Tag: Indivior

04/2/24

Is Indivior a Good Steward of Its Opioid Treatments?

Image by Лечение Наркомании from Pixabay

Fierce Pharma reported in 2020 that the former Indivior CEO was sentenced to six months in federal prison for his role in misleading officials about the supposed dangers of Suboxone tablets. He was also fined $100,000 and forfeited another $500,000. But it seems now he’d like to be a consultant to individuals or companies attempting to bring a new drug to market. However, the FDA rejected that plan for now. On February 27, 2023 he was debarred by the FDA for “5 years from providing services in any capacity to a person that has an approved or pending drug product application.” What was he involved in that resulted in his prison sentence and debarment by the FDA?

According to Fierce Pharma, on October 23rd, 2023, Indivior agreed to pay $385 million to settle lawsuits in the U.S. brought by drug wholesalers claiming it illegally suppressed generic competition for Suboxone. But that’s not all. The company also agreed in June of 2023 to pay $102.5 million to settle a 2016 lawsuit charging that Indivior’s actions when switching from a tablet to an oral film form version of Suboxone was done to extend its monopoly with Suboxone. AND in August of 2023, it offered $30 million to settle with health plans making similar claims. This was in addition to the $300 million Indivior paid in 2021 to resolve claims it “falsely and aggressively” marketed the drug, which led to the misuse of state Medicaid funds.

All this happened after Indivior was sued in 2020 by its former parent company, Reckitt Benckiser, seeking $1.34 billion in damages tied to its marketing scheme for Suboxone film. Then on December 20, 2023 Indivior announced that it had entered into a settlement agreement with Actavis Laboratories, a subsidiary of Teva Pharmaceuticals, to resolve patent disputes regarding Actavis’s Abbreviated New Drug Application (ANDA) for generic buprenorphine and naloxone sublingual film. Under the settlement, Actavis can launch the generic film products in ANDA no earlier than January 31, 2025.

It seems Indivior as a company is trying to leave its chaotic and costly past behind. In About Us, Indivior said it “is a global pharmaceutical company working to help change patients’ lives by pioneering life-transforming treatment for addiction and other serious mental illnesses.” Their vision is to provide access to evidence-based treatment to the millions of people across the globe who suffer from substance use and serious mental illness. They also say they take their role as a steward of their medications extremely seriously:

We cultivate a culture of integrity and commit ourselves to the highest standards of governance. We believe our long-term success is directly linked to operating in a responsible way and in a way that minimizes our impact on the environment. We support efforts to educate around safety and proper use of our medication-assisted treatments.

Origins of Indivior

In case you’re not familiar with the company, here is a brief history of Indivior from Wikipedia and “The Opioid Buzzard.” It was established as the buprenorphine division of Reckitt Benckiser in 1994. Suboxone and Subutex were approved for the treatment of opioid addiction in October of 2002. They were both sublingual (under the tongue) tablets. Suboxone consists of buprenorphine and naloxone; Subutex was just buprenorphine. They came to market in 2003.

In 2007 Reckitt Benkiser (RB) acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. RB knew its patent exclusivity for Suboxone and Subutex would expire in 2009, so they submitted a New Drug Application for the film version of Suboxone, which was approved in August of 2010. In their 2011 annual report (no longer retrievable from its website), RB indicated to their shareholders that competition from generics could take up to 80% of the revenue and profit from the U.S. Suboxone market. But they expected “that the Suboxone film will help to mitigate the impact.”

In September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. They said they would take the tablet form off the market to “protect public health and safety.” The very same day RB filed a “Citizen’s Petition” with the FDA calling for the agency to postpone the approval of generic version of Suboxone in the interests of public safety. Subutex tablets were discontinued in 2011 and Suboxone tablets met the same fate in in 2012. For more on this action by RB, see “The Opioid Buzzard.”

In December 2014 Reckitt Benckiser made the buprenorphine division a separate company named Indivior. By February 2015, it was capitalized on the London Stock Exchange at $3.1 billion. And on April 9th 2019, a federal grand jury indicted Indivior for allegedly engaging in an illicit national scheme to promote Suboxone. See “The Pied Pipers of Suboxone” for more on this topic.

