RELEXXII

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

1 INDICATIONS AND USAGE RELEXXII is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults (up to the age of 65 years) and pediatric patients 6 years of age and older [ see Clinical Studies ( 14 )] . Limitations of Use The use of RELEXXII 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 )] . RELEXXII ® is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults (up to the age of 65 years) and pediatric patients 6 years of age and older ( 1 ). Limitations of Use The use of RELEXXII 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 ).

2 DOSAGE AND ADMINISTRATION Administer once daily in the morning with or without food. ( 2.2 ) Swallow whole with liquid. Do not chew, divide, or crush. ( 2.2 ) Recommended dosage for patients new to methylphenidate ( 2.3 ): Pediatric patients 6 to 17 years Starting dosage is 18 mg once daily. Dosage may be increased by 18 mg once per day at weekly intervals. Maximum dosage for pediatric patients 6 to 12 years: 54 mg once daily. Maximum dosage for pediatric patients 13 to 17 years: 72 mg once daily. Adults (up to 65 years) Starting dosage is 18 mg or 36 mg once daily. Dosage may be increased by 18 mg once daily at weekly intervals. Maximum dosage: 72 mg once daily. 2.1 Pretreatment Screening Prior to treating patients with RELEXXII, 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 RELEXXII [see Warnings and Precautions ( 5.11 )]. 2.2 General Administration Information Administer RELEXXII orally once daily in the morning with or without food. Swallow RELEXXII whole with liquid. Do not chew, divide, or crush [see Warnings and Precautions ( 5.8 )] . 2.3 Dosage Recommendations for Patients New to Methylphenidate Table 1 includes the starting dosage and dosage recommendations for RELEXXII in pediatric patients 6 to 17 years and adults who are not currently taking methylphenidate or other stimulants. Table 1: Dosage Recommendations for RELEXXII in Pediatric Patients 6 to 17 years and Adults Patient Population RELEXXII Recommended Starting Dosage RELEXXII Dosage Range Pediatric patients 6 to 12 years 18 mg once daily 18 mg to 54 mg once daily 13 to 17 years 18 mg once daily 18 mg to 72 mg once daily (not to exceed 2 mg/kg/day) Adults 18 (up to 65 years) 18 mg or 36 mg once daily 18 mg to 72 mg once daily 2.4 Dosage Recommendations for Patients Currently Using Methylphenidate The recommended starting dosage of RELEXXII for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 mg to 60 mg daily is provided in Table 2. Table 2: Recommended Starting Dosage when Converting from Methylphenidate Regimens to RELEXXII Current Methylphenidate Daily Dosage Recommended Starting Dosage of RELEXXII 5 mg methylphenidate twice daily or three times daily 18 mg once daily in the morning 10 mg methylphenidate twice daily or three times daily 36 mg once daily in the morning 15 mg methylphenidate twice daily or three times daily 54 mg once daily in the morning 20 mg methylphenidate twice daily or three times daily 72 mg once daily in the morning 2.5 Dose Titration Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved clinical response at a lower dose. Daily dosages above 54 mg in pediatric patients 6 to 12 years and above 72 mg in pediatric patients 13 to 17 years have not been studied and are not recommended. Daily dosages above 72 mg are not recommended in adults. Dosage strengths of 27 mg, 45 mg, and 63 mg are available for additional titration options based on clinical response. 2.6 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reaction occur, reduce the dosage, or, if necessary, discontinue RELEXXII. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue RELEXXII.

3 DOSAGE FORMS AND STRENGTHS RELEXXII (methylphenidate hydrochloride extended-release tablets) are available in the following strengths: 18 mg: yellow with “TL706” imprinted in black ink 27 mg: gray with “TL707” imprinted in black ink 36 mg: white with “TL708” imprinted in black ink 45 mg: pink with “TL711” imprinted in black ink 54 mg: pink with “TL709” imprinted in black ink 63 mg: orange with “TL700” imprinted in black ink and 72 mg: blue with “TL710” imprinted in black ink. Extended-release tablets:18 mg, 27 mg, 36 mg, 45 mg, 54 mg, 63 mg, and 72 mg ( 3 )

4 CONTRAINDICATIONS RELEXXII is contraindicated in patients: with a known hypersensitivity to methylphenidate or other components of RELEXXII. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions ( 6.2 )] . receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a MAOI, because of the risk of hypertensive crisis [see Drug Interactions ( 7.1 )] . Known hypersensitivity to methylphenidate or other components of RELEXXII ( 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 Box Warning, Warnings and Precautions ( 5.1 ), and Drug Abuse and Dependence ( 9.2 , 9.3 )] Known hypersensitivity to methylphenidate or other ingredients [see Contraindications ( 4 )] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4) and 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 )] Potential for Gastrointestinal Obstruction [see Warnings and Precautions ( 5.8 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.9 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.10 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (>5%) were: Pediatric patients 6 to 17 years: abdominal pain upper ( 6.1 ) Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertical Pharmaceuticals, LLC at 1-800-444-5164 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of RELEXXII for the treatment of ADHD is based on adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets. Below is a display of adverse reactions from those adequate and well-controlled studies in ADHD. Adults and pediatric patients 6 to 17 years with ADHD were evaluated in six controlled clinical studies and eleven open-label clinical studies (see Table 3). Safety was assessed by collecting adverse reactions, vital signs, weights, and electrocardiograms (ECGs), and by performing physical examinations and laboratory analyses. A total of 3,906 patients participated in the clinical trials. Table 3: Exposure in Double-Blind and Open-Label Clinical Studies of Another Formulation of Methylphenidate Hydrochloride Extended-Release Tablets Patient Population N Dosage Range Pediatric patients 6 to 12 years 2216 18 mg to 54 mg once daily Pediatric patients 13 to 17 years 502 18 mg to 72 mg once daily Adults 1188 18 mg to 108 mg* once daily * 108 mg is 1.5 times the maximum recommended dosage of RELEXXII. The most common adverse reactions in double-blind clinical trials (>5%) were: Pediatric patients 6 to 17 years: abdominal pain upper (see Table 4). Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (see Table 5). The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased . Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Pediatric Patients 6 to 17 Years Table 4 lists the adverse reactions reported in 1% or more of another formulation of methylphenidate hydrochloride extended-release tablet-treated pediatric patients (6 to 17 years) in four placebo-controlled, double-blind clinical trials. Table 4: Adverse Reactions Reported by ≥1% of Pediatric Patient …

