(CNN) The maker of a little red pill intended to treat a rare condition is raking in hundreds of millions of dollars a year as it aggressively targets frail and elderly nursing home residents for whom the drug may be unnecessary or even unsafe, a CNN investigation has found.
And much of the money is coming straight from the federal government.
The pill, called Nuedexta, is approved to treat a disorder marked by sudden and uncontrollable laughing or crying -- known as pseudobulbar affect, or PBA. This condition afflicts less than 1% of all Americans, based on a calculation using the drugmaker's own figures, and it is most commonly associated with people who have multiple sclerosis (MS) or ALS, also known as Lou Gehrig's disease.
Nuedexta's financial success, however, is being propelled by a sales force focused on expanding the drug's use among elderly patients suffering from dementia and Alzheimer's disease, and high-volume prescribing and advocacy efforts by doctors receiving payments from the company, CNN found.
Since 2012, more than half of all Nuedexta pills have gone to long-term care facilities. The number of pills rose to roughly 14 million in 2016, a jump of nearly 400% in just four years, according to data obtained from QuintilesIMS, which tracks pharmaceutical sales. Total sales of Nuedexta reached almost $300 million that year.
Nuedexta is being increasingly prescribed in nursing homes even though drugmaker Avanir Pharmaceuticals acknowledges in prescribing information that the drug has not been extensively studied in elderly patients -- prompting critics to liken its use to an uncontrolled experiment. The one study the company conducted solely on patients with Alzheimer's (a type of dementia) had 194 subjects and found that those on Nuedexta experienced falls at more than twice the rate as those on a placebo.
Avanir declined repeated requests to be interviewed for this article. In an emailed statement, the company said PBA is often "misunderstood" and that the condition can affect people with dementia and other neurological disorders, which are common among residents in long-term care facilities. A company website states PBA can afflict up to roughly 40% of dementia patients -- a figure that is based on an Avanir-funded survey and was repeatedly disputed by medical experts interviewed by CNN, including some of those paid by Avanir.
Nuedexta is approved by the Food and Drug Administration (FDA) to treat anyone with PBA, including those with a variety of neurological conditions such as dementia. But geriatric physicians, dementia researchers and other medical experts told CNN that PBA is extremely rare in dementia patients; several said it affects 5% or less. And state regulators have found doctors inappropriately diagnosing nursing home residents with PBA to justify using Nuedexta to treat patients whose confusion, agitation and unruly behavior make them difficult to manage.
"There has to be a diagnosis for every drug prescribed, and that diagnosis has to be real ... it cannot be simply made up by a doctor," said Kathryn Locatell, a geriatric physician who helps the California Department of Justice investigate cases of elder abuse in nursing homes. "There is little to no medical literature to support the drug's use in nursing home residents (with dementia) -- the population apparently being targeted."
CNN identified dozens of cases across the country since 2013 in which state nursing home inspectors questioned the use of Nuedexta.
In a Los Angeles nursing home last year, regulators found that more than a quarter of its residents -- 46 of 162 -- had been placed on Nuedexta, noting that a facility psychiatrist had given a talk about the drug to employees. This psychiatrist was a paid speaker for Avanir.
At another facility in 2015, also in Southern California, an employee admitted to inspectors that a resident had been given a diagnosis of PBA to "somehow justify the use" of Nuedexta, even though its intended purpose was to control the resident's "mood disturbances" and yelling out.
And an Ohio doctor paid by Avanir has come under government investigation for allegedly receiving kickbacks for prescribing the drug and fraudulently diagnosing patients with PBA in order to secure Medicare coverage -- though the doctor has denied any wrongdoing.
The federal government foots the bill for a big portion of the money being spent on Nuedexta in the form of Medicare Part D prescription drug funding, for people 65 and over and the disabled. In 2015, the most recent year for which data is available, this Medicare program spent $138 million on Nuedexta -- up more than 400% from just three years earlier.