Indivior Products for Opioid Use Disorder

The Indivior products currently available in the U.S. to treat opioid use disorder include: Suboxone, a buprenorphine and naloxone sublingual film, Opvee, a nalmefene nasal spray for the emergency treatment of known or suspected overdose of opioids, and Sublocade, an extended-release injection of buprenorphine. Opvee and Sublocade are newer products than Soboxone and will be described below.

NPR noted Opvee was developed by Opiant Pharmaceuticals, which was acquired by Indivior in March of 2023. Opvee was approved by the FDA in May of 2023 and is similar to Narcan which contains naloxone. It apparently has a longer-acting effect than naloxone, which has some experts concerned. Nevertheless, Nora Volkow, the director of the National Institute on Drug Abuse, said: “The whole aim of this was to have a medication that would last longer but also reach into the brain very rapidly.”

An adverse side effect of opioid reversal drugs like Narcan and Opvee is they create intense withdrawal symptoms including: nausea, diarrhea, muscle cramps, anxiety, restlessness or irritability, increased blood pressure, rapid heart rate, body aches, and others. Important Safety Information for Opvee cautioned that the use of Opvee (leading to abrupt postoperative reversal of opioid depression) “may result in adverse cardiovascular effects” in people with preexisting CV disorders. So, these patients should be closely monitored in a healthcare setting. And it warns that some patients may become aggressive when an opioid overdose is reversed (treated) with Opvee.

With naloxone (Narcan), these symptoms could last 30 or 40 minutes. With Opvee (nalmefene) they can last six hours or more, “requiring extra treatment and management by health professionals.” GoodRx Health said: Opvee’s half-life is about 11 hours, while Narcan’s half-life is about 2 hours. Read between the lines here. A person uses opioids to experience the high or euphoria AND to avoid withdrawal. So Opvee immediately blocks the high and brings on withdrawal. It extends the withdrawal symptoms to six hours or more, with the potential of the treated person wanting nothing less than to find more opioids to cope with the withdrawal and driving them to use a higher dose of opioids to overcome the nalmefene—with the potential of adverse cardiovascular effects in people with preexisting CV disorders.

If this “treatment” occurs, as is likely, outside of a healthcare facility, the person or persons who administered the Opvee will have to convince person to go to an emergency department or other healthcare facility. There is a better chance of success if the withdrawal symptoms only last 30 or 40 minutes than six hours or more. No wonder some individuals get aggressive when treated with Opvee. Should it be limited to use with overdose victims who are already in a healthcare facility or by emergency responders like EMT or police?

Dr. Lewis Nelson of Rutgers University, a former advisor to the FDA, said the risk of long-lasting withdrawal is something they try to avoid. He added a second or third dose of naloxone is easy enough to give and works perfectly well.

Indivior said it is still considering what to charge for its drug. It will compete in the same market as naloxone, where most buyers are local governments and community groups that distribute to first responders and those at risk of overdose. Indivior has told investors that Opvee could eventually generate annual sales between $150 million to $250 million.

Sublocade was approved by the FDA in November of 2017. It is a monthly injection of buprenorphine to treat individuals with moderate to severe opioid use disorder. “It is indicated for patients that have been on a stable dose of buprenorphine treatment for a minimum of seven days.” It is a drug-device combination product that is injected under the skin (subcutaneously) as a solution, but forms a solid deposit or depot of buprenorphine. After the initial formation of the depot, buprenorphine is released as the depot biodegrades.

The monthly injection of buprenorphine in Sublocade is another treatment option for opioid use disorder (OUD). It has the advantage of gradually releasing buprenorphine at a controlled rate, meaning that the levels of buprenorphine stay consistent in the blood throughout the month. In a study reported on in the above-linked description on how Sublocade works, Indivior provided a chart illustrating how buprenorphine levels were delivered at sustained levels, after a required preliminary period of daily oral buprenorphine for at least 7 days to control withdrawal symptoms. The required daily use of oral buprenorphine helps assure the healthcare provider the person did in fact stop their use of opioids before they began their daily use of Suboxone because buprenorphine acts as a partial antagonist, blocking the ability of many opioids to cause an effect.

