METHYLPHENIDATE: 31,008 Adverse Event Reports & Safety Profile

Methylphenidate hydrochloride extended-release tablet is a central nervous system (CNS) stimulant. Methylphenidate hydrochloride extended-release tablets are available in four 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 C 14 H 19 NO 2

• HCl. Its structural formula is: Methylphenidate HCl, USP is a white to off-white fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Methylphenidate hydrochloride extended-release tablets also contains the following inert ingredients: butylated hydroxytoluene, cellulose acetate, colloidal silicon dioxide, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Red #40/Allura Red AC Aluminum Lake, hypromellose, phosphoric acid, poloxamer, polyethylene oxide, povidone, sodium chloride, stearic acid, succinic acid. In addition 18 mg contains Opadry Purple (FD&C Blue #2/Indigo Carmine Aluminum Lake, FD&C Red #40/Allura Red AC Aluminum Lake, hypromellose 3 mPas, hypromellose 6 mPas, polyethylene glycol, polysorbate, titanium dioxide), 27 mg contains Opadry Pink (D&C Red #27/Phloxine Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, hypromellose 3 mPas, hypromellose 6 mPas, polyethylene glycol, polysorbate, titanium dioxide), 36 mg contains Opadry Orange (FD&C Red #40/Allura Red AC Aluminum Lake, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake, hypromellose 3 mPas, hypromellose 6 mPas, polyethylene glycol, polysorbate, titanium dioxide), 54 mg contains Opadry Blue (FD&C Blue #2/Indigo Carmine Aluminum Lake, hypromellose 3 mPas, hypromellose 6 mPas, polyethylene glycol, polysorbate, titanium dioxide).

Opacode

Black contains black iron oxide, hypromellose 6 mPas, propylene glycol. "Meets USP Dissolution Test 12"

11.1 System Components and Performance Methylphenidate hydrochloride extended-release tablets uses osmotic pressure to deliver methylphenidate HCl at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice on the drug-layer end of the tablet. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. The membrane controls the rate at which water enters the tablet core, which in turn controls drug delivery. Furthermore, the drug release rate from the system increases with time over a period of 6 to 7 hours due to the drug-concentration gradient incorporated into the two drug layers of methylphenidate hydrochloride extended-release tablets. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell along with insoluble core components. 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. “FDA approved dissolution test specifications differ from USP”.

INDICATIONS AND USAGE Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Methylphenidate HCl Oral Solution is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.

Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.

Attention Deficit

Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Methylphenidate HCl Oral Solution is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.

Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.

AND ADMINISTRATION

• The recommended starting dose for patients new to or converting from another formulation of methylphenidate is 10 mg. ( 2.2 )
• Methylphenidate transdermal system should be applied to the hip area (using alternating sites) 2 hours before an effect is needed and should be removed 9 hours after application. Methylphenidate transdermal system may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. ( 2.2 , 2.3 )
• Dosage should be titrated to effect. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient. ( 2.2 )

2.1 Pretreatment Screening Prior to treating patients with methylphenidate transdermal system, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2) ] .
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methylphenidate transdermal system [see Warnings and Precautions (5.15) ] .

2.2 Recommended Dosage It is recommended that methylphenidate transdermal system be applied to the hip area 2 hours before an effect is needed and should be removed 9 hours after application. Dosage should be titrated to effect. The recommended dose titration schedule is shown in the table below. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient.

Table

1 Methylphenidate Transdermal System - Recommended Titration Schedule (Patients New to Methylphenidate)

Upward

Titration, if Response is Not Maximized Week 1 Week 2 Week 3 Week 4 Transdermal System Size 9.6 cm 2 14.4 cm 2 19.2 cm 2 28.8 cm 2 Nominal Delivered Dose Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. (mg/9 hours) 10 mg 15 mg 20 mg 30 mg Delivery Rate (1.1 mg/hr) (1.6 mg/hr) (2.2 mg/hr) (3.3 mg/hr) Patients converting from another formulation of methylphenidate should follow the above titration schedule due to differences in bioavailability of methylphenidate transdermal system compared to other products.

