DEXMETHYLPHENIDATE: 2,100 Adverse Event Reports & Safety Profile

AZSTARYS (serdexmethylphenidate and dexmethylphenidate) capsules contain dexmethylphenidate, a CNS stimulant, and serdexmethylphenidate, a prodrug of dexmethylphenidate. AZSTARYS capsules are intended for oral administration and each capsule contains a fixed molar ratio of 30% dexmethylphenidate and 70% serdexmethylphenidate. AZSTARYS contains 26.1/5.2, 39.2/7.8, or 52.3/10.4 mg of serdexmethylphenidate/ dexmethylphenidate (equivalent to 28/6, 42/9, or 56/12 mg of serdexmethylphenidate chloride/ dexmethylphenidate hydrochloride, respectively. The combined molar dose of serdexmethylphenidate and dexmethylphenidate in each dosage strength of AZSTARYS is equivalent to 20, 30, or 40 mg dexmethylphenidate hydrochloride, respectively (equivalent to 17.3, 25.9 or 34.6 mg dexmethylphenidate free base, respectively). The chemical name of serdexmethylphenidate chloride is 3-((( 1S )-1-carboxy-2-hydroxyethyl)carbamoyl)-1-(((( 2R )-2-(2-( 1R )-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridinium chloride. Its molecular formula is C 25 H 30 N 3 O 8 +

• Cl - , and its structural formula is: Serdexmethylphenidate chloride is a white to off-white crystalline powder. Its solutions are acid to litmus. It is freely soluble in water, soluble in methanol, and slightly soluble in alcohol and acetone. Its molecular weight is 535.98 g/mol. Dexmethylphenidate is the d-threo enantiomer of racemic d,l -methylphenidate hydrochloride. The chemical name of dexmethylphenidate hydrochloride is methyl ( R )-2-phenyl-2-(( R )-piperidin-2-yl)acetate hydrochloride. Its molecular formula is C 14 H 19 NO 2
• HCl, and its structural formula is: Dexmethylphenidate hydrochloride is a white to off-white 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 g/mol. Inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, and talc. Each strength capsule also contains colorant ingredients in the capsule shell as follows: 26.1/5.2 mg: Black Iron Oxide, FD&C Blue No. 1, Titanium Dioxide 39.2/7.8 mg: Black Iron Oxide, FD&C Blue No. 1, FD&C Red No. 40, Titanium Dioxide 52.3/10.4 mg: Black Iron Oxide, FD&C Red No. 40, FD&C Yellow No. 6, Titanium Dioxide chemical structure-1 chemical structure-2

AND USAGE Dexmethylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older. The effectiveness of dexmethylphenidate hydrochloride extended-release in the treatment of ADHD in patients aged 6 years and older was established in 2 placebo-controlled studies in patients meeting DSM-IV criteria for ADHD [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 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go”; excessive talking; blurting answers; can’t wait turn; intrusive.

The Combined

Types requires both inattentive and hyperactive-impulsive criteria to be met.

Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics. Need for Comprehensive Treatment Program Dexmethylphenidate hydrochloride extended-release capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms. Long-Term Use The effectiveness of dexmethylphenidate hydrochloride extended-release for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use dexmethylphenidate hydrochloride extended-release for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3 ) ]. Dexmethylphenidate hydrochloride extended-release is a CNS stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older. ( 1 )

AND ADMINISTRATION Dexmethylphenidate Hydrochloride Extended-release Capsules is for oral administration once daily in the morning.

Dexmethylphenidate Hydrochloride

Extended-release Capsules may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below).

Dexmethylphenidate Hydrochloride

Extended-release Capsules and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosage should be individualized according to the needs and responses of the patient. Patients new to methylphenidate: Recommended starting dose is 5 mg once daily for pediatric patients and 10 mg once daily for adults with or without food in the morning ( 2.2 ). Patients currently on methylphenidate: Dexmethylphenidate Hydrochloride Extended-release Capsules dosage is half the current total daily dosage of methylphenidate ( 2.2 ). Patients currently on dexmethylphenidate immediate-release tablets: Give the same daily dose of Dexmethylphenidate Hydrochloride Extended-release Capsules ( 2.2 ) Titrate weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients ( 2.2 ). Maximum recommended daily dose: 30 mg in pediatric patients and 40 mg in adults ( 2.2 ). Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce ( 2.3 ).