Should the person decide to stop taking Sublocade, the terminal half-life of Sublocade is 43 to 60 days. According to Drugs.com, it usually takes four to five half-lives for a drug to be totally eliminated from the body. So, no trace of buprenorphine from Sublocade should be found after 172 to 300 days. This raises the potential use of Sublocade as a tool for slow tapering once the individual has reached a steady-state (4-6 months), instead of treatment with Sublocade continuing indefinitely.

A Slow Buprenorphine Taper with Sublocade?

Dr. Leeds, a Suboxone doctor in Fort Lauderdale FL, described just such a way Sublocade could be used to taper off Suboxone. He said many patients often want to know from their first visit to a Suboxone doctor if there is a way to eventually get off Suboxone. Their reason is the buprenorphine in Suboxone is an opioid drug and causes physical dependence like all opioids. If a patient taking Suboxone quits treatment early, they will develop withdrawal symptoms. A gradual taper is the solution to minimize the physical opioid withdrawal symptoms.

However, the medication is not well-designed for a taper. Doctors who help their patients with tapering off Suboxone quickly realize that the Suboxone sublingual films are not available in enough dosage increments to all for proper gradual tapering.

In order to avoid serious withdrawal symptoms, a patient most often must reduce their dosage gradually, to the lowest dose possible, such as buprenorphine 0.25mg daily, or even less. Unfortunately, the lowest Suboxone dose is 2mg.

Additionally, the manufacturer, in the Suboxone prescribing information, states that patients should not cut or split the tablets or films. Suboxone makers are clearly not interested in helping patients with tapering off Suboxone.

Dr. Leeds noted that since the subcutaneous buprenorphine shot takes many months to fully wear off, “it does seem possible that it might help some patients with the tapering process.” However, the buprenorphine taper would be off-label and experimental at this point. There would be no available guidance from experts, “because Sublocade has not been widely used for Suboxone tapering.”

For the present, he does not recommend finding a doctor willing to use Sublocade to taper off Suboxone. But he encouraged interested people to reach out to researchers and research centers in the field of opioid use disorder treatment. “If Suboxone scientists are aware that people are interested in this research, they might decide to seek funding for such studies.” He also suggested there may be doctors who are using Sublocade off-label for Suboxone tapering, who may have anecdotal information to help other interested doctors.

Drugmakers are quick to recommend that doctors get their patients onto their medications. Yet, they do little to guide doctors in getting patients off of these meds when treatment has been completed.

Are you listening, Indivior? You describe yourself as “a global pharmaceutical company working to change patients’ lives by pioneering life-transforming treatment for addiction.” You further said you believed your “long-term success was directly linked to operating in a responsible way.” Is it responsible to neglect to provide guidance for individuals who would like to taper off their use of Suboxone and Sublocade, which are opioids—meaning they make their users physically dependent on them. Does the safe and proper use of your medication-assisted treatments require you to ignore those who want a safe and proper method of tapering off of them?

If you truly take the stewardship of your medications extremely seriously, shouldn’t you be willing to fund research into Suboxone tapering with Sublocade?

12/3/19

The Pied Pipers of Suboxone

© Lucas Salcedo | artstation.com/artwork/JEY5D

Reckitt Benckiser, the company that brought Suboxone to market, settled allegations that the company wrongly marketed and promoted Suboxone, resulting in the improper expense to state Medicaid funds. Reckitt will pay $700 million to settle the allegations. New York State Attorney General, Letitia James, said in a release dated October 23, 2019, that no company is above the law: “Reckitt misled the public about the real impacts of Suboxone and encouraged physicians to wrongly prescribe it, while cheating New York out of tens of millions of dollars in the process.” FiercePharma reported that would bring Reckitt total settlements this year to just over $2 billion, putting its Suboxone marketing investigations behind it, once and for all.

On April 9th 2019, a federal grand jury indicted Indivior, formerly part of Reckitt Benckiser Pharmaceuticals Inc., for allegedly engaging in an illicit nationwide scheme to promote Suboxone. Reckitt Benkiser had spun off Indivior Inc., meaning the two became separate companies in December of 2014. The U.S.’s criminal trial against Indivior is scheduled to begin on May 11, 2020. Then the U.S. Department of Justice announced on July 11, 2019 that Reckitt Benckiser agreed to pay $1.4 billion to resolve potential criminal and civil liability related to a federal investigation of the marketing of Suboxone.

