FDA Approves Adhansia XR (methylphenidate hydrochloride) Extended-Release Capsules for the Treatment of ADHD

In continuation of my update on methylphenidate

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.

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).

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.

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.

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.

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.

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. 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. 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.  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. 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

REf: https://en.wikipedia.org/wiki/Methylphenidate

Animal Study Suggests Ritalin Won't Harm the Heart

    

In continuation of my update on Ritalin 

Ritalin, a widely used stimulant drug to treat attention-deficit/hyperactivity disorder (ADHD), likely poses no risk of heart damage in children, new research in monkeys suggests.

The findings are "very reassuring," said the study's principal investigator, Dr. Steven Lipshultz.

Each year, more than 1.8 million children in the United States take drugs to treat ADHD. Concerns have been raised that Ritalin, Concerta and other forms of methylphenidate could harm children's hearts.

Some studies have reported an increase in sudden cardiac death among children taking methylphenidate or other stimulant drugs for ADHD.

But this new study found that five years of high doses of methylphenidate did not damage the hearts of 30 rhesus monkeys. That length of time is similar to how long children and adults would use the drugs.

"Even high-dose chronic [methylphenidate] stimulant therapy did not result in any evidence of abnormal structures or function in the hearts of the monkeys," said Lipshultz, chair of pediatrics at the University at Buffalo School of Medicine and Biomedical Sciences, in New York.

However, his team cautioned that the results of animal research are not automatically applicable to humans.

One ADHD specialist unconnected to the study agreed.

"The [animal] study cannot be automatically applicable to humans," said Dr. Victor Fornari, who directs child and adolescent psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y.

Still, the findings "provide compelling evidence of the cardiac safety of this important evidence-based treatment for ADHD," Fornari said.

About 10 percent of U.S. children have been diagnosed with ADHD and related disorders. Up to 70 percent of them take prescription stimulant drugs, so possible heart risks associated with the drugs are a major concern, study author Lipshultz said in a university news release.

The U.S. Food and Drug Administration has ordered some prescription stimulants to carry black box warnings stating that children with underlying heart disease should use these medications with caution.

In Canada, a stimulant drug was removed from the market after it was linked to a small number of sudden cardiac deaths. Sales of the drug later resumed.

"This controversy has persisted without answer," Lipshultz said. "Yet the number of prescriptions for these medications for children with ADHD continues to expand."

Another expert said the new findings should help ease concerns.

The study results "are overall re-assuring in terms of cardiac safety and long-term use of stimulants for ADHD in otherwise healthy individuals," said Dr. Andrew Adesman, chief of developmental and behavioral pediatrics at Cohen Children's Medical Center in New Hyde Park, N.Y.

However, he added that the study "does not address clinical concerns about the safety of stimulants in individuals with certain types of heart disease."

Therefore, "health care providers need to continue to screen children for cardiac problems prior to prescribing stimulant medications like Ritalin, Concerta or Adderall, since there are some individuals who may still be at increased risk for potentially serious heart problems if treated with stimulant medication," Adesman said.

Lipshultz noted that the findings are good news for another type of pediatric patient: young cancer survivors.

"I have cared for children and adolescents who have survived childhood cancer, who now are experiencing severe learning disabilities as a result of their cancer therapies. They become my patients because their hearts have been damaged, an unfortunate effect of the successful treatment of their childhood cancer," he said.

"Current recommendations state that children such as these, with underlying heart disease, should avoid chronic stimulant therapy because of the concern that it could further damage their hearts," he explained. "However, these prescription stimulants often allow these children to do much better with their learning progress."

The new findings suggest that, in many cases, these medications can be prescribed to these children as well, Lipshultz said.

FDA Approves Jornay PM (methylphenidate) Extended-Release Capsules for Attention Deficit Hyperactivity Disorder (ADHD)

In continuation of my update on methylphenidate

Ironshore Pharmaceuticals & Development, Inc. (“Ironshore”) a wholly owned subsidiary of Highland Therapeutics Inc. (“Highland”) announced,  that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Jornay PM (methylphenidate) (formerly known as HLD200) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older. Jornay PM is a novel formulation of methylphenidate which is taken in the evening and has demonstrated improvement in the severity of ADHD symptoms in the early morning and throughout the day. Jornay PM is the first drug utilizing Ironshore’s proprietary drug delivery platform, Delexis®. Ironshore plans to initiate the commercial launch of Jornay PM in the first half of 2019.