2.1 Pretreatment Screening Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants including Dexmethylphenidate Hydrochloride Extended-release Capsules, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for Dexmethylphenidate Hydrochloride Extended-release Capsules use <span class="opacity-50 text-xs">[see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9) ]</span> .

2.2 Treatment of ADHD Patients New to Methylphenidate The recommended starting dosage of Dexmethylphenidate Hydrochloride Extended-release Capsules for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are: Pediatric patients: Start with 5 mg orally once daily in the morning with or without food. Adult patients: Start with 10 mg orally once daily in the morning with or without food.

Patients

Currently on Methylphenidate The recommended starting dose of Dexmethylphenidate Hydrochloride Extended-release Capsules for patients currently using methylphenidate is half the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate immediate-release tablets may be given the same daily dose of Dexmethylphenidate Hydrochloride Extended-release Capsules.

Titration Schedule

The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended.

Maintenance/Extended

Treatment Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Dexmethylphenidate Hydrochloride Extended-release Capsules and adjust dosage as needed.

2.3 Administration Instructions Dexmethylphenidate Hydrochloride Extended-release Capsules is administered orally and may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

2.4 Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue Dexmethylphenidate Hydrochloride Extended-release Capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Agitation, marked anxiety, and tension ( 4.1 ) Known hypersensitivity to methylphenidate or product components ( 4.2 ) Glaucoma ( 4.3 ) History of motor tics or a family history or diagnosis of Tourette’s syndrome ( 4.4 ) During, or within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI) ( 4.5 )

4.1 Agitation Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

4.2 Hypersensitivity to Methylphenidate Dexmethylphenidate hydrochloride extended-release is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of the product. Hypersensitivity reactions, including angioedema and anaphylactic reactions, have been observed in patients treated with methylphenidate <span class="opacity-50 text-xs">[see Adverse Reactions (6.5 , 6.6 )]</span>.

4.3 Glaucoma Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with glaucoma.

4.4 Tics Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>.

4.5 Monoamine Oxidase Inhibitors Dexmethylphenidate hydrochloride extended-release is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).

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) , Drug Abuse and Dependence ( 9.2 , 9.3 )]
• Known hypersensitivity to methylphenidate or other ingredients of dexmethylphenidate hydrochloride extended-release capsules [see Contraindications (4) ]
• Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) , 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) ]
• Priapism [see Warnings and Precautions (5.5) ]
• Peripheral Vasculopathy, Including Raynaud’s Phenomenon [see Warnings and Precautions (5.6) ]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7) ]
• Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8) ]
• Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9) ]
• Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10) ] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo):
• Pediatric patients 6 to 17 years: dyspepsia, decreased appetite, headache, and anxiety ( 6.1 ).
• Adults: dry mouth, dyspepsia, headache, pharyngolaryngeal pain, and anxiety ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc. at 1-877-770-3183 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse

Reactions in Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Pediatric Patients with ADHD The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules in 100 (103 randomized)pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17). This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of dexmethylphenidate hydrochloride extended-release capsules 5 mg to 30 mg/day who met The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD [ see Clinical Studies (14.1)].

Most Common Adverse

Reactions (incidence of greater than or equal to 5% and at least twice placebo): dyspepsia, decreased appetite, headache and anxiety.

Adverse Reactions

Leading to Discontinuation : 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate immediate-release tablets experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each).

Table

1 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride extended-release capsules doses of 5 to 30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release capsules and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release capsules was at least twice the incidence in placebo-treated patients.

Table

1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) With A System organ class Adverse reaction Dexmethylphenidate Hydrochloride Extended-Release Capsules N = 53 Placebo N=47 Gastrointestinal disorders 38% 19% Dyspepsia 8% 4% Metabolism and nutrition disorders 34% 11% Decreased appetite 30% 9% Nervous system d isorders 30% 13% Headache 25% 11% Psychiatric disorders 26% 15% Anxiety 6% 0 Abbreviation: ADHD, attention deficit hyperactivity disorder Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking dexmethylphenidate hydrochloride extended-release capsules up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride extended-release capsules for which the incidence was at least 5% and greater than the incidence among placebo-treated patients.