After the April 9, 2019 indictment against Indivior, FiercePharma reported the company said the allegations were “wholly unsupported by either the facts or the law.” Indivior’s Chairman said the company “never deliberately diverted its product.” In an open letter he claimed the company went beyond what the law required in its education campaign to doctors and by reporting multiple physicians to the appropriate authorities. He further claimed the DOJ indictment can’t be justified on any fair reading of the facts or the law. “But we will contest these charges vigorously and we are confident in our position.”

It is not clear if Indivior is as confident in its position following the DOJ announcement. “RB Group has agreed to cooperate fully with all investigations and prosecutions by the Department of Justice related, in any way, to Suboxone.” Indivior may find it is fighting against the interests of its former parent company, Reckitt Benckiser. The DOJ said:

According to the indictment, Indivior—including during the time when it was a subsidiary of RB Group—promoted the film version of Suboxone (Suboxone Film) to physicians, pharmacists, Medicaid administrators, and others across the country as less-divertible and less-abusable and safer around children, families, and communities than other buprenorphine drugs, even though such claims have never been established.The indictment further alleges that Indivior touted its “Here to Help” internet and telephone program as a resource for opioid-addicted patients. Instead, however, Indivior used the program, in part, to connect patients to doctors it knew were prescribing Suboxone and other opioids to more patients than allowed by federal law, at high doses, and in a careless and clinically unwarranted manner.The indictment also alleges that, to further its scheme, Indivior announced a “discontinuance” of its tablet form of Suboxone based on supposed “concerns regarding pediatric exposure” to tablets, despite Indivior executives’ knowledge that the primary reason for the discontinuance was to delay the Food and Drug Administration’s approval of generic tablet forms of the drug.The indictment alleges Indivior’s scheme was highly successful, fraudulently converting thousands of opioid-addicted patients over to Suboxone Film and causing state Medicaid programs to expand and maintain coverage of Suboxone Film at substantial cost to the government.

Meanwhile, as alluded to above in the above news release from the DOJ, Indivior has been fighting a legal battle to delay generic approval for Suboxone. On June 14, 2018, the FDA approved Mylan Technologies Inc. and Dr. Reddy’s Laboratories SA to market the first generic versions of buprenorphine and naloxone sublingual film (Suboxone). Then on June 15th, the U.S. District Court of New Jersey granted Indivior a temporary injunction against Dr Reddy’s, compelling it to immediately stop its launch activities with Suboxone film. According to FiercePharma, Indivior has filed patent infringement lawsuits against both Mylan and Dr Reddy’s. Indivior will have to pay Dr Reddy’s $18 million to satisfy losses or damages incurred during the temporary restraining order if the generics company is successful in its legal defense.

When the U.S. Court of Appeals found that Indivior was not likely to succeed on the claimed patent infringement and ruled the lower court’s preliminary injunction be lifted, Indivior then tried blocking the appeals court ruling by taking the issue to the Supreme Court. Chief Justice John Roberts denied Indivior’s motion to stay the appeals court mandate on February 19th, 2019, clearing the way for Dr Reddy’s to market its generic version of Suboxone as the litigation continues. Dr Reddy’s immediately began shipping its generic version, as the original injunction did not stop it from manufacturing the drug. Indivior then announced it would launch its own generic version of Suboxone in the U.S. on February 20th. Mylan, which had made a deal with Indivior, announced it will launch its generic version on February 22nd.

Then on July 12, 2019, the U.S. Federal Circuit Court of Appeals in Washington upheld lower court rulings that “Dr. Reddy’s did not infringe two Indivior patents related to Suboxone.” Two other companies, Teva and Alvogen were also found to not have infringed on Indivior patents. Writing for the majority, Circuit Judge Alan Lourie said that while Indivior’s patents should not be voided, it failed to show that they covered Dr. Reddy’s and Alvogen’s drying processes for their products. This was the day after Reckitt Benckiser agreed to pay $1.4 billion to settle a federal investigation of the marketing of Suboxone noted above. Indivior said the settlement was separate from its own case.