Medicare is supposed to pay for drug uses that have been proven safe and effective for the population they are intended to treat or that have been otherwise supported by a specific collection of medical research. Nuedexta is currently only approved by the FDA for patients who have PBA. So experts say that Medicare coverage of the drug, which has been crucial to its financial success, relies on the diagnosis of this single condition. So-called "off-label" prescribing, in which doctors use the drug to treat patients who have not been diagnosed with PBA, would typically not be covered.
The Centers for Medicare & Medicaid Services (CMS) declined to comment on the growing use of Nuedexta in nursing homes.
Thousands of the doctors prescribing Nuedexta have received money, or at least a meal, from its maker -- a legal but controversial practice in the industry. Between 2013 and 2016, Avanir and its parent company, Otsuka, paid doctors nearly $14 million for Nuedexta-related consulting, promotional speaking and other services, according to government data. The companies also spent $4.6 million on travel and dining costs, both for speakers and for doctors being targeted by salespeople.
A CNN analysis also found that nearly half the Nuedexta claims filed with Medicare in 2015 came from doctors who had received money or other perks from the company (ranging from a few dollars' worth of food or drink to hundreds of thousands of dollars in direct payments).
Pharmaceutical companies are allowed to pay a doctor to promote a drug to colleagues and other medical professionals. It is illegal, however, for doctors to prescribe the drug in exchange for kickback payments from a manufacturer.
Several of these paid advocates of Nuedexta argue that PBA manifests differently depending on the person. With dementia patients, they say, the typical crying or laughing outbursts seen in multiple sclerosis patients may be absent. Instead, symptoms may include moaning, wailing, hitting a wheelchair over and over again or repeating the same phrase. And they are adamant that the medication can be life-changing for patients, touting how safe and benign it is.
"I never hear, 'hey doc, we put a patient on this and had really bad side effects,'" said Jason Kellogg, a geriatric psychiatrist who sees patients at nursing homes across California. Kellogg has received $612,000 in payments, meals and travel from Avanir and its parent company between 2013 and 2016, according to government data. He was a top Medicare prescriber for the drug in 2015, the most recent year for which data is available.
Kellogg, who said he was involved in early company testing of the drug for PBA, said Nuedexta is "such a blessing in psychiatry."
"In our treatments, we don't have many meds that are well tolerated, and I would hate if someone took that away from me," he said.
During the FDA approval process, two key doctors on the committee raised concerns about Nuedexta being used for PBA in Alzheimer's patients. They both strongly recommended that Nuedexta only be approved for PBA in patients with MS or ALS. They argued that evidence it would be effective in other conditions was "weak," that not enough was known about the safety of the drug in the elderly, and that it was unclear that PBA even existed in Alzheimer's patients. Despite these concerns, the agency approved Nuedexta in 2010 for treating PBA in patients who have neurological conditions such as dementia.
Soon after Nuedexta hit the market in 2011, doctors, nurses and family members began filing reports of potential harm -- ranging from rashes, dizziness and falls to comas and death. Nuedexta was listed as a "suspect" medication in nearly 1,000 so-called adverse event reports received by the FDA detailing side effects, drug interactions and other issues, CNN found. While the FDA uses these voluntary reports to monitor potential issues with a drug, a report does not mean that a suspected medication has been ruled the cause of the harm.
The FDA declined to comment on these adverse events or the concerns raised about Nuedexta during the approval process. But it did say that after any drug is approved, the agency continues to review safety information from a variety of sources (including adverse event data) and will take action as needed -- such as updating a medication's label, restricting its use or even taking it off the market entirely.
Lon Schneider, director of the University of Southern California's California Alzheimer's Disease Center, reviewed information from roughly 500 of the reports which CNN obtained through a Freedom of Information Act request. Schneider, a physician specializing in geriatric and dementia care, said he was concerned about the problems stemming from potential interactions between Nuedexta and other powerful medications intended to treat problematic behaviors.
He warned that given how medicated the elderly typically are, adding just one more pill -- especially one that hasn't been extensively tested -- could be dangerous.
One report filed by a nurse practitioner in 2015 detailed the rapid decline of an 86-year-old Alzheimer's patient after Nuedexta was added to the psychotropic medications she took including Zoloft (an antidepressant), Xanax (an antianxiety drug) and Risperidone (an antipsychotic). Nuedexta had been prescribed to treat PBA and "weeping with underlying Alzheimer's dementia."
