ABUSE SECTION.

9.2 Abuse. CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines have high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].To reduce the abuse of CNS stimulants, including Focalin XR, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and reevaluate the need for Focalin XR use.

ADVERSE REACTIONS SECTION.

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 Focalin XR [see Contraindications (4)] Hypertensive Crisis with Concomitant Use of 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 Raynauds Phenomenon [see Warnings and Precautions (5.6)] Long-Term Suppression of Growth [see Warnings and Precautions (5.7)] 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 Focalin XR [see Contraindications (4)] Hypertensive Crisis with Concomitant Use of 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 Raynauds Phenomenon [see Warnings and Precautions (5.6)] Long-Term Suppression of Growth [see Warnings and Precautions (5.7)] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo):Pediatric patients 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 Novartis Pharmaceuticals Corporation at 1-888-669-6682, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Pediatric patients to 17 years: dyspepsia, decreased appetite, headache, and anxiety. (6.1). Adults: dry mouth, dyspepsia, headache, pharyngolaryngeal pain, and anxiety. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Clinical Trials Experience With Focalin XR in Pediatric Patients With ADHDThe safety data in this section is based on data from 7-week controlled clinical study of Focalin XR in 100 (103 randomized) pediatric patients with ADHD ages to 17 years (ages to 12, = 86; ages 13 to 17, = 17).This study was randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of Focalin XR 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 Focalin (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 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible Focalin XR doses of 5-30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with Focalin XR and for which the incidence in patients treated with Focalin XR 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 ADHDAbbreviation: ADHD, attention deficit hyperactivity disorder.System Organ ClassAdverse ReactionFocalin XRN 53PlaceboN 47Gastrointestinal Disorders38%19% Dyspepsia8%4%Metabolism and Nutrition Disorders34%11% Decreased appetite30%9%Nervous System Disorders30%13% Headache25%11%Psychiatric Disorders26%15% Anxiety6%0%Table below enumerates the incidence of dose-related adverse reactions that occurred during fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking Focalin XR up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with Focalin XR 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 ADHDAbbreviation: ADHD, attention deficit hyperactivity disorder.System Organ ClassAdverse ReactionFocalin XR10 mg/dayN 64Focalin XR20 mg/dayN 60Focalin XR30 mg/dayN 58PlaceboN 63Gastrointestinal Disorders22%23%29%24%Vomiting2%8%9%0%Metabolism and Nutritional Disorders16%17%22%5%Anorexia5%5%7%0Psychiatric Disorders19%20%38%8%Insomnia5%8%17%3%Depression003%0Mood swings0%0%3%2%Other Adverse ReactionsIrritability0%2%5%0%Nasal congestion0%0%5%0%Pruritus0%0%3%0%Clinical Trials Experience With Focalin XR in Adult Patients With ADHDThe safety data in this section is based on data from 5-week controlled clinical study of Focalin XR in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least months.This study was randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of Focalin XR 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 Focalin XR-treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the Focalin XR discontinued due to insomnia and jittery, respectively and two patients (1.2%) in the Focalin XR discontinued due to anorexia and anxiety, respectively.Table enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed Focalin XR doses of 20, 30, and 40 mg/day. The table includes only those events that occurred in 5% or more of patients in Focalin XR dose group and for which the incidences in patients treated with Focalin XR appeared to increase with dose.Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHDSystem Organ ClassAdverse ReactionFocalin XR20 mgN 57Focalin XR30 mgN 54Focalin XR40 mgN 54PlaceboN 53Gastrointestinal Disorders28%32%44%19% Dry mouth7%20%20%4% Dyspepsia5%9%9%2%Nervous System Disorders37%39%50%28% Headache26%30%39%19%Psychiatric Disorders40%43%46%30% Anxiety5%11%11%2%Respiratory, Thoracic, and Mediastinal Disorders16%9%15%8% Pharyngolaryngeal pain4%4%7%2%Two other adverse reactions occurring in clinical trials with Focalin XR at frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively).Table summarizes changes in vital signs and weight that were recorded in the adult study (N 218) of Focalin XR in the treatment of ADHD.Table 4: Changes (Mean +- SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment-AdultsFocalin XR20 mg(N 57)Focalin XR30 mg(N 54)Focalin XR40 mg(N 54)Placebo(N 53)Pulse (bpm)3.1 +- 11.14.3 +- 11.76.0 +- 10.1-1.4 +- 9.3Diastolic BP (mmHg)-0.2 +- 8.21.2 +- 8.92.1 +- 8.00.3 +- 7.8Weight (kg)-1.4 +- 2.0-1.2 +- 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Musculoskeletal: rhabdomyolysisImmune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxisAdverse Reactions Reported With All Ritalin and Focalin FormulationsThe following adverse reactions associated with the use of all Ritalin and Focalin formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Infections and Infestations: nasopharyngitisBlood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemiaImmune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxisMetabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patientsPsychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed moodNervous 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 drugsEye Disorders: blurred vision, difficulties in visual accommodationCardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectorisRespiratory, Thoracic, and Mediastinal Disorders: coughGastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsiaHepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injurySkin 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, rhabdomyolysisInvestigations: weight loss (adult ADHD patients)Additional Adverse Reactions Reported With Other Methylphenidate ProductsThe list below shows adverse reactions not listed with Ritalin and Focalin 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, exanthemasPsychiatric Disorders: affect lability, mania, disorientation, libido changesNervous System Disorders: migraine Eye Disorders: diplopia, mydriasisCardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystoleVascular Disorders: peripheral coldness, Raynauds phenomenon Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspneaGastrointestinal Disorders: diarrhea, constipationSkin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruptionMusculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitchingRenal and Urinary Disorders: hematuriaReproductive System and Breast Disorders: gynecomastiaGeneral Disorders: fatigue, hyperpyrexiaUrogenital Disorders: priapism.

BOXED WARNING SECTION.

