Adlon Therapeutics L.P. Announces Two New Publications of Adhansia XR® (methylphenidate HCl) Extended-Release Capsules CII Data

STAMFORD, Conn.–(BUSINESS WIRE)–Adlon Therapeutics L.P., a subsidiary of Purdue Pharma L.P., announced two recent online publications of studies related to the efficacy, safety and pharmacokinetics of Adhansia XR® (methylphenidate hydrochloride) extended-release capsules CII (investigationally known as PRC-063).

Research published in the Journal of Child and Adolescent Psychopharmacology examined the efficacy and safety of Adhansia XR in children 6 to 12 years of age with Attention-Deficit/Hyperactivity Disorder (ADHD) in a laboratory classroom setting.¹ The publication in the Journal of Clinical Psychopharmacology evaluated the pharmacokinetics of Adhansia XR in healthy adults 18 to 45 years of age in three randomized, open-label crossover studies.² Both articles have been published online as open access with full text available ahead of print. Details on study design and outcomes for the published studies are included below.

The Full Prescribing Information for Adhansia XR contains a Boxed Warning emphasizing that CNS stimulants, including Adhansia XR, other methylphenidate-containing products, and amphetamines have a high potential for abuse and dependence. Healthcare professionals should assess the risk of abuse prior to prescribing Adhansia XR and monitor for signs of abuse and dependence while patients are on therapy.³

“These published studies are the result of collaborative efforts from our clinical and research partners. We recognize and are grateful for these partnerships, which have contributed to our commitment to addressing the needs of patients with ADHD, along with their caregivers and healthcare professionals,” said Julie Ducharme, BPharm, MSc, PhD, vice president and chief scientific officer, Purdue Pharma. “In addition, we continue to support initiatives that provide information about the safe and responsible use of prescription stimulant medications as scheduled medications that must be responsibly used, stored and disposed.”

Adhansia XR is not appropriate for all patients, and healthcare professionals should work with their patients to determine the most appropriate treatment option. (Read more…) Additionally, Adhansia XR is contraindicated in patients with a known hypersensitivity to methylphenidate or product components, as well as patients receiving concurrent treatment with a monoamine oxidase inhibitor (MAOI) or who have used an MAOI within the preceding 14 days.³

The Full Prescribing Information for Adhansia XR, including Boxed Warning, is available at this link. Please see Important Safety Information for Adhansia XR below, including the Boxed Warning, Contraindications, Warnings and Precautions including the potential for abuse and dependence, serious cardiovascular events, blood pressure and heart rate increases, psychiatric adverse reactions, priapism, peripheral vasculopathy, long-term suppression of growth, allergic-type reactions, and Adverse Reactions.³

Journal of Child and Adolescent Psychopharmacology publication of “Efficacy and Safety of Multilayer, Extended-Release Methylphenidate (PRC-063) in Children 6–12 Years of Age with Attention-Deficit/Hyperactivity Disorder: A Laboratory Classroom Study,” authored by Ann C. Childress, MD; Matthew N. Brams, MD; Andrew J. Cutler, MD; Graeme A.E. Donnelly, MSc (Purdue Pharma Canada); and Sailaja Bhaskar, BPharm, PhD, MBA (Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.), can be reviewed at this link.

The randomized, double-blind, parallel group, dose-optimized, placebo-controlled Phase 3 study examined the safety and efficacy of PRC-063 in the treatment of ADHD in children aged 6-12. During a six-week, open-label, dose-optimization phase, participants began treatment at 25 mg/day of PRC-063 and were titrated until an optimal dose was reached (maximum dose of 85 mg/day; mean optimized dose was 48 mg/day). During the double-blind period, participants were randomized to receive treatment with their optimal dose of PRC-063 or placebo for one week. Efficacy was assessed in a laboratory classroom setting on the final day of the double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale. Safety was assessed measuring adverse events (AEs), vital signs, and electrocardiograms.¹

