BRIEF SUMMARY

 Serdexmethylphenidate (Mar 2021)

Indn- For the treatment of Attention Deficit Hyperactivity                                                                                 

Comp- Capsules (serdexmethylphenidate/dexmethylphenidate): 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, 52.3 mg/10.4 mg.

Pediatric Patients 6 to 12 years: Recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. Dosage may be increased to 52.3 mg/10.4 mg daily or decreased to 26.1 mg/5.2 mg daily after one week. Maximum recommended dosage is 52.3 mg/10.4 mg once daily.

 • Adults and Pediatric Patients 13 to 17 years: Recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. Increase the dosage after one week to 52.3 mg/10.4 mg once daily.

 • Administer with or without food.

ADR-   the most common (>5% and twice the rate of placebo) adverse reactions are appetite decreased, insomnia, nausea, vomiting, dyspepsia, abdominal pain, weight decreased, anxiety, dizziness, irritability, affect lability, tachycardia, and blood pressure increased.

CI- Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days.

 WARNINGS -

 • Serious Cardiovascular Reactions: Sudden death has been reported at  recommended doses in pediatric patients with structural cardiac abnormalities . In adults, sudden death, stroke, and myocardial infarction have been reported.

Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmias, or coronary artery disease.

Pat Inform-

Controlled Substance Status/High Potential for Abuse and Dependence-             Advise patients  that the drug is a federally controlled substance, and it can be abused or lead to dependence 

Instruct patients that they should not give to anyone else.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 11

Name of the Drug-    AZSTARYS

Active Ingredient -    Serdexmethylphenidate and Dexmethylpheniidate

Pharmacological Classification-    For the treatment of Attention Deficit Hyperactivity                                                                                                                                                     Date of Approval-          3/2/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                      AZSTARYS safely and effectively.                                                                                  See full prescribing information for AZSTARYS. AZSTARYS (serdexmethylphenidate and dexmethylphenidate) capsules, for oral use, CII [controlled substance schedule pending for serdexmethylphenidate]

Initial U.S. Approval: [pending controlled substance scheduling]

WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning.

•CNS stimulants, including AZSTARYS, other methylphenidatecontaining 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

INDICATIONS AND USAGE

 AZSTARYS is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older.-

 ADVERSE REACTIONS

 Based on accumulated data from other methylphenidate products, the most common (>5% and twice the rate of placebo) adverse reactions are appetite decreased, insomnia, nausea, vomiting, dyspepsia, abdominal pain, weight decreased, anxiety, dizziness, irritability, affect lability, tachycardia, and blood pressure increased.

CONTRAINDICATIONS-

 • Known hypersensitivity to serdexmethylphenidate, methylphenidate, or product components.

 • Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days.

 WARNINGS AND PRECAUTIONS

 • Serious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulant treatment at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported.

Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmias, or coronary artery disease.

 • Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider the benefits and risks in patients for whom an increase in blood pressure or heart rate would be problematic.

 • Psychiatric Adverse Reactions: Use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychiatric illness. Evaluate for bipolar disorder prior to AZSTARYS use.

 • Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed.

 • Peripheral Vasculopathy, including Raynaud's Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants.

 • Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients.

 DOSAGE AND ADMINISTRATION

 • Pediatric Patients 6 to 12 years: Recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. Dosage may be increased to 52.3 mg/10.4 mg daily or decreased to 26.1 mg/5.2 mg daily after one week. Maximum recommended dosage is 52.3 mg/10.4 mg once daily.

 • Adults and Pediatric Patients 13 to 17 years: Recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. Increase the dosage after one week to 52.3 mg/10.4 mg once daily.

 • Administer with or without food.

 • Swallow capsules whole or open and sprinkle onto applesauce or add to water.

 • To avoid substitution errors and overdosage, do not substitute for other methylphenidate products on a milligram-per-milligram basis. 

 DOSAGE FORMS AND STRENGTHS-                                                                                  • Capsules (serdexmethylphenidate/dexmethylphenidate): 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, 52.3 mg/10.4 mg. 

 PATIENT COUNSELING INFORMATION

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

Controlled Substance Status/High Potential for Abuse and Dependence-             Advise patients and their caregivers that AZSTARYS is a federally controlled substance, and it can be abused or lead to dependence 

Instruct patients that they should not give AZSTARYS to anyone else.

Advise patients to store AZSTARYS in a safe place, preferably locked, to prevent abuse.

Advise patients and their caregivers to comply with laws and regulations on drug disposal.

Advise patients and their caregivers to dispose of remaining, unused, or expired AZSTARYS through a medicine take-back program if available

. Serious Cardiovascular Risks -Advise patients and caregivers that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with AZSTARYS

. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease 

Blood Pressure and Heart Rate Increases- Advise patients and their caregivers that AZSTARYS can elevate blood pressure and heart rate

Psychiatric Risks Advise patients and their caregivers that AZSTARYS, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history or psychotic symptoms or mania 

Priapism Advise patients and their caregivers of the possibility of painful or prolonged penile erections (priapism).

Instruct the patient to seek immediate medical attention in the event of priapism 

Circulation Problems in Fingers and Toes [Peripheral vasculopathy, including Raynaud's phenomenon]

• Instruct patients about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.

• Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.

• Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking AZSTARYS

. • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients 

Suppression of Growth Advise patients and their caregivers that AZSTARYS can cause slowing of growth and weight loss

Advise patients and their caregivers to administer AZSTARYS capsules whole or opened and sprinkled over applesauce or added to water.

If sprinkled, advise patients and their caregivers to consume all the drug/food mixture immediately or within 10 minutes of mixing and not to store for future use 

Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to AZSTARYS during pregnancy

Lactation-                                                                                                                      Advise nursing mother to monitor infants exposed to AZSTARYS through breastmilk for agitation, poor feeding, and reduced weight gain

. Distributed by: Corium, Inc. Reference ID: 475586625 4558 50th Street, SE Grand Rapids, MI 4951

 CLINICAL PHARMACOLOGY

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.

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

Cardiac Electrophysiology -                                                                                        The effect of serdexmethylphenidate on QTc interval was evaluated in a randomized, doubleblind, placebo-controlled, human abuse potential study (intranasal administration) in 46 healthy subjects

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.

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.

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.

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.

8 USE IN SPECIFIC POPULATIONS

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

Risk Summary- There are no available data on AZSTARYS use in pregnant women to evaluate for a drugassociated 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

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 andmiscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

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.

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.

3.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.

4.Geriatric Use -                                                                                                         Clinical trials of AZSTARYS did not include any patients aged 65 years and over.

 DRUG ABUSE AND DEPENDENCE

1. Controlled Substance -                                                                                         AZSTARYS contains dexmethylphenidate hydrochloride, a Schedule II controlled substance, and serdexmethylphenidate. (Controlled substance schedule of serdexmethylphenidate to be determined after review by the Drug Enforcement Administration.)

.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 

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.

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.

 OVERDOSAGE

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.

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.