2.3 Application The parent or caregiver should be encouraged to use the administration chart included with each carton of methylphenidate transdermal system to monitor application and removal time, and method of disposal. It is recommended that parents or caregivers apply and remove the transdermal system for children; responsible adolescents may apply or remove the transdermal system themselves if appropriate. If a transdermal system was removed without the parent or caregiver's knowledge, or if a transdermal system is missing from the carton, the parent or caregiver should be encouraged to ask the child when and how the transdermal system was removed.

The Medication

Guide includes a timetable to calculate when to remove methylphenidate transdermal system, based on the 9-hour application time. The adhesive side of methylphenidate transdermal system should be placed on a clean, dry area of the hip. The area selected should not be oily, damaged, or irritated. Apply methylphenidate transdermal system to the hip area avoiding the waistline, since clothing may cause the transdermal system to rub off. When applying the transdermal system the next morning, place on the opposite hip at a new site if possible. If patients or caregivers experience difficulty separating the transdermal system from the release liner or observe transfer of adhesive to the liner, tearing and/or other damage to the transdermal system during removal from the liner, the transdermal system should be discarded and a new transdermal system should be applied. Patients or caregivers should inspect the release liner to ensure that no adhesive containing medication has transferred to the liner. If adhesive transfer has occurred, the transdermal system should be discarded. Refer to the Instructions for Use for recommendations for discarding used methylphenidate transdermal systems. Methylphenidate transdermal system should be applied immediately after opening the individual pouch and removing the protective liner. Do not use if the individual pouch seal is broken or if the transdermal system appears to be damaged. Do not cut transdermal systems. Only intact transdermal systems should be applied. The transdermal system should then be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure that there is good contact of the transdermal system with the skin, especially around the edges. Exposure to water during bathing, swimming, or showering can affect transdermal system adherence. Methylphenidate transdermal systems should not be applied or re-applied with dressings, tape, or other common adhesives. In the event that a transdermal system does not fully adhere to the skin upon application, or becomes partially or fully detached during wear time, the transdermal system should be discarded and a new transdermal system may be applied at a different site. The total recommended wear time for that day should remain 9 hours regardless of the number of transdermal systems used. All patients should be advised to avoid exposing the methylphenidate transdermal system application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the transdermal system [see Warnings and Precautions (5.10) ] . When heat is applied to methylphenidate transdermal system after transdermal system application, both the rate and the extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold [see Clinical Pharmacology (12.3) ] . This increased absorption can be clinically significant and result in overdose of methylphenidate [see Overdosage (10) ] . Methylphenidate transdermal systems should not be stored in refrigerators or freezers.

2.4 Removal of Methylphenidate Transdermal System Methylphenidate transdermal systems should be peeled off slowly. If necessary, transdermal system removal may be facilitated by gently applying an oil-based product (i.e., petroleum jelly, olive oil, or mineral oil) to the transdermal system edges, gently working the oil underneath the transdermal system edges. If any adhesive remains on the skin following transdermal system removal, an oil-based product may be applied to transdermal system sites in an effort to gently loosen and remove any residual adhesive that remains following transdermal system removal. In the unlikely event that a transdermal system remains tightly adhered despite these measures, the patient or caregiver should contact the physician or pharmacist. Nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) should not be used to remove methylphenidate transdermal systems or adhesive.

2.5 Dose/Wear Time Reduction and Discontinuation Methylphenidate transdermal system may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. Plasma concentrations of d -methylphenidate generally begin declining when the transdermal system is removed, although absorption may continue for several hours. Individualization of wear time may help manage some of the side effects caused by methylphenidate. If aggravation of symptoms or other adverse events occur, the dosage or wear time should be reduced, or, if necessary, the drug should be discontinued. Residual methylphenidate remains in used transdermal systems when worn as recommended.

4 CONTRAINDICATIONS

• Known hypersensitivity to the product ( 4.1 )
• Marked anxiety, tension, or agitation ( 4.2 )
• Glaucoma ( 4.3 )
• Tics or a family history or diagnosis of Tourette’s syndrome ( 4.4 )
• Do not use methylphenidate hydrochloride extended-release tablets in patients currently using or within 2 weeks of using an MAO inhibitor ( 4.5 )

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.6 )]</span> .