The above consequences have been coming for several years. And Reckitt Benckiser and Indivior are complicit in the actions taken by both companies to position themselves as the primary service provider for buprenorphine-based MAT in the U.S. But their actions to delay generic buprenorphine/naloxone didn’t just begin during the time period described above.

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products  (Suboxone and Subutex tablets) until 2009, but they had a strategy to circumvent the pending loss. First, they acquired the rights for the sublingual film version of Suboxone in 2008. Then in October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone, which was approved by the FDA in August of 2010.

In its 2011 annual report, Reckitt Benckiser thought generic versions of Suboxone could take up 80% of the revenue and profit from the U.S. Suboxone market. However, they expected Suboxone film would help “to mitigate the impact.” Then in September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. The FDA thought the study Reckitt Benckiser cited (and paid for) did not demonstrate any difference in its safety profile of abuse formulations between Suboxone tablets and film.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market (Suboxone tablets) to make room for a newly patented successor (Suboxone film). A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month. See “The Opioid Buzzard” for more on this.

Whether you look at Reckitt Benckiser or Indivior you can see a pattern of systematic steps to maintain a monopoly on the buprenorphine-naloxone end of the MAT, medical-assisted treatment, market. This resulted in 2019 with over $2 billion in settlements for improper, illegal marketing tactics with Suboxone for Reckitt Benckiser. Indivior is next, as the federal government indicted it for an illicit scheme to market Suboxone. Yet Indivior still projects a rosy future for its products. It has a new buprenorphine product, monthly depot shot of buprenorphine called Sublocade, and Perseris, which is an extended release injectable of risperidone for schizophrenia that launched in February of 2019. But there are additional changes in the MAT market that contribute to Indivior’s optimism.

The first quarter financial report by Indivior for 2019 reported that U.S. net revenue grew 2% as Suboxone Film share loss was more than offset by “underlying market growth, strong initial sell-in of the Group’s authorized generic film product and net revenue from SUBLOCADE™.” Operating Highlights for the first quarter included continued growth of the U.S. buprenorphine market, driven primarily by Government channels. The share erosion since the “at risk” launch of generic buprenorphine/naloxone film products in February 2019 was lower than anticipated. Suboxone Film market share ended the quarter with a 53% market share. “Sandoz Inc. launched an Indivior authorized generic buprenorphine/naloxone film and captured the leading position among allgeneric film products” by the end of the first quarter. Shaun Thaxter, the CEO of Indivior, said their first quarter performance only strengthened their confidence that they are “putting the building blocks in place for a return to sustained growth” with Sublocade and Perseris. He looked forward to reporting progress throughout the year.

His optimism seems to rest on how the market for buprenorphine products continues to grow, benefitting from legislative changes that have expanded opioid use disorder (OUD) treatment funding and treatment capacity. This was accomplished by increasing the number of patients that physicians could treat from 100 to 275.

Recognising the foregoing factors, we are introducing FY 2019 financial guidance. A key element of guidance is of course the performance of SUBLOCADE™, our new monthly buprenorphine extended-release injection, and here we made good progress in executing our plans: Q1 net revenue of $11m puts us on track to meet our FY 2019 guidance for net revenue of $50m-$70m. We continue to believe SUBLOCADE™ to be a transformational treatment for opioid dependence and we will not be distracted in our efforts to bring this important new option to patients in the US. Separately, while not a material contributor to our full-year guidance, we are nonetheless encouraged by the initial market reception to PERSERIS™, our monthly risperidone injection for schizophrenia, which we launched towards the end of the first quarter.

Thaxter said Indivior remained “undaunted in the pursuit of our Vision to improve the lives of patients suffering from addiction and its co-occurring disorders.” Yet the above story seems to point to another Vision—sustained growth and profitability—that blinds them from seeing where they are potentially taking us. Is this self-described “leader and innovator” in OUD treatment leading towards a “treatment” strategy that increases rather than decreases the number of those who are chained to an opioid? Like in the story of the Pied Piper, are we dancing to the tune of Indivior, unaware we are being led into the river of OUD instead of being saved from it?

