2.1 Pretreatment Screening

Prior to initiating treatment with ADHANSIA 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)].

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, and periodically re-evaluate the need for ADHANSIA XR use [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].

2.2 General Dosing Information

Administer ADHANSIA XR orally once daily in the morning with or without food.

The recommended starting dose of ADHANSIA XR for patients 6 years or older is 25 mg once daily. Titrate the dose in increments of 10 to 15 mg at intervals of no less than 5 days. Dosages higher than 100 mg daily in adults and 85 mg daily in pediatric patients have not been evaluated in clinical trials and are not recommended. Although efficacy was demonstrated in short-term controlled trials in adults at dosages of 100 mg daily, dosages above 85 mg daily were associated with a disproportionate increase in the incidence of certain adverse reactions. In short-term controlled trials in pediatric patients, efficacy was demonstrated at dosages of 70 mg daily, but dosages 70 mg daily and higher were associated with a disproportionate increase in the incidence of certain adverse reactions [see Adverse Reactions (6.1), Clinical Studies (14)]. Individualize dosage adjustments based upon assessment of clinical benefit and tolerability with careful consideration of the dose-related adverse reactions.

ADHANSIA XR may be taken whole or the capsule may be opened and the entire contents sprinkled onto a tablespoon of applesauce or yogurt. The entire mixture should be consumed immediately or within 10 minutes. If the mixture is not consumed within 10 minutes after mixing, it should be discarded and not stored. Patients should take the entire contents of the capsule sprinkled on the chosen food in its entirety, without chewing. The dose of a single capsule should not be divided. Patients should not take anything less than one capsule per day.

In the event of a missed dose, do not administer later in the day. Do not administer additional medication to make up for the missed dose [see Adverse Reactions (6.1), Clinical Studies (14)].

Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of ADHANSIA XR, and adjust dosage as needed.

2.3 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue the drug. ADHANSIA XR should be periodically discontinued to assess the patient's condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue ADHANSIA XR.

2.4 Switching from Other Methylphenidate Products

If switching from other methylphenidate products, discontinue that treatment, and titrate with ADHANSIA XR using the titration schedule above.

Do not substitute ADHANSIA XR for other methylphenidate products on a milligram-per-milligram basis because of different methylphenidate base compositions and differing pharmacokinetic profiles [see Description (11) and Clinical Pharmacology (12.3)].

5.1 Potential for Abuse and Dependence

CNS stimulants, including ADHANSIA XR, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Drug Abuse and Dependence (9.2, 9.3)].

5.2 Serious Cardiovascular Events

Sudden death, stroke and myocardial infarction have occurred in adults treated with CNS stimulant treatment at recommended doses. Sudden death has occurred in pediatric patients with structural cardiac abnormalities and other serious cardiac problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during ADHANSIA XR treatment.

5.3 Blood Pressure and Heart Rate Increases

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). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions

Exacerbation of Pre-Existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing ADHANSIA XR. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% in placebo-treated patients.

5.5 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon

CNS stimulants, including ADHANSIA XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.7 Long-Term Suppression of Growth

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 consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have 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 period of development.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including ADHANSIA XR. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.8 Allergic-Type Reactions: FD&C Yellow No. 5

ADHANSIA XR 45 mg capsules contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity [see Contraindications (4)].

6.1 Clinical Trial 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 Other Methylphenidate Products in Children, Adolescents, and Adults with ADHD

Commonly reported (≥2% of the methylphenidate group and twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.

Clinical Trials Experience with ADHANSIA XR

ADHANSIA XR was studied in adults (18 to 72 years) and pediatric patients (6 to 17 years) who met Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for ADHD.

The safety data for adults is based on three randomized, double-blind, placebo-controlled studies in doses of 25 mg to 100 mg per day. The safety data for pediatric patients (6 to 17 years) is based on two randomized, double-blind, placebo-controlled studies in doses of 25 mg to 85 mg per day.

The total number of patients exposed to ADHANSIA XR during 1 to 4-week long, controlled treatment periods is 1168; this included 719 adult patients and 449 pediatric patients [156 (6 to 12 years); 293 (12 to 17 years)], from two clinical trials in adults, one in pediatric patients ages 12 to 17 years, and one in pediatric patients ages 6 to 12 years [see Clinical Studies (14)].

Adverse Reactions Leading to Discontinuation of Treatment

In controlled adult trials for Study 1, 3% of both of ADHANSIA XR-treated patients and placebo-treated patients discontinued due to adverse reactions. In an adult workplace environment study (Study 2), 10% of ADHANSIA XR-treated patients discontinued due to adverse reactions compared to 0% of placebo-treated patients. The following adverse reactions led to discontinuation at a frequency of 2% of ADHANSIA XR-treated patients: nausea, bronchitis, gastroenteritis viral, viral infection, blood pressure increased, and hypomania.

In an adult laboratory classroom study (Study 5), 3.5% of ADHANSIA XR-treated patients discontinued due to adverse reactions during the open-label titration period. There were no discontinuations due to adverse reactions during the double-blind period of the study.

