These Highlights Do Not Include All The Information Needed To Use Aptensio Xr®

Limitations of Use

The use of Aptensio XR 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)].

Storage and Handling

APTENSIO XR (methylphenidate hydrochloride extended-release) capsules should be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in tight container (USP).

APTENSIO XR has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. APTENSIO XR can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including APTENSIO XR, 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.

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 occured during methylphenidate withdrawal (drug holidays or during discontinuation).

APTENSIO XR patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

APTENSIO XR contains methylphenidate hydrochloride, a central nervous system (CNS) stimulant. APTENSIO XR 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. APTENSIO XR is 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 HCl 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 HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its molecular formula is C₁₄H₁₉NO₂∙HCl. Its structural formula is:

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. Its molecular weight is 269.77.

Inactive Ingredients: ammonio methacrylate copolymer, type B; colloidal silicon dioxide (added if necessary); gelatin; hypromelloses; methacrylic acid copolymer, type C; polyethylene glycol; sugar spheres; talc; titanium oxide; and triethyl citrate.

Each strength capsule also contains colorant ingredients in the capsule shell as follows:

10 mg: FD&C Blue No. 1

15 mg: D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40

20 mg: D&C Red No. 33, D&C Yellow No. 10

30 mg: FD&C Blue No. 1, FD&C Red No. 3

40 mg: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40

50 mg: D&C Yellow No. 10, FD&C Green No. 3

60 mg: Black Iron Oxide

The safety and effectiveness of APTENSIO XR have not been established in pediatric patients below the age of 6 years.

Safety and efficacy of APTENSIO XR were evaluated in a multicenter, placebo-controlled, double-blind, parallel group study in 119 children 4 to <6 years of age with ADHD followed by a 12-month open-label extension in 44 of these children. In these studies, patients experienced high rates of adverse reactions, most notably weight loss. Comparing weights prior to initiation of APTENSIO XR (in the safety and efficacy study) to weights after 12 months of treatment (in the open-label extension), 20 of 39 patients with data (50%) had lost enough weight to decrease 10 or more percentiles on a Centers for Disease Control growth chart for weight. In addition, systemic drug exposures in patients 4 to <6 years of age were higher than those observed in older children and adolescents at the same dose (2 to 3 fold higher C_max and AUC). Therefore, the benefits of APTENSIO XR do not outweigh the risks in pediatric patients 4 to <6 years of age.

The safety and effectiveness of APTENSIO XR have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14)].

Clinical trials of APTENSIO XR did not include any patients aged 65 years and over. In general, dose selection for an elderly patient start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

The efficacy of APTENSIO XR for the treatment of ADHD was established in a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over trial in pediatric patients aged 6 to 12 years and a second randomized, double-blind, multicenter, placebo-controlled, fixed–dose trial in pediatric patients 6 to 17 years.

• Hypersensitivity to methylphenidate or other components of the product. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.1)].
• Concomitant treatment with monoamine oxidase inhibitors, and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

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), and Drug Abuse and Dependence (9.2, 9.3)]
• Hypersensitivity to Methylphenidate [see Contraindications (4)]
• Hypertensive Crisis with Concomitant Use of 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)]
• 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)]

Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7)

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

The recommended starting dose of APTENSIO XR in patients 6 years and older is 10 mg once daily orally in the morning with or without food. Advise patients to establish a routine pattern with regard to meals. The dose should be individualized according to the needs and response of the patient.

The dose may be titrated weekly in increments of 10 mg. Daily doses above 60 mg have not been studied and are not recommended.

APTENSIO XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14)].

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

APTENSIO XR contains methylphenidate, a Schedule II controlled substance.

Prior to treating patients with APTENSIO XR, 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 APTENSIO XR [see Warnings and Precautions (5.10)].

• 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 APTENSIO XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing APTENSIO XR. (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 APTENSION XR 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: APTENSIO XR-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 APTENSIO XR 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 APTENSIO XR, 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)

• Recommended starting dose for patients 6 years and older: 10 mg once daily with or without food in the morning. Dosage may be increased weekly in increments of 10 mg per day. Daily dosage above 60 mg is not recommended. (2.1)
• Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce. (2.1)

• 10 mg Extended-Release Capsules – light turquoise blue cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "10 mg" on the body)
• 15 mg Extended-Release Capsules – orange cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "15 mg" on the body)
• 20 mg Extended-Release Capsules – yellow cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "20 mg" on the body)
• 30 mg Extended-Release Capsules – blue violet cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "30 mg" on the body)
• 40 mg Extended-Release Capsules – pink cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "40 mg" on the body)
• 50 mg Extended-Release Capsules – green cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "50 mg" on the body)
• 60 mg Extended-Release Capsules – gray cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "60 mg" on the body)

The following adverse reactions have been identified during post approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthems NEC

Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal, severe hepatic injury

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System: Convulsion, Grand mal convulsion, Dyskinesia, serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics

Psychiatric Disorders: Disorientation, Libido changes

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

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.

APTENSIO XR 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.

