Andre Wang, PharmD

Attention-deficit/hyperactivity disorder (ADHD) affects 11% of school-aged children, and more than 75% of these cases will continue into adulthood.

 Without proper diagnosis and treatment, ADHD can lead to serious consequences, including school failure, social difficulties, depression, substance abuse, or job failure. Extensive clinical research has led to well-developed diagnostic criteria and multiple treatment options for ADHD. Serdexmethylphenidate and dexmethylphenidate (Azstarys; Corium), also called ser/dex, is a dexmethylphenidate-based prodrug for ADHD in patients 6 years and older.

Although the mechanism of action for serdexmethylphenidate is not well understood, investigators believe it is mostly converted to dexmethylphenidate in the lower gastrointestinal tract. The combination of immediate-release dexmethylphenidate and slow-absorbed serdexmethylphenidate allows a quick onset and all-day effect.

A 4-week randomized, double-blind, placebo-controlled, parallel-group, classroom study (NCT03292952) evaluated the efficacy of ser/dex versus placebo for the treatment of ADHD in patients 6 to 12 years old. Study results showed a statistically significant lowering of the primary efficacy end point, which was the mean change from baseline of the Swanson, Kotkin, Agler, M-Flynn, and Pelham-Combined (SKAMP-C) ­­scores averaged across the test day.

Diagnostic and Statistical Manual of Mental Disorders

 (Fifth Edition) criteria and received a diagnosis of ADHD. Patients underwent a 5-day washout period, then a 3-week open-label dose-optimization period followed by a 1-week randomized, double-blind treatment phase. At the end of the 1-week treatment period, raters evaluated the attention and behavior of subjects in a laboratory classroom using the SKAMP-C scale. Assessments were conducted at 0.5, 1, 2, 4, 8, 10, 12, and 13 hours post dose. The overall mean change in SKAMP-C score from baseline (17.9 for both arms of the study) in the ser/dex arm was –4.87 and 0.54 for the placebo arm, which was statistically significant. The proportion of composite responders was similar regardless of age, gender, ethnicity, or race. The trial demonstrated superiority over placebo for the primary end point.

The most commonly reported adverse effects (AEs) were headache (5.41%), upper abdominal pain (4.05%), pharyngitis (2.7%), and insomnia (2.7%). There were no serious AEs, nor all-cause mortality reported. Ser/dex is a controlled substance, central nervous system (CNS) stimulant, methylphenidate-containing product, and amphetamine, so there is a boxed warning for a high potential for abuse and dependence. As with many CNS stimulants, there is potential for serious cardiovascular reactions, increased blood pressure and heart rate, psychiatric AEs, peripheral vasculopathy, and long-term growth suppression.

Ser/dex has not been studied in pregnant women; animal embryo-fetal development studies conducted in rats and rabbits showed no malformations. No data are available on the presence of serdexmethylphenidate in human breast milk, effects on the breastfed infant, or effects on milk production. There is limited published literature on dexmethylphenidate present in human breast 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 AEs on the breastfed infant and no effects on milk production. Ser/dex has not been studied in individuals 65 years and older.

The recommended dose for patients 6 to 12 years old is a starting dosage of 39.2 mg/7.8 mg orally once daily in the morning. The dosage may be increased to the maximum dose of 52.3 mg/10.4 mg daily or decreased to 26.1 mg/5.2 mg daily after 1 week. For adults and patients 13 to 17 years old, the recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. The dosage can be increased after 1 week to 52.3 mg/10.4 mg once daily. Ser/dex can be administered without regard to food, and patients can 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.

About ADHD. CHADD. Updated 2018. Accessed June 30, 2021. https://chadd.org/wp-content/uploads/2018/03/aboutADHD.pdf

KP415 classroom study in children (6-12 years of age) with ADHD

 ClinicalTrials.gov. Updated June 30, 2021. Accessed June 30, 2021. 

https://clinicaltrials.gov/ct2/show/results/NCT03292952?term=03292952&draw=2&rank=1&view=results

Azstarys. Prescribing Information. Corium, Inc; 2021

 Accessed June 30, 2021. https://www.corium.com/products/AZSTARYS/AZSTARYS_PI_ENGLISH_US.pdf

is a PGY-1 pharmacy resident at UConn John Dempsey Hospital in Farmington, Connecticut.

is the university director of pharmacy residency programs at UConn Health in Farmington, Connecticut.