WARNING: ABUSE AND DEPENDENCE. CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines, have 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 Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].. WARNING: ABUSE AND DEPENDENCESee full prescribing information for complete boxed warning.CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines, have 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). CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines, have 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility. CarcinogenesisLifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas was seen at daily dose of approximately 60 mg/kg/day. This dose is approximately times the MRHD of 60 mg/day of racemic methylphenidate given to children on mg/m2 basis. Hepatoblastoma is 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.Racemic methylphenidate did not cause any increase in tumors in lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately times the MRHD (children) of 60 mg/day of racemic methylphenidate in children on mg/m2 basis.In 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate.MutagenesisDexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of weak clastogenic response.Impairment of FertilityNo human data on the effect of methylphenidate on fertility are available.Fertility studies have not been conducted with dexmethylphenidate. Racemic methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day of racemic methylphenidate given to adolescents on mg/m2 basis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. Figure Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration of x 20 mg Focalin XR (n=24) Capsules and x 10 mg Focalin Immediate-Release Tablets (n=25).. 12.1 Mechanism of Action. Dexmethylphenidate hydrochloride is CNS stimulant. The mode of therapeutic action in ADHD is not known.. 12.2 Pharmacodynamics. Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic methylphenidate. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.Cardiac ElectrophysiologyAt the recommended maximum total daily dosage of 40 mg, Focalin XR does not prolong the QTc interval to any clinically relevant extent.. 12.3 Pharmacokinetics. AbsorptionFocalin XR produces bi-modal plasma concentration-time profile (i.e., distinct peaks approximately hours apart) when orally administered to healthy adults. The initial rate of absorption for Focalin XR is similar to that of Focalin tablets as shown by the similar rate parameters between the formulations, i.e., first peak concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1.5 hours (typical range to hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) is slightly longer for Focalin XR given once daily (about 6.5 hours; range, 4.5 to hours) compared to Focalin tablets given in doses hours apart (see Figure 1), although the ranges observed are greater for Focalin XR.Focalin XR given once daily exhibits lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and fewer peak and trough fluctuations than Focalin tablets given in doses given hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1).The ratio of geometric mean of AUC(0-inf) and Cmax after administration of Focalin XR given once daily are 1.02 and 0.86 respectively, to the same total dose of Focalin tablets given in doses hours apart. The variability in Cmax, Cmin, and AUC is similar between Focalin XR and Focalin immediate-release tablets with approximately 3-fold range in each.Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism, the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration x 20 mg Focalin XR (n 24) Capsules and x 10 mg Focalin Immediate-Release Tablets (n 25)After single dose administration, Focalin XR demonstrated dose proportional pharmacokinetics (PK) in the range of mg to 40 mg.For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration (2)].DistributionThe plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows volume of distribution of 2.65 +- 1.11 L/kg.EliminationPlasma dexmethylphenidate concentrations decline monophasically following oral administration of Focalin XR. The mean terminal elimination half-life of dexmethylphenidate was about hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of to hours. Dexmethylphenidate was eliminated with mean clearance of 0.40 +- 0.12 L/hr/kg after intravenous administration.MetabolismIn humans, dexmethylphenidate is metabolized primarily via de-esterification to d--phenyl-piperidine acetic acid (also known as d-ritalinic acid). This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo-enantiomer.ExcretionAfter oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl- methylphenidate was dl-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.Studies in Specific PopulationsMale and Female PatientsAfter administration of Focalin XR, the first peak (Cmax1), was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization.Racial or Ethnic GroupsThere is insufficient experience with the use of Focalin XR to detect ethnic variations in pharmacokinetics.Pediatric PatientsThe pharmacokinetics of dexmethylphenidate after Focalin XR administration have not been studied in pediatrics less than 18 years of age. When similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and patients with ADHD between and years of age, the time to the first peak was similar, although the time until the between peak minimum, and the time until the second peak were delayed and more variable in pediatric patients compared to adults. After administration of the same dose to pediatric patients and adults, concentrations in pediatric patients were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight.Patients with Renal ImpairmentThere is no experience with the use of Focalin XR in patients with renal impairment. Since renal clearance is not an important route of methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of Focalin XR.Patients with Hepatic ImpairmentThere is no experience with the use of Focalin XR in patients with hepatic impairment.Drug Interaction StudiesMethylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Pediatric Patients. randomized, double-blind, placebo-controlled, parallel-group study (Study 1) was conducted in 103 pediatric patients (ages to 12, = 86; ages 13 to 17, = 17) who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 1).Patients were randomized to receive either flexible-dose of Focalin XR (5 to 30 mg/day) or placebo once daily for weeks. During the first weeks of treatment, patients were titrated to their optimal dose and remained on this optimal dose for the last weeks of the study without dose changes or interruption.Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for Focalin XR and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the DSM-IV total subscale score of the Conners ADHD/DSM-IV Scales for teachers (CADS-T). The CADS-T includes the ADHD Index (12 texts) and the DSM-IV total subscale (18 texts, total score range: to 54); the latter is divided into inattentive (9 texts) and hyperactive-impulsive (9 texts) subscales. Teachers assessed behavior observed during the school day by completing the CADS-T weekly. decrease in the CADS-T DSM-IV total subscale score from baseline indicates improvement.The CADS-T total scores showed statistically significant treatment effect in favor of Focalin XR than placebo (Table 6). There were insufficient adolescents enrolled in this study to assess the efficacy for Focalin XR in the adolescent population. However, pharmacokinetic considerations and evidence of effectiveness of immediate-release Focalin in adolescents support the effectiveness of Focalin XR in this population.Table 6: Summary of Efficacy Results from ADHD Study in Pediatric Patients (6 17 years) (Study 1)Abbreviations: ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons. aDifference (drug minus placebo) in least-squares mean change from baseline.Study NumberTreatment GroupPrimary Efficacy Measure: CADS-T Total ScoreMean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea (95% CI)Study 1Focalin XR 5-30 mg/day(n 52)33.3 (9.18)16.41 (1.8)10.64 (5.38, 15.91)Placebo(n 45)34.9 (10.03)5.77 (1.93)--In additional cross-over studies (Studies and 3) in pediatric patients ages to 12 years, who received 20 mg Focalin XR or placebo, Focalin XR was found to have statistically significant treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn Pelham (SKAMP) rating scale total scores at all-time points after dosing in each study (0.5, 1, 3, 4, 5, 7, 9, 10, 11, and 12 hours in Study and 1, 2, 4, 6, 8, 9, 10, 11, and 12 hours in the Study 3). SKAMP is validated 13-text teacher-rated scale that assesses manifestations of ADHD in classroom setting. treatment effect was also observed 0.5 hours after administration of Focalin XR 20 mg in an additional study of ADHD patients ages to 12 years.. 14.2 Adult Patients. randomized, double-blind, placebo-controlled, parallel-group (Study 4) was conducted in 221 adult patients ages 18 to 60 years who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 4).Patients were randomized to receive either fixed dose of Focalin XR (20, 30, or 40 mg/day) or placebo once daily for weeks. Patients randomized to Focalin XR were initiated on 10 mg/day starting dose and titrated in increments of 10 mg/week to the randomly assigned fixed dose. Patients were maintained on their fixed dose (20, 30, or 40 mg/day) for minimum of weeks.Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for Focalin XR and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the investigator-administered DSM-IV Attention-Deficit/Hyperactivity Disorder Rating Scale (DSM-IV ADHD-RS).The DSM-IV ADHD-RS is an 18-text questionnaire with score range of to 54 points that measures the core symptoms of ADHD and includes both hyperactive/impulsive and inattentive subscales.All Focalin XR doses (20, 30, and 40 mg/day) showed statistically significant treatment effect compared to placebo. There was no obvious increase in effectiveness with increasing the dose.Table 7: Summary of Efficacy Results from ADHD Study in Adults (Study 4)Abbreviations: ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons. aDifference (drug minus placebo) in least-squares mean change from baseline. Study NumberTreatment GroupPrimary Efficacy Measure: ADHD-RS Total ScoreMean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea (95% CI)Study 4Focalin XR 20 mg/day(n 57)36.8 (7.2)13.27 (1.44)5.71 (1.64, 9.78)Focalin XR 30 mg/day(n 54)36.9 (8.07)12.86 (1.48)5.31 (1.18, 9.44)Focalin XR 40 mg/day(n 54)36.9 (8.25)16.51 (1.48)8.96 (4.83, 13.08)Placebo(n 53)37.5 (7.82)7.55 (1.49)--.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Clinical Trials Experience With Focalin XR in Pediatric Patients With ADHDThe safety data in this section is based on data from 7-week controlled clinical study of Focalin XR in 100 (103 randomized) pediatric patients with ADHD ages to 17 years (ages to 12, = 86; ages 13 to 17, = 17).This study was randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of Focalin XR 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 Focalin (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 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible Focalin XR doses of 5-30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with Focalin XR and for which the incidence in patients treated with Focalin XR 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 ADHDAbbreviation: ADHD, attention deficit hyperactivity disorder.System Organ ClassAdverse ReactionFocalin XRN 53PlaceboN 47Gastrointestinal Disorders38%19% Dyspepsia8%4%Metabolism and Nutrition Disorders34%11% Decreased appetite30%9%Nervous System Disorders30%13% Headache25%11%Psychiatric Disorders26%15% Anxiety6%0%Table below enumerates the incidence of dose-related adverse reactions that occurred during fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking Focalin XR up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with Focalin XR 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 ADHDAbbreviation: ADHD, attention deficit hyperactivity disorder.System Organ ClassAdverse ReactionFocalin XR10 mg/dayN 64Focalin XR20 mg/dayN 60Focalin XR30 mg/dayN 58PlaceboN 63Gastrointestinal Disorders22%23%29%24%Vomiting2%8%9%0%Metabolism and Nutritional Disorders16%17%22%5%Anorexia5%5%7%0Psychiatric Disorders19%20%38%8%Insomnia5%8%17%3%Depression003%0Mood swings0%0%3%2%Other Adverse ReactionsIrritability0%2%5%0%Nasal congestion0%0%5%0%Pruritus0%0%3%0%Clinical Trials Experience With Focalin XR in Adult Patients With ADHDThe safety data in this section is based on data from 5-week controlled clinical study of Focalin XR in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least months.This study was randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of Focalin XR 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 Focalin XR-treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the Focalin XR discontinued due to insomnia and jittery, respectively and two patients (1.2%) in the Focalin XR discontinued due to anorexia and anxiety, respectively.Table enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed Focalin XR doses of 20, 30, and 40 mg/day. The table includes only those events that occurred in 5% or more of patients in Focalin XR dose group and for which the incidences in patients treated with Focalin XR appeared to increase with dose.Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHDSystem Organ ClassAdverse ReactionFocalin XR20 mgN 57Focalin XR30 mgN 54Focalin XR40 mgN 54PlaceboN 53Gastrointestinal Disorders28%32%44%19% Dry mouth7%20%20%4% Dyspepsia5%9%9%2%Nervous System Disorders37%39%50%28% Headache26%30%39%19%Psychiatric Disorders40%43%46%30% Anxiety5%11%11%2%Respiratory, Thoracic, and Mediastinal Disorders16%9%15%8% Pharyngolaryngeal pain4%4%7%2%Two other adverse reactions occurring in clinical trials with Focalin XR at frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively).Table summarizes changes in vital signs and weight that were recorded in the adult study (N 218) of Focalin XR in the treatment of ADHD.Table 4: Changes (Mean +- SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment-AdultsFocalin XR20 mg(N 57)Focalin XR30 mg(N 54)Focalin XR40 mg(N 54)Placebo(N 53)Pulse (bpm)3.1 +- 11.14.3 +- 11.76.0 +- 10.1-1.4 +- 9.3Diastolic BP (mmHg)-0.2 +- 8.21.2 +- 8.92.1 +- 8.00.3 +- 7.8Weight (kg)-1.4 +- 2.0-1.2 +- 1.9-1.7 +- 2.3-0.1 +- 3.9.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Hypersensitivity to methylphenidate or other components of Focalin XR. Hypersensitivity reactions, such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1)].Concomitant treatment with monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7.1)].. Hypersensitivity to methylphenidate or other components of Focalin XR. Hypersensitivity reactions, such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1)].. Concomitant treatment with monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7.1)].. Known hypersensitivity to methylphenidate or other components of Focalin XR. (4)Concurrent treatment with monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. (4). Known hypersensitivity to methylphenidate or other components of Focalin XR. (4). Concurrent treatment with monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. (4).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance. Focalin XR contains dexmethylphenidate hydrochloride, Schedule II controlled substance.