The study was completed by 147 participants. In the primary efficacy analysis, significant improvements were demonstrated with PRC-063 versus placebo (p< 0.0001) when SKAMP-Combined scores were averaged over the 13-hour full day laboratory classroom (least squares mean difference=-8.6, 95% confidence interval=-10.6 to -6.6). Additionally, the SKAMP-Combined scores were statistically significantly improved at all post-dose time points starting at hour 1 and continuing to hour 13, for PRC-063 compared to placebo. These study results showed that PRC-063 was effective in improving attention and reducing symptoms in children aged 6-12 years with ADHD when compared with placebo.

The most common AEs by preferred term reported during the open-label, dose-optimization phase were decreased appetite (35.3%), abdominal pain upper (16.7%), affect lability (14.1%), weight decreased (11.5%), headache (10.9%), irritability (10.3%) and insomnia (10.3%). There was no evidence of an increased incidence of AEs with increased dose level. All AEs were of mild or moderate intensity and no SAEs were reported.¹

Journal of Clinical Psychopharmacology publication of “Randomized Controlled Crossover Trials of the Pharmacokinetics of PRC-063, a Novel Multilayer Extended-Release Formulation of Methylphenidate, in Healthy Adults,” authored by Martin Katzman, BSc, MD, FRCP(C); Greg Mattingly, MD; Larry J. Klassen, BSc, MD, FRCP(C); Marc J. Cataldo, PharmD (Purdue Pharma L.P.); and Graeme A. E. Donnelly, MSc (Purdue Pharma Canada), can be reviewed at this link.

Three randomized, open-label crossover studies evaluated the pharmacokinetics of PRC-063 in healthy, non-obese men and women aged 18 to 45 years.²

• Study I was a four-way crossover study that investigated a single dose of PRC-063 100 mg versus three-times-daily (TID) immediate-release (IR) methylphenidate 60 mg (20 mg given every 4 hours for 3 doses) under fasted and fed conditions to stress the absorption and tolerability of the product.²

• Study II was a two-way crossover study that investigated PRC-063 100 mg (45 + 55 mg capsules) once daily versus IR methylphenidate 20 mg TID (given every 4 hours for 3 doses) after an overnight fast of at least 10 hours on day 5 of treatment.²

• Study III was a four-way crossover study that investigated a single dose of PRC-063 100mg (45 + 55 mg capsules), administered after an overnight fast of at least 10 hours either as intact capsules or as capsule contents sprinkled on 1 tablespoon (15 mL) of unsweetened apple sauce, ice cream or yogurt.²

In Study I, PRC-063 demonstrated biphasic absorption, with two distinct peak plasma concentrations. Intake of a high-fat, high-calorie meal did not increase the peak plasma methylphenidate concentration (C_max) or extent of absorption (area under the curve), however; it resulted in slower uptake versus a fasted state. During repeated dosing, as examined in Study II, steady state was reached with no further accumulation of methylphenidate from day three. At steady state, PRC-063 gave higher evening and trough plasma methylphenidate levels than immediate-release methylphenidate (3 times daily). In Study III, the pharmacokinetics of PRC-063 sprinkled on food were found to be comparable to that of intact capsules.²

These studies indicate that PRC-063 can be taken with or without food, the capsule contents can be sprinkled on certain types of soft foods with no significant changes in absorption, and steady-state plasma concentrations are reached from day 3.

All randomized participants were evaluated for safety. Across studies, the most common AEs in the healthy individuals taking PRC-063 were initial insomnia (30%), headache (23%), dry mouth (16%) and heart rate increased (16%). All AEs were mild or moderate. There were no serious adverse events (SAEs).²

About Adhansia XR®

Adhansia XR was developed by Purdue Pharma (Canada). The medication was granted marketing authorization from Health Canada in December 2017 and is currently marketed in Canada as FOQUEST™ for the treatment of ADHD. In the U.S., the medication was approved by the U.S. Food and Drug Administration (FDA) for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in patients six years and older in February 2019.