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&apos;s syndrome <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.4 )]</span>.

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) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions ( 5.1 )] Hypersensitivity to Methylphenidate [see Contraindications ( 4.1 )]

Monoamine Oxidase

Inhibitors [see Contraindications ( 4.2 ) and Drug Interactions ( 7.1 )] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )]

Increased Blood

Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )]

Psychiatric Adverse

Reactions [see Warnings and Precautions ( 5.4 )] Seizures [see Warnings and Precautions ( 5.5 )] Priapism [see Warnings and Precautions ( 5.6 )]

Peripheral

Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions ( 5.7 )] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.8 )] Potential for Gastrointestinal Obstruction [see Warnings and Precautions ( 5.9 )]

Hematologic

Monitoring [see Warnings and Precautions ( 5.10 )]

Acute Angle Closure

Glaucoma [see Warnings and Precautions ( 5.11 )]

Increased Intraocular

Pressure and Glaucoma [see Warnings and Precautions ( 5.12 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.13 )] 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 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, 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 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 hydrochloride extended-release based on the comprehensive assessment of the available adverse event information. A causal association for methylphenidate hydrochloride extended-release 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. The most common adverse reaction in double-blind clinical trials (>5%) in 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. ( 6.1 and 6.2 ) The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased. ( 6.3 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. Children and Adolescents Table 4 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.

Table

4.

Adverse Reactions

Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets System/Organ Class Adverse Reaction Methylphenidate Hydrochloride Extended-Release Tablets (n=321) % Placebo (n=318) % Gastrointestinal Disorders Abdominal pain upper Vomiting 6.2 2.8 3.8

1.6 General Disorders and Administration Site Conditions Pyrexia 2.2

0.9 Infections and Infestations Nasopharyngitis 2.8

2.2 Nervous System Disorders Dizziness 1.9 0 Psychiatric Disorders Insomnia* 2.8

0.3 Respiratory, Thoracic and Mediastinal Disorders Cough Oropharyngeal pain 1.9 1.2 0.9 0.9 *Terms of Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia. The majority of adverse reactions were mild to moderate in severity.

Adults Table

5 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets-treated adults in 2 placebo-controlled, double-blind clinical trials.

Table

5.

Adverse Reactions

Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials* System/Organ Class Adverse Reaction Methylphenidate Hydrochloride Extended-Release Tablets ( n=415) % Placebo (n=212) % Cardiac Disorders Tachycardia Palpitations 4.8 3.1 0

0.9 Ear and Labyrinth Disorders Vertigo 1.7 0 Eye Disorders Vision blurred 1.7

0.5 Gastrointestinal Disorders Dry mouth Nausea Dyspepsia Vomiting Constipation 14.0 12.8 2.2 1.7 1.4 3.8 3.3 0.9 0.5

0.9 General Disorders and Administration Site Conditions Irritability 5.8

1.4 Infections and Infestations Upper respiratory tract infection 2.2

0.9 Investigations Weight decreased 6.5

3.3 Metabolism and Nutrition Disorders Decreased appetite Anorexia 25.3 1.7 6.6 0 Musculoskeletal and Connective Tissue Disorders Muscle tightness 1.9 0 Nervous System Disorders Headache Dizziness Tremor Paresthesia Sedation Tension headache 22.2 6.7 2.7 1.2 1.2 1.2 15.6 5.2 0.5 0 0

0.5 Psychiatric Disorders Insomnia Anxiety Initial insomnia Depressed mood Nervousness Restlessness Agitation Aggression Bruxism Depression Libido decreased Affect lability Confusional state Tension 12.3 8.2 4.3 3.9 3.1 3.1 2.2 1.7 1.7 1.7 1.7 1.4 1.2 1.2 6.1 2.4 2.8 1.4 0.5 0 0.5 0.5 0.5 0.9 0.5 0.9 0.5

0.5 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 1.7

1.4 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 5.1 0.9 * Included doses up to 108 mg. The majority of ADRs were mild to moderate in severity.

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: 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

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 &gt;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 &gt;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 &gt;0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

6.4 Blood Pressure and Heart Rate Increases In the laboratory classroom clinical trials in children (Studies 1 and 2), both methylphenidate hydrochloride extended-release 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 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 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 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 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 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 and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3)]</span> .