Almost immediately, the woman experienced weakness and fatigue to the point that she was barely able to talk and was described as being "almost unresponsive." The dose of Nuedexta was increased, and her symptoms worsened. The drug was discontinued about a week later, but she failed to recover. She remained unable to eat or drink and her kidneys failed -- ultimately leading to her death.
"The patient seemed to be doing fine," the nurse practitioner reported, "until she was placed on Nuedexta."
The combination of two generic drugs that makes up Nuedexta -- a cough suppressant and heart medication -- was once available from specialty pharmacists willing to combine the ingredients for less than $1 a pill, according to a US Senate report on rising prescription drug prices.
Now the FDA-approved medication costs as much as $12.60 a pill, wholesale pricing data from First Databank shows. That can add up to more than $9,000 a year, though the amount a patient actually pays depends on factors including individual insurance coverage. Medicare Part D spending on the drug averaged $3,400 per patient in 2015.
It is Avanir's main product and biggest moneymaker. It has gained attention with the public through its television commercial featuring actor Danny Glover seesawing between laughter and tears. And it was this drug's financial potential that attracted Japanese pharmaceutical giant Otsuka to the boutique California firm, purchasing Avanir for $3.5 billion several years ago. Otsuka declined to comment for this story.
Avanir investor documents have stated that only a small fraction -- 100,000 of the 1.8 million patients suffering from moderate to severe PBA -- live in long-term care facilities. Yet the company has described nursing homes as key to its growth.
On a 2013 earnings call, Rohan Palekar, a top executive who eventually became CEO but is no longer with the company, said Avanir had "just scratched the surface of its full potential" in nursing homes, according to an online transcript. He said the company aimed to get Nuedexta prescribed in far more facilities. Palekar did not respond to requests for comment.
To rack up these prescriptions, salespeople identified doctors, nurses and pharmacists who could serve as advocates for the drug, according to interviews with former Avanir employees and internal documents and emails reviewed by CNN. Salespeople then worked closely with these advocates to identify potential patients. In one case, a salesperson worked with a doctor's office manager to pull patients' charts, identify those who should be screened for PBA and make sure that Nuedexta brochures were inserted in their files. The sales force also coached doctors and facility employees on how to fight for Medicare coverage of the drug if it was initially refused.
Federal laws restrict the tactics pharmaceutical sales representatives can use to sell a medication. They can't give favor or payments in exchange for a doctor prescribing the drug. They can't have any contact with private patient records, without the patient's consent. And they can't promote use of a drug off-label, in a way that hasn't been approved by the FDA.
Internal company emails obtained by CNN show a culture filled with intense pressure to get the drug sold and how Avanir sales representatives were encouraged to directly target dementia and Alzheimer's patients -- a practice which is legal as long as these patients also had PBA.
In an email from several years ago, one of the company's regional managers, Kevin Tiffany, bluntly urged his salespeople to spend "99.9 percent" of their time focused on such patients.
Devoting time to other conditions more commonly associated with PBA amounted to "diluting your chances," wrote Tiffany, a senior sales manager in California.
"Give yourself the best chance to win," Tiffany added.
Tiffany, who no longer works for Avanir, declined to comment through an attorney.
Other emails from managers show how the government's crackdown on dangerous antipsychotic drugs -- which were once widely used to control unruly and erratic behavior in nursing home patients -- created an opportunity for Avanir.
After receiving the FDA's most severe "black box" warning for an increased risk of death in elderly dementia patients, antipsychotics are now closely monitored by government regulators, who penalize and lower the ratings of facilities that overuse them. Internal company communications show Avanir salespeople were directed to specifically target facilities that historically used high levels of antipsychotic medications -- facilities that would see Nuedexta as an attractive alternative.
Some of these tactics employed by Avanir salespeople cross into ethical gray areas, said medical ethicists and other experts who were read the emails and sales training documents or provided with details from them.
