Methylphenidate Hydrochloride Tablet, Extended Release
FDA Label NDC 62175-310

Methylphenidate HCl 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.

Methylphenidate HCl Extended-Release Tablets is 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.

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.

Methylphenidate HCl Extended-Release Tablets is 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.

Methylphenidate HCl Extended-Release Tablets should be administered orally once daily in the morning with or without food.

Methylphenidate HCl 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)].

The recommended starting dose of Methylphenidate HCl 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).

The recommended dose of Methylphenidate HCl 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.

Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.

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.

There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Methylphenidate HCl Extended-Release Tablets. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods.

The effectiveness of Methylphenidate HCl 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 HCl 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.

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.

Methylphenidate HCl Extended-Release Tablets is available in the following dosage strengths: 18 mg tablets are pink and imprinted with “18”, 27 mg tablets are yellow and imprinted with “27”, 36 mg tablets are pink and imprinted with “36”, and 54 mg tablets are pink and imprinted with “54”.

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

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

Methylphenidate HCl Extended-Release Tablets is contraindicated in patients with glaucoma.

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

Methylphenidate HCl Extended-Release Tablets is 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)].

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.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, including Methylphenidate HCl 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.

Stimulants, including Methylphenidate HCl 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.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication-treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. 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.

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

Because the Methylphenidate HCl Extended-Release Tablet is nondeformable and does not appreciably change in shape in the GI tract, Methylphenidate HCl 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 HCl Extended-Release Tablets should only be used in patients who are able to swallow the tablet whole [see Patient Counseling Information (17)].

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

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 HCl Extended-Release Tablets included exposures in a total of 3906 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, ECGs, and by performing physical examinations and laboratory analyses.

Table 3. Methylphenidate HCl Extended-Release Tablets Exposure in Double-Blind and Open-Label Clinical Studies

Patient Population	N	Dose Range
Children	2216	18 to 54 mg once daily
Adolescents	502	18 to 72 mg once daily
Adults	1188	18 to 108 mg once daily

Adverse 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 HCl Extended-Release Tablets based on the comprehensive assessment of the available adverse event information. A causal association for Methylphenidate HCl 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.

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

This section includes adverse reactions reported by Methylphenidate HCl 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 HCl Extended-Release Tablets -treated subjects who participated in open-label and postmarketing clinical trials.

Blood and Lymphatic System Disorders: Leukopenia

Eye Disorders: Accommodation disorder, Dry eye

Vascular Disorders: Hot flush

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea

General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst

Infections and Infestations: Sinusitis

Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence

Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic

Reproductive System and Breast Disorders: Erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Rash, Rash macular

Vascular Disorders: Hypertension

Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 Methylphenidate HCl 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 HCl 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 HCl 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 HCl 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%).

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 HCl 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.

In the laboratory classroom clinical trials in children (Studies 1 and 2), both Methylphenidate HCl 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 HCl 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 HCl 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 HCl 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 HCl 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 HCl 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 HCl 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)].

The following additional adverse reactions have been identified during postapproval use of Methylphenidate HCl 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 purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles

Eye Disorders: Diplopia, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased

Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes

Reproductive System and Breast Disorders: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

Methylphenidate HCl 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)].

Because of possible increases in blood pressure, Methylphenidate HCl Extended-Release Tablets should be used cautiously with vasopressor agents [see Warnings and Precautions (5.1)].

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.

The effect of Methylphenidate HCl Extended-Release Tablets on labor and delivery in humans is unknown.

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 HCl Extended-Release Tablets is 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.

Methylphenidate HCl 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.

Methylphenidate HCl Extended-Release Tablets has not been studied in patients greater than 65 years of age.

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

As noted in the Box Warning, Methylphenidate HCl 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 HCl 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 HCl 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 HCl 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 HCl 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 HCl Extended-Release Tablets (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, Methylphenidate HCl Extended-Release Tablets produced statistically significantly lower subjective responses on these two scales than IR MPH. Methylphenidate HCl 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 HCl Extended-Release Tablets is 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 HCl 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 HCl Extended-Release Tablets in the community is unknown.

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.

Signs and symptoms of Methylphenidate HCl 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.

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 HCl Extended-Release Tablets overdosage has not been established.

The prolonged release of methylphenidate from Methylphenidate HCl Extended-Release Tablets should be considered when treating patients with overdose.

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.

Methylphenidate HCl Extended-Release Tablets is a central nervous system (CNS) stimulant. Methylphenidate HCl Extended-Release Tablets is 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:

Chemical Structure (Methylphenidate Hydrochloride Extended Release Tab 1)

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 HCl Extended-Release Tablets also contains the following inert ingredients: carboxymethylcellulose sodium, colloidal silicon dioxide, corn starch, ethocel, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, talc, titanium dioxide and triethyl citrate. The 18, 36, and 54 mg tablets also contain synthetic red iron oxide. The 27 mg tablets also contain yellow iron oxide.