6.5 Postmarketing Experience The following additional adverse reactions have been identified during post-approval 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 purpura Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders: Diplopia, Increased intraocular pressure, 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, Motor and Verbal Tics 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&apos;s phenomenon

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. Children and Adolescents Table 4 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.

Table

4.

Adverse Reactions

Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets System/Organ Class Adverse Reaction Methylphenidate Hydrochloride Extended-Release Tablets (n=321) % Placebo (n=318) % Gastrointestinal Disorders Abdominal pain upper Vomiting 6.2 2.8 3.8

1.6 General Disorders and Administration Site Conditions Pyrexia 2.2

0.9 Infections and Infestations Nasopharyngitis 2.8

2.2 Nervous System Disorders Dizziness 1.9 0 Psychiatric Disorders Insomnia* 2.8

0.3 Respiratory, Thoracic and Mediastinal Disorders Cough Oropharyngeal pain 1.9 1.2 0.9 0.9 *Terms of Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia. The majority of adverse reactions were mild to moderate in severity.

Adults Table

5 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets-treated adults in 2 placebo-controlled, double-blind clinical trials.

Table

5.

Adverse Reactions

Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials* System/Organ Class Adverse Reaction Methylphenidate Hydrochloride Extended-Release Tablets ( n=415) % Placebo (n=212) % Cardiac Disorders Tachycardia Palpitations 4.8 3.1 0

0.9 Ear and Labyrinth Disorders Vertigo 1.7 0 Eye Disorders Vision blurred 1.7

0.5 Gastrointestinal Disorders Dry mouth Nausea Dyspepsia Vomiting Constipation 14.0 12.8 2.2 1.7 1.4 3.8 3.3 0.9 0.5

0.9 General Disorders and Administration Site Conditions Irritability 5.8

1.4 Infections and Infestations Upper respiratory tract infection 2.2

0.9 Investigations Weight decreased 6.5

3.3 Metabolism and Nutrition Disorders Decreased appetite Anorexia 25.3 1.7 6.6 0 Musculoskeletal and Connective Tissue Disorders Muscle tightness 1.9 0 Nervous System Disorders Headache Dizziness Tremor Paresthesia Sedation Tension headache 22.2 6.7 2.7 1.2 1.2 1.2 15.6 5.2 0.5 0 0

0.5 Psychiatric Disorders Insomnia Anxiety Initial insomnia Depressed mood Nervousness Restlessness Agitation Aggression Bruxism Depression Libido decreased Affect lability Confusional state Tension 12.3 8.2 4.3 3.9 3.1 3.1 2.2 1.7 1.7 1.7 1.7 1.4 1.2 1.2 6.1 2.4 2.8 1.4 0.5 0 0.5 0.5 0.5 0.9 0.5 0.9 0.5

0.5 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 1.7

1.4 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 5.1 0.9 * Included doses up to 108 mg. The majority of ADRs were mild to moderate in severity.

AND PRECAUTIONS

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 )
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 )
• Psychiatric Adverse Reactions: Prior to initiating methylphenidate transdermal system, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate transdermal system. ( 5.4 )
• Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.5 )
• Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. ( 5.6 )
• Peripheral Vasculopathy, including Raynaud’s phenomenon: Careful observation for digital changes is necessary during methylphenidate transdermal system treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7 )
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.8 )
• Chemical Leukoderma: Methylphenidate transdermal system use may result in a persistent loss of skin pigmentation at and around the application site. Loss of pigmentation, in some cases, has been reported at other sites distant from the application site. Monitor for signs of skin depigmentation. Discontinue methylphenidate transdermal system if it occurs. ( 5.9 )
• Contact Sensitization: Use of methylphenidate transdermal system may lead to contact sensitization. Treatment should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of methylphenidate transdermal system and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the transdermal system site. ( 5.10 )
• External Heat: Patients should be advised to avoid exposing the methylphenidate transdermal system application site to direct external heat sources. When heat is applied to methylphenidate transdermal system after application, both the rate and extent of absorption are significantly increased. ( 5.11 )
• Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. ( 5.12 )
• Acute Angle Closure Glaucoma: Methylphenidate transdermal system-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.13 )
• Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate transdermal system to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. ( 5.14 )
• Motor and Verbal Tics and Worsening of Tourette’s Syndrome: Before initiating methylphenidate transdermal system, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.15 )

