dexmethylphenidate hydrochloride

sadasdasd 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 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 ).

2 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 take …

3 DOSAGE FORMS AND STRENGTHS 5 mg extended-release capsules – two-piece hard-gelatin capsule with aqua-blue-opaque cap and aqua-blue-opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5550” on body. 10 mg extended-release capsules – two-piece hard-gelatin capsule with ivory-opaque cap and ivory-opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5551” on body. 15 mg extended-release capsules – two-piece hard-gelatin capsule with blue-green-opaque cap and blue-green-opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5552” on body. 20 mg extended-release capsules – two-piece hard-gelatin capsule with white-opaque cap and white-opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5553” on body. 25 mg extended-release capsules – two-piece hard-gelatin capsule with aqua blue opaque cap and white opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5045” on body. 30 mg extended-release capsules – two-piece hard-gelatin capsule with ivory-opaque cap and white-opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5554” on body. 35 mg extended-release capsules – two-piece hard-gelatin capsule with aqua blue opaque cap and ivory opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5046” on body. 40 mg extended-release capsules – two-piece hard-gelatin capsule with blue-green cap and white-opaque body, filled with white to off-white pellets. Imprinted in black ink with “TEVA” on cap and “5562” on body. Extended-release capsules: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg of dexmethylphenidate hydrochloride ( 3 ).

4 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 ).

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 dexmethylphenidate hydrochloride extended-release capsules [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 Raynaud’s 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 6 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 Camber Pharmaceuticals, Inc., at 1-866-495-8330, 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. Clinical Trials Experience with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Pediatric Patients with ADHD The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules in 100 (103 randomized) pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17). This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of dexmethylphenidate hydrochloride extended-release capsules 5 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 dexmethylphenidate hydrochloride 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 1 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride extended-release capsules doses of 5-30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release capsules and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release capsules was at least twice the incidence in placebo-treated patients. Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking dexmethylphenidate hydrochloride extended-release capsules up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride extended-release capsules for which the incidence was at least 5% and greater than the incidence among placebo-treated patients. Clin …

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). Halogenated Anesthetics: Avoid use of Dexmethylphenidate Hydrochloride Extended-release Capsules on the day of surgery if halogenated anesthetics will be used ( 7.1 ). 7.1 Clinically Important Interactions with Dexmethylphenidate Hydrochloride Extended-Release Capsules Table 5 presents clinically important drug interactions with Dexmethylphenidate Hydrochloride Extended-release Capsules. Table 5: Clinically Important Drug Interactions with Dexmethylphenidate Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including Dexmethylphenidate 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 Dexmethylphenidate Hydrochloride Extended-Release Capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Antihypertensive Drugs Clinical Impact Dexmethylphenidate 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. Examples Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and Dexmethylphenidate Hydrochloride Extended-Release Capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of Dexmethylphenidate Hydrochloride Extended-Release Capsules in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane

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 dexmethylphenidate hydrochloride extended-release capsules, 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 ( 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 dexmethylphenidate hydrochloride extended-release capsules, 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 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 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 dexmethylphenidate hydroc …

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

11 DESCRIPTION Dexmethylphenidate hydrochloride extended-release capsules contains dexmethylphenidate hydrochloride, a CNS stimulant. Dexmethylphenidate hydrochloride is the d­-threo enantiomer of racemic methylphenidate hydrochloride. Dexmethylphenidate hydrochloride extended-release capsules are an extended-release formulation of dexmethylphenidate with a bi-modal release profile. Each bead-filled dexmethylphenidate hydrochloride extended-release 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 a delayed release of dexmethylphenidate. Dexmethylphenidate hydrochloride extended-release capsules are intended for oral administration and are available as 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg extended-release capsules. 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: Dexmethylphenidate hydrochloride is a white 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. Its molecular weight is 269.77 g/mol. Inactive ingredients: Polyethylene glycol, sugar spheres (which contain corn starch and sucrose), ammonio methacrylate copolymer, methacrylic acid and methyl methacrylate copolymer, triethyl citrate, talc, acetone, isopropyl alcohol, titanium dioxide, gelatin and sodium lauryl sulfate. The ink ingredients common for all strengths are shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, and strong ammonia solution. Additional ink ingredients in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 40 mg strengths are black iron oxide and potassium hydroxide, 35 mg strength is red iron oxide. Each strength capsule also contains colorant ingredients in the capsule shell as follows: 5 mg: FD&C blue No. 1, FD&C red No. 3, FD&C yellow No. 6 and D&C yellow No. 10 10 mg: contains no colorants 15 mg: FD&C yellow No. 6 and D&C yellow No. 10 20 mg: FD&C red No. 40, FD&C blue No. 1 and D&C yellow No. 10 25 mg: FD&C yellow No. 6 and D&C yellow No. 10 30 mg: contains no colorants 35 mg: Iron oxide yellow 40 mg: FD&C yellow No. 6 and D&C yellow No. 10 structure

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 dexmethylphenidate 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 Dexmethylphenidate hydrochloride extended-release capsules are available containing 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of dexmethylphenidate hydrochloride. 5 mg extended-release capsules are hard gelatin capsule size “2” light brown cap and white opaque body, imprinted with “M5” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-229-01 bottles of 100 capsules 10 mg extended-release capsules are hard gelatin capsule size “2” white opaque cap and white opaque body, imprinted with “M10” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-230-01 bottles of 100 capsules 15 mg extended-release capsules are hard gelatin capsule size “1” yellow opaque cap and white opaque body, imprinted with “M15” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-231-01 bottles of 100 capsules 20 mg extended-release capsules are hard gelatin capsule size “1” light brown cap and white opaque body, imprinted with “M20” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-232-01 bottles of 100 capsules 25 mg extended-release capsules are hard gelatin capsule size “0” yellow opaque cap and white opaque body, imprinted with “M25” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-233-01 bottles of 100 capsules 30 mg extended-release capsules are hard gelatin capsule size “00” white opaque cap and white opaque body, imprinted with “M30” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-234-01 bottles of 100 capsules 35 mg extended-release capsules are hard gelatin capsule size “00” light yellow opaque cap and light yellow opaque body, imprinted with “M35” on cap and “AC” on body in red ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-235-01 bottles of 100 capsules 40 mg extended-release capsules are hard gelatin capsule size “00” yellow opaque cap and white opaque body, imprinted with “M40” on cap and “AC” on body in black ink filled with white to off white spherical pellets. They are available as follows: NDC 31722-236-01 bottles of 100 capsules Store at 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP). Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired dexmethylphenidate hydrochloride extended-release capsules by a 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 dexmethylphenidate hydrochloride extended-release capsules with an undesirable, non-toxic substance to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and discard dexmethylphenidate hydrochloride extended-release capsules in the household trash.