Articles

Ser/dex is a dexmethylphenidate-based prodrug for ADHD in patients 6 years and older.

New Prodrug for ADHD in School-aged Children

On January 22, 2021, the FDA approved voclosporin (Lupkynis; Aurinia Pharmaceuticals) for the treatment of adult patients with active lupus nephritis (LN) in combination with a background immunosuppressive therapy regimen. Voclosporin is an oral calcineurin inhibitor immunosuppressant. Its activity results in inhibition of lymphocyte proliferation, production of T-cell cytokines, and expression of T-cell activation surface antigens. This is the first FDA-approved oral therapy for LN, a condition that can cause irreversible kidney damage and increase risk of kidney failure, cardiac events, and death.

The results of a 52-week randomized, double-blind, placebo-controlled trial (NCT03021499) demonstrate the efficacy of voclosporin in participants with a diagnosis of systemic lupus erythematosus and class III or IV LN (alone or in combination with class V LN) or class V LN. Renal biopsy was performed to classify LN based on the International Society of Nephrology/Renal Pathology Society’s standards. A total of 357 participants were randomized to receive either voclosporin 23.7 mg twice daily (n = 179) or placebo (n = 178). All participants received background immunosuppressant therapy (ie, oral mycophenolate mofetil [MMF] targeted to a dose of 1 gram twice daily and corticosteroid therapy adjusted to achieve a dose of 2.5 mg/d by week 16 of the study). The primary efficacy end point of the study is the proportion of patients achieving complete renal response at week 52; urine protein/creatinine ratio (UPCR) of less than or equal to 0.5 mg/mg and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of greater than 20% or no treatment- or disease-related eGFR-associated event (ie, decrease in renal creatinine clearance or glomerular filtration rate, or increase in blood creatinine, serum creatinine, renal impairment, renal failure, or acute renal failure) at time of assessment. At week 52, a higher proportion of participants achieved complete renal response in the voclosporin arm than the placebo arm (40.8% vs 22.5%; OR, 2.7; 95% CI, 1.6-4.3; 

 < .001). Moreover, administration of voclosporin compared with placebo is associated with a reduction in the time to UPCR of less than or equal to 0.5 mg/mg (median time of 169 days vs 372 days; HR, 2.0; 95% CI, 1.5-2.7). Overall, a greater proportion of participants who received voclosporin for 1 year in addition to background therapy achieved a reduction in kidney inflammation in comparison with those who received background therapy alone.

Prior to initiating therapy with voclosporin, obtain a baseline eGFR and blood pressure. Monitor renal function and blood pressure regularly throughout treatment with voclosporin. The most common adverse effects (AEs) include decreased eGFR (26%), hypertension (19%), diarrhea (19%), headache (15%), anemia (12%), and cough (11%). Other potential AEs include lymphoma, serious infections, nephrotoxicity, neurotoxicity, hyperkalemia, corrected QT interval prolongation, and pure red cell aplasia.

Voclosporin is a CYP3A4 substrate. Coadministration with moderate and strong CYP3A4 inducers should be avoided. Voclosporin is a P-glycoprotein inhibitor; other medications may require a dose reduction when used in combination with voclosporin. Dose adjustments are recommended in severe renal impairment and mild to moderate hepatic impairment. Voclosporin should be avoided in pregnant patients because of the alcohol content of the drug formulation. Patients taking voclosporin should avoid live vaccines.

Voclosporin is administered as a 7.9-mg capsule. It must be swallowed whole on an empty stomach. Recommended starting dose is 23.7 mg orally every 12 hours. Voclosporin is approved in combination with MMF and corticosteroids. Concomitant administration of voclosporin and cyclophosphamide should be avoided; further study is required to establish safety and efficacy of the combination. Do not stop or change the dose of voclosporin without consulting a health care provider.

Lupkynis. Prescribing information. Aurinia Pharmaceuticals; 2021. Accessed March 8, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213716s000lbl.pdf