APTENSIO XR has a high potential for abuse and misuse. The use of APTENSIO XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. APTENSIO XR 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 APTENSIO XR, 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 APTENSIO XR, 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 APTENSIO XR in a safe place, preferably locked, and instruct patients to not give APTENSIO XR to anyone else. Throughout APTENSIO XR treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

There have been reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, APTENSIO XR-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

APTENSIO XR (methylphenidate hydrochloride extended-release) capsules are available as follows:

10 mg Capsules – light turquoise blue cap/white body, (imprinted with "APTENSIO XR" on cap and "10 mg" on the body)

15 mg Capsules – orange cap/white body, (imprinted with "APTENSIO XR" on cap and "15 mg" on the body)

20 mg Capsules – yellow cap/white body, (imprinted with "APTENSIO XR" on cap and "20 mg" on the body)

30 mg Capsules – blue violet cap/white body, (imprinted with "APTENSIO XR" on cap and "30 mg" on the body)

40 mg Capsules – pink cap/white body, (imprinted with "APTENSIO XR" on cap and "40 mg" on the body)

50 mg Capsules – green cap/white body, (imprinted with "APTENSIO XR" on cap and "50 mg" on the body)

60 mg Capsules – gray cap/white body, (imprinted with "APTENSIO XR" on cap and "60 mg" on the body)

APTENSIO XR has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including APTENSIO XR, 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 APTENSIO XR, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout APTENSIO XR treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].

If paradoxical aggravation of symptoms or other adverse reactions occur; the dosage should be reduced, or, if necessary, discontinue APTENSIO XR.

If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue APTENSIO XR.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases.

Monitor all APTENSIO XR-treated patients for hypertension and tachycardia.

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].

Prescribe APTENSIO XR to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor APTENSIO XR-treated patients with a history of abnormally increased IOP or open angle glaucoma.

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 APTENSIO XR use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, or other serious cardiac disease.

NDC 42858-401-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

10 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-402-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

15 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-403-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

20 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-404-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

30 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-405-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

40 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-406-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

50 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-407-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

60 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

APTENSIO XR is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

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-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period.

Closely monitor growth (weight and height) in APTENSIO XR-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

CNS stimulants, including APTENSIO XR, 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 and at the therapeutic dosages 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 APTENSIO XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for APTENSIO XR-treated patients who develop signs or symptoms of peripheral vasculopathy.

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating APTENSIO XR, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor APTENSIO XR-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.

Limitations of Use

The use of Aptensio XR 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)].

Storage and Handling

APTENSIO XR (methylphenidate hydrochloride extended-release) capsules should be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in tight container (USP).

APTENSIO XR has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. APTENSIO XR can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including APTENSIO XR, 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.

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 occured during methylphenidate withdrawal (drug holidays or during discontinuation).

APTENSIO XR patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

APTENSIO XR contains methylphenidate hydrochloride, a central nervous system (CNS) stimulant. APTENSIO XR 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. APTENSIO XR is 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 HCl 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 HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its molecular formula is C₁₄H₁₉NO₂∙HCl. Its structural formula is:

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. Its molecular weight is 269.77.

Inactive Ingredients: ammonio methacrylate copolymer, type B; colloidal silicon dioxide (added if necessary); gelatin; hypromelloses; methacrylic acid copolymer, type C; polyethylene glycol; sugar spheres; talc; titanium oxide; and triethyl citrate.

Each strength capsule also contains colorant ingredients in the capsule shell as follows:

10 mg: FD&C Blue No. 1

15 mg: D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40

20 mg: D&C Red No. 33, D&C Yellow No. 10

30 mg: FD&C Blue No. 1, FD&C Red No. 3

40 mg: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40

50 mg: D&C Yellow No. 10, FD&C Green No. 3

60 mg: Black Iron Oxide

The safety and effectiveness of APTENSIO XR have not been established in pediatric patients below the age of 6 years.

Safety and efficacy of APTENSIO XR were evaluated in a multicenter, placebo-controlled, double-blind, parallel group study in 119 children 4 to <6 years of age with ADHD followed by a 12-month open-label extension in 44 of these children. In these studies, patients experienced high rates of adverse reactions, most notably weight loss. Comparing weights prior to initiation of APTENSIO XR (in the safety and efficacy study) to weights after 12 months of treatment (in the open-label extension), 20 of 39 patients with data (50%) had lost enough weight to decrease 10 or more percentiles on a Centers for Disease Control growth chart for weight. In addition, systemic drug exposures in patients 4 to <6 years of age were higher than those observed in older children and adolescents at the same dose (2 to 3 fold higher C_max and AUC). Therefore, the benefits of APTENSIO XR do not outweigh the risks in pediatric patients 4 to <6 years of age.

The safety and effectiveness of APTENSIO XR have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14)].

Clinical trials of APTENSIO XR did not include any patients aged 65 years and over. In general, dose selection for an elderly patient start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

The efficacy of APTENSIO XR for the treatment of ADHD was established in a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over trial in pediatric patients aged 6 to 12 years and a second randomized, double-blind, multicenter, placebo-controlled, fixed–dose trial in pediatric patients 6 to 17 years.