"It definitely feels like it is too much in the business of prescribing and not in the business of conveying information," said Michael Santoro, a Santa Clara University professor and an expert in pharmaceutical industry ethics."It feels like (the salespeople) are actually participating in the prescribing decision."
In its statement, Avanir said that the company was committed to "an ethical culture," uses methods "that are consistent with the law" and that its goal is "to give doctors truthful, accurate and balanced information so they can decide on the proper treatment for their patients."
Avanir executives have long touted plans for securing FDA approval for Nuedexta's use to treat dementia patients who don't have PBA -- setting their sights on the more widespread condition of agitation in dementia and Alzheimer's patients, characterized by emotional and physical outbursts and restless behaviors. The company announced clinical trials for testing a version of the medication for this use in 2015, but those have not yet been completed. Without additional FDA approval for the drug's use in those conditions, salespeople cannot promote Nuedexta for that purpose. They can only market its use for dementia patients who also have PBA.
There are currently no FDA-approved drugs for treating dementia-related agitation, and other drug makers have been penalized for marketing drugs for this use. Abbott Laboratories Inc., for instance, pleaded guilty in 2012 to illegally marketing an anticonvulsant called Depakote in nursing homes as a way to control agitated and aggressive dementia patients. But the drug had only been approved for treating seizures, bipolar disorder and migraines. The company ultimately paid a total of $1.6 billion in civil and criminal penalties.
Those who care for the elderly remain eager for tools to manage these behaviors, however. Some caregivers say investments in increased staffing can reduce the need for medications. But such measures are expensive and don't always work, so some facilities opt for pharmaceutical solutions that can help make their many patients easier to treat."Rather than taking someone off an antipsychotic" and opting to treat the patient in ways that don't require medication, "providers search for a different 'magic bullet,'" said Helen Kales, a geriatric psychiatrist and University of Michigan professor.
In one case, the executive director of a California assisted living facility tried to push Nuedexta on a dementia patient to address her "aggressive" behavior, according to emails reviewed by CNN. The director at the facility, Oakmont of Mariner Point in Alameda, California, told the patient's son, Jason Laveglia, that the medication wasn't an antipsychotic and threatened to evict his mother if she wasn't put on the medication.
"(I)f her behavior cannot be muted through prescription means, I would have no choice but to pursue delivering a 30-day eviction notice," Joan Riordan wrote to Laveglia last year.
Laveglia turned to the state for help, and by the time officials investigated weeks later, Riordan no longer worked at the facility. Social service officials ultimately found that her eviction attempt had violated state law. A spokesperson for the facility would not comment on the state's findings, but said it "does not endorse or recommend Nuedexta nor any other medication" and that staff should not be involved in medical decisions.
In an interview with CNN, Riordan disputed the idea that her emails served as an official eviction notice. Riordan, who is not a doctor, said that she had recommended Nuedexta after learning about the medication from a local psychiatrist and had seen it help a number of other aggressive dementia patients without the dangers and sedative effects of an antipsychotic.
"I've seen it just work wonders with people," she said. "It was the only intervention I could come up with. We needed to do something not only for her own benefit, but also for the people around her."
When asked whether her residents had PBA, Riordan told CNN she had never heard of the condition and had no knowledge of whether they had received such a diagnosis.
Across the country, the use of Nuedexta in nursing homes has prompted concerns among state regulators whose job is to ensure adherence to federal guidelines and protect residents from being given unnecessary drugs -- especially those used as chemical restraints. But to date, the red flags raised by these regulators have been largely left buried in nursing home inspection reports and have drawn little public attention.
CNN identified more than 80 cases in 19 states since 2013 where inspectors cited nursing homes for inappropriate monitoring and use of Nuedexta -- often because residents hadn't exhibited any symptoms of PBA. Many of the cases -- about 40% -- were clustered in Southern California, where Avanir is based and where former employees said there has been aggressive marketing.
At the Montrose Healthcare Center near Los Angeles, three nursing home residents were given Nuedexta without a doctor's prescription or approval, according to one inspection report. All were cognitively impaired. One was known to call out for help, while another would cry when their family left the facility. But employees acknowledged that they had never seen the residents laugh or cry involuntarily -- the hallmark indicators of PBA.