In a controlled trial (Study 3) in pediatric patients (12 to 17 years), 3% of ADHANSIA XR-treated patients discontinued due to adverse reactions compared to 0% of placebo-treated patients. The most frequent adverse reactions leading to discontinuation in at least 1% of ADHANSIA XR-treated patients and at a rate greater that placebo was irritability (1%). Two patients taking ADHANSIA XR 70 or 85 mg had delirium leading to discontinuation.

In a controlled trial (Study 4) in pediatric patients (6 to 12 years), 1% of ADHANSIA XR-treated patients discontinued due to adverse reactions compared to 0% of placebo-treated patients.

Adult Patients with ADHD

The most common adverse reactions (incidence of ≥5% and at least twice placebo) of ADHANSIA XR occurring in controlled trials in adults (Study 1) were insomnia, dry mouth, and decreased appetite.

Table 1 lists the adverse reactions that occurred ≥2% of adult patients and greater than placebo among ADHANSIA XR-treated adult patients in Study 1.

The most common adverse reactions (incidence of ≥5%) of ADHANSIA XR occurring in adults in the open-label dose-optimization period of Study 5 were headache, decreased appetite, insomnia, irritability, upper respiratory tract infection, dry mouth, nausea, anxiety, and fatigue.

Table 2 lists adverse reactions that occurred ≥2% of adult patients in the ADHANSIA XR-treated patients and greater than placebo-treated patients for the double-blind period of study 5.

Pediatric Patients (12 to 17 years) with ADHD

The most common (incidence ≥5% and at least twice placebo) adverse reactions reported in pediatric patients (12 to 17 years) were decreased appetite, insomnia, and weight decreased.

Table 3 lists the adverse reactions that occurred ≥2% of pediatric patients (12 to 17 years) and greater than placebo among ADHANSIA XR-treated pediatric patients (12 to 17 years).

Pediatric Patients (6 to 12 years) with ADHD

Study 4, conducted in pediatric patients 6 to 12 years of age, was comprised of a 6-week open-label dose-optimization phase in which all patients received ADHANSIA XR (n=156; mean dose 48 mg), followed by a 1-week, double-blind controlled phase in which patients were randomized to continue ADHANSIA XR (n=75) or switch to placebo (n=73). During the open-label ADHANSIA XR treatment phase, adverse reactions reported in > 5% of patients included: decreased appetite (35%), upper abdominal pain (15%), affect lability (13%), nausea or vomiting (13%), weight decreased (12%), insomnia (10%), irritability (10%), headache (10%), and heart rate increased (5%). Because of the trial design (6-week open-label active treatment phase followed by a 1-week, randomized, double-blind, placebo-controlled withdrawal), the adverse reaction rates described in the double-blind phase are lower than expected in clinical practice. No difference occurred in the incidence of adverse reactions between ADHANSIA XR and placebo during the 1-week, double-blind, placebo-controlled treatment phase.

6.2 Post-marketing Experience

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, mydriasis, visual impairment

General Disorders: chest pain, chest discomfort, hyperpyrexia

Hepatobiliary disorders: hepatocellular injury, acute hepatic failure

Immune System Disorders: hypersensitivity reactions such as angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritus, rashes, eruptions, and exanthemas

Investigations: alkaline phosphatase increased, bilirubin increased, hepatic enzyme increased, platelet count decreased, white blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: arthralgia, myalgia, muscle twitching, rhabdomyolysis

Nervous System Disorders: convulsion, grand mal convulsion, dyskinesia, serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: disorientation, hallucination, hallucination auditory, hallucination visual, libido changes, logorrhea, mania

Skin and Subcutaneous Tissue Disorders: alopecia, erythema

Urogenital System: priapism

Vascular Disorders: Raynaud’s phenomenon

7.1 Clinically Important Drug Interactions

Table 3 presents clinically important drug interactions with ADHANSIA XR.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHANSIA XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.

Risk Summary

Published studies and post-marketing reports on methylphenidate use during pregnancy are insufficient to identify 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 embryo-fetal studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 7 and 11 times, respectively, the maximum recommended human dose (MRHD) of 85 mg/day given to adolescents on a mg/m2 basis. However, fetal spina bifida was observed in rabbits at a dose 36 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 4 times the MRHD given to adolescents [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

CNS stimulants, such as ADHANSIA XR, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Data

Animal Data

In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose. which is approximately 36 times the maximum recommended human dose (MRHD) of 85 mg/day given to adolescents on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD given to adolescents on a mg/m2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD given to adolescents on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day. (2 times the MRHD given to adolescents on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equivalent to the MRHD given to adolescents on a mg/m2 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. 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 ADHANSIA XR and any potential adverse effects on the breastfed infant from ADHANSIA XR 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

Safety and effectiveness of ADHANSIA XR in pediatric patients under the age of 6 years have not been established.

The safety and effectiveness of ADHANSIA XR have been established in one adequate and well-controlled 6-week study in pediatric patients ages 6 to 12 years, and in one adequate and well-controlled 4-week study in pediatric patients ages 12 to 17 years [see Clinical Studies (14)]. The long-term efficacy of methylphenidate in pediatric patients has not been established.

