methylphenidate hydrochloride

RECENT MAJOR CHANGES Indications and Usage (1) 09/2025 Warnings and Precautions (5.7) 09/2025

1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), in pediatric patients 6 to 12 years of age [see Clinical Studies (14) ] . Limitations of Use The use of methylphenidate 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) ] . Methylphenidate hydrochloride extended-release capsule is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 12 years of age ( 1 ). Limitations of Use The use of methylphenidate hydrochloride extended-release capsules are 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 ).

2 DOSAGE AND ADMINISTRATION N/A Administer orally once daily in the morning (2.2) . Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce (2.2) . Should not be crushed, chewed, or divided ( 2.2 ). Patients new to methylphenidate: Start at 20 mg daily, titrating the dose weekly in 10-mg increments. Doses above 60 mg daily are not recommended (2.3) . For patients currently using methylphenidate hydrochloride tablets: Dosage is based on current dose regimen (2.4) . If switching from other methylphenidate products, discontinue treatment and titrate with methylphenidate hydrochloride extended-release capsules (2.4) . 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release capsules, 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 methylphenidate hydrochloride extended-release capsules [see Warnings and Precautions (5.10) ] . 2.2 General Dosing Information The recommended starting dose for methylphenidate hydrochloride extended-release capsule is 20 mg once daily. Increase dosage gradually, in increments of 10 mg weekly. Daily dosage above 60 mg is not recommended. When a lower initial dose is appropriate, patients may begin treatment with 10 mg. Administer methylphenidate hydrochloride extended-release capsules orally once daily in the morning. Methylphenidate hydrochloride extended-release capsules may be swallowed as whole capsules or may be administered by sprinkling the capsule contents on a small amount of applesauce ( see specific instructions below ). Methylphenidate 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 applesauce should not be warm because it could affect the modified release properties of this formulation. 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. 2.3 Patients Currently Using Methylphenidate Hydrochloride Tablets The recommended dose of methylphenidate hydrochloride extended-release capsules for patients currently taking methylphenidate hydrochloride tablets twice daily is provided below in Table 1. Table 1: Recommended Dose Conversion from Methylphenidate Hydrochloride Tablets Previous Methylphenidate Hydrochloride Tablets dose Recommended Methylphenidate Hydrochloride Extended-Release Capsules dose 5 mg methylphenidate hydrochloride tablets twice daily 10 mg once daily 10 mg methylphenidate hydrochloride tablets twice daily 20 mg once daily 15 mg methylphenidate hydrochloride tablets twice daily 30 mg once daily 20 mg methylphenidate hydrochloride tablets twice daily 40 mg once daily 30 mg methylphenidate hydrochloride tablets twice daily 60 mg once daily 2.4 Switching from Other Methylphenidate Products If switching from other methylphenidate products, discontinue that treatment, and titrate with methylphenidate hydrochloride extended-release capsules using the titration schedule. Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because different methylphenidate base compositions and differing pharmacokinetic profiles [see Description (11) , Clinical Pharmacology (12.3) ] . Clinical judgment should be used when selecting the starting dose. Daily dosage above 60 mg is not recommended. 2.5 Dosage Reduction and Discontinuation If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride extended-release capsules. If improvement is not observed after appropriate dosage adjustment o …

3 DOSAGE FORMS AND STRENGTHS Methylphenidate Hydrochloride Extended-Release Capsules are available as follows: 10 mg - Capsule with turquoise blue opaque cap and white opaque body printed with A854 on the cap and 10 mg on the body in black ink. 15 mg - Capsule with cream opaque cap and white opaque body printed with A862 on the cap and 15 mg on the body in black ink. 20 mg - Capsule with grey opaque cap and white opaque body printed with A869 on the cap and 20 mg on the body in black ink. 30 mg - Capsule with blue opaque cap and white opaque body printed with A873 on the cap and 30 mg on the body in black ink. 40 mg - Capsule with yellow opaque cap and white opaque body printed with A891 on the cap and 40 mg on the body in black ink. 50 mg - Capsule with green opaque cap and white opaque body printed with A895 on the cap and 50 mg on the body in black ink. 60 mg - Capsule with pink opaque cap and white opaque body printed with A902 on the cap and 60 mg on the body in black ink. Extended-release capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg of methylphenidate hydrochloride, which is equivalent to 8.6 mg, 13.0 mg, 17.3 mg, 25.9 mg, 34.6 mg, 43.2 mg, and 51.9 mg of methylphenidate free base, respectively, per capsule. ( 3 )

4 CONTRAINDICATIONS Methylphenidate hydrochloride extended-release capsules are contraindicated in patients with: known hypersensitivity to methylphenidate or other component of methylphenidate hydrochloride extended-release capsules. Angioedema has been reported in patients treated with methylphenidate hydrochloride extended-release capsules. Anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions (6) ] . Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crisis [see Drug Interactions (7) ] . Methylphenidate hydrochloride extended-release capsules contain sucrose. Therefore, patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine. Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release capsules. ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. ( 4 ) Use in patients with patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency. ( 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 methylphenidate hydrochloride extended-release capsules [see Contraindications (4) ] Hypertensive crisis when used concomitantly with 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) ] Most common adverse reactions (greater than 5% during incidence) were headache, insomnia, upper abdominal pain, decreased appetite, and anorexia (6) . To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc., at 1-877-770-3183 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 practice. The clinical program for methylphenidate hydrochloride extended-release capsules consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received methylphenidate hydrochloride extended-release capsules in doses of 10 to 40 mg per day. Safety of methylphenidate hydrochloride extended-release capsules was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of methylphenidate hydrochloride extended-release capsules in children with ADHD aged 6 to 12 years. All subjects received methylphenidate hydrochloride extended-release capsules for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the 2-week double-blind treatment phase of this study, patients received either placebo or methylphenidate hydrochloride extended-release capsules at their individually-titrated dose (range, 10 mg to 40 mg). Adverse reactions with an incidence greater than 5% during the initial 4-week single-blind methylphenidate hydrochloride extended-release capsules titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia. Adverse reactions with an incidence greater than 2% among methylphenidate hydrochloride extended-release capsules-treated subjects, during the 2-week double-blind phase of the clinical study, are shown in Table 2. Table 2: Adverse Reactions in Greater Than 2% Methylphenidate Hydrochloride Extended-Release Capsules-Treated Subjects in the 2-Week Double-Blind Phase Preferred Term Methylphenidate Hydrochloride Extended-Release Capsules N = 65 N (%) Placebo N = 71 N (%) Anorexia 2 (3.1) 0 (0) Insomnia 2 (3.1) 0 (0) Adverse Reactions Associated with Discontinuation of Treatment In the 2-week double-blind treatment phase of a placebo-controlled parallel-g …