Regulators learned of these prescriptions in 2015, after a family member discovered that her relative was receiving Nuedexta without her consent. While researching the medication, she learned it could be dangerous for her family member because of other medications she took for a serious heart condition.
The doctors for all three residents denied ever prescribing Nuedexta. State investigators later discovered nursing staff had obtained the prescriptions without a doctor's approval, which they are not authorized to do. They also found that at least two nurses at the facility had attended a sales seminar about Nuedexta, where they were given a doctor's sample prescription for the medication. The facility said in a statement that it had addressed the concerns raised by the state inspection report and suggested that outside pressure had been at play.
"Our Center does not condone the pressuring of nurses by pharmaceutical reps and physicians to favor certain medications," the facility said. "Should they feel pressured to administer medications they do not feel are appropriate, our nurses can and should bring it to our immediate attention so we may assist them in advocating for their patients."
In New Jersey, St. Vincent's Healthcare and Rehab Center was cited by regulators last year because six residents were prescribed Nuedexta even though no symptoms of PBA had been documented. A representative of the facility told CNN it takes a "close look at all medications prescribed to ensure appropriate use."
One resident in the report told the facility's psychiatrist there was a legitimate reason for their sadness: "All I really want is a companion. I am lonely." In the case of another resident given the medication, a nurse said the resident's crying was an expression of frustration, and that this had improved with a change in routine.
Two other residents at the facility were originally prescribed Nuedexta for "Dementia with Behaviors."
Those diagnoses were then crossed out or rewritten -- replaced with "PBA."
At first, Alex Carington couldn't figure out why her 85-year-old mother, Lenore Greenfield, was on Nuedexta, a pill Carington had never heard of. A psychiatrist had prescribed the medication after visiting the elderly woman in her Los Angeles nursing home while she was sleeping, Carington said. Even when the drug appeared to do nothing to ease her mother's sadness, confusion or emotional outbursts as she battled dementia, she said the doctor kept her on it.
"Something about this whole thing made me think money was behind it," Carington, who lived near her mother's facility and visited her often, wrote at the time in an online comment on the blog of a psychiatrist who had questioned Nuedexta's aggressive advertising.
As she began to look into her mother's doctor, she discovered he had received more than $100,000 from Avanir in just over a year.
Outraged, she finally got her mother taken off Nuedexta for good. Now, around two years later, she is in a new nursing home and Carington believes she is doing much better.
See photo story: Why was my mother prescribed this pill?
Her mother's doctor was Romeo Isidro, a speaker for Avanir and one of the physicians paid the most by the drugmaker. Between 2013 and 2016, Isidro received more than $500,000 in payments, travel and meals from Avanir and its parent company. According to internal company documents, he was an advocate for Nuedexta as early as 2012, the year after it hit the market.
He had more than 100 patients in 11 facilities on the drug that year.
In Avanir training documents, a California salesperson explained how he worked to get Isidro to prescribe Nuedexta. Now a senior sales manager at the company, Chris Burch wrote in 2012 that he and his colleague saw or spoke to Isidro about twice a week -- regularly calling and texting him, and visiting him at both his office and nursing homes. Burch wrote that Isidro was at first skeptical about the condition of PBA, but after he successfully used Nuedexta to treat possible symptoms of it in one patient, he became more comfortable prescribing the medication. Burch then explained how he had directly targeted facilities where Isidro worked, finding employees who could serve as "advocate(s)" to help identify potential Nuedexta candidates for Isidro.
"He is now a speaker and I ask him to advocate in his facilities, corporate facilities, and (to) other psychiatrists, internists and pharmacies," Burch, who did not respond to requests for comment, wrote in a form used by the company to track certain prescribers.
CNN attempted to contact Isidro by phone and by visiting his office, where two stacks of PBA and Nuedexta pamphlets sat on a table in the waiting room. He declined to be interviewed but ultimately provided a written statement saying that he had "never prescribed medication for financial incentives" and that he prescribes Nuedexta to patients who he has properly diagnosed with PBA.