DEPENDENCE SECTION.

9.3 Dependence. ToleranceTolerance (a state of adaptation in which exposure to drug results in reduction of the drugs desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including Focalin XR.DependencePhysical dependence (which is manifested by withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants, including Focalin XR. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

DESCRIPTION SECTION.

11 DESCRIPTION. Focalin XR contains dexmethylphenidate hydrochloride, CNS stimulant. Dexmethylphenidate hydrochloride is the d-threo enantiomer of racemic methylphenidate hydrochloride. Focalin XR is an extended-release formulation of dexmethylphenidate with bi-modal release profile. Each bead-filled Focalin XR capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of dexmethylphenidate and delayed release of dexmethylphenidate. Focalin XR is intended for oral administration and is available as mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg extended-release capsules.Chemically, dexmethylphenidate hydrochloride is methyl -phenyl-2-piperidineacetate hydrochloride, (R,R)-(+)-. Its molecular formula is C14H19NO2oHCl. Its structural formula is: Note asymmetric carbon centerDexmethylphenidate hydrochloride is 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: ammonio methacrylate copolymer, gelatin, methacrylic acid copolymer, polyethylene glycol, sugar spheres, talc, titanium dioxide, and triethyl citrate.Each strength capsule also contains colorant ingredients in the capsule shell as follows:5 mg: E132 FD&C Blue No. 210 mg: FDA/E172 iron oxide yellow15 mg: FD&C Blue No. 2, FDA/E172 iron oxide yellow20 mg: contains no colorants25 mg: E132 FD&C Blue No. 230 mg: FDA/E172 iron oxide yellow35 mg: E132 FD&C Blue No. 2, FDA/E172 iron oxide yellow40 mg: E132 FD&C Blue No. 2, FDA/E172 iron oxide yellow. mg: E132 FD&C Blue No. 2. 10 mg: FDA/E172 iron oxide yellow. 15 mg: FD&C Blue No. 2, FDA/E172 iron oxide yellow. 20 mg: contains no colorants. 25 mg: E132 FD&C Blue No. 2. 30 mg: FDA/E172 iron oxide yellow. 35 mg: E132 FD&C Blue No. 2, FDA/E172 iron oxide yellow. 40 mg: E132 FD&C Blue No. 2, FDA/E172 iron oxide yellow. Dexmethylphenidate hydrochloride structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Patients new to methylphenidate: Recommended starting dose is 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: Focalin XR dosage is half (1/2) the current total daily dosage of methylphenidate. (2.2)Patients currently on Focalin (dexmethylphenidate) immediate-release tablets: Give the same daily dose of Focalin XR. (2.2)Titrate weekly in increments of 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). Patients new to methylphenidate: Recommended starting dose is 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: Focalin XR dosage is half (1/2) the current total daily dosage of methylphenidate. (2.2). Patients currently on Focalin (dexmethylphenidate) immediate-release tablets: Give the same daily dose of Focalin XR. (2.2). Titrate weekly in increments of 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 Focalin XR, assess for the presence of cardiac disease (i.e., perform careful history, including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)].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 reevaluate the need for Focalin XR use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].. 2.2 Treatment of Attention Deficit Hyperactivity Disorder. Patients New to MethylphenidateThe recommended starting dosage of Focalin XR 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 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 MethylphenidateThe recommended starting dose of Focalin XR for patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate.Patients currently using Focalin (dexmethylphenidate) immediate-release tablets may be given the same daily dose of Focalin XR.Titration ScheduleThe dose may be titrated weekly in increments of 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 TreatmentPharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Focalin XR and adjust dosage as needed.. Pediatric patients: Start with 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.. 2.3 Administration Instructions. Focalin XR 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 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 Focalin XR. If improvement is not observed after appropriate dosage adjustment over one-month period, the drug should be discontinued.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. mg extended-release capsules light blue opaque cap and body (imprinted with NVR on cap and D5 on the body)10 mg extended-release capsules light caramel opaque cap and body (imprinted with NVR on cap and D10 on the body)15 mg extended-release capsules green opaque cap and body (imprinted with NVR on cap and D15 on the body)20 mg extended-release capsules white opaque cap and body (imprinted with NVR on cap and D20 on the body)25 mg extended-release capsules light blue opaque cap and white opaque body (imprinted with NVR on cap and D25 on the body)30 mg extended-release capsules light caramel opaque cap and white opaque body (imprinted with NVR on cap and D30 on the body)35 mg extended-release capsules light blue opaque cap and light caramel opaque body (imprinted with NVR on cap and D35 on the body)40 mg extended-release capsules green opaque cap and white opaque body (imprinted with NVR on cap and D40 on the body). mg extended-release capsules light blue opaque cap and body (imprinted with NVR on cap and D5 on the body). 10 mg extended-release capsules light caramel opaque cap and body (imprinted with NVR on cap and D10 on the body). 15 mg extended-release capsules green opaque cap and body (imprinted with NVR on cap and D15 on the body). 20 mg extended-release capsules white opaque cap and body (imprinted with NVR on cap and D20 on the body). 25 mg extended-release capsules light blue opaque cap and white opaque body (imprinted with NVR on cap and D25 on the body). 30 mg extended-release capsules light caramel opaque cap and white opaque body (imprinted with NVR on cap and D30 on the body). 35 mg extended-release capsules light blue opaque cap and light caramel opaque body (imprinted with NVR on cap and D35 on the body). 40 mg extended-release capsules green opaque cap and white opaque body (imprinted with NVR on cap and D40 on the body). Extended-Release Capsules: mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg of dexmethylphenidate hydrochloride. (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. Focalin XR contains dexmethylphenidate hydrochloride, Schedule II controlled substance.. 