2.1 Pretreatment Screening

Prior to initiating treatment with AZSTARYS, 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, monitor for signs of abuse and overdose, and periodically re-evaluate the need for AZSTARYS use [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].

2.2 Recommended Dosage

Pediatric Patients 6 to 12 years of age

• The recommended starting dosage of AZSTARYS is 39.2 mg serdexmethylphenidate/7.8 mg dexmethylphenidate once daily in the morning.
• The dosage may be increased after one week to a dosage of 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate per day, or decreased after one week to a dosage of 26.1 mg serdexmethylphenidate/5.2 mg dexmethylphenidate per day, depending on response and tolerability.
• Maximum recommended dosage is 52.3 mg serdexmethylphendiate/10.4 mg dexmethyphenidate once daily.

Adults and Pediatric Patients 13 to 17 years of age

• The recommended starting dosage of AZSTARYS is 39.2 mg serdexmethylphenidate/7.8 mg dexmethylphenidate once daily in the morning.
• Increase the dosage after one week to a dosage of 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate per day.
• Maximum recommended dosage is 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate once daily.

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

2.3 Administration Information

Administer AZSTARYS orally once daily in the morning with or without food [see Clinical Pharmacology (12.3)].

AZSTARYS capsules may be taken whole, or opened and the entire contents sprinkled into 50 mL of water or over 2 tablespoons of applesauce. Consume all the drug/food mixture immediately or within 10 minutes of mixing; do not store for future use [see Clinical Pharmacology (12.3)].

2.4 Switching from Other Methylphenidate Products

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

Do not substitute AZSTARYS for other methylphenidate products on a milligram-per-milligram basis because these products have different pharmacokinetic profiles from AZSTARYS and may have different methylphenidate base composition [see Description (11), Clinical Pharmacology (12.3)].

2.5 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur; the dosage should be reduced, or, if necessary, the drug should be discontinued. AZSTARYS should be periodically discontinued to assess the pediatric patient’s condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

5.1 Potential for Abuse and Dependence

CNS stimulants, including AZSTARYS, 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 Boxed Warning and Drug Abuse and Dependence (9.2, 9.3)].

5.2 Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during AZSTARYS 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 beats per minute). 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 mood 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 AZSTARYS. 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 used to treat ADHD, including AZSTARYS, 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. In a long-term, open-label safety study with AZSTARYS conducted in pediatric patients 6 to 12 years of age with ADHD, there was a lower than expected increase in height and weight compared to pediatric patients of the same age and sex, on average [see Adverse Reactions (6.1)].

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

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 Other Methylphenidate Products in Pediatric Patients and Adults with ADHD

Commonly reported (≥ 5% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: decreased appetite, decreased weight, nausea, abdominal pain, dyspepsia, vomiting, insomnia, anxiety, affect lability, irritability, dizziness, increased blood pressure, and tachycardia.

Clinical Trials Experience with AZSTARYS in Pediatric Patients (6 to 12 years) with ADHD

Short-Term Study

A short-term study conducted in pediatric patients 6 to 12 years of age with ADHD was comprised of a 3-week, open-label, dose optimization phase in which all patients received AZSTARYS (n=155), followed by a 1-week, double-blind, controlled phase in which patients were randomized to continue AZSTARYS (n=74) or switch to placebo (n=76). Because of the study design, the reported adverse reaction rates cannot be used to predict the rates that may be expected in clinical practice.

Long-Term Study

A long-term, open-label safety study was conducted in pediatric patients 6 to 12 years of age with ADHD who either completed the short-term study or were de novo patients. This study was comprised of a 3-week dose optimization phase for patients not recently treated with AZSTARYS followed by a 12-month treatment phase for all patients during which 238 patients received open- label AZSTARYS and had evaluable safety data. A total of 154 patients were treated for 12 months. Because of the open-label, uncontrolled design of this study, the reported adverse reaction rates cannot be assessed in terms of a causal relationship to AZSTARYS treatment.

To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]); z- scores normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change less than 0.5 SD is considered not clinically significant.

In this study, the mean increase in weight from baseline to Month 12 was 3.4 kg among study completers. The mean change in z-score from baseline to Month 12 was -0.20, indicating a lower than expected increase in body weight compared to children of the same age and sex, on average. Most of the weight z-score decline occurred in the first 4 months of treatment.