Methylphenidate HCl Extended-Release Tablets meet USP Dissolution Test 3.

Methylphenidate HCl Extended-Release Tablets uses extended-release bead technology to deliver methylphenidate HCl at a controlled rate. The system, which resembles a conventional tablet in appearance, is comprised of a tablet core containing the extended-release beads and the core is covered 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. The tablet disintegrates and then polymer coatings on the beads control the release of methylphenidate HCl over the 12 hour dosing period.

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.

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

Methylphenidate HCl Extended-Release Tablets was 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 4^th edition (DSM-IV) criteria for ADHD.

Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared Methylphenidate HCl 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 HCl 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 HCl Extended-Release Tablets. The scores for Methylphenidate HCl 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 HCl 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.

Figure 2 (Methylphenidate Hydrochloride Extended Release Tab 3)

In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP

Swanson, Kotkin, Agler, M-Fynn, and Pelham

Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)

Figure 3 (Methylphenidate Hydrochloride Extended Release Tab 4)

In a randomized, double-blind, multi-center, placebo-controlled trial (Study 4) involving 177 patients, Methylphenidate HCl Extended-Release Tablets was 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 HCl 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 HCl Extended-Release Tablets was statistically significantly superior to placebo.

Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared Methylphenidate HCl 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 HCl 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 HCl 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 HCl Extended-Release Tablets was 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 HCl 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 HCl 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.

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

Methylphenidate HCl Extended-Release Tablets is available in 18 mg, 27 mg, 36 mg, and 54 mg dosage strengths.  The 18 mg tablets are pink and imprinted with “18”, 27 mg tablets are yellow and imprinted with “27”, 36 mg tablets are pink and imprinted with “36”, and 54 mg tablets are pink and imprinted with “54”. All four dosage strengths are supplied in bottles containing 100 tablets.

See Medication Guide

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 [see Warnings and Precautions (5.4)].

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud’s Phenomenon]

Instruct patients beginning treatment with Methylphenidate HCl Extended-Release Tablets about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and 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 HCl Extended-Release Tablets.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Methylphenidate (meth-ill-fen-i-date) HCl Extended-Release Tablets, USP
CII

CIA75798H
Rev. 09/2019

Read the Medication Guide that comes with Methylphenidate HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets.

3. Painful and prolonged erections (priapism)

Painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately.

4. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s Phenomenon]:

•            Fingers or toes may feel numb, cool, painful

•            Fingers or toes may change color from pale, to blue, to red

Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.

Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking Methylphenidate HCl Extended-Release Tablets.

What Is Methylphenidate HCl Extended-Release Tablets?

Methylphenidate HCl Extended-Release Tablets is a central nervous system stimulant prescription medicine. It is used for the treatment of attention deficit and hyperactivity disorder (ADHD). Methylphenidate HCl Extended-Release Tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.

Methylphenidate HCl Extended-Release Tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.

Who should not take Methylphenidate HCl Extended-Release Tablets?

Methylphenidate HCl Extended-Release Tablets should not be taken if you or your child:

• is very anxious, tense, or agitated
• has an eye problem called glaucoma
• has tics or Tourette's syndrome, or a family history of Tourette's syndrome. Tics are hard-to-control repeated movements or sounds.
• is taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.
• is allergic to anything in Methylphenidate HCl Extended-Release Tablets. See the end of this Medication Guide for a complete list of ingredients.

Methylphenidate HCl Extended-Release Tablets should not be used in children less than 6 years old because it has not been studied in this age group.

Methylphenidate HCl Extended-Release Tablets may not be right for you or your child. Before starting Methylphenidate HCl Extended-Release Tablets, tell your or your child's doctor about all health conditions (or a family history of) including:

• heart problems, heart defects, or high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette's syndrome
• seizures or have had an abnormal brain wave test (EEG)
• circulation problems in fingers and toes
• esophagus, stomach, or small or large intestine problems

Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.

Can Methylphenidate HCl Extended-Release Tablets 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. Methylphenidate HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets.

Your doctor will decide whether Methylphenidate HCl Extended-Release Tablets can be taken with other medicines.

Especially tell your doctor if you or your child takes:

• anti-depression medicines including MAOIs
• seizure medicines
• blood thinner medicines
• blood pressure medicines
• cold or allergy medicines that contain decongestants

Know the medicines that you or your child takes.

Keep a list of your medicines with you to show your doctor and pharmacist.