9.2 Abuse. CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines have high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].To reduce the abuse of CNS stimulants, including Focalin XR, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and reevaluate the need for Focalin XR use.. 9.3 Dependence. ToleranceTolerance (a state of adaptation in which exposure to drug results in reduction of the drugs desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including Focalin XR.DependencePhysical dependence (which is manifested by withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants, including Focalin XR. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7.1)Halogenated Anesthetics: Avoid use of Focalin XR on the day of surgery if halogenated anesthetics will be used. (7.1). Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7.1). Halogenated Anesthetics: Avoid use of Focalin XR on the day of surgery if halogenated anesthetics will be used. (7.1). 7.1 Clinically Important Drug Interactions With Focalin XR. Table presents clinically important drug interactions with Focalin XR.Table 5: Clinically Important Drug Interactions With Focalin XRMonoamine Oxidase Inhibitors (MAOIs)Clinical ImpactConcomitant use of MAOIs and CNS stimulants, including Focalin XR, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)].InterventionConcomitant use of Focalin XR with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.Examplesselegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blueAntihypertensive DrugsClinical ImpactFocalin XR may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)]. InterventionMonitor blood pressure and adjust the dosage of the antihypertensive drug as needed.ExamplesPotassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonistsHalogenated Anesthetics Clinical ImpactConcomitant use of halogenated anesthetics and Focalin XR may increase the risk of sudden blood pressure and heart rate increase during surgery.InterventionAvoid use of Focalin XR in patients being treated with anesthetics on the day of surgery.Exampleshalothane, isoflurane, enflurane, desflurane, sevofluraneRisperidoneClinical ImpactCombined use of methylphenidate with risperidone when there is change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS).InterventionMonitor for signs of EPS.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Focalin XR has not been studied in the geriatric population.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Focalin XR (dexmethylphenidate hydrochloride) extended-release capsules are available as follows:5 mg capsules (NDC 0078-0430-05) light-blue, (imprinted NVR D5) supplied in bottles of 10010 mg capsules (NDC 0078-0431-05) light caramel (imprinted NVR D10) supplied in bottles of 10015 mg capsules (NDC 0078-0493-05) green (imprinted NVR D15) supplied in bottles of 10020 mg capsules (NDC 0078-0432-05) white (imprinted NVR D20) supplied in bottles of 10025 mg capsules (NDC 0078-0608-05) light-blue and white (imprinted NVR D25) supplied in bottles of 10030 mg capsules (NDC 0078-0433-05) light caramel and white (imprinted NVR D30) supplied in bottles of 10035 mg capsules (NDC 0078-0609-05) light-blue and light caramel (imprinted NVR D35) supplied in bottles of 10040 mg capsules (NDC 0078-0434-05) green and white (imprinted NVR D40) supplied in bottles of 100Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].Dispense in tight container (USP).DisposalComply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Focalin XR by medicine takeback program or by medicine take-back program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix Focalin XR with an undesirable, non-toxic substance to make it less appealing to children and pets. Place the mixture in container, such as sealed plastic bag and discard Focalin XR in the household trash.. mg capsules (NDC 0078-0430-05) light-blue, (imprinted NVR D5) supplied in bottles of 100. 10 mg capsules (NDC 0078-0431-05) light caramel (imprinted NVR D10) supplied in bottles of 100. 15 mg capsules (NDC 0078-0493-05) green (imprinted NVR D15) supplied in bottles of 100. 20 mg capsules (NDC 0078-0432-05) white (imprinted NVR D20) supplied in bottles of 100. 25 mg capsules (NDC 0078-0608-05) light-blue and white (imprinted NVR D25) supplied in bottles of 100. 30 mg capsules (NDC 0078-0433-05) light caramel and white (imprinted NVR D30) supplied in bottles of 100. 35 mg capsules (NDC 0078-0609-05) light-blue and light caramel (imprinted NVR D35) supplied in bottles of 100. 40 mg capsules (NDC 0078-0434-05) green and white (imprinted NVR D40) supplied in bottles of 100.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Focalin XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14)].. Focalin XR is central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-approved patient labeling (Medication Guide).Controlled Substance Status/High Potential for Abuse and DependenceAdvise patients that Focalin XR is controlled substance, and it can be abused and lead to dependence. Instruct patients that they should not give Focalin XR to anyone else. Advise patients to store Focalin XR in safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired Focalin XR by medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.1, 9.2, 9.3), How Supplied/Storage and Handling (16)].Serious Cardiovascular RisksAdvise patients that there is potential serious cardiovascular risk, including sudden death, myocardial infarction, stroke, and hypertension with Focalin XR use. Instruct patients to contact healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].Blood Pressure and Heart Rate IncreasesInstruct patients that Focalin XR can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].Psychiatric RisksAdvise patients that Focalin XR, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].PriapismAdvise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)].Circulation Problems in Fingers and Toes (Peripheral Vasculopathy, Including Raynauds Phenomenon)Instruct patients beginning treatment with Focalin XR about the risk of peripheral vasculopathy, including Raynauds 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 Focalin XR. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].Suppression of Growth Advise patients that Focalin XR may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].Pregnancy RegistryAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including Focalin XR, during pregnancy [see Use in Specific Populations (8.1)].Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936T2021-93.

LACTATION SECTION.