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ) 7.1 Clinically Important Drug Interactions Table 6 presents clinically important drug interactions with RELEXXII. Table 6: Drugs Having Clinically Important Interactions with RELEXXII Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants 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: Do not administer RELEXXII concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Antihypertensive Drugs Clinical Impact: RELEXXII 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 RELEXXII may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Avoid use of RELEXXII 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 RELEXXII, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388. Risk Summary Published studies and post-marketing 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 are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy ( see Clinical Considerations). No effects on morphological development were observed in development studies with oral administration of methylphenidate to pregnant rats at doses up to 4 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. However, malformations were observed in rabbits at a dose 54 times the MRHD given to adults. 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 RELEXXII, 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 development studies conducted in rats and rabbits, methylphenidate was administered at doses up to 30 and 200 mg/kg/day, respectively. Methylphenidate has been shown to cause malformations in rabbits when given in doses of 200 mg/kg/day, which is approximately 54 times the MRHD on a mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 4-fold the MRHD 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 CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RELEXXII and any potential adverse effects on the breastfed infant from RELEXXII or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of RELEXXII have not been established in pediatric patients below the age of 6 years. In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. The safety and effectiveness of RELEXXII for the treatment of ADHD have been established in pediatric patients 6 to 17 years. Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including RELEXXII. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment in …

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

11 DESCRIPTION RELEXXII contains methylphenidate, a CNS stimulant, present as methylphenidate hydrochloride salt. Chemically, methylphenidate hydrochloride is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C 14 H 19 NO 2 •HCl. Its structural formula is: Methylphenidate hydrochloride is a white, odorless 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. It has a pKa of 8.71 (at 21.5°C). Its molecular weight is 269.77. RELEXXII is for oral administration and is available in the following strengths: 18 mg, 27 mg, 36 mg, 45 mg, 54 mg, 63 mg, and 72 mg containing methylphenidate hydrochloride (equivalent to 15.6 mg, 23.4 mg, 31.1 mg, 38.9 mg, 46.7 mg, 54.5 mg, and 62.3 mg methylphenidate respectively). RELEXXII contains the following inactive ingredients: cellulose acetate, colloidal silicon dioxide, ferrosoferric oxide, hypromellose, iron oxide black, lactose monohydrate, magnesium stearate, phosphoric acid, polyethylene glycol, polyethylene oxide, sodium chloride, succinic acid, titanium dioxide, triacetin. RELEXXII also contains the following color additives: 27 mg: FD&C Yellow #6 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake 45 mg: FD&C Red #40 Aluminum Lake 54 mg: FD&C Yellow #6 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #2 Aluminum Lake 18 and 63 mg: iron oxide red, iron oxide yellow 72 mg: FD&C Blue #1 Aluminum Lake System Components and Performance RELEXXII uses osmotic pressure to deliver methylphenidate hydrochloride at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice on the drug-layer end of the tablet. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. The membrane controls the rate at which water enters the tablet core, which in turn controls drug delivery. Furthermore, the drug release rate from the system increases with time over a period of 6 to 7 hours due to the drug-concentration gradient incorporated into the two drug layers of core of RELEXXII. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell along with insoluble core components. It is possible that RELEXXII may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. RELEXXII 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. The pharmacokinetic profile of RELEXXII 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 RELEXXII ® (methylphenidate hydrochloride extended-release tablets) are available as: 18 mg yellow tablets with "TL706" imprinted in black ink NDC 68025-095-30 in 30-count bottle NDC 68025-095-10 in 100-count bottle 27 mg gray tablets with "TL707" imprinted in black ink NDC 68025-096-30 in 30-count bottle NDC 68025-096-10 in 100-count bottle 36 mg white tablets with "TL708" imprinted in black ink NDC 68025-097-30 in 30-count bottle NDC 68025-097-10 in 100-count bottle 45 mg pink tablets with "TL711" imprinted in black ink NDC 68025-088-30 in 30-count bottle 54 mg pink tablets with "TL709" imprinted in black ink NDC 68025-098-30 in 30-count bottle NDC 68025-098-10 in 100-count bottle 63 mg orange tablets with "TL700" imprinted in black ink NDC 68025-089-30 in 30-count bottle 72 mg blue tablets with "TL710" imprinted in black ink NDC 68025-084-30 in 30-count bottle Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from humidity.