According to independent research reports commissioned by Ironshore, control over the symptoms of ADHD during the early morning routine remains a significant concern for parents of children with ADHD. As previously reported in the Journal of Child and Adolescent Psychopharmacology, a majority of surveyed parents of children with ADHD report that the symptoms associated with ADHD in the early morning are described as “moderate” or “severe” during this time period.1

Commenting on the approval, David Lickrish, President & CEO stated, “Some manufacturers have adjusted the ratio of immediate-release and extended-release features in different formulations of methylphenidate to achieve an earlier onset. Our approach to drug development was to start from the desired pharmacokinetic profile and then work to develop a purpose-built technology capable of achieving that profile. I believe that the unique Delexis® drug delivery platform is a disruptive technology that has many applications and opportunities in several therapeutic categories.”

Delexis is a novel and proprietary drug delivery technology that contains two functional film coatings that act synergistically to achieve a unique pharmacokinetic profile. The first layer delays the initial release of drug for up to 10 hours while the second layer helps to control the rate of release of the active pharmaceutical ingredient throughout the day.

Dr. Bev Incledon, Head of Research and Development at Ironshore stated, “Developing a drug using a different delivery technology that will provide an additional option for patients and the physicians who treat them takes time. After 10 years of unrelenting determination, those efforts have finally been rewarded with the approval of Jornay PM. I want to thank and congratulate the many people who helped to make this possible including the formulation scientists, the Research & Development Team, the Investigators and the patients who participated in the clinical trials.”

The effectiveness of Jornay PM was established in two separate Pivotal Phase III, multicenter, randomized, double-blind, placebo-controlled studies conducted in a total of 278 pediatric patients aged 6 to 12 years with a diagnosis of ADHD per DSM-5 criteria. In addition to the traditional scales that assess efficacy in ADHD clinical trials such as the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale and the ADHD Rating Scale (ADHD-RS-IV), Ironshore’s pivotal trials assessed Jornay PM’s efficacy in the early morning period using the morning subscale of the Parent Rating of Evening and Morning Behavior-Revised (PREMB-R AM) scale and the Before School Functioning Questionnaire (BSFQ).

In Study 1, improvement in ADHD manifestations in a classroom setting was demonstrated by the primary endpoint, an average of all post-dosed SKAMP combined scores measured during a 12-hour period (8:00 a.m. to 8:00 p.m.), and improvement in ADHD manifestations in the early morning was demonstrated by the secondary endpoint, PREMB-R AM.

In Study 2, improvement in ADHD manifestations throughout the day was demonstrated by the primary endpoint, ADHD-RS-IV, and improvement in ADHD manifestations before school was demonstrated by the secondary endpoint, the BSFQ, which is intended to assess early morning before school activities from the time the child awakens and some behaviors not specific to early morning.

Commenting on the approval, Dr. Randy Sallee, Chief Medical Officer at Ironshore stated, “Many parents of children with ADHD note that the early morning routine is often one of the most chaotic times of the day. The idea of dosing the medication the night before was our moon-shot solution to meeting this need. The approval of Jornay PM is a welcome treatment option for healthcare providers, patients and their caregivers that may affect the way physicians think about ADHD treatment going forward.”

https://en.wikipedia.org/wiki/Methylphenidate

Two-drug combo helps adolescents with ADHD, aggression

Prescribing both a stimulant and an antipsychotic drug to children with physical aggression and attention-deficit/hyperactivity disorder (ADHD), along with teaching parents to use behavior management techniques, reduces aggressive and serious behavioral problems in the children, according to a study conducted by researchers at The Ohio State University Wexner Medical Center….