5.1 Abuse, Misuse, and Addiction Methylphenidate transdermal system has a high potential for abuse and misuse. The use of methylphenidate transdermal system exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate can be diverted for non-medical use into illicit channels or distribution <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.2) ]</span> . Misuse and abuse of CNS stimulants, including methylphenidate transdermal system, can result in overdose and death <span class="opacity-50 text-xs">[see Overdosage (10) ]</span> , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate transdermal system, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their caregivers or families about these risks. Advise patients to store methylphenidate transdermal system in a safe place, preferably locked, and instruct patients to not give methylphenidate transdermal system to anyone else. Throughout methylphenidate transdermal system treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. Methylphenidate transdermal system has special disposal instructions. Instruct patients to find a take back location to dispose of unused or expired methylphenidate transdermal system. If a take back program is unavailable, instruct them to: 1. Remove methylphenidate transdermal system from its pouch, separate it from its liner, fold it in half with the adhesive sides touching each other, and immediately flush the used transdermal system down the toilet, and 2. Place the pouch and liner in a container, close the container, and throw out the container in the trash (advise patients not to flush the pouch and liner down the toilet).

5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate transdermal system use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all methylphenidate transdermal system-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disease CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating methylphenidate transdermal system treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New

Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms, (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate transdermal system.

5.5 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.

5.6 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on the methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate transdermal system-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.7 Peripheral Vasculopathy, including Raynaud’s phenomenon Stimulant medications, including methylphenidate transdermal system, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during methylphenidate transdermal system treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate transdermal system-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.8 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate transdermal system is not approved for use and is not recommended in pediatric patients below 6 years of age <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric 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 pediatric patients who received methylphenidate for 7 days per week throughout the year had 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 development period. Closely monitor growth (weight and height) in methylphenidate transdermal system-treated pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.9 Chemical Leukoderma Methylphenidate transdermal system use may result in a persistent loss of skin pigmentation at and around the application site. Loss of pigmentation, in some cases, has been reported at other sites distant from the application site. Chemical leukoderma can mimic the appearance of vitiligo, particularly when the loss of skin pigmentation involves areas distant from the application site. Individuals with a history of vitiligo and/or a family history of vitiligo may be more at risk. Skin depigmentation may persist even after methylphenidate transdermal system use is discontinued. Monitor for signs of skin depigmentation, and advise patients to immediately inform their healthcare provider if changes in skin pigmentation occur. Discontinue use of the methylphenidate transdermal system in patients with chemical leukoderma.

5.10 Contact Sensitization In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with methylphenidate transdermal system using a 9-hour wear time, one subject (0.3%) was confirmed by transdermal system testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at methylphenidate transdermal system application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to oral methylphenidate. Use of methylphenidate transdermal system may lead to contact sensitization. Methylphenidate transdermal system should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of methylphenidate transdermal system and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the transdermal system site. Confirmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing. Patients sensitized from use of methylphenidate transdermal system, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive transdermal system-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of methylphenidate transdermal system. Patients who develop contact sensitization to methylphenidate transdermal system and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to methylphenidate transdermal system may not be able to take methylphenidate in any form.

5.11 Patients Using External Heat Patients should be advised to avoid exposing the methylphenidate transdermal system application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the transdermal system. When heat is applied to methylphenidate transdermal system after application, both the rate and extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . This increased absorption can be clinically significant and can result in overdose of methylphenidate <span class="opacity-50 text-xs">[see Overdosage (10) ]</span> .

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

5.13 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate transdermal system-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

5.14 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Prescribe methylphenidate transdermal system to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate transdermal system -treated patients with a history of abnormally increased IOP or open angle glaucoma.