For more on Indivior and Sublocade, see “Opioid Epidemic Price Gouging.” For further information on Reckitt Benckiser and its attempts to prolong a market for Suboxone, see “A Double-Edged Drug.”

01/23/18

Opioid Epidemic Price Gouging

© Karen Roach | 123rf.com

The FDA recently approved Sublocade, the first once-monthly buprenorphine injection in its fight against the opioid epidemic. Indivior, the company which also sells Suboxone film, projected it would be available on the market sometime in the first quarter of 2018. Sublocade is a drug-device combination product. “It is injected by a healthcare professional (HCP) under the skin as a solution, and the delivery system form a solid deposit, or depot, containing buprenorphine.” The initial procedure will to be to start with daily stabilizing doses of Suboxone for at least seven days before the first injection of Sublocade.

After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Prescribing information for Sublocade said the recommended protocol was two monthly doses of 300 mg followed by 100 mg monthly maintenance doses. “Increasing the maintenance dose to 300 mg monthly may be considered for patients for whom the benefits outweigh the risks.” Sublocade will come in prefilled syringes of 100 mg and 300 mg. It will carry a boxed warning of the risk of serious harm or death if used intravenously.

The Indivior announcement of Sublocade’s approval indicated Sublocade will be distributed through a restricted distribution system, “which is intended to prevent the direct distribution to a patient.” This restricted release to only healthcare professionals is because of the risk of serious harm or death if someone were to attempt intravenous self-administration of Sublocade. Intriguingly, the boxed warning in the prescribing information wasn’t as clear on the intent of the restricted distribution system to prevent patients from having direct access to Sublocade. The harder it is to get a hold of Sublocade, the harder it will be to figure out a way to hack into the buprenorphine it contains.

The FDA is requiring postmarketing studies to assess four things. First, whether patients would benefit from a higher dose. Second, whether Sublocade can be safely started without a dose stabilization period of Suboxone. Third, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly. Fourth, to determine a process for transitioning patients stabilized long term on Suboxone film to a monthly dose of Sublocade without the loaded dose in the first two months of treatment.

I assume the study to see if patients would benefit from a higher dose fits into the above prescribing information that maintenance doses could be increased up to 300 mg monthly. But I have this nagging question of whether Indivior felt unsure about the safety risk of maintenance doses above 100 mg. So they wanted to be safe rather than sorry, knowing there was always Suboxone film to supplement Sublocade in a pinch. And postmarketing studies could look at whether higher maintenance doses put people at risk in some way.

The procedure of having an initial “dose stabilization” period on Suboxone before injecting Sublocade helps ensure the individual has really stopped using opioids before their injection. The required postmarketing study will help evaluate whether that’s necessary. My initial thoughts are that given the significant amount of buprenorphine in the depot, clinically the dose stabilization period should remain, especially if this is done when the person is an outpatient. If the person’s pattern of use isn’t stable enough to reach a week of daily Suboxone use, they should probably try inpatient drug treatment to stabilize first before Sublocade.

Depots containing either 100 mg or 300 mg have a significant amount of buprenorphine. So I’m concerned about thoughts of assessing the feasibility of administering Sublocade at longer inter-dose intervals, which would require even higher doses. I guess the thinking behind the longer inter-dose interval study is anticipating of having/keeping Sublocade patients on the treatment for an indeterminate length of time, perhaps years.

Except for the supposed convenience of a once-monthly shot, why would someone who is stable on Suboxone film long term want to switch to Sublocade? If you have demonstrated the discipline, stability and willingness to successfully maintain opioid abstinence with Suboxone, why switch to Sublocade? I do know why Indivior would want you to switch. The average monthly cost for Suboxone is $132, while the average monthly cost for Sublocade is $1,580. The cost for Sublocade puts it in the ballpark for Vivitrol, which costs around  $1,687 per month.

STAT News quoted one addiction professional who said: “It’s potentially a game changer. . . . This could become first-line [medication] for opioid addiction.” But Sublocade is just the first injectable buprenorphine product to be approved. A similar medication, known as CAM 2038, is made by Braeburn Pharmaceuticals and it could be get FDA approval by January 19, 2018. The president and CEO of Braeburn said: “This new technology has the potential to greatly influence the way patients are treated today. . . [It can] free patients from the daily decision and reminder of the disease.” Did this guy ignore or just forget about the Warnings and Precautions on the Sublocade medication guide?