8.2 Lactation. Risk SummaryDexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Focalin XR and any potential adverse effects on the breastfed infant from Focalin XR or from the underlying maternal condition.Clinical ConsiderationsMonitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Dexmethylphenidate hydrochloride is CNS stimulant. The mode of therapeutic action in ADHD is not known.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility. CarcinogenesisLifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas was seen at daily dose of approximately 60 mg/kg/day. This dose is approximately times the MRHD of 60 mg/day of racemic methylphenidate given to children on mg/m2 basis. Hepatoblastoma is 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.Racemic methylphenidate did not cause any increase in tumors in lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately times the MRHD (children) of 60 mg/day of racemic methylphenidate in children on mg/m2 basis.In 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate.MutagenesisDexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of weak clastogenic response.Impairment of FertilityNo human data on the effect of methylphenidate on fertility are available.Fertility studies have not been conducted with dexmethylphenidate. Racemic methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day of racemic methylphenidate given to adolescents on mg/m2 basis.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Human ExperienceSigns and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.Overdose ManagementConsult with Certified Poison Control Center (1-800-222-1222) for the latest recommendations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0078-0430-05 Rx onlyFocalin XR(R) (dexmethylphenidate HCl)extended-release capsules5 mg100 capsulesDispense with MedicationGuide attached or providedseparately.NOVARTIS. PRINCIPAL DISPLAY PANELNDC 0078-0430-05Rx onlyFocalin XR(R)(dexmethylphenidate HCl)extended-release capsules5 mg100 capsulesDispense with Medication Guide attached or provided separately.NOVARTIS.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Focalin XR in pediatric patients less than years have not been established.The safety and effectiveness of Focalin XR for the treatment of ADHD have been established in pediatric patients ages to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14.2)]. The long-term efficacy of Focalin XR in pediatric patients has not been established.Long-Term Suppression of GrowthGrowth should be monitored during treatment with stimulants, including Focalin XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].Juvenile Animal Toxicity DataRats treated with racemic methylphenidate early in the postnatal period through sexual maturation demonstrated decrease in spontaneous locomotor activity in adulthood. deficit in acquisition of specific learning task was observed in females only. The doses at which these findings were observed are at least times the MRHD of 60 mg/day given to children on mg/m2 basis.In study conducted in young rats, racemic methylphenidate was administered orally at doses of up to 100 mg/kg/day for weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately times the MRHD of 60 mg/day of racemic methylphenidate given to children on mg/m2 basis) or greater, and deficit in the acquisition of specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was mg/kg/day (approximately 0.5 times the MRHD given to children on mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic methylphenidate. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.Cardiac ElectrophysiologyAt the recommended maximum total daily dosage of 40 mg, Focalin XR does not prolong the QTc interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFocalin XR produces bi-modal plasma concentration-time profile (i.e., distinct peaks approximately hours apart) when orally administered to healthy adults. The initial rate of absorption for Focalin XR is similar to that of Focalin tablets as shown by the similar rate parameters between the formulations, i.e., first peak concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1.5 hours (typical range to hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) is slightly longer for Focalin XR given once daily (about 6.5 hours; range, 4.5 to hours) compared to Focalin tablets given in doses hours apart (see Figure 1), although the ranges observed are greater for Focalin XR.Focalin XR given once daily exhibits lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and fewer peak and trough fluctuations than Focalin tablets given in doses given hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1).The ratio of geometric mean of AUC(0-inf) and Cmax after administration of Focalin XR given once daily are 1.02 and 0.86 respectively, to the same total dose of Focalin tablets given in doses hours apart. The variability in Cmax, Cmin, and AUC is similar between Focalin XR and Focalin immediate-release tablets with approximately 3-fold range in each.Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism, the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration x 20 mg Focalin XR (n 24) Capsules and x 10 mg Focalin Immediate-Release Tablets (n 25)After single dose administration, Focalin XR demonstrated dose proportional pharmacokinetics (PK) in the range of mg to 40 mg.For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration (2)].DistributionThe plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows volume of distribution of 2.65 +- 1.11 L/kg.EliminationPlasma dexmethylphenidate concentrations decline monophasically following oral administration of Focalin XR. The mean terminal elimination half-life of dexmethylphenidate was about hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of to hours. Dexmethylphenidate was eliminated with mean clearance of 0.40 +- 0.12 L/hr/kg after intravenous administration.MetabolismIn humans, dexmethylphenidate is metabolized primarily via de-esterification to d--phenyl-piperidine acetic acid (also known as d-ritalinic acid). This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo-enantiomer.ExcretionAfter oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl- methylphenidate was dl-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.Studies in Specific PopulationsMale and Female PatientsAfter administration of Focalin XR, the first peak (Cmax1), was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization.Racial or Ethnic GroupsThere is insufficient experience with the use of Focalin XR to detect ethnic variations in pharmacokinetics.Pediatric PatientsThe pharmacokinetics of dexmethylphenidate after Focalin XR administration have not been studied in pediatrics less than 18 years of age. When similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and patients with ADHD between and years of age, the time to the first peak was similar, although the time until the between peak minimum, and the time until the second peak were delayed and more variable in pediatric patients compared to adults. After administration of the same dose to pediatric patients and adults, concentrations in pediatric patients were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight.Patients with Renal ImpairmentThere is no experience with the use of Focalin XR in patients with renal impairment. Since renal clearance is not an important route of methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of Focalin XR.Patients with Hepatic ImpairmentThere is no experience with the use of Focalin XR in patients with hepatic impairment.Drug Interaction StudiesMethylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Musculoskeletal: rhabdomyolysisImmune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxisAdverse Reactions Reported With All Ritalin and Focalin FormulationsThe following adverse reactions associated with the use of all Ritalin and Focalin formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Infections and Infestations: nasopharyngitisBlood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemiaImmune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxisMetabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patientsPsychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed moodNervous 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 drugsEye Disorders: blurred vision, difficulties in visual accommodationCardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectorisRespiratory, Thoracic, and Mediastinal Disorders: coughGastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsiaHepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injurySkin 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, rhabdomyolysisInvestigations: weight loss (adult ADHD patients)Additional Adverse Reactions Reported With Other Methylphenidate ProductsThe list below shows adverse reactions not listed with Ritalin and Focalin 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, exanthemasPsychiatric Disorders: affect lability, mania, disorientation, libido changesNervous System Disorders: migraine Eye Disorders: diplopia, mydriasisCardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystoleVascular Disorders: peripheral coldness, Raynauds phenomenon Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspneaGastrointestinal Disorders: diarrhea, constipationSkin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruptionMusculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitchingRenal and Urinary Disorders: hematuriaReproductive System and Breast Disorders: gynecomastiaGeneral Disorders: fatigue, hyperpyrexiaUrogenital Disorders: priapism.