Do not start any new medicine while taking Methylphenidate HCl Extended-Release Tablets without talking to your doctor first.

How should Methylphenidate HCl Extended-Release Tablets be taken?

• Take Methylphenidate HCl Extended-Release Tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.
• Do not chew, crush, or divide the tablets. Swallow Methylphenidate HCl Extended-Release Tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow Methylphenidate HCl Extended-Release Tablets whole. A different medicine may need to be prescribed.
• Methylphenidate HCl Extended-Release Tablets can be taken with or without food.
• Take Methylphenidate HCl Extended-Release Tablets once each day in the morning. Methylphenidate HCl Extended-Release Tablets is an extended-release tablet. It releases medication into your/your child's body throughout the day.
• From time to time, your doctor may stop Methylphenidate HCl Extended-Release Tablets treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking Methylphenidate HCl Extended-Release Tablets. Children should have their height and weight checked often while taking Methylphenidate HCl Extended-Release Tablets. Methylphenidate HCl Extended-Release Tablets treatment may be stopped if a problem is found during these check-ups.
• If you or your child takes too many Methylphenidate HCl Extended-Release Tablets or overdoses, call your doctor or poison control center right away, or get emergency treatment.

What are possible side effects of Methylphenidate HCl Extended-Release Tablets?

See "What is the most important information I should know about Methylphenidate HCl Extended-Release Tablets?" for information on reported heart and mental problems.

Other serious side effects include:

• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
• blockage of the esophagus, stomach, small or large intestine in patients who already have a narrowing in any of these organs

Common side effects include:

decreased appetite dry mouth trouble sleeping dizziness stomach ache increased sweating

headache nausea anxiety weight loss irritability

Stimulants may impair the ability of you or your child to operate potentially hazardous machinery or vehicles. You or your child should exercise caution until you/your child is reasonably certain that Methylphenidate HCl Extended-Release Tablets does not adversely affect your/your child's ability to engage in such activities.

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 list of possible side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Kremers Urban Pharmaceuticals Inc. at 1-844-834-0530.

How should I store Methylphenidate HCl Extended-Release Tablets?

• Store Methylphenidate HCl Extended-Release Tablets in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from moisture.
• Keep Methylphenidate HCl Extended-Release Tablets and all medicines out of the reach of children.

General information about Methylphenidate HCl Extended-Release Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Methylphenidate HCl Extended-Release Tablets for a condition for which it was not prescribed. Do not give Methylphenidate HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Methylphenidate HCl Extended-Release Tablets that was written for healthcare professionals. For more information about Methylphenidate HCl Extended-Release Tablets call 1-844-834-0530.

What are the ingredients in Methylphenidate HCl Extended-Release Tablets?

Active Ingredient: methylphenidate HCl

Inactive Ingredients: carboxymethylcellulose sodium, colloidal silicon dioxide, corn starch, ethocel, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, talc, titanium dioxide and triethyl citrate. The 18, 36, and 54 mg tablets also contain synthetic red iron oxide. The 27 mg tablets also contain yellow iron oxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Kremers Urban Pharmaceuticals Inc.
Seymour, IN 47274

CIA75798H
Rev. 09/2019

PRINCIPAL DISPLAY PANEL - 18 mg Tablet Bottle Label

NDC 62175-310-37

Methylphenidate HCl
Extended-Release Tablets, USP

18 mg

PHARMACIST: Dispense the
accompanying Medication Guide
to each patient.

Rx Only

100 TABLETS

18 mg 100 Count (Methylphenidate Hydrochloride Extended Release Tab 5)

PRINCIPAL DISPLAY PANEL - 27 mg Tablet Bottle Label

NDC 62175-311-37

Methylphenidate HCl
Extended-Release Tablets, USP

27 mg

PHARMACIST: Dispense the
accompanying Medication Guide
to each patient.

Rx Only

100 TABLETS

27 mg 100 Count (Methylphenidate Hydrochloride Extended Release Tab 6)

PRINCIPAL DISPLAY PANEL - 36 mg Tablet Bottle Label

NDC 62175-311-37

Methylphenidate HCl
Extended-Release Tablets, USP

36 mg

PHARMACIST: Dispense the
accompanying Medication Guide
to each patient.

Rx Only

100 TABLETS

36 mg 100 Count (Methylphenidate Hydrochloride Extended Release Tab 7)

PRINCIPAL DISPLAY PANEL - 54 mg Tablet Bottle Label

NDC 62175-313-37

Methylphenidate HCl
Extended-Release Tablets, USP

54 mg

Rx Only

PHARMACIST: Dispense the
accompanying Medication Guide
to each patient.

100 TABLETS

54 mg 100 Count (Methylphenidate Hydrochloride Extended Release Tab 8)