Adlon Therapeutics L.P. Announces FDA Approval for Adhansia XR™ (methylphenidate HCl) Extended-Release Capsules CII for the Treatment of ADHD

In a simulated workplace environment study in adult patients with
ADHD, Adhansia XR demonstrated statistically significant improvement in
attention over placebo at one hour and at 16 hours post-dose

STAMFORD, Conn.–(BUSINESS WIRE)–Adlon Therapeutics L.P., a subsidiary of Purdue Pharma L.P., announced
that the U.S. Food and Drug Administration (FDA) approved Adhansia XR™
(methylphenidate hydrochloride) extended-release capsules CII, a central
nervous system (CNS) stimulant, for the treatment of
Attention-Deficit/Hyperactivity Disorder (ADHD) in patients six years
and older. In a simulated Adult Workplace Environment (AWE) study,
Adhansia XR demonstrated statistically significant improvement over
placebo at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at hour 14
post-dose.1

Methylphenidate medications, when used as prescribed and in conjunction
with behavioral therapy and lifestyle interventions, are one of the
preferred first-line treatments for certain patients diagnosed with
ADHD,” said Marcelo Bigal, MD, PhD, chief medical officer, Purdue
Pharma, and general manager, Adlon Therapeutics. “We are pleased to
receive FDA approval for Adhansia XR, a new option for appropriate
patients with ADHD who may benefit from a treatment with efficacy
demonstrated at one hour and 16 hours post-dose in adults, and we look
forward to making it available later this year.”

The Full Prescribing Information for Adhansia XR contains a boxed
warning for abuse and dependence. 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.

Some of my patients with ADHD, especially those who are balancing
school or work and participating in social or civic activities, require
the ability to sustain attention throughout the day,” said Andrew J.
Cutler, MD, chief medical officer, Meridien Research, and an
investigator on Adhansia XR clinical studies. “The approval of Adhansia
XR offers a methylphenidate treatment option with a longer duration of
efficacy, which may be appropriate for these patients.”

Adhansia XR is not appropriate for all patients, and healthcare
professionals should work with their patients to determine the most
appropriate treatment option. 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.

The Full Prescribing Information for Adhansia XR, including Boxed
Warning, is available at this link.
Additionally, 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.

ADHD affects a significant number of adolescents and adults and, when
not optimally treated, can negatively impact various aspects of their
lives. A subset of these patients experience impairment throughout the
day. While Adhansia XR is not appropriate for all patients, a
methylphenidate medication available in a single daily dose that, in
adults, demonstrated efficacy at one hour and at 16 hours post-dose, has
the potential to address the needs of certain individuals with ADHD,”
said Craig Landau, MD, president and CEO, Purdue Pharma. “We are
committed to providing information on safe prescribing practices for
this medication and initiatives to support the responsible use, storage,
and disposal of all medications in this class.”

The FDA approval of Adhansia XR was based on four clinical studies
evaluating the efficacy and safety of Adhansia XR in patients who met DSM-5
criteria for ADHD. Eight hundred and eighty-three (883) patients were
exposed to Adhansia XR during 1- to 4-week long, controlled treatment
periods (434 adult patients and 449 pediatric patients [156 (6 to 12
years); 293 (12 to 17 years)] from two clinical studies in adults, one
analog classroom trial over a 13-hour study day in pediatric patients
ages 6 to 12 years, and one safety and efficacy study in pediatric
patients ages 12 to 17 years). The safety data for adult patients are
based on two randomized, double-blind, placebo-controlled studies in
doses of 25 mg to 100 mg per day. The safety data for pediatric patients
(6 to 17 years) are based on randomized, double-blind,
placebo-controlled studies in doses of 25 mg to 85 mg per day.1

A double-blind, randomized, placebo-controlled crossover AWE study
evaluated Adhansia XR in adult patients with ADHD. Efficacy assessments
were conducted at pre-dose and 1, 2, 5, 8, 11, 14, and 16 hours
post-dose. The primary endpoint was the mean Permanent Measure of
Performance Total scores (PERMP-T), averaged across all time points
compared to placebo. PERMP-T, an objective, validated skill-adjusted
math test, is the combined score obtained by adding PERMP-A (number of
math problems attempted) and PERMP-C (number of math problems answered
correctly).1