It says: “Buprenorphine can be abused in a manner similar to other opioids; Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Sublocade.” Pain treatment should be with a non-opioid analgesic whenever possible. “If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect.” Sublocade won’t free patients of the daily reminder of the disease, because it is the daily reminder.

STAT said long-acting buprenorphine could make future inroads within the criminal justice system. “In recent years judges, wardens, and health officials have warmed up to Vivitrol, citing fears that daily tablets of buprenorphine can be diverted or abused.” Additionally, the criminal justice system has been more receptive to Vivitrol because Alkermes has been doing targeted marketing with them to promote Vivitrol for a number of years. However, the approval of Sublocade adds a second monthly injectable alongside Vivitrol and potentially could diminish “one of the biggest competitive advantages held by Vivitrol.”

STAT also pointed to another likely financial incentive for Invidior to put Sublocade into the market. Medicaid spending on buprenorphine last year was five times higher than for Vivtrol. But those spending statistics could be partly due to the cost discrepancy between monthly Vivitrol and Suboxone and not the preference for buprenorphine. However, it is likely Invidior will be able to slice off a nice chunk of non-negotiated drug price income for Sublocade from Medicaid.

Another STAT article discussed a study published in The Lancet, Lee et al., that found both Vivitrol and Suboxone had comparable effectiveness outcomes during 24 weeks of outpatient treatment. STAT quoted Dr. Nora Volkow, director of NIDA as saying she hoped the study will change the widespread prejudice patients don’t do as well on naltrexone as they do on buprenorphine.  Apparently it didn’t. In the very same STAT article, two different doctors, not involved in the study, said the study showed buprenorphine was more effective than Vivitrol. However, the lead author of the study, Dr. Joshua Lee told STAT: “Both medications worked quite similarly and, therefore, both should be discussed as treatment options.”

The study findings pointed to by the two doctors included the following: its easier to initiate and patients stay with the treatment (buprenorphine) longer. Fewer participants successfully started Vivitrol treatment, as it required a three day period for detoxification, whereas Suboxone participants could begin as soon as the onset of withdrawal symptoms began. The differences in induction rates were 72% for Vivitrol and 94% for Suboxone.

Naltrexone (Vivitrol) is an antagonist, meaning if there were residual levels of opioids in a participant’s body they would immediately be thrown into acute withdrawal. The delay was medically necessary. Naltrexone is also not an opioid, while Suboxone (buprenorphine) is. The induction period with Vivitrol was expected by the study authors themselves to be more difficult. They didn’t get the easement of acute opioid withdrawal that the Suboxone group did—and yet, 72% were successfully inducted into the study.

Curiously one individual pointed to where many of the overdoses in the study occurred after detox, apparently indicating more occurred with Vivitrol. Yet she failed to comment on the fact that of the five fatal overdoses in the study, THREE were in the Suboxone group!

There were more relapse events (defined as 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.) for the Vivitrol group, but “most or all of this difference [was] accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.” The more difficult time intiating patients into Vivitrol treatment effected the over relapse rates. “However, once initiated, both medications were equally safe and effective.”

The Lee et al. study was actually the second study to demonstrate that Vivitrol was as effective as Suboxone in maintaining short-term abstinence. The previous study was a smaller Norwegian study, Tanum et al., that followed its participants for 12 weeks. The bottom line is replicated results are more difficult to rationalize away.

Diversion and abuse of Suboxone has been evident from the time it was approved by the FDA. The approval of Sublocade would hopefully nullify the diversion and abuse problems experienced with Suboxone, if you have the money or insurance for it.

Bringing buprenorphine into the realm of “a restricted delivery system” to prevent direct distribution to patients also seems to be where some justification for the added cost factor comes in. But I wonder to what extent dispensing Vivitrol and Sublocade in a medical setting can justify the high cost. Is there price gouging going on? This is now the second time that technological innovation has extended patent exclusivity for Indivior’s buprenorphine products. Read more about how Reckitt Benckiser, the parent company to Indivior and Indivior itself accomplished this in “The Opioid Buzzard.”

