Focalin

Boxed Warning 10/2023 Dosage and Administration ( 2.1 , 2.2 ) 10/2023 Warnings and Precautions ( 5.1 , 5.2 , 5.8 , 5.9 , 5.10 ) 10/2023

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

2 DOSAGE AND ADMINISTRATION • Administer orally twice daily, 4 hours apart with or without food ( 2 ). • For patients new to methylphenidate: Recommend starting dose of 5 mg once daily (2.5 mg twice daily) ( 2.2 ). • For patients currently taking methylphenidate: Initiate Focalin therapy with half (1/2) the current total daily dose of methylphenidate ( 2.2 ). • Titrate weekly in increments of 2.5 to 5 mg to a maximum of 20 mg/day (10 mg twice daily) ( 2.2 ). 2.1 Pretreatment Screening Prior to treating patients with Focalin, assess: • for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.2 )] . • the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating Focalin [see Warnings and Precautions ( 5.10 )] . 2.2 Recommended Dosage Patients New to Methylphenidate The recommended starting dose of Focalin for pediatric patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg daily (2.5 mg twice daily) with or without food. Patients Currently on Methylphenidate The recommended starting dose of Focalin for pediatric patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate. Titration Schedule The dose may be titrated weekly in increments of 2.5 mg to 5 mg to a maximum of 20 mg daily (10 mg twice daily). The dose should be individualized according to the needs and response of the patient. 2.3 Administration Instructions Focalin is administered orally twice daily, at least 4 hours apart. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue Focalin. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

3 DOSAGE FORMS AND STRENGTHS Focalin (dexmethylphenidate hydrochloride) tablets are D-shaped, embossed “D” on upper convex face and dosage strength on lower convex face in the following colors: • 2.5 mg tablets – blue • 5 mg tablets – yellow • 10 mg tablets – white Tablets: 2.5 mg, 5 mg, and 10 mg ( 3 ).

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

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] • Known hypersensitivity to methylphenidate or other ingredients of Focalin [see Contraindications ( 4 )] • Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] • Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] • Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] • Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] • Priapism [see Warnings and Precautions ( 5.5 )] • Peripheral Vasculopathy, Including Raynaud’s phenomenon [see Warnings and Precautions ( 5.6 )] • Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.7 )] • Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.8 )] • Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.9 )] • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.10 )] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, fever, nausea, and anorexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Studies with Focalin in Pediatric Patients with ADHD The safety data in this section is based on data related to Focalin exposure during the premarketing development program in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). These participants received Focalin 5, 10, or 20 mg/day. The 684 ADHD patients (ages 6 to 17 years) were evaluated in 2 controlled clinical studies, 2 clinical pharmacology studies, and 2 open-label long-term safety studies. Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): abdominal pain, fever, anorexia, and nausea Adverse Reactions Leading to Discontinuation: Overall, 50 of 684 (7.3%) pediatric patients treated with Focalin experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each). Table 1 enumerates adverse reactions for two, placebo-controlled, parallel group studies in pediatric patients with ADHD taking Focalin doses of 5, 10, and 20 mg/day. The table includes only those reactions that occurred in patients treated with Focalin for which the incidence was at least 5% and twice the incidence among placebo-treated patients. Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD Abbreviation: ADHD, attention deficit hyperactivity disorder. System organ class Adverse reactions Focalin (N = 79) Placebo (N = 82) Body as a whole Abdominal pain 15% 6% Fever 5% 1% Digestive system Anorexia 6% 1% Nausea 9% 1% 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal: rhabdomyolysis Immune System Disorders: hypersensitivity reactions, such as angioedema, anaphylactic reactions Adverse Reactions Reported with All Ritalin and Fo …

7 DRUG INTERACTIONS • Antihypertensive Drugs : Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). 7.1 Clinically Important Drug Interactions with Focalin Table 2 presents clinically important drug interactions with Focalin. Table 2: Clinically Important Drug Interactions with Focalin Monoamine Oxidase Inhibitors (MAOIs) Clinical impact Concomitant use of MAOIs and CNS stimulants, including Focalin, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )] . Intervention Concomitant use of Focalin with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical impact Focalin may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )] . Intervention Adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical impact Concomitant use of halogenated anesthetics and Focalin may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Monitor blood pressure and avoid use of Focalin in patients being treated with anesthetics on the day of surgery. Risperidone Clinical impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Intervention Monitor for signs of EPS.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Focalin, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a 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 during pregnancy (see Clinical Considerations) . Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to 5 times the maximum recommended human dose (MRHD) of 20 mg/day given to adults based on plasma levels. A decrease in pup weight in males was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 5 times the MRHD of 20 mg/day given to adults based on plasma levels. Plasma levels in adults were comparatively similar to plasma levels in adolescents (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as Focalin, 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. Data Animal Data In 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 5 and 1 times, respectively, those in adults dosed with the MRHD of 20 mg/day. 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 Summary Dexmethylphenidate 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 a 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 mother’s clinical need for Focalin and any potential adverse effects on the breastfed infant from Focalin or from the underlying maternal condit …

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

11 DESCRIPTION Focalin contains dexmethylphenidate hydrochloride, a CNS stimulant. Dexmethylphenidate hydrochloride is the d-threo enantiomer of racemic methylphenidate hydrochloride. Focalin is available as 2.5 mg, 5 mg, and 10 mg strength tablets for oral administration. Chemically, dexmethylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, (R,R’)-(+)-. Its molecular formula is C 14 H 19 NO 2 •HCl. Its structural formula is: Note: * = asymmetric carbon centers Dexmethylphenidate hydrochloride is a white to off-white powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol. Inactive ingredients: FD&C blue no.1 #5516 aluminum lake (2.5 mg tablets), D&C yellow #10 aluminum lake (5 mg tablets), the 10 mg tablet contains no dye; lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate. Dexmethylphenidate hydrochloride structural formula.

10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: • Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. • CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. • Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Focalin (dexmethylphenidate hydrochloride) tablets (D-shaped, embossed “D” on upper convex face and dosage strength on lower convex face) are available as follows: • 2.5 mg tablets (NDC 66758-250-01) blue, supplied in bottles of 100 • 5 mg tablets (NDC 66758-251-01) yellow, supplied in bottles of 100 • 10 mg tablets (NDC 66758-252-01) white, supplied in bottles of 100 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in tight, light-resistant container (USP).