The mean increase in height from baseline to Month 12 was 4.9 cm among completers. Using the same z-score analysis for height, the mean change in z-score from baseline to Month 12 was - 0.21, indicating a lower than expected increase in height compared to pediatric patients of the same age and sex, on average.

6.2 Postmarketing 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, palpitations, increased heart rate

Eye Disorders: diplopia, mydriasis, visual impairment, blurred vision

General Disorders: chest pain, chest discomfort, hyperpyrexia

Gastrointestinal Disorders: dry mouth

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 NEC, rashes, eruptions, and exanthemas NEC

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, muscle cramps

Nervous System Disorders: convulsion, grand mal convulsion, dyskinesia, serotonin syndrome in combination with serotonergic drugs, nervousness, headache, tremor, drowsiness, vertigo

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

Skin and Subcutaneous Tissue Disorders: alopecia, erythema, hyperhidrosis

Urogenital System: priapism

Vascular Disorders: Raynaud's phenomenon

7.1 Clinically Important Interactions with AZSTARYS

Table 1 presents clinically important drug interactions with AZSTARYS.

8.1 Pregnancy

Pregnancy Exposure Registry

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

Risk Summary

There are no available data on AZSTARYS use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes; however, AZSTARYS contains dexmethylphenidate and serdexmethylphenidate, a prodrug of dexmethylphenidate. 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 use during pregnancy (see Clinical Considerations). Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to 3 times the maximum recommended human dose (MRHD) of 40 mg/day dexmethylphenidate hydrochloride 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 dexmethylphenidate to rats throughout pregnancy and lactation at doses 3 times the MRHD of 40 mg/day dexmethylphenidate hydrochloride given to adults based on plasma levels (see Data).

No evidence of developmental effects were found in an embryo-fetal development study with oral administration of serdexmethylphenidate to rabbits during organogenesis at doses up to approximately 49 times the MRHD of 52 mg/day serdexmethylphenidate 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 AZSTARYS, 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 hydrochloride 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 hydrochloride 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 3 and 1 times, respectively, those in adults dosed with 40 mg/day dexmethylphenidate hydrochloride.

Racemic methylphenidate hydrochloride 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.

No evidence of developmental effects were found in an embryo-fetal development study with oral administration of serdexmethylphenidate in rabbits during organogenesis at doses of up to 374 mg/kg/day. At the highest dose tested, the plasma level [area under the curve (AUC)] of serdexmethylphenidate in pregnant rabbits was approximately 49 times that in adults dosed with 52 mg/day serdexmethylphenidate.

8.2 Lactation

Risk Summary

There are no available data on the presence of serdexmethylphenidate in human milk, effects on the breastfed infant, or effects on milk production. 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 AZSTARYS and any potential adverse effects on the breastfed infant from AZSTARYS or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, and reduced weight gain.

8.4 Pediatric Use

The safety and effectiveness of AZSTARYS have been established in pediatric patients ages 6 to 17 years of age for the treatment of ADHD. Use of AZSTARYS in patients 6 to 12 years of age is supported by a randomized, double-blind, placebo-controlled, parallel group trial in 155 pediatric patients with ADHD and a 12-month open-label long term safety trial in 238 patients [see Adverse Reactions (6.1), Clinical Studies (14)]. Use of AZSTARYS in pediatric patients 13 to 17 years of age is supported by additional pharmacokinetics analysis showing similar plasma concentration-time profiles of dexmethylphenidate in adolescents and adults after administration of the same dose of AZSTARYS [see Clinical Studies (14)].

The long-term efficacy of methylphenidate in pediatric patients has not been established.

The safety and effectiveness of AZSTARYS in pediatric patients less than 6 years have not been established.

Long Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including AZSTARYS. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Juvenile Animal Toxicity Data

Rats treated with racemic 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 MRHD of 40 mg/day dexmethylphenidate hydrochloride given to children on a mg/m2 basis.