He also wrote about the first success he had seen with the drug, and how it helped him wean an elderly patient off of dangerous psychotropic medications -- noting that her inappropriate crying and screaming symptoms reminded him of a visit from a Nuedexta representative who had told him about PBA. He said Avanir approached him about becoming a speaker, and that he agreed in order to share his first-hand experience with the medication -- not to promote it.
"Since learning about PBA, I have become more skilled at recognizing it in my patients, which would in turn produce increased numbers of patients on Nuedexta," he wrote. "I am not an advocate for a particular drug or pharmaceutical companies. I am an advocate for my patients and their families."
In response to questions about Carington's mother, he said he couldn't comment on specific patients but that memories are not "infallible." He urged CNN to substantiate any claims with medical records about her case. Carington provided her mother's records to CNN, which confirmed that Isidro had diagnosed her with PBA and prescribed her Nuedexta, which she remained on for months.
A different speaker paid by Avanir, a pharmacist in northern California, appeared to suggest during a 2012 presentation that doctors could broaden the use of Nuedexta when prescribing, according to an audio recording obtained by CNN. A person in attendance, who recorded the event, identified the pharmacist as Flora Brahmbhatt.
"I'm definitely pushing this a little bit, perhaps considered off label ... but maybe it's effective on some of the other behaviors too that we find challenging," the pharmacist said in her presentation, which was sponsored by Avanir. "There are certain nursing home chains, specifically in Southern California, that are saying, 'Hey, if you have somebody with dementia that has a behavior issue, try them on Nuedexta before you put them on a psychotropic (medication.)' It's a little aggressive, I'll say that. But CMS isn't making it easy for us to use antipsychotics anymore."
She went on to discuss how a PBA diagnosis was essential for the medication to be "covered by insurance and not be off-label," as well as how PBA's definition of inappropriate laughing and crying could be interpreted by physicians. At one point, she told an Avanir employee in the room that they could cover their ears.
"We don't have anybody from the FDA in here. I'm telling you ... you can extrapolate that to mean any kind of socially inappropriate behavior when you've ruled out other causes," she said. "If they have an episodic behavior and they have an underlying neurological condition, you can pretty much come up with a diagnosis."
When contacted by CNN about the event and asked about the recorded statements, Brahmbhatt said she hadn't given presentations about Nuedexta for many years. She said she didn't give permission to be recorded and didn't recall making those statements. "I don't know if I said this stuff," she said. "It was five years ago, at best." She was read several of the quotes from the recording but declined to listen to it. An attorney representing Brahmbhatt contacted CNN after publication and said that Brahmbhatt denies making the statements in the audio recording.
Former FDA investigator Larry Stevens, who now works for the consulting firm The FDA Group, said it is a violation of federal law for a paid speaker to promote a drug for anything other than its FDA-approved use.
Yet another paid speaker, the Ohio physician accused of accepting kickbacks in exchange for prescribing Nuedexta, has been under government investigation. Internal Avanir documents show Cleveland neurologist Deepak Raheja was a top prescriber of the drug from the beginning, in 2011. Between 2013 and 2016, he received $289,000 in payments, meals and travel.
In addition to allegedly accepting kickbacks, Raheja is accused of fraudulently diagnosing patients with PBA in order to secure Medicare coverage for off-label use and increasing dosages of Nuedexta beyond what is recommended, according to a letter obtained by CNN. The letter, circulated by the Centers for Medicare & Medicaid Services (CMS) in January, alerted insurance providers that work with Medicare about the fraud allegations so that they could take "appropriate measures."
Medicare officials said the agency could not comment on pending or active investigations. When contacted by CNN, Raheja denied that he had received kickbacks or been involved in any kind of Medicare fraud in his 25 years of practice.
He also said he no longer prescribes Nuedexta.
After this story was published, the Los Angeles City Attorney announced an investigation into Avanir, as well as the marketing and prescribing of Nuedexta. Also, this story was updated to reflect a statement from Flora Brahmbhatt's attorney made after publication.