Adhansia XR capsules contain multilayered beads, which are composed of an immediate-release layer which contains approximately 20 percent of the methylphenidate dose, and a controlled-release layer which contains approximately 80 percent of the methylphenidate dose, for oral administration. The MLR™ (multi-layer release) technology is a controlled-release delivery system patented by Purdue Pharma.

Please see Important Safety Information, including Boxed Warning, Warnings & Precautions, and Adverse Reactions below.

IMPORTANT SAFETY INFORMATION³

WARNING: ABUSE AND DEPENDENCE CNS stimulants, including Adhansia XR, 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.

CONTRAINDICATIONS

Adhansia XR^® is contraindicated in patients with a known hypersensitivity to methylphenidate or other components of Adhansia XR. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products. Adhansia XR is also contraindicated in patients receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a MAOI, because of the risk of hypertensive crisis.

WARNINGS AND PRECAUTIONS

Potential for Abuse and Dependence

CNS stimulants, including Adhansia XR, 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.

Serious Cardiovascular Events

Sudden death, stroke and myocardial infarction have occurred in adults treated with CNS stimulant treatment at recommended doses. Sudden death has occurred in pediatric patients with structural cardiac abnormalities and other serious cardiac problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Adhansia XR treatment.

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 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

Psychiatric Adverse Reactions

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

CNS stimulants may induce a manic or mixed 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).

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 Adhansia XR. 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.

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.

Peripheral Vasculopathy, including Raynaud’s Phenomenon

CNS stimulants, including Adhansia XR, used to treat ADHD 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.

Long-Term Suppression of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

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

Allergic-Type Reactions FD&C Yellow No. 5

Adhansia XR 45 mg capsules contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

ADVERSE REACTIONS

The most common (≥5% and twice the rate of placebo) adverse reactions occurring with Adhansia XR in adults are insomnia, dry mouth, and decreased appetite.

The most common (≥5% and twice the rate of placebo) adverse reactions occurring with Adhansia XR in pediatric patients are decreased appetite, insomnia, weight decreased, and upper abdominal pain.

PREGNANCY EXPOSURE REGISTRY

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

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please read the Full Prescribing Information, including Boxed Warning.

About Adlon Therapeutics L.P.

Adlon Therapeutics L.P., a subsidiary of Purdue Pharma L.P., is a specialty pharmaceutical company committed to providing treatment options for patients who suffer from the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). Our mission is to serve patients and the ADHD community by developing innovative medicines and supporting responsible prescription stimulant utilization through awareness, research, and supporting policies that align with the appropriate diagnosis and treatment of ADHD. For more information, please visit www.adlontherapeutics.com or follow us on Twitter and LinkedIn.

References:

¹ Childress, Ann C., Brams, Matthew N., Cutler, Andrew J., Donnelley, Graeme A.E., Bhaskar, Sailaja. Efficacy and Safety of Multilayer, Extended-Release Methylphenidate (PRC-063) in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder. Journal of Child and Adolescent Psychopharmacology. Ahead of print. http://doi.org/10.1089/cap.2020.0109. Accessed November 2020.

² Katzman, Martin A., Mattingly, Greg, Klassen, Larry J., Cataldo, Marc J., Donnelly, Graeme A.E. Randomized Controlled Crossover Trials of the Pharmacokinetics of PRC-063, a Novel Multilayer Extended-Release Formulation of Methylphenidate, in Healthy Adults. Journal of Clinical Psychopharmacology. 40(6), 579–587. https://doi.org/10.1097/JCP.0000000000001277. Accessed November 2020.

³ Purdue Pharma L.P. Adhansia XR Full Prescribing Information. July 2019. Accessed June 2020. Retrieved from http://app.adlontherapeutics.com/adhansia-xr/fpi.pdf.

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