Long Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including ADHANSIA XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].

Juvenile Animal Toxicity Data

Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 3 times the maximum recommended human dose (MRHD) of 85 mg/day given to children on a mg/m2 basis.

In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 3 times the MRHD of 85 mg/day given to children on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (6 times the MRHD given to children on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.25 times the MRHD given to children on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

ADHANSIA XR has not been studied in the patients over the age of 72 years.

9.1 Controlled Substance

ADHANSIA XR contains methylphenidate, a Schedule II controlled substance.

9.2 Abuse

CNS stimulants including ADHANSIA XR, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.

Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants including ADHANSIA XR, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for ADHANSIA XR use.

9.3 Dependence

Dependence

ADHANSIA XR may produce physical dependence from continued therapy. Physical dependence is a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

ADHANSIA XR may produce tolerance from continued therapy. Tolerance is a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Absorption

ADHANSIA XR contains a racemic mixture of d- and l-methylphenidate and produces two distinct peak concentrations (Cmax). The 1st median (range) time to Cmax occurred at about 1.5 (1- 2.5) hours and the 2nd about 12 (8.5- 16.0) hours after ADHANSIA XR administration. Following administration of ADHANSIA XR (100 mg once daily) and 60 mg of immediate-release (IR) methylphenidate (administered as 20 mg three times daily 4 hours apart) under fasted condition for 5 consecutive days to 21 healthy adult subjects, 1std,l-methylphenidate mean Cmax was about 22% higher but the 2nd mean Cmax was similar for ADHANSIA XR compared to IR methylphenidate at steady state. The mean extent of exposure (AUC0-24h) and minimum concentration (Cmin) of d,l-methylphenidate were about 50% and 288% higher, respectively for ADHANSIA XR compared to IR methylphenidate at steady state. (Figure 1). Following administration of ADHANSIA XR (100 mg once daily), the steady-state was reached from day 3.

Figure 1: Mean Concentration-Time Profiles for d,l-Methylphenidate on Day 5 After Daily Dosing

Effect of Food

High fat, high caloric meal (800 to 1000 calories) does not affect Cmax and extent of absorption (AUC) of d,l-methylphenidate when taken with ADHANSIA XR. The time to 1st and 2nd Cmax was increased by about 1 hour after administration with a high fat meal compared to under fasting condition. The absorption and exposure to d, l-methylphenidate were similar when ADHANSIA XR (100 mg) was administered following an overnight fast as an intact capsule or sprinkled on a tablespoonful of applesauce and yogurt in healthy adult subjects.

Effect of Alcohol

In vitro studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from ADHANSIA XR. No increase in the rate of release of methylphenidate from ADHANSIA XR was observed with the alcohol concentrations of 5%, 20%, and 40% at hour 1 and for 5% and 20% at hour 2. A faster release, 71% and 61% for 70 mg and 100 mg, respectively, was observed with the alcohol concentration of 40% at hour 2.

In an in vivo alcohol interaction study, in fasted healthy adults, ADHANSIA XR 70 mg extended-release capsules with 40% alcohol concentration resulted in a 1.4-fold increase in the peak plasma methylphenidate concentration and a 1.3-fold increase in the extent of absorption.

Elimination

The mean plasma elimination half-life for d, l-methylphenidate was about 7 hours in healthy volunteers.

Metabolism

In humans, methylphenidate is metabolized primarily via de-esterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

Excretion

After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.

Specific Populations

Male and Female Patients

There is insufficient experience with the use of ADHANSIA XR to detect gender variations in pharmacokinetics.

Racial or Ethnic Groups

There is insufficient experience with the use of ADHANSIA XR to detect ethnic variations in pharmacokinetics.

Pediatric Patients

Results of the pharmacokinetic studies demonstrated that the pharmacokinetic profile in pediatric patients (6 to 12 years) is comparable to the pharmacokinetic profile in adults and pediatric patients (13 to 17 years) based on adjustment for body-weight.

Pharmacokinetic studies of racemic methylphenidate after oral administration of ADHANSIA XR has been conducted in pediatric patients (6 to 17 years) with ADHD. Following administration of ADHANSIA XR, the median (range) 1st and 2nd peak plasma concentration for d, l-methylphenidate occurred in about 2 (1-4) and 10 (8-14) hours, respectively in pediatric patients (6 to 12 years) and 2 (1 – 4) and 11(8 – 14) hours, respectively in pediatric patients (13 to 17 years). The mean plasma elimination half-life for d, l-methylphenidate was about 4 to 7 hours in pediatric patients (6 to 12 years) and 5 hours in pediatric patients (13 to 17 years).

Patients with Renal Impairment

There is no experience with the use of ADHANSIA XR in patients with renal impairment. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid metabolite. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of ADHANSIA XR.

Patients with Hepatic Impairment

There is no experience with the use of ADHANSIA XR in patients with hepatic impairment.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 85 mg/day given to children on a mg/m2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 3 times the MRHD given to children on a mg/m2 basis.

In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.

Mutagenesis

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 5 times the maximum recommended human dose of 85 mg/day given to adolescents on a mg/m2 basis.