For the "Treatment of Severe Childhood Aggression (TOSCA) Study," 168 children ages 6 to 12 who had been diagnosed with ADHD and displayed significant physical aggression were divided into two groups. All study participants received a psychostimulant drug called OROS methylphenidate (left structure) and their parents received behavioral parent training for nine weeks. The researchers called this treatment combination "basic" because both are evidence-based and have been shown to be helpful for improving both ADHD and aggression.

Researchers wanted to see if they could expand or augment this treatment by adding a second medication. If there was room for improvement at the end of the third week, a placebo was added for the "basic group," while the antipsychotic drug risperidone (right above structure)  was added for participants in the "augmented group."

Compared to the "basic group," the "augmented group" who received the stimulant drug and parent training plus risperidone showed significant improvement (on average with moderately better behavior) on the Nisonger Child Behavior Rating Form (NCBRF) Disruptive-Total Scale, the NCBRF Social Competence subscale and the Reactive Aggression part of the Antisocial Behavior Scale.

While there is always some risk with the addition of a second drug to the treatment package, the two drugs seemed to neutralize some of each other's potential side effects. For instance, children in the augmented group did not seem to have as much trouble falling asleep, once the risperidone was added, Aman said.

"We conducted this study because we viewed the combination of ADHD and significant physical aggression -- especially the aggression -- as a serious situation," Aman said. "It is not uncommon to use more than one medicine for other serious situations, such as when treating cancer or epilepsy for instance. Although doctors have often used stimulants and antipsychotics together in recent years, we did not have good evidence until now that they would work more effectively when carefully staged and given together."

Ref : http://dx.doi.org/10.1016/j.jaac.2013.09.022

Two-drug combo helps adolescents with ADHD, aggression

Methylphenidate facilitates recovery from drug addiction...

A brain-scanning study at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory, conducted with collaborators from Stony Brook University, reveals that an oral dose of methylphenidate, commonly known as Ritalin, improves impaired brain function and enhances cognitive performance in people who are addicted to cocaine.

Researchers were encouraged by the fact that, methylphenidate does decrease behaviors such as risk taking and impulsivity and improves brain function and cognitive performance in a range of other conditions that also affect the brain's prefrontal cortex, including attention deficit hyperactivity disorder (ADHD), some forms of dementia, and certain kinds of brain injury. To begin with Goldstein's (lead researcher)  group performed functional magnetic resonance imaging (fMRI) on 13 cocaine users and 14 healthy control subjects who were asked to perform a cognitive task after being given either a low oral dose of methylphenidate (20 milligrams) or a placebo. The task involved pushing a button to correctly identify the color of a printed word; some words had to do with drug use, others were "neutral." Subjects received monetary rewards for correct answers. The scientists were particularly interested in two parts of the prefrontal cortex previously shown to be impaired during this cognitive activity in cocaine-addicted individuals.

"These regions help to regulate emotion, cognition, and behavior in response to salient stimuli - the things we find particularly interesting or relevant," Goldstein said. "Because drug users have deficits in these regions, they may have less ability to regulate their emotions and exert cognitive control over certain behaviors."

Researchers found that,  compared  with cocaine users given placebos - who (compared to healthy controls) exhibited reduced function in these prefrontal cortex regions - cocaine users given a low dose of methylphenidate had improved brain function such that they were more like the healthy control subjects. The subjects given methylphenidate were also less likely to make "errors of commission" (pressing a button incorrectly or prematurely), a measure of impulsivity, while performing the cognitive task than subjects given a placebo. Furthermore, the greater the improvement in task accuracy with methylphenidate, the larger the increase in fMRI signal in the prefrontal cortex regions of interest, showing that the improvements in brain function were directly related to improved cognitive performance.

Though future studies need to evaluate whether these results can be generalized to other tasks or activities that involve these specific brain regions, but these results do suggest that by enhancing prefrontal cortex function and associated cognitive performance - particularly the decrease in impulsivity - methylphenidate could help to improve clinical outcomes in people seeking to overcome drug addiction…

  

 Ref : http://www.pnas.org/content/early/2010/08/30/1011455107.full.pdf+html?sid=be34425f-b8cc-4a90-8929-03aca9f8bbe4