hydrochloride extended-release tablets (108 mg) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, methylphenidate hydrochloride extended-release tablets (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation-Euphoria) responses produced by 60 mg IR MPH.In another study (n=49), both doses of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, methylphenidate hydrochloride extended-release tablets produced statistically significantly lower subjective responses on these two scales than IR MPH. Methylphenidate hydrochloride extended-release tablets (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 22% of the total amount of methylphenidate in methylphenidate hydrochloride extended-release tablets are available for immediate release from the drug overcoat [see System Components and Performance (11.1)].Although these findings reveal a relatively lower response to methylphenidate hydrochloride extended-release tablets on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of methylphenidate hydrochloride extended-release tablets in the community is unknown.

9.3 Dependence

As noted in the Box Warning, careful supervision is required during 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.

10.1 Signs And Symptoms

Signs and symptoms of methylphenidate hydrochloride extended-release tablets overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, muscle twitching, convulsion, grand mal convulsion, confusional state, hallucinations (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmia, hypertension, rhabdomyolysis, mydriasis, and dry mouth.

10.2 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 pyrexia.Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate hydrochloride extended-release tablets overdosage has not been established.The prolonged release of methylphenidate from methylphenidate hydrochloride extended-release tablets should be considered when treating patients with overdose.

10.3 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.

11 Description

Methylphenidate Hydrochloride Extended-Release Tablets, USP are a central nervous system (CNS) stimulant. Methylphenidate Hydrochloride Extended-Release Tablets, USP are available in four tablet strengths. Each extended-release tablet for once-a-day oral administration contains 18, 27, 36, or 54 mg of methylphenidate HCl, USP and is designed to have a 12-hour duration of effect. Chemically, methylphenidate HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C14H19NO2•HCl. Its structural formula is:Methylphenidate HCl, USP is a white, odorless 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.Methylphenidate Hydrochloride Extended-Release Tablets, USP also contain the following inert ingredients: colloidal silicon dioxide, ethylcellulose, ferrosoferric oxide (18 mg, 27 mg, 54 mg), hypromellose, iron oxide yellow (18 mg, 27 mg), lactose monohydrate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer, microcrystalline cellulose, polyethylene glycol, polysorbate (36 mg), red iron oxide (54 mg), talc, titanium dioxide, and triethyl citrate.The extended-release tablets are printed with opacode® black ink containing ammonium hydroxide, ferrosoferric oxide, propylene glycol and shellac glaze.FDA approved dissolution test specifications differ from USP.

11.1 System Components And Performance

Methylphenidate Hydrochloride Extended-Release Tablets, USP use a precisely designed process to deliver methylphenidate hydrochloride at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises a hydrophilic matrix active core surrounded by a delayed-release controlling coating with an immediate release drug overcoat. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. After the delayed release coating dissolves, water enters the core tablet to form hydrophilic gel, and methylphenidate is released in a controlled fashion resulting in Cmax at 6 to 8 hours. The non-absorbed components of the tablet pass through the gastrointestinal tract and are eliminated in the stool. It is possible that methylphenidate hydrochloride extended-release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

12.1 Mechanism Of Action

Methylphenidate HCl 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.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.

14 Clinical Studies

Methylphenidate hydrochloride extended-release tablets were demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD.

14.1 Children

Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was methylphenidate hydrochloride extended-release tablets versus placebo.Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for methylphenidate hydrochloride extended-release tablets. The scores for methylphenidate hydrochloride extended-release tablets and placebo for the three studies are presented in Figure 2.Figure 2. Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with methylphenidate hydrochloride extended-release tablets once daily (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean.In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP* laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with methylphenidate hydrochloride extended-release tablets versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for methylphenidate hydrochloride extended-release tablets and placebo.*Swanson, Kotkin, Agler, M-Fynn, and PelhamFigure 3. Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)

14.2 Adolescents

In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, methylphenidate hydrochloride extended-release tablets were demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of methylphenidate hydrochloride extended-release tablets (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that methylphenidate hydrochloride extended-release tablets were statistically significantly superior to placebo.

14.3 Adults

Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day).Study 5 demonstrated the effectiveness of methylphenidate hydrochloride extended-release tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to methylphenidate hydrochloride extended-release tablets and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that methylphenidate hydrochloride extended-release tablets were statistically significantly superior to placebo.Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg). Patients were randomized to receive methylphenidate hydrochloride extended-release tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of methylphenidate hydrochloride extended-release tablets were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.

15 References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.

16 How Supplied/Storage And Handling

Methylphenidate Hydrochloride Extended-Release Tablets, USP are available in 18 mg, 27 mg, 36 mg, and 54 mg dosage strengths. 18 mg tablets are yellow, capsule shaped film coated tablets, and imprinted with “A18” on one side and plain on the other side, 27 mg tablets are gray, capsule shaped film coated tablets, and imprinted with “A27” on one side and plain on the other side, 36 mg tablets are white, capsule shaped film coated tablets, and imprinted with “A36” on one side and plain on the other side, and 54 mg tablets are red, capsule shaped film coated tablets, and imprinted with “A54” on one side and plain on the other side.18 mg:Bottle of 100 tablets with child-resistant closure  NDC 0527-3310-3727 mg:Bottle of 100 tablets with child-resistant closure  NDC 0527-3311-3736 mg: Bottle of 100 tablets with child-resistant closure  NDC 0527-3312-3754 mg:Bottle of 100 tablets with child-resistant closure  NDC 0527-3313-37

17 Patient Counseling Information

See Medication Guide

* Please review the disclaimer below.

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