FDA label efdeb634-de79-46cb-97b0-e94c35a9228d

WARNING: DRUG DEPENDENCE Methylphenidate hydrochloride extended-release tablets should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. WARNING: DRUG DEPENDENCE See full prescribing information for complete boxed warning. Methylphenidate hydrochloride extended-release tablets should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence, with varying degrees of abnormal behavior.

What is the most important information I should know about methylphenidate hydrochloride extended-release tablets? The following have been reported with use of methylphenidate HCl and other stimulant medicines: 1. Heart-related problems: • sudden death in patients who have heart problems or heart defects • stroke and heart attack in adults • increased blood pressure and heart rate Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride extended-release tablets. Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release tablets. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking methylphenidate hydrochloride extended-release tablets. 2. Mental (Psychiatric) problems: All Patients • new or worse behavior and thought problems • new or worse bipolar illness • new or worse aggressive behavior or hostility Children and Teenagers • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child has any new or worsening mental symptoms or problems while taking methylphenidate hydrochloride extended-release tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

Methylphenidate hydrochloride extended-release tablets is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep methylphenidate hydrochloride extended-release tablets in a safe place to prevent misuse and abuse. Selling or giving away Methylphenidate hydrochloride extended-release tablets may harm others, and is against the law. Tell your doctor if you or your child has (or has a family history of) ever abused or been dependent on alcohol, prescription medicines, or street drugs.

5 WARNINGS 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) Increase in Blood Pressure: Monitor patients for changes in heart rate and blood pressure and use with caution in patients for whom an increase in blood pressure or heart rate would be problematic. (5.1) Psychiatric Adverse Events: Use of stimulants may cause treatment-emergent psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with preexisting psychiatric illness. Clinical evaluation for Bipolar Disorder is recommended prior to stimulant use. Monitor for aggressive behavior. (5.2) Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. (5.3) 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 painful or prolonged penile erections or priapism are observed. (5.4) 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. (5.5) Visual Disturbance: difficulties with accommodation and blurring of vision have been reported with stimulant treatment. (5.7) Long-Term Suppression of Growth: monitor height and weight at appropriate intervals in pediatric patients. (5.6) Gastrointestinal obstruction with preexisting GI narrowing. (5.8) Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. (5.9) 5.1 Serious Cardiovascular Events 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 deaths, 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. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mm Hg) and average heart rate (about 3 to 6 bpm) [see Adverse Reactions (6.5)] , 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. 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. 5.2 Psychiatric Adverse Events Preexisting Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. 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. Emergence of New Psychotic or Manic Symptoms Treatment-emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients 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. Aggression Aggressive behavior or hostility is often observed in patients with ADHD, and has been reported in clinical trials and the postmarketing 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. 5.3 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. 5.4 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, including methylphenidate hydrochloride extended-release tablets, in both pediatric and adult patients [see Adverse Reactions (6.6)] . Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.5 Peripheral Vasculopathy, including Raynaud’s Phenomenon Stimulants, including methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. 5.6 Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-­treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause similar suppression of growth; however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.7 Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. 5.8 Potential for Gastrointestinal Obstruction Because the methylphenidate hydrochloride extended-release tablet is nondeformable and does not appreciably change in shape in the GI tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the tablet whole [see Patient Counseling Information (17)] . 5.9 Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Drug Dependence [see Box Warning] Hypersensitivity to Methylphenidate [see Contraindications (4.1)] Agitation [see Contraindications (4.2)] Glaucoma [see Contraindications (4.3)] Tics [see Contraindications (4.4)] Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1)] Serious Cardiovascular Events [see Warnings and Precautions (5.1)] Psychiatric Adverse Events [see Warnings and Precautions (5.2)] Seizures [see Warnings and Precautions (5.3)] Priapism [see Warnings and Precautions (5.4)] Long-Term Suppression of Growth [see Warnings and Precautions (5.6)] Visual Disturbance [see Warnings and Precautions (5.7)] Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8)] Hematologic Monitoring [see Warnings and Precautions (5.9)] The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis [see Adverse Reactions (6.1)]. The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Adverse Reactions (6.3)]. The development program for methylphenidate hydrochloride extended-release tablets included exposures in a total of 3,906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses. 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 tablets based on the comprehensive assessment of the available adverse event information. A causal association for methylphenidate hydrochloride extended-release tablets often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of adverse reactions were mild to moderate in severity. 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 Camber Pharmaceuticals, Inc. at 1-866-495-8330 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. 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. 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 >0.5% in the methylphenidate hydrochloride extended-release tablets patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%). In the 11 open-label studies of children, adolescents, and adults, 266 methylphenidate hydrochloride extended-release tablets patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). 6.4 Tics In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with methylphenidate hydrochloride extended-release tablets. In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). The treatment period was up to 9 months with mean treatment duration of 7.2 months. 6.5 Blood Pressure and Heart Rate Increases In the laboratory classroom clinical trials in children (Studies 1 and 2), both methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -­0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind treatment (3.6 and -1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were -1.2 and -0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.1)] . 6.6 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of methylphenidate hydrochloride extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders: Diplopia, Mydriasis, Visual impairment General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes Reproductive System and Breast Disorders: Priapism Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema Vascular Disorders: Raynaud’s phenomenon