• Hypersensitivity to methylphenidate or other components of the product. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.1)].
• Concomitant treatment with monoamine oxidase inhibitors, and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

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), and Drug Abuse and Dependence (9.2, 9.3)]
• Hypersensitivity to Methylphenidate [see Contraindications (4)]
• Hypertensive Crisis with Concomitant Use of 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)]
• 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)]

Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7)

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

The recommended starting dose of APTENSIO XR in patients 6 years and older is 10 mg once daily orally in the morning with or without food. Advise patients to establish a routine pattern with regard to meals. The dose should be individualized according to the needs and response of the patient.

The dose may be titrated weekly in increments of 10 mg. Daily doses above 60 mg have not been studied and are not recommended.

APTENSIO XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14)].

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

APTENSIO XR contains methylphenidate, a Schedule II controlled substance.

Prior to treating patients with APTENSIO XR, 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 APTENSIO XR [see Warnings and Precautions (5.10)].

• 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 APTENSIO XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing APTENSIO XR. (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 APTENSION XR 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: APTENSIO XR-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 APTENSIO XR 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 APTENSIO XR, 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)

• Recommended starting dose for patients 6 years and older: 10 mg once daily with or without food in the morning. Dosage may be increased weekly in increments of 10 mg per day. Daily dosage above 60 mg is not recommended. (2.1)
• Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce. (2.1)

• 10 mg Extended-Release Capsules – light turquoise blue cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "10 mg" on the body)
• 15 mg Extended-Release Capsules – orange cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "15 mg" on the body)
• 20 mg Extended-Release Capsules – yellow cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "20 mg" on the body)
• 30 mg Extended-Release Capsules – blue violet cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "30 mg" on the body)
• 40 mg Extended-Release Capsules – pink cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "40 mg" on the body)
• 50 mg Extended-Release Capsules – green cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "50 mg" on the body)
• 60 mg Extended-Release Capsules – gray cap/white body
  
  (imprinted with "APTENSIO XR" on cap and "60 mg" on the body)

The following adverse reactions have been identified during post approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthems NEC

Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal, severe hepatic injury

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System: Convulsion, Grand mal convulsion, Dyskinesia, serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics

Psychiatric Disorders: Disorientation, Libido changes

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

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.

APTENSIO XR 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.

APTENSIO XR has a high potential for abuse and misuse. The use of APTENSIO XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. APTENSIO XR 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 APTENSIO XR, 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 APTENSIO XR, 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 APTENSIO XR in a safe place, preferably locked, and instruct patients to not give APTENSIO XR to anyone else. Throughout APTENSIO XR treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

There have been reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, APTENSIO XR-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

APTENSIO XR (methylphenidate hydrochloride extended-release) capsules are available as follows:

10 mg Capsules – light turquoise blue cap/white body, (imprinted with "APTENSIO XR" on cap and "10 mg" on the body)

15 mg Capsules – orange cap/white body, (imprinted with "APTENSIO XR" on cap and "15 mg" on the body)

20 mg Capsules – yellow cap/white body, (imprinted with "APTENSIO XR" on cap and "20 mg" on the body)

30 mg Capsules – blue violet cap/white body, (imprinted with "APTENSIO XR" on cap and "30 mg" on the body)

40 mg Capsules – pink cap/white body, (imprinted with "APTENSIO XR" on cap and "40 mg" on the body)

50 mg Capsules – green cap/white body, (imprinted with "APTENSIO XR" on cap and "50 mg" on the body)

60 mg Capsules – gray cap/white body, (imprinted with "APTENSIO XR" on cap and "60 mg" on the body)

APTENSIO XR has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including APTENSIO XR, 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 APTENSIO XR, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout APTENSIO XR treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].

If paradoxical aggravation of symptoms or other adverse reactions occur; the dosage should be reduced, or, if necessary, discontinue APTENSIO XR.

If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue APTENSIO XR.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases.

Monitor all APTENSIO XR-treated patients for hypertension and tachycardia.

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].

Prescribe APTENSIO XR to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor APTENSIO XR-treated patients with a history of abnormally increased IOP or open angle glaucoma.

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 APTENSIO XR use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, or other serious cardiac disease.

NDC 42858-401-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

10 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-402-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

15 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-403-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

20 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-404-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

30 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-405-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

40 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-406-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

50 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

NDC 42858-407-45

Aptensio XR™

(methylphenidate HCl

extended-release)

capsules

CII

60 mg

Dispense the accompanying

Medication Guide to each patient.

Rhodes

Once Daily

R_x only

90 Capsules

APTENSIO XR is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

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-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period.

Closely monitor growth (weight and height) in APTENSIO XR-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

CNS stimulants, including APTENSIO XR, 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 and at the therapeutic dosages 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 APTENSIO XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for APTENSIO XR-treated patients who develop signs or symptoms of peripheral vasculopathy.

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating APTENSIO XR, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor APTENSIO XR-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.