In a study conducted in young rats, racemic methylphenidate hydrochloride 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 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day racemic methylphenidate hydrochloride [approximately 3 times the maximum recommended human dose (MRHD) of 40 mg of dexmethylphenidate hydrochloride given to children on a mg/m2 basis] or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (6 times the MRHD of 40 mg of dexmethylphenidate hydrochloride given to children on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day racemic methylphenidate hydrochloride (less than the MRHD of 40 mg of dexmethylphenidate hydrochloride given to children on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Serdexmethylphenidate was administered orally to juvenile rabbits at doses up to 280 mg/kg/day (approximately 50 times the MRHD of 52 mg/day serdexmethylphenidate given to children on a mg/m2 basis), respectively, for 6 months, starting at postnatal Day 28 and continuing through sexual maturity (postnatal Day 196). No adverse findings were observed at the highest dose of serdexmethylphenidate.

8.5 Geriatric Use

Clinical trials of AZSTARYS did not include any patients aged 65 years and over.

9.1 Controlled Substance

AZSTARYS contains dexmethylphenidate hydrochloride, a Schedule II controlled substance, and serdexmethylphenidate, a Schedule IV controlled substance.

9.2 Abuse

CNS stimulants including AZSTARYS, 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. 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. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking AZSTARYS as prescribed.

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. Individuals who abuse 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 AZSTARYS, 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 AZSTARYS use.

9.3 Dependence

Physical Dependence

AZSTARYS 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

AZSTARYS 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.

10.1 Signs and Symptoms

Signs and symptoms of acute methylphenidate overdose, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.

10.2 Management of Overdose

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with methylphenidate. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosages. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Dexmethylphenidate

Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic d,l-methylphenidate. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

In vitro studies with serdexmethylphenidate showed little or no binding of the prodrug to monoaminergic reuptake transporters.

Cardiac Electrophysiology

The effect of serdexmethylphenidate on QTc interval was evaluated in a randomized, double-blind, placebo-controlled, human abuse potential study (intranasal administration) in 46 healthy subjects. At a mean concentration 40 times the Cmax for the highest dose of AZSTARYS (52.3/10.4 mg base equivalent), serdexmethylphenidate does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Serdexmethylphenidate is a prodrug of dexmethylphenidate. Following a single dose administration of 52.3 mg/10.4 mg AZSTARYS and 40 mg of an dexmethylphenidate hydrochloride extended-release (ER) capsule in healthy volunteers under fasted conditions:

• The mean peak plasma concentration (Cmax) of dexmethylphenidate was 14.0 ng/mL and 28.2 ng/mL, respectively;
• The mean area under concentration curve (AUC) of dexmethylphenidate was 186 hour*ng/mL and 248 hour*ng/mL, respectively.

The plasma PK profiles of dexmethylphenidate following administration of AZSTARYS or dexmethylphenidate hydrochloride extended-release (ER) capsule are presented in Figure 1.

Approximate linear PK was demonstrated for dexmethylphenidate following single dose administration of AZSTARYS in the dose range of 26.1 mg/5.2 mg to 52.3 mg/10.4 mg. Steady state of dexmethylphenidate was approached after the third once-daily dose. At steady-state, dexmethylphenidate mean exposures (Cmax and AUC0-24h) were approximately 37% higher relative to a single-dose administration of AZSTARYS. No accumulation of serdexmethylphenidate was observed after once-daily administration of AZSTARYS. The mean relative exposure of serdexmethylphenidate to dexmethylphenidate based on molar concentrations for Cmax, Cmin, and AUC0-24hr was about 101%, 8.5%, and 55.7%, respectively, following multiple once-daily oral dosing under fasted conditions.

Absorption

Cross-study calculation estimated an absolute oral bioavailability for serdexmethylphenidate of less than 3%. The median time to reach Cmax of serdexmethylphenidate and dexmethylphenidate (Tmax) is about 2 hours following a single dose administration of AZSTARYS under fasted conditions. Following oral administration of serdexmethylphenidate single moiety alone, dexmethylphenidate Tmax is reached at about 8 hours post dose.

Effect of Food

No clinically meaningful differences in the exposure of dexmethylphenidate were observed when administered after an overnight fast, with a high-fat, high-caloric meal, or sprinkled onto applesauce or water. The median time to peak plasma concentration (Tmax) was lengthened from 2 to 4-4.5 hours in the presence of food.