While receiving Adhansia XR, adults achieved statistically significant
improvement over placebo, achieving greater mean PERMP-T scores averaged
across all time points on the AWE days (post-dose score of 281.3 vs.
254.5; difference of 26.80, 95% CI [15.19, 38.41]). The secondary
efficacy endpoints were onset and duration of clinical effect, as
assessed by the treatment difference in PERMP-T scores at post-dose time
points. Adhansia XR demonstrated statistically significant improvement
over placebo at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at hour
14 post-dose.1

In this study, 10% of Adhansia XR-treated patients discontinued due to
adverse reactions compared to 0% of placebo-treated patients. The
following adverse reactions led to discontinuation at a frequency of 2%
of Adhansia XR-treated patients: nausea, bronchitis, viral
gastroenteritis, viral infection, increased blood pressure, and
hypomania.1

Sudden death, stroke and myocardial infarction have occurred in patients
treated with CNS stimulants at recommended doses. Additional information
about serious cardiovascular risks can be found in the Important Safety
Information section below.

Adhansia XR will be available in six capsule strengths (25, 35, 45, 55,
70, and 85 mg), allowing for flexible dosing. The recommended starting
dose of Adhansia XR for patients six years or older is 25 mg once daily.Healthcare professionals should titrate the dose in increments of
10 mg to 15 mg at intervals of no less than five days. Adhansia XR
should be taken orally once daily in the morning, with or without food.
Capsules may be taken whole or, for patients who have difficulty
swallowing, capsules may be opened and the entire contents sprinkled
onto a tablespoon of applesauce or yogurt. The entire mixture should be
consumed without crushing or chewing, immediately or within 10 minutes.
If the mixture is not consumed within 10 minutes after mixing, it should
be discarded and not stored. The dose of a single capsule should not be
divided and patients should not take anything less than one capsule per
day. In the event of a missed dose, patients should not take their
medication later in the day.1

Prior to initiating treatment with Adhansia XR, healthcare professionals
should also assess for the presence of cardiac disease (i.e., perform a
careful history, family history of sudden death or ventricular
arrhythmia, and physical exam). 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. After prescribing
and while patients are on therapy, healthcare professionals should
maintain careful prescription records, educate patients and their
families about abuse and proper storage and disposal of CNS stimulants,
and periodically re-evaluate the need for Adhansia XR use.1

Dosages above 85 mg daily in adults and 70 mg and above daily in
pediatric patients are associated with disproportionate increases in the
incidence of certain adverse reactions. If paradoxical aggravation of
symptoms or other adverse reactions occur, healthcare professionals
should reduce the dosage, or, if necessary, discontinue treatment with
Adhansia XR. Treatment with Adhansia XR should also be periodically
discontinued to assess the patient’s condition. If improvement is not
observed in a patient after appropriate dosage adjustment over a
one-month period, healthcare providers should discontinue treatment with
Adhansia XR.1 Healthcare professionals should refer to the
Full Prescribing Information for additional Dosage and Administration
information.

Prescription stimulants, which include methylphenidate, the active
ingredient in Adhansia XR, are federally controlled substances (CII) and
have a high potential for abuse and dependence.1,2 The
selling or giving away of methylphenidate medications may harm others or
lead to death, and is against the law.1,3 It is important for
healthcare professionals to ask patients if they or a family member have
ever misused prescription medicines or abused alcohol or street drugs.1,4
Patients should be counseled that they should not give Adhansia XR to
anyone else, and to keep methylphenidate medications in a safe place,
such as a locked cabinet, to help prevent accidental exposure,
diversion, and abuse.1,5 They should also be advised to
dispose of remaining, unused, or expired Adhansia XR by a medicine
take-back program at authorized collection sites such as pharmacies or
law enforcement locations, if available.1,6 If no take-back
program or authorized collector is available, patients should mix
Adhansia XR with an undesirable, nontoxic substance to make it less
appealing to children and pets, place the mixture in a container such as
a sealed plastic bag, and discard of it in the household trash.1
Patients should be encouraged to read the Medication Guide that
accompanies their stimulant prescription, which contains the most
important FDA-approved information that a patient should know about the
medication.7

According to the National
Institute of Mental Health
and the Centers
for Disease Control and Prevention
, medications for ADHD should be
used as a part of a total treatment program that may include
psychotherapy, education or training, or a combination of treatments.8,9
Only a healthcare professional can diagnose ADHD, and diagnosis requires
a comprehensive patient evaluation. Diagnostic criteria is provided in
the American Psychiatric Association’s Diagnostic and Statistical
Manual, Fifth edition (DSM-5)
.10

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

 

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.

