Azstarys

Pretreatment Screening

Prior to treating patients 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 ].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating AZSTARYS [see Warnings and Precautions ].

 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, depending on response and tolerability.
• Maximum recommended dosage is 52.3 mg serdexmethylphenidate/10.4 mg dexmethylphenidate once daily.

Administration Instructions

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

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 ].

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 , Clinical Pharmacology ].

Dosage Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue AZSTARYS. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue AZSTARYS.

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.

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.

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 , Clinical Studies ]. 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 ]. 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 and Adverse Reactions ].

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.

Geriatric Use

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