12/20/16

The Opioid Buzzard

© Andrea Izzotti | 123rf.com

The U.S. is in the midst of a health crisis from the use and abuse of opioids. Since 1999, the rate of overdose deaths from opioids—prescription pain relievers and heroin—nearly quadrupled. On an average day in the U.S. more than 650,000 opioid prescriptions are dispensed; 3,900 people begin nonmedical use of opioids; 580 people start using heroin; and 78 people die from an opioid-related overdose. Economically, there is a $20 billion cost in emergency department and inpatient care for opioid poisoning each year; and $55 billion spent on health and social costs related to prescription opioid abuse.

In order to address this opioid epidemic, the U.S. Department of Health and Human Services (HHS) launched an initiative in March of 2015 aimed at improving prescribing practices, expanding the access to and use of medication-assisted treatment and expanding the use of naloxone. So far, the Substance Abuse and Mental Health administration (SAMHSA) has awarded $10.7 million to 11 high-burden states for medication-assisted treatment (MAT). Applications were due in May of 2016 and awards were to be made to an additional 11 states. The above information and statistics were drawn from a Health and Human Services report, “The Opioid Epidemic: By the Numbers.”

Then in July of 2016, the HHS Secretary announced new rules that permit doctors licensed to dispense buprenorphine to see as many as 274 patients per year. The old limit was 100. HHS estimated that change permits as many as 70,000 more people to access buprenorphine. The former limit of 100 was seen by many as a barrier to individuals seeking to access MAT. “The rule aims to increase access to medication-assisted treatment and associated behavioral health supports for tens of thousands of people with opioid use disorders, while preventing diversion.” Clearly buprenorphine products like Suboxone are seen as a crucial element in our attempts to combat the opioid health crisis.

There are issues with this approach to treatment for the opioid crisis that I’ve addressed previously in articles such as: “The Seduction of Opioid Substitution” and “A Double-Edged Drug.” Here I want to look at how the company that brought buprenorphine treatment to market, Indivior/Reckitt Benckiser, tried to position itself as the primary service provider for buprenorphine-based MAT in the U.S. It’s kind of like a buzzard chasing off smaller scavengers from the carcass of an overdose victim. At one point, Reckitt Benckiser had 85% of the U.S. MAT market—almost all of it subsidized by taxpayers.

In 1994 Reckitt Benckiser established the Buprenorphine Business Group to develop buprenorphine as a treatment for opioid dependence. In 2000 legislation (DATA 2000) was passed in the U.S. permitting office-based treatment of opioid dependence. In 2002 the FDA approved Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone) for the treatment of opioid dependence in the U.S. These products came to market in 2003. In 2007 the initial cap of 30 patients was raised to 100 for physicians with at least one year’s experience with buprenorphine. That same year Reckitt Benckiser acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. Then in 2010 Suboxone sublingual film was launched in the U.S. Subutex tablets were discontinued in 2011; and Suboxone tablets met the same fate in 2012. In December of 2014, Reckitt Benckiser spun its specialty pharmaceutical company into a separate business and Indivior was born.

This history was taken directly from the Indivior website, where the company estimated they had treated 5 million individuals in the U.S. with Suboxone film and tablets and Subutex tablets. Here are some additional facts to add to the above timeline from a 2013 article, “Pharma Gamemanship.”

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products until 2009. But they had a plan to circumvent the pending loss. As noted above, they acquired the rights for the sublingual film version of Suboxone in 2008. In October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone; and it was approved in August of 2010. Reckitt Benckiser has patent exclusivity on the newer film version until 2023.

In their 2011 annual report (no longer retrievable from its website), RB indicated to their shareholders that competition from generics could take up to 80% of the revenue and profit from the U.S. Suboxone market. But they expected “that the Suboxone film will help to mitigate the impact.” In September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. They said they would take the tablet form off the market to “protect public health and safety.”

The very same day RB filed a “Citizen’s Petition” with the FDA calling for the agency to postpone the approval of generic version of Suboxone in the interests of public safety. Reporting for The Daily Beast, Christopher Moraff said the “data