Table

2: Dose-Related Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD System organ class Adverse reaction Dexmethylphenidate Hydrochloride Extended-Release Capsules 10 mg/day N = 64 Dexmethylphenidate Hydrochloride Extended-Release Capsules 20 mg/day N = 60 Dexmethylphenidate Hydrochloride Extended-Release Capsules 30 mg/day N = 58 Placebo N=63 Gastrointestinal disorders 22% 23% 29% 24% Vomiting 2% 8% 9% 0% Metabolism and nutritional disorders 16% 17% 22% 5% Anorexia 5% 5% 7% 0% Psychiatric disorders 19% 20% 38% 8% Insomnia 5% 8% 17% 3% Depression 0% 0% 3% 0% Mood swings 0% 0% 3% 2% Other adverse deactions Irritability 0% 2% 5% 0% Nasal congestion 0% 0% 5% 0% Pruritus 0% 0% 3% 0% Abbreviation: ADHD, attention deficit hyperactivity disorder.

Adverse

Reactions in Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Adult Patients with ADHD The safety data in this section is based on data from a 5-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least 6 months. This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of dexmethylphenidate hydrochloride extended-release capsules 20 mg, 30 mg, or 40 mg daily who met DSM-IV criteria for ADHD [ see Clinical Studies ( 14.2 )].

Most Common Adverse

Reactions (incidence of greater than or equal to 5% and at least twice placebo): dry mouth, dyspepsia, headache, anxiety, and pharyngolaryngeal pain.

Adverse Reactions

Leading to Discontinuation : During the double-blind phase of the study, 10.7% of the dexmethylphenidate hydrochloride extended-release capsules - treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the dexmethylphenidate hydrochloride extended-release capsules discontinued due to insomnia and jittery, respectively and two patients (1.2%) in the dexmethylphenidate hydrochloride extended-release capsules discontinued due to anorexia and anxiety, respectively.

Table

3 enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed dexmethylphenidate hydrochloride extended-release capsules doses of 20, 30, or 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate hydrochloride extended-release capsules dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release capsules appeared to increase with dose.

Table

3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHD System organ class Adverse reaction Dexmethylphenidate Hydrochloride Extended-Release Capsules 20 mg N=57 Dexmethylphenidate Hydrochloride Extended-Release Capsules 30 mg N=54 Dexmethylphenidate Hydrochloride Extended-Release Capsules 40 mg N=54 Placebo N=53 Gastrointestinal disorders 28% 32% 44% 19% Dry mouth 7% 20% 20% 4% Dyspesia 5% 9% 9% 2% Nervous system disorders 37% 39% 50% 28% Headache 26% 30% 39% 19% Psychiatric disorders 40% 43% 46% 30% Anxiety 5% 11% 11% 2% Respiratory, thoracic and mediastinal disorders 16% 9% 15% 8% Pharyngolaryngeal pain 4% 4% 7% 2% Two other adverse reactions occurring in clinical trials with dexmethylphenidate hydrochloride extended-release capsules at a frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively).

Table

4 summarizes changes in vital signs and weight that were recorded in the adult study (N=218) of dexmethylphenidate hydrochloride extended-release capsules in the treatment of ADHD.

Table

4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment-Adults Dexmethylphenidate Hydrochloride Extended-Release Capsules 20 mg (N=57)

Dexmethylphenidate Hydrochloride

Extended-release Capsules 30 mg (N=54)

Dexmethylphenidate Hydrochloride

Extended-Release Capsules 40 mg (N=54) Placebo (N=53) Pulse (bpm ) 3.1 ± 11.1 4.3 ± 11.7 6.0 ± 10.1 -1.4 ±

9.3 Diastolic BP (mmHg) -0.2 ± 8.2 1.2 ± 8.9 2.1 ± 8 0.3 ±

7.8 Weight (kg) -1.4 ± 2 -1.2 ± 1.9 -1.7 ± 2.3 -0.1 ± 3.9

6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal: rhabdomyolysis Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Adverse Reactions Reported With All Methylphenidate Hydrochloride and Dexmethylphenidate Hydrochloride Formulations The following adverse reactions associated with the use of all methylphenidate hydrochloride and dexmethylphenidate hydrochloride formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Infections and Infestations: nasopharyngitis Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs Eye Disorders: blurred vision, difficulties in visual accommodation Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris Respiratory, Thoracic, and Mediastinal Disorders: cough Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus Investigations: weight loss (adult ADHD patients)