 

IMPORTANT SAFETY INFORMATION1

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 treatment 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, and decreased weight.

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.

Please read the Full
Prescribing Information
, including Boxed Warning.

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

Prescription Medications: Risks of Addiction, Misuse, Abuse, and
Diversion

For information on addiction, misuse, abuse, and diversion of
prescription medications, please visit the National
Institute on Drug Abuse
.

Addiction is a chronic, relapsing disease that can last a lifetime and
lead to death, and requires treatment. The Substance Abuse and Mental
Health Services Administration’s (SAMHSA) confidential and anonymous
Behavioral Health Treatment Services Locator can be accessed here,
and their free and confidential National Helpline can be reached through
1-800-662-HELP (4357) and 1-800-487-4889 (TTY).

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
adults.11

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.1 The MLR® (multi-layer release)
technology is a controlled-release delivery system patented by Purdue
Pharma.

Adhansia XR will be commercialized by Adlon Therapeutics, a subsidiary
of Purdue Pharma L.P.

About Adlon Therapeutics L.P.

Adlon Therapeutics L.P. is a biopharmaceutical company dedicated to
developing and providing treatment options for
Attention-Deficit/Hyperactivity Disorder (ADHD) and related disorders.
Our initial focus is on adults and adolescents who have been diagnosed
with ADHD. Adlon is a subsidiary of Purdue Pharma L.P. For more
information, please visit www.adlontherapeutics.com.

References

1 Purdue Pharma L.P. Adhansia XR Full Prescribing
Information. Feb 2019. Accessed Mar 1, 2019. Retrieved from http://app.adlontherapeutics.com/adhansia-xr/fpi.pdf.
2
United States Drug Enforcement Administration. Drug Scheduling. Accessed
Jan 2, 2019. Retrieved from https://www.dea.gov/drug-scheduling.
3
Legal Information Institute. 21 U.S. Code § 829 – Prescriptions.
Accessed Jan 4, 2019. Retrieved from https://www.law.cornell.edu/uscode/text/21/829.
4
National Institutes of Health, National Institute of Drug Abuse.
Research Report Series: Prescription Drug Abuse. Revised October 2011.
Accessed Jan 11, 2019. Retrieved from https://www.drugabuse.gov/sites/default/files/rxreportfinalprint.pdf.
5
Rannazzisi JT and Caverly MW. United States Department of Justice, Drug
Enforcement Administration, Office of Diversion Control. Practitioner’s
manual: an informational outline of the Controlled Substances Act. 2006.
Accessed Jan 2, 2019. Accessed Jan 2, 2019. Retrieved from https://www.deadiversion.usdoj.gov/pubs/manuals/pract/pract_manual012508.pdf.
6
National Institute on Drug Abuse. Misuse of Prescription Drugs: How can
prescription drug misuse be prevented? 2018. Accessed on Jan 4, 2019.
Retrieved from https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/how-can-prescription-drug-misuse-be-prevented.
7
U.S. Food and Drug Administration. Medication Guides. Page last updated:
August 8, 2018. Accessed Jan 2, 2019. Retrieved from: https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm.
8
The National Institute of Mental Health Information Resource Center,
National Institute of Mental Health. Attention-deficit/hyperactivity
disorder (ADHD). Page last updated March 2016. Accessed Jan 2, 2019.
Retrieved from https://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
9
Division of Human Development and Disability, National Center on Birth
Defects and Developmental Disabilities, Centers for Disease Control and
Prevention. Attention-deficit/hyperactivity disorder (ADHD). Page last
updated September 2018. Accessed Jan 2, 2019. Retrieved from https://www.cdc.gov/ncbddd/adhd/treatment.html.
10
American Psychiatric Association. Attention-deficit/hyperactivity
disorder. In Diagnostic and Statistical Manual of Mental Disorders
(5th ed.)
. Arlington, VA: American Psychiatric Publishing; 2013.
11
Purdue Pharma (Canada). Foquest Product Monograph. Dec 5, 2017. Accessed
Feb 19, 2019. Retrieved from http://purdue.ca/wp-content/uploads/2017/12/Foquest-PM-EN.pdf.

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