FDA label 59cd1285-2c56-6765-e063-6294a90a58cb

WARNING: ABUSE AND DEPENDENCE CNS stimulants, including methylphenidate hydrochloride extended-release capsules (LA), other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warning and Precautions (5.1) , Drug Abuse and Dependence (9.2 , 9.3) ] . WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. CNS stimulants, including methylphenidate hydrochloride extended-release capsules (LA), other methylphenidate- containing products, and amphetamines, have a high potential for abuse and dependence ( 5.1 , 9.2 , 9.3 ). Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy ( 5.1 , 9.2 )

5 WARNINGS AND PRECAUTIONS Serious Cardiovascular Events : Sudden death has been reported in association with CNS-stimulant treatment at usual doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm arrhythmias, or coronary artery disease ( 5.2 ). Blood Pressure and Heart Rate Increases : Monitor blood pressure and pulse. Consider the benefits and risk in patients for whom an increase in blood pressure or heart rate would be problematic ( 5.3 ). Psychiatric Adverse Reactions : Use of stimulants may cause psychotic or manic symptoms in patients with no prior history or exacerbation of symptoms in patients with preexisting psychiatric illness. Evaluate for preexisting psychotic or bipolar disorder prior to methylphenidate hydrochloride extended-release capsules (LA) use ( 5.4 ). 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 ( 5.5 ). 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 ( 5.6 ). Long-Term Suppression of Growth : Monitor height and weight at appropriate intervals in pediatric patients ( 5.7 ). 5.1 Potential for Abuse and Dependence CNS stimulants, including methylphenidate hydrochloride extended-release capsules (LA), other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning , Drug Abuse and Dependence (9.2 , 9.3) ]. 5.2 Serious Cardiovascular Reactions Sudden death, stroke, and myocardial infarction have been reported in adults with CNS-stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during methylphenidate hydrochloride extended-release capsules (LA) treatment. 5.3 Blood Pressure and Heart Rate Increases CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Preexisting 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 Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating 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 recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release capsules (LA). 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 to 0 in placebo-treated patients. 5.5 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. 5.6 Peripheral Vasculopathy, Including Raynaud's Phenomenon CNS Stimulants, including methylphenidate hydrochloride extended-release capsules (LA), used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.7 Long-Term Suppression of Growth CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in pediatric patients 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 patients over 36 months (to the ages of 10-13 years), suggests that consistently medicated pediatric patients (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. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including methylphenidate hydrochloride extended-release capsules (LA). Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse and Dependence [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2 , 9.3) ] Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride extended-release capsules (LA) [see Contraindications (4) ] Hypertensive crisis when used concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7.1) ] Serious Cardiovascular Reactions [see Warnings and Precautions (5.2) ] Blood Pressure and Heart Rate Increases [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 [see Warnings and Precautions (5.7) ] Most common adverse reactions (greater than 5% during incidence) were headache, insomnia, upper abdominal pain, decreased appetite and anorexia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 practice. The clinical program for methylphenidate hydrochloride extended-release capsules (LA) consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received methylphenidate hydrochloride extended-release capsules (LA) in doses of 10 to 40 mg per day. Safety of methylphenidate hydrochloride extended-release capsules (LA) was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of methylphenidate hydrochloride extended-release capsules (LA) in children with ADHD aged 6 to 12 years. All subjects received methylphenidate hydrochloride extended-release capsules (LA) for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the 2-week double-blind treatment phase of this study, patients received either placebo or methylphenidate hydrochloride extended-release capsules (LA) at their individually-titrated dose (range, 10 to 40 mg). Adverse reactions with an incidence greater than 5% during the initial 4-week single-blind methylphenidate hydrochloride extended-release capsules (LA) titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. Adverse reactions with an incidence greater than 2% among methylphenidate hydrochloride extended-release capsules (LA) -treated subjects, during the 2-week double-blind phase of the clinical study, are shown in Table 2: Table 2: Adverse Reactions in Greater Than 2% Methylphenidate Hydrochloride Extended-Release Capsules (LA)-Treated Subjects in the 2-Week Double-Blind Phase Preferred Term Methylphenidate Hydrochloride Extended-Release Capsules (LA) N = 65 N (%) Placebo N = 71 N (%) Anorexia 2 (3.1) 0 (0.0) Insomnia 2 (3.1) 0 (0.0) Adverse Events Associated with Discontinuation of Treatment In the 2-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, one methylphenidate hydrochloride extended-release capsules (LA)-treated subject (1/65, 1.5%) discontinued due to an adverse event (depressed mood). In the single-blind titration period of this study, subjects received methylphenidate hydrochloride extended-release capsules (LA) for up to 4 weeks. During this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (2 patients), hypomania, anxiety, depressed mood, fatigue, migraine, and lethargy. 6.2 Postmarketing Experience The following adverse reactions have been identified during the post approval use of methylphenidate products. 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. Adverse Reactions Reported With Methylphenidate Hydrochloride Tablets, Methylphenidate Hydrochloride Extended-Release Tablets, and Methylphenidate Hydrochloride Extended- Release Capsules (LA) 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 children Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood 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 Investigations: weight loss (adult ADHD patients) Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed with methylphenidate hydrochloride tablets, methylphenidate hydrochloride extended-release tablets, or methylphenidate hydrochloride extended-release capsules (LA) formulations that have been reported with other methylphenidate-containing products. 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 Eye Disorders: diplopia, mydriasis Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole Vascular Disorders: peripheral coldness, Raynaud's phenomenon 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

<table width="85%" ID="table2"><caption>Table 2: Adverse Reactions in Greater Than 2% Methylphenidate Hydrochloride Extended-Release Capsules (LA)-Treated Subjects in the 2-Week Double-Blind Phase</caption><col width="25%" align="left" valign="top"/><col width="37%" align="center" valign="top"/><col width="38%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Preferred Term</th><th styleCode="Rrule">Methylphenidate Hydrochloride Extended-Release Capsules (LA) <content styleCode="underline"> N = 65 </content> N (%) </th><th styleCode="Rrule">Placebo <content styleCode="underline">N = 71</content> N (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anorexia</td><td styleCode="Rrule">2 (3.1)</td><td styleCode="Rrule">0 (0.0)</td></tr><tr><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">2 (3.1)</td><td styleCode="Rrule">0 (0.0)</td></tr></tbody></table>