Vascular

Disorders: peripheral coldness, Raynaud's phenomenon Additional Adverse Reactions Reported with Other Methylphenidate Products The list below shows adverse reactions not listed with methylphenidate hydrochloride and dexmethylphenidate hydrochloride formulations that have been reported with other methylphenidate products based on clinical trials data and post-marketing spontaneous reports. Blood and Lymphatic Disorders: pancytopenia Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas Psychiatric Disorders: affect lability, mania, disorientation, libido changes Nervous System Disorders: migraine, motor and verbal tics Eye Disorders: diplopia, increased intraocular pressure, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching Renal and Urinary Disorders: hematuria Reproductive System and Breast Disorders: gynecomastia General Disorders: fatigue, hyperpyrexia Urogenital Disorders: priapism

AND PRECAUTIONS Serious Cardiovascular Events: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Stimulant products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. ( 5.1 )

Increased Blood

Pressure and Heart Rate: have been reported. Monitor patients for changes in blood pressure and heart rate. Caution should be exercised in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate. ( 5.2 )

Assess Cardiovascular

Status: Prior to stimulant treatment, assess for cardiac disease with history and exam and, if suggested by findings, conduct further cardiac evaluation. Patients with emerging symptoms suggestive of cardiac disease should undergo a prompt cardiac evaluation. ( 5.3 )

Psychotic

Symptoms: may be exacerbated in patients with psychotic disorders. ( 5.4 )

Bipolar

Disorder: Use with particular care in ADHD patients with comorbid Bipolar Disorder. Before initiating stimulant therapy, obtain a detailed psychiatric history for patients with comorbid depressive symptoms, in order to determine risk for Bipolar Disorder. ( 5.5 ) Emergence of New Psychotic or Manic Symptoms: Treatment-emergent psychotic or manic symptoms without a prior history can be caused by stimulants at usual doses. Discontinuation of stimulant therapy may be indicated. ( 5.6 ) Aggression: Monitor for appearance of or worsening of aggressive behavior or hostility. ( 5.7 ) Long-Term Suppression of Growth: Monitor height and weight in pediatric patients at appropriate intervals. Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. ( 5.8 ) Seizures: The threshold for seizures may be lowered. In the presence of seizure, discontinue treatment. ( 5.9 ) Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed. ( 5.10 )

Peripheral

Vasculopathy, Including Raynaud’s Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants. ( 5.11 )

Visual

Disturbance: Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. ( 5.12 )

Hematologic

Monitoring: Periodic monitoring of CBC with differential is advised during prolonged therapy. ( 5.14 )

5.1 Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults

Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.

5.2 Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

5.3 Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

5.4 Preexisting Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

5.5 Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

5.6 Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.

5.7 Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the post marketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.

5.8 Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In the 7-week, double-blind, placebo-controlled study of dexmethylphenidate hydrochloride extended-release, the mean weight gain was greater for patients receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended-release (-0.5 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.9 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.

5.10 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.11 Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including dexmethylphenidate hydrochloride extended-release, 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 postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

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

5.13 Use in Children Under Six Years of Age Dexmethylphenidate hydrochloride extended-release should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.

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

INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ).

Halogenated

Anesthetics: Avoid use of dexmethylphenidate hydrochloride tablets on the day of surgery if halogenated anesthetics will be used ( 7.1 ).

7.1 Clinically Important Drug Interactions With Dexmethylphenidate Hydrochloride Tablets Table 2 presents clinically important drug interactions with dexmethylphenidate hydrochloride tablets.

Table

2: Clinically Important Drug Interactions With Dexmethylphenidate Hydrochloride Tablets Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact

Concomitant use of MAOIs and CNS stimulants, including dexmethylphenidate hydrochloride 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 dexmethylphenidate hydrochloride 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 Dexmethylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )].

Intervention

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 dexmethylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery.

Intervention

Monitor blood pressure and avoid use of dexmethylphenidate hydrochloride tablets in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane Risperidone Clinical Impact 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)

Intervention

Monitor for signs of EPS