Distribution

Plasma protein binding of serdexmethylphenidate and dexmethylphenidate is approximately 56% and 47%, respectively, at 5 µM (about 60-fold higher than the therapeutic concentrations at the highest recommended dose). The mean apparent volume of distribution for serdexmethylphenidate was about 29.3 L/kg after AZSTARYS administration. Dexmethylphenidate shows a mean volume of distribution of 2.65 L/kg after intravenous administration.

Elimination

The mean plasma terminal elimination half-life of serdexmethylphenidate and dexmethylphenidate in healthy adult subjects was about 5.7 hours and 11.7 hours, respectively, following a single dose of 52.3 mg/10.4 mg AZSTARYS. The mean apparent clearance for serdexmethylphenidate was about 3.6 L/hr/kg after AZSTARYS administration. Dexmethylphenidate was eliminated with a mean clearance of 0.40 L/hr/kg after intravenous administration.

Metabolism

Serdexmethylphenidate is a prodrug of dexmethylphenidate and is likely converted to dexmethylphenidate mainly in the lower gastrointestinal tract. Enzymes involved in the conversion process are not identified.

Dexmethylphenidate is metabolized primarily via de-esterification to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid). Ritalinic acid has little or no pharmacological activity. There is no in vivo interconversion to the l-threo-enantiomer observed.

Excretion

After oral dosing of radiolabeled serdexmethylphenidate in humans, about 62% and 37% of the radioactivity was recovered in urine and feces, respectively. Metabolite ritalinic acid accounted for approximately 63% of the total recovered dose in urine and feces. About 0.4% and 11% of the dose was excreted as unchanged serdexmethylphenidate in the urine and feces, respectively.

After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic d,l-methylphenidate was d,l-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of unchanged methylphenidate accounted for 0.5% of an intravenous dose.

Specific Populations

Sex

No significant pharmacokinetic differences based on sex have been observed for AZSTARYS.

Race

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

Age

The shapes of the plasma concentration time profiles for dexmethylphenidate were similar in pediatric patients (6 to 17 years of age) with ADHD and healthy adults. After the same dose administration of AZSTARYS, dexmethylphenidate exposure in pediatric patients (13 to 17 years of age) and adults was about half of that in pediatric patients 6 to 12 years of age. Plasma concentrations of dexmethylphenidate when adjusted for dose and body weight were similar across all age groups.

Renal Impairment

There is no experience with the use of AZSTARYS in patients with renal impairment. Since renal clearance is not an important route of serdexmethylphenidate or methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of AZSTARYS.

Hepatic Impairment

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

Drug Interaction Studies

Clinical Studies

CYP2D6 substrate: No clinically significant differences in desipramine (CYP2D6 substrate) were observed when coadministered with methylphenidate.

In Vitro Studies

Alcohol: No clinically significant differences in the rate or amount of release of either serdexmethylphenidate or methylphenidate were observed with alcohol concentrations of 5% and 40%.

Cytochrome P450 (CYP) enzymes: Serdexmethylphenidate and methylphenidate do not appear to be substrates, inducers or inhibitors of CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.

Transporters: Serdexmethylphenidate does not appear to be a substrate or inhibitor of P-gp, BCRP, OATP1B1/3, OAT1/3, OCT2, or MATE1/2-K.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime studies to evaluate the carcinogenic potential of serdexmethylphenidate have not been conducted.

Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate hydrochloride.

In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas was seen at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the MRHD of 40 mg of dexmethylphenidate hydrochloride 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.

Racemic methylphenidate hydrochloride 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 5 times the MRHD of 40 mg of dexmethylphenidate hydrochloride on a mg/m2 basis.

In a 24-week carcinogenicity study with racemic methylphenidate 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 concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate hydrochloride.

Mutagenesis

Serdexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mammalian cell micronucleus assay using human peripheral blood lymphocytes, in the in vivo rat bone barrow micronucleus assay, or in the in vivo rat alkaline comet assay.

Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary (CHO) cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response.

Impairment of Fertility

Racemic methylphenidate hydrochloride 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 10-times the MRHD of 40 mg of dexmethylphenidate hydrochloride on a mg/m2 basis.