AZSTARYS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AZSTARYS (AZSTARYS).
AZSTARYS is a prodrug of dexmethylphenidate, a central nervous system stimulant. The exact mechanism of action in attention deficit hyperactivity disorder (ADHD) is unknown, but it is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron, increasing their levels in the extraneuronal space.
| Metabolism | AZSTARYS is a prodrug that is converted to dexmethylphenidate primarily through enzymatic hydrolysis by carboxylesterase 1 (CES1). The active metabolite dexmethylphenidate is further metabolized primarily via deesterification to ritalinic acid, with minor hydroxylation pathways. |
| Excretion | Renal: 90% (primarily as metabolites, with 50-70% as the major metabolite (-)-phensuximide glucuronide). Fecal: <5%. |
| Half-life | Serdexmethylphenidate: 1.5 hours; dexmethylphenidate: 3.5 hours. The terminal half-life of total dexmethylphenidate after AZSTARYS is approximately 6.5 hours, supporting once-daily dosing. |
| Protein binding | Serdexmethylphenidate: 94% (bound to albumin); dexmethylphenidate: 15-20%. |
| Volume of Distribution | Serdexmethylphenidate: 5.6 L/kg; dexmethylphenidate: 2.7 L/kg. High Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: 100% for serdexmethylphenidate (prodrug); dexmethylphenidate from the prodrug is 87% bioavailable relative to equivalent dexmethylphenidate dose. |
| Onset of Action | Oral: 1 hour (based on early time points in clinical trials showing significant improvement in attention symptoms). |
| Duration of Action | Up to 13 hours (once-daily dosing; sustained effect throughout the day as demonstrated in a laboratory classroom study). |
Initial: 39.2 mg oral once daily in the morning; titrate weekly by 19.6 mg increments as needed; maximum dose: 78.4 mg once daily.
| Dosage form | CAPSULE |
| Renal impairment | eGFR 15-29 mL/min: not recommended; eGFR <15 mL/min: contraindicated. No dose adjustment for eGFR >=30 mL/min. |
| Liver impairment | Child-Pugh A: no dose adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: not recommended. |
| Pediatric use | Age 6-12 years: initial 19.6 mg oral once daily; titrate weekly by 19.6 mg; max 78.4 mg. Age 13-17 years: same as adult dosing. |
| Geriatric use | No specific studies in elderly; initiate at low end of dosing range due to increased sensitivity to sympathomimetics. Monitor cardiovascular status. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AZSTARYS (AZSTARYS).
| Breastfeeding | Excreted in human milk; M/P ratio not established. Limited data suggest potential for adverse effects in nursing infants (e.g., irritability, poor feeding). Decision to breastfeed should weigh risks and benefits; consider alternative feeding if drug is essential. |
| Teratogenic Risk | Pregnancy Category C. First trimester: Animal studies show increased risk of fetal malformations (e.g., cardiac, skeletal). Second/third trimester: Potential for preterm delivery, low birth weight, and neonatal withdrawal symptoms (e.g., irritability, feeding difficulties) due to chronic exposure. |
■ FDA Black Box Warning
AZSTARYS has a high potential for abuse and misuse, which can lead to dependence. Misuse may cause sudden death or serious cardiovascular adverse events.
| Serious Effects |
["Hypersensitivity to methylphenidate products or any component of AZSTARYS","Concurrent treatment with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI","Glaucoma","Tics or family history of Tourette's syndrome","Severe anxiety, tension, or agitation"]
| Precautions | ["Serious cardiovascular events: Sudden death, stroke, and myocardial infarction have been reported in patients with structural cardiac abnormalities or other serious heart problems.","Blood pressure and heart rate increase: Monitor closely for tachycardia and hypertension.","Psychiatric adverse events: May precipitate psychotic or manic symptoms in patients with no prior history, or exacerbate symptoms in those with pre-existing psychiatric disorders.","Priapism: Prolonged and painful erections may occur, requiring immediate medical attention.","Peripheral vasculopathy: Including Raynaud's phenomenon, monitor for digital changes.","Long-term suppression of growth: Monitor growth in pediatric patients during treatment."] |
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| Fetal Monitoring |
| Monitor maternal blood pressure, heart rate, and weight gain. Assess fetal growth via ultrasound every 4-6 weeks. Monitor for signs of preterm labor or placental insufficiency. Postnatal: Observe neonate for withdrawal symptoms. |
| Fertility Effects | Based on animal data, may impair female fertility (decreased conception rates). Human data insufficient. Reversible upon discontinuation. No known effects on male fertility. |
| Food/Dietary |
| High-fat meals delay time to peak concentration (Tmax) by approximately 2 hours but do not affect overall exposure (AUC). Avoid alcohol as it may alter drug release characteristics. No specific food restrictions; can be taken with or without food. |
| Clinical Pearls | AZSTARYS (serdexmethylphenidate and dexmethylphenidate) is a prodrug combination with immediate-release and delayed-release components. Onset of action occurs within 1 hour, and duration is approximately 13 hours. It can be taken with or without food, but high-fat meals delay peak concentration. Avoid use in patients with pre-existing cardiovascular disease, hypertension, hyperthyroidism, glaucoma, or history of drug abuse. Monitor for growth suppression in children, weight loss, and insomnia. Avoid concomitant use with MAOIs or within 14 days of discontinuation. May exacerbate tics or Tourette syndrome. Use with caution in patients with seizure disorder or those taking CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) due to increased dexmethylphenidate exposure. |
| Patient Advice | Take exactly as prescribed; do not crush or chew capsules. · Avoid alcohol while taking this medication. · Report any chest pain, shortness of breath, or palpitations immediately. · May cause dizziness or blurred vision; avoid driving until effects are known. · Use with caution in patients with history of drug dependence or abuse. · Keep out of reach of children; do not share medication. · Store at room temperature away from moisture and heat. |