7 DRUG INTERACTIONS Antihypertensive Drugs : Monitor blood pressure and heart. Adjust dosage of antihypertensive drug as needed (7.1) . 7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Capsules Table 3 presents clinically important drug interactions with methylphenidate hydrochloride extended-release capsules Table 3: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release capsules, 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 methylphenidate hydrochloride extended-release capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical impact Methylphenidate hydrochloride extended-release capsules may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3) ] . Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical impact Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of methylphenidate hydrochloride extended-release capsules 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 methylphenidate hydrochloride extended-release during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. Risk Summary Limited published studies report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at the highest dose of 60 mg/kg/day (6 times the MRHD given to adolescents) [see Data] . The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as methylphenidate hydrochloride extended-release, 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, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adolescents on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (1.5 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published literature, based on breast milk sampling from five 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. However, 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 methylphenidate hydrochloride extended-release and …

12.1 Mechanism of Action Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.

11 DESCRIPTION Methylphenidate hydrochloride extended-release capsules contain methylphenidate hydrochloride, USP a central nervous system (CNS) stimulant. Methylphenidate hydrochloride extended-release capsules contain multi layered beads, which are composed of an immediate-release layer which contains approximately 40% of the methylphenidate dose, and a controlled release layer which contains approximately 60% of the methylphenidate dose. Methylphenidate hydrochloride extended-release capsules are available in seven capsule strengths. Each extended-release capsule for once-a-day oral administration contains 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg of methylphenidate hydrochloride USP, which is equivalent to 8.6 mg, 13.0 mg, 17.3 mg, 25.9 mg, 34.6 mg, 43.2 mg, or 51.9 mg of methylphenidate free base, respectively. Chemically, methylphenidate hydrochloride, USP is d,l (racemic) methyl α-phenyl-2­piperidineacetate hydrochloride. Its structural formula is: C 14 H 19 NO 2 •HCl M.W. 269.77 Methylphenidate hydrochloride, USP is a white to off-white, odorless, fine crystalline 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. Inactive Ingredients: ammonio methacrylate copolymer type B, fumaric acid, gelatin, hypromellose 2910, methacrylic acid copolymer type A, polyethylene glycol 400, polyethylene glycol 8000, sugar spheres (which contains sucrose and corn starch), talc, titanium dioxide and triethyl citrate. The 10 mg capsules also contain FD&C Blue #1. The 15 mg capsules also contain FD&C Yellow #6. The 20 mg capsules also contain black iron oxide. The 30 mg capsules also contain FD&C Blue#1 and FD&C Red #3. The 40 mg capsules also contain yellow iron oxide. The 50 mg capsules also contain FD&C Blue #1 and yellow iron oxide. The 60 mg capsules also contain FD&C Blue #1 and FD&C Red #40. Black printing ink SW-9008/SW-9009 contains black iron oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. 1

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. The pharmacokinetic profile of methylphenidate hydrochloride extended-release capsules should be considered when treating patients with overdose. 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 How Supplied Methylphenidate hydrochloride extended-release capsules are available in six strengths: Methylphenidate hydrochloride extended-release capsules, 10 mg are green cap and white body, opaque capsules, imprinted with ‘CP’ over ‘401’ on the cap and ‘10 mg’ on the body. They are available as: Bottles of 100: NDC 0115-1736-01 Methylphenidate hydrochloride extended-release capsules, 20 mg are blue cap and white body, opaque capsules, imprinted with ‘CP’ over ‘402’ on the cap and ‘20 mg’ on the body. They are available as: Bottles of 100: NDC 0115-1737-01 Methylphenidate hydrochloride extended-release capsules, 30 mg are brown cap and white body, opaque capsules, imprinted with ‘CP’ over ‘403’ on the cap and ‘30 mg’ on the body. They are available as: Bottles of 100: NDC 0115-1738-01 Methylphenidate hydrochloride extended-release capsules, 40 mg are yellow cap and white body, opaque capsules, imprinted with ‘CP’ over ‘404’ on the cap and ‘40 mg’ on the body. They are available as: Bottles of 100: NDC 0115-1739-01 Methylphenidate hydrochloride extended-release capsules, 50 mg are navy blue cap and white body, opaque capsules, imprinted with ‘CP’ over ‘405’ on the cap and ‘50 mg’ on the body. They are available as: Bottles of 100: NDC 0115-1740-01 Methylphenidate hydrochloride extended-release capsules, 60 mg are white opaque capsule imprinted with ‘CP’ over ‘406’ on the cap and ‘60 mg’ on the body. They are available as: Bottles of 100: NDC 0115-1741-01 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of the reach of children.