24 HR dexmethylphenidate hydrochloride 10 MG Extended Release Oral Capsule [Focalin]

INDICATIONS AND USAGE Dexmethylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14 )]. Limitations of Use The use of dexmethylphenidate hydrochloride extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7) , Use in Specific Populations (8.4) ] . Dexmethylphenidate hydrochloride extended-release capsules are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) ( 1 ). Limitations of Use The use of dexmethylphenidate hydrochloride extended-release capsules is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).

DOSAGE AND ADMINISTRATION Dexmethylphenidate Hydrochloride Extended-release Capsules is for oral administration once daily in the morning. Dexmethylphenidate Hydrochloride Extended-release Capsules may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Dexmethylphenidate Hydrochloride Extended-release Capsules and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosage should be individualized according to the needs and responses of the patient. Patients new to methylphenidate: Recommended starting dose is 5 mg once daily for pediatric patients and 10 mg once daily for adults with or without food in the morning ( 2.2 ). Patients currently on methylphenidate: Dexmethylphenidate Hydrochloride Extended-release Capsules dosage is half the current total daily dosage of methylphenidate ( 2.2 ). Patients currently on dexmethylphenidate immediate-release tablets: Give the same daily dose of Dexmethylphenidate Hydrochloride Extended-release Capsules ( 2.2 ) Titrate weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients ( 2.2 ). Maximum recommended daily dose: 30 mg in pediatric patients and 40 mg in adults ( 2.2 ). Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce ( 2.3 ). 2.1 Pretreatment Screening Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants including Dexmethylphenidate Hydrochloride Extended-release Capsules, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [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 re-evaluate the need for Dexmethylphenidate Hydrochloride Extended-release Capsules use [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9) ] . 2.2 Treatment of ADHD Patients New to Methylphenidate The recommended starting dosage of Dexmethylphenidate Hydrochloride Extended-release Capsules for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are: Pediatric patients: Start with 5 mg orally once daily in the morning with or without food. Adult patients: Start with 10 mg orally once daily in the morning with or without food. Patients Currently on Methylphenidate The recommended starting dose of Dexmethylphenidate Hydrochloride Extended-release Capsules for patients currently using methylphenidate is half the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate immediate-release tablets may be given the same daily dose of Dexmethylphenidate Hydrochloride Extended-release Capsules. Titration Schedule The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended. Maintenance/Extended Treatment Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Dexmethylphenidate Hydrochloride Extended-release Capsules and adjust dosage as needed. 2.3 Administration Instructions Dexmethylphenidate Hydrochloride Extended-release Capsules is administered orally and may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. 2.4 Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue Dexmethylphenidate Hydrochloride Extended-release Capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ). Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse ( 5.3 ). Psychiatric Adverse Reactions : Prior to initiating dexmethylphenidate hydrochloride extended-release, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dexmethylphenidate hydrochloride extended-release ( 5.4 ). Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.5 ). Peripheral Vasculopathy, including Raynaud’s Phenomenon : Careful observation for digital changes is necessary during dexmethylphenidate hydrochloride extended-release treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 ). Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted ( 5.7 ). Acute Angle Closure Glaucoma: Dexmethylphenidate hydrochloride extended-release -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist ( 5.8 ). Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe dexmethylphenidate hydrochloride extended-release to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma ( 5.9 ). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating dexmethylphenidate hydrochloride extended-release, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate ( 5.10 ). 5.1 Abuse, Misuse, and Addiction Dexmethylphenidate hydrochloride extended-release has a high potential for abuse and misuse. The use of dexmethylphenidate hydrochloride extended-release exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dexmethylphenidate hydrochloride extended-release can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 )] . Misuse and abuse of CNS stimulants, including dexmethylphenidate hydrochloride extended-release, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing dexmethylphenidate hydrochloride extended-release, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store dexmethylphenidate hydrochloride extended-release in a safe place, preferably locked, and instruct patients to not give dexmethylphenidate hydrochloride extended-release to anyone else. Throughout dexmethylphenidate hydrochloride extended-release treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients With Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid dexmethylphenidate hydrochloride extended-release use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases. Monitor all dexmethylphenidate hydrochloride extended-release-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating dexmethylphenidate hydrochloride extended-release treatment, screen patients for risk factors for developing manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing dexmethylphenidate hydrochloride extended-release. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Dexmethylphenidate hydrochloride extended-release-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, Including Raynaud's Phenomenon CNS stimulants, including dexmethylphenidate hydrochloride extended-release, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports at and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during dexmethylphenidate hydrochloride extended-release treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for dexmethylphenidate hydrochloride extended-release-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. In a 7-week, double-blind, placebo-controlled study of dexmethylphenidate hydrochloride extended-release, the mean weight gain was greater for pediatric patients (ages 6 to 17 years) receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended-release (-0.5 kg). Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate

CONTRAINDICATIONS • Hypersensitivity to methylphenidate or other components of dexmethylphenidate hydrochloride extended-release capsules. 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 dexmethylphenidate hydrochloride extended-release capsules ( 4 ). • Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 ).

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dexmethylphenidate hydrochloride is a central nervous system (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 increase the release of these monoamines into the extraneuronal space. Cardiac Electrophysiology At the recommended maximum total daily dosage of 40 mg, dexmethylphenidate hydrochloride extended-release does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Absorption Dexmethylphenidate hydrochloride extended-release capsules produce a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when orally administered to healthy adults. The initial rate of absorption for dexmethylphenidate hydrochloride extended-release capsules is similar to that of dexmethylphenidate hydrochloride tablets as shown by the similar rate parameters between the 2 formulations, i.e., first peak concentration (C max1 ), and time to the first peak (t max1 ), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (t minip ) is slightly shorter, and time to the second peak (t max2 ) is slightly longer for dexmethylphenidate hydrochloride extended-release capsules given once daily (about 6.5 hours; range, 4.5 to 7 hours) compared to dexmethylphenidate hydrochloride tablets given in 2 doses 4 hours apart (see Figure 1), although the ranges observed are greater for dexmethylphenidate hydrochloride extended-release capsules. Dexmethylphenidate hydrochloride extended-release capsules given once daily exhibits a lower second peak concentration (C max2 ), higher interpeak minimum concentrations (C minip ), and fewer peak and trough fluctuations than dexmethylphenidate hydrochloride tablets given in 2 doses given 4 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 C max after administration of dexmethylphenidate hydrochloride extended-release capsules given once daily are 1.02 and 0.86 respectively, to the same total dose of dexmethylphenidate hydrochloride tablets given in 2 doses 4 hours apart. The variability in C max , C min , and AUC is similar between dexmethylphenidate hydrochloride extended-release capsules and Focalin immediate-release tablets with approximately a 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 1 x 20 mg Dexmethylphenidate Hydrochloride Extended-Release (n = 24) Capsules and 2 x 10 mg Focalin Immediate-Release Tablets (n = 25) After single-dose administration, dexmethylphenidate hydrochloride extended-release demonstrated dose proportional pharmacokinetics (PK) in the range of 5 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) ] . Distribution The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65 ± 1.11 L/kg. Elimination Plasma dexmethylphenidate concentrations decline monophasically following oral administration of dexmethylphenidate hydrochloride extended-release capsules. The mean terminal elimination half-life of dexmethylphenidate was about 3 hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of 2 to 3 hours. Dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg after intravenous administration. Metabolism In humans, dexmethylphenidate is metabolized primarily via de-esterification to d - α -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. Excretion After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic ( d,l- ) methylphenidate was d,l -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 Populations Male and Female Patients After administration of dexmethylphenidate hydrochloride extended-release capsule, the first peak, (C max1 ) 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 Groups There is insufficient experience with the use of dexmethylphenidate hydrochloride extended-release to detect ethnic variations in pharmacokinetics. Pediatric Patients The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride extended-release capsule administration have not been studied in pediatrics less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and 3 patients with ADHD between 7 and 9 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 Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release 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 dexmethylphenidate hydrochloride extended-release. Patients with Hepatic Impairment There is no experience with the use of dexmethylphenidate hydrochloride extended-release in patients with hepatic impairment. Drug Interaction Studies Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a 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 co-administration did not increase plasma concentrations of the CYP2D6 substrate desipramine. Figure 1