5.15 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Before initiating methylphenidate transdermal system, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate transdermal system -treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

PRECAUTIONS General Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methylphenidate hydrochloride chewable tablets should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with methylphenidate hydrochloride chewable tablets are usually not indicated. Long-term effects of methylphenidate hydrochloride chewable tablets in children have not been well established. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate hydrochloride chewable tablets, which can lead to overdose and death, and proper disposal of any unused drug (see WARNINGS and PRECAUTIONS, DRUG ABUSE AND DEPENDENCE , OVERDOSAGE ) . Advise patients to store methylphenidate hydrochloride chewable tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride chewable tablets to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate hydrochloride chewable tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease (see WARNINGS).

Increased Blood

Pressure and Heart Rate Advise patients that methylphenidate hydrochloride chewable tablets can elevate blood pressure and heart rate (see WARNINGS).

Psychiatric Adverse Reactions

Advise patients that methylphenidate hydrochloride chewable tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania (see WARNINGS).

Priapism

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism .

Circulation

Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients beginning treatment with methylphenidate hydrochloride chewable 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 hydrochloride chewable tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Suppression of Growth in Pediatric Patients Advise patients, caregivers, and family members that methylphenidate hydrochloride chewable tablets can cause slowing of growth and weight loss (see Warnings).

Increased Intraocular

Pressure and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride chewable tablets (see Warnings). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride chewable tablets. Instruct the patients to notify their healthcare provider if emergence or worsening of tics or Tourette’s syndrome occurs (see WARNINGS). Choking – Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention. Directions – Take this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning. Phenylketonurics – Phenylalanine is a component of aspartame.

Each

2.5 mg methylphenidate hydrochloride chewable tablet contains 0.35 mg of phenylalanine; each 5 mg methylphenidate hydrochloride chewable tablet contains 0.70 mg of phenylalanine and each 10 mg methylphenidate hydrochloride chewable tablet contains 1.40 mg of phenylalanine.

Drug Interactions Monoamine Oxidase

Inhibitors (MAOI) Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride chewable tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure (see CONTRAINDICATIONS ). Concomitant use of methylphenidate hydrochloride chewable tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.

Antihypertensive Drugs

Methylphenidate hydrochloride chewable tablets may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.

Risperidone

Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS. Methylphenidate hydrochloride chewable tablets may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate hydrochloride chewable tablets may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with methylphenidate hydrochloride chewable tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 4 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. The genotoxic potential of methylphenidate has not been evaluated in an in vivo assay. Usage in Pregnancy Adequate animal reproduction studies to establish safe use of methylphenidate hydrochloride chewable tablet during pregnancy have not been conducted. However, in a recently conducted study, methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 167 times and 78 times the maximum recommended human dose on a mg/kg and a mg/m 2 basis, respectively. In rats, teratogenic effects were not seen when the drug was given in doses of 75 mg/kg/day, which is approximately 62.5 and 13.5 times the maximum recommended human dose on a mg/kg and a mg/m 2 basis, respectively. Therefore, until more information is available, methylphenidate should not be prescribed for women of childbearing age unless, in the opinion of the physician, the potential benefits outweigh the possible risks.

INTERACTIONS N/A Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed (7) Halogenated anesthetics: Avoid use of Methylphenidate hydrochloride extended-release tablets on the day of surgery if halogenated anesthetics will be used (7) Risperidone: The combined use of methylphenidate with risperidone when there is a change in dose of either or both medications may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS (7) .

7.1 Clinically Important Interactions with Methylphenidate hydrochloride extended-release tablets Table 1 presents clinically important drug interactions with Methylphenidate hydrochloride extended-release tablets.

Table

1: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI)

Clinical Impact

Concomitant use of MAOIs and CNS stimulants, including Methylphenidate hydrochloride extended-release tablets can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [ see Contraindications (4) ] .

Intervention

Concomitant use of Methylphenidate hydrochloride extended-release tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Antihypertensive Drugs Clinical Impact Methylphenidate hydrochloride extended-release tablets may decrease the effectiveness of drugs used to treat hypertension [ see Warnings and Precautions (5.3) ] .

Intervention

Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.

Examples

Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and Methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery.

Intervention

Avoid use of Methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane Risperidone The combined use of methylphenidate with risperidone when there is a change in dose of either or both medications may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.