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Focalin XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/.Risk SummaryDexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations). Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to times the maximum recommended human dose (MRHD) of 20 mg/day given to adults based on plasma levels. decrease in pup weight in males was observed in pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses times the MRHD of 20 mg/day given to adults based on plasma levels (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsCNS stimulants, such as Focalin XR, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.DataAnimal DataIn embryo-fetal development studies conducted in rats and rabbits, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of malformations was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, post-weaning body weight gain was decreased in male offspring at the highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels [area under the curves (AUCs)] of dexmethylphenidate in pregnant rats and rabbits were approximately and times, respectively, those in adults dosed with 20 mg/day. Plasma levels in adults were comparatively similar to plasma levels in adolescents.Racemic methylphenidate has been shown to cause malformations (increased incidence of fetal spina bifida) in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: June 2021MEDICATION GUIDEFOCALIN XR(R) (foh-kuh-lin XR)(dexmethylphenidate hydrochloride, USP) extended-release capsules CIIWhat is the most important information should know about FOCALIN XRFOCALIN XR is federal controlled substance (CII) because it can be abused or lead to dependence. Keep FOCALIN XR in safe place to prevent misuse and abuse. Selling or giving away FOCALIN XR may harm others, and is against the law. Tell your doctor if you or your child have abused or been dependent on alcohol, prescription medicines, or street drugs. The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines: 1. Heart-related problems: osudden death in patients who have heart problems or heart defects ostroke and heart attack in adults oincreased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or family history of these problems.Your doctor should check you or your child carefully for heart problems before starting FOCALIN XR.Your doctor should check you or your childs blood pressure and heart rate regularly during treatment with FOCALIN XR. 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 FOCALIN XR. 2. Mental (psychiatric) problems: All Patients onew or worse behavior and thought problems onew or worse bipolar illness onew or worse aggressive behavior or hostility onew 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 family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking FOCALIN XR, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. What is FOCALIN XRFOCALIN XR is central nervous system stimulant (CNS) prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). FOCALIN XR may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.FOCALIN XR should be used as part of total treatment program for ADHD that may include counseling or other therapies.Who should not take FOCALIN XR:FOCALIN XR should not be taken if you or your child:are allergic to methylphenidate hydrochloride, or any of the ingredients in FOCALIN XR. See the end of this Medication Guide for complete list of ingredients in FOCALIN XR.are taking or have taken within the past 14 days an anti-depression medicine called monoamine oxidase inhibitor (MAOI).FOCALIN XR may not be right for you or your child. Before starting FOCALIN XR, tell your or your childs doctor about all health conditions (or family history of), including:heart problems, heart defects, high blood pressuremental problems, including psychosis, mania, bipolar illness, or depressioncirculation problems in fingers or toesif you are pregnant or plan to become pregnant. It is not known if FOCALIN XR will harm your unborn baby.There is pregnancy registry for females who are exposed to ADHD medications, including FOCALIN XR, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to FOCALIN XR and their baby. If you or your child becomes pregnant during treatment with FOCALIN XR, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. if you are breastfeeding or plan to breastfeed. FOCALIN XR passes into your breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with FOCALIN XR.Tell your doctor about all of the medicines that you or your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. FOCALIN XR and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking FOCALIN XR.Your doctor will decide whether FOCALIN XR can be taken with other medicines.Especially tell your doctor if you or your child takes:anti-depression medicines, including MAOIsblood pressure medicines (anti-hypertensives)Know the medicines that you or your child takes. Keep list of your medicines with you to show your doctor and pharmacist.You should not take FOCALIN XR on the day of your operation if certain type of anesthetic is used. This is because there is chance of sudden rise in blood pressure and heart rate during the operation.Do not start any new medicine while taking FOCALIN XR without talking to your doctor first.How should FOCALIN XR be takenTake FOCALIN XR exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.Take FOCALIN XR once each day in the morning. FOCALIN XR is an extended-release capsule.FOCALIN XR can be taken with or without food. Taking FOCALIN XR with food may slow the time it takes for the medicine to start working.Swallow FOCALIN XR capsules whole with water or other liquids. Do not chew, crush, or divide the capsules or the beads in the capsule. If you or your child cannot swallow the capsule, open it and sprinkle the small beads of medicine over spoonful of applesauce and swallow it right away without chewing.From time-to-time, your doctor may stop FOCALIN XR treatment for while to check ADHD symptoms.Your doctor may do regular checks of the blood, heart, and blood pressure while taking FOCALIN XR.Children should have their height and weight checked often while taking FOCALIN XR. FOCALIN XR treatment may be stopped if problem is found during these check-ups.In case of poisoning, call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.What are the possible side effects of FOCALIN XRFOCALIN XR may cause serious side effects, including: osee What is the most important information should know about FOCALIN XR for information on reported heart and mental problems. opainful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by doctor immediately. ocirculation problems in fingers and toes (peripheral vasculopathy, including Raynauds phenomenon): ofingers or toes may feel numb, cool, painful ofingers or toes may change color from pale, to blue, to red Tell your doctor if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. oCall your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking FOCALIN XR. oSlowing of growth (height and weight) in children Common side effects include: Children (6-17 years) odyspepsiaodecreased appetiteoheadacheoanxietyAdultsodry mouthodyspepsiaoheadacheoanxietyopharyngolaryngeal painCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store FOCALIN XRStore FOCALIN XR in safe place and in tightly closed container at room temperature between 68F to 77F (20C to 25C).Dispose of remaining, unused, or expired FOCALIN XR by medicine take-back program at authorized collection sites, such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix FOCALIN XR with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in container, such as sealed plastic bag and throw away (discard) FOCALIN XR in the household trash.Keep FOCALIN XR and all medicines out of the reach of children.General information about the safe and effective use of FOCALIN XR.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or doctor for information about FOCALIN XR that is written for healthcare professionals. Do not use FOCALIN XR for condition for which it was not prescribed. Do not give FOCALIN XR to other people, even if they have the same symptoms that you have. It may harm them and it is against the law.What are the ingredients in FOCALIN XRActive ingredient: dexmethylphenidate hydrochloride Inactive ingredients: ammonio methacrylate copolymer, FD&C Blue (5 mg, 15 mg, 25 mg, 35 mg, and 40 mg strengths), FDA/E172 yellow iron oxide (10 mg, 15 mg, 30 mg, 35 mg, and 40 mg strengths), gelatin, ink Tan SW-8010, methacrylic acid copolymer, polyethylene glycol, sugar spheres, talc, titanium dioxide, and triethyl citrate. Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936 (C) Novartis For more information, call 1-888-669-6682.T2021-94. FOCALIN XR is central nervous system stimulant (CNS) prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). FOCALIN XR may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.. FOCALIN XR should be used as part of total treatment program for ADHD that may include counseling or other therapies.. are allergic to methylphenidate hydrochloride, or any of the ingredients in FOCALIN XR. See the end of this Medication Guide for complete list of ingredients in FOCALIN XR.. are taking or have taken within the past 14 days an anti-depression medicine called monoamine oxidase inhibitor (MAOI).. heart problems, heart defects, high blood pressure. mental problems, including psychosis, mania, bipolar illness, or depression. circulation problems in fingers or toes. if you are pregnant or plan to become pregnant. It is not known if FOCALIN XR will harm your unborn baby.There is pregnancy registry for females who are exposed to ADHD medications, including FOCALIN XR, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to FOCALIN XR and their baby. If you or your child becomes pregnant during treatment with FOCALIN XR, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. There is pregnancy registry for females who are exposed to ADHD medications, including FOCALIN XR, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to FOCALIN XR and their baby. If you or your child becomes pregnant during treatment with FOCALIN XR, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/.. if you are breastfeeding or plan to breastfeed. FOCALIN XR passes into your breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with FOCALIN XR.. anti-depression medicines, including MAOIs. blood pressure medicines (anti-hypertensives). You should not take FOCALIN XR on the day of your operation if certain type of anesthetic is used. This is because there is chance of sudden rise in blood pressure and heart rate during the operation.. Take FOCALIN XR exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.. Take FOCALIN XR once each day in the morning. FOCALIN XR is an extended-release capsule.. FOCALIN XR can be taken with or without food. Taking FOCALIN XR with food may slow the time it takes for the medicine to start working.. Swallow FOCALIN XR capsules whole with water or other liquids. Do not chew, crush, or divide the capsules or the beads in the capsule. If you or your child cannot swallow the capsule, open it and sprinkle the small beads of medicine over spoonful of applesauce and swallow it right away without chewing.. From time-to-time, your doctor may stop FOCALIN XR treatment for while to check ADHD symptoms.. Your doctor may do regular checks of the blood, heart, and blood pressure while taking FOCALIN XR.. Children should have their height and weight checked often while taking FOCALIN XR. FOCALIN XR treatment may be stopped if problem is found during these check-ups.. In case of poisoning, call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.. Store FOCALIN XR in safe place and in tightly closed container at room temperature between 68F to 77F (20C to 25C).. Dispose of remaining, unused, or expired FOCALIN XR by medicine take-back program at authorized collection sites, such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix FOCALIN XR with an undesirable, nontoxic substance, such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in container, such as sealed plastic bag and throw away (discard) FOCALIN XR in the household trash.. Keep FOCALIN XR and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

2.1 Pretreatment Screening. Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including Focalin XR, assess for the presence of cardiac disease (i.e., perform careful history, including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)].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 reevaluate the need for Focalin XR use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Focalin XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/.Risk SummaryDexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations). Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to times the maximum recommended human dose (MRHD) of 20 mg/day given to adults based on plasma levels. decrease in pup weight in males was observed in pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses times the MRHD of 20 mg/day given to adults based on plasma levels (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsCNS stimulants, such as Focalin XR, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.DataAnimal DataIn embryo-fetal development studies conducted in rats and rabbits, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of malformations was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, post-weaning body weight gain was decreased in male offspring at the highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels [area under the curves (AUCs)] of dexmethylphenidate in pregnant rats and rabbits were approximately and times, respectively, those in adults dosed with 20 mg/day. Plasma levels in adults were comparatively similar to plasma levels in adolescents.Racemic methylphenidate has been shown to cause malformations (increased incidence of fetal spina bifida) in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.. 8.2 Lactation. Risk SummaryDexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Focalin XR and any potential adverse effects on the breastfed infant from Focalin XR or from the underlying maternal condition.Clinical ConsiderationsMonitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.. 8.4 Pediatric Use. The safety and effectiveness of Focalin XR in pediatric patients less than years have not been established.The safety and effectiveness of Focalin XR for the treatment of ADHD have been established in pediatric patients ages to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14.2)]. The long-term efficacy of Focalin XR in pediatric patients has not been established.Long-Term Suppression of GrowthGrowth should be monitored during treatment with stimulants, including Focalin XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].Juvenile Animal Toxicity DataRats treated with racemic methylphenidate early in the postnatal period through sexual maturation demonstrated decrease in spontaneous locomotor activity in adulthood. deficit in acquisition of specific learning task was observed in females only. The doses at which these findings were observed are at least times the MRHD of 60 mg/day given to children on mg/m2 basis.In study conducted in young rats, racemic methylphenidate was administered orally at doses of up to 100 mg/kg/day for weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately times the MRHD of 60 mg/day of racemic methylphenidate given to children on mg/m2 basis) or greater, and deficit in the acquisition of specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was mg/kg/day (approximately 0.5 times the MRHD given to children on mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.. 8.5 Geriatric Use. Focalin XR has not been studied in the geriatric population.

WARNINGS AND PRECAUTIONS SECTION.

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 existing psychotic or bipolar disorder prior to Focalin XR 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 Raynauds Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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). 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 existing psychotic or bipolar disorder prior to Focalin XR 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 Raynauds Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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 Focalin XR, other methylphenidate-containing products, and amphetamines, have 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 serious 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 Focalin XR treatment.. 5.3 Blood Pressure and Heart Rate Increases. CNS stimulants cause an increase in blood pressure (mean increase approximately to mmHg) and heart rate (mean increase approximately to beats per minute). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.. 5.4 Psychiatric Adverse Reactions. Exacerbation of Preexisting PsychosisCNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.Induction of Manic Episode in Patients With Bipolar DisorderCNS stimulants may induce manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disorder, or depression).New Psychotic or Manic SymptomsCNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Focalin XR. In 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 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 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 Raynauds Phenomenon. CNS stimulants, including Focalin XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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 Raynauds 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.In 7-week, double-blind, placebo-controlled study of Focalin XR, the mean weight gain was greater for pediatric patients (ages to 17 years) receiving placebo (+ 0.4 kg) than for patients receiving Focalin XR (- 0.5 kg).Careful follow-up of weight and height in pediatric patients ages 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 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for days per week throughout the year) have temporary slowing in growth rate (on average, total of about cm less growth in height and 2.7 kg less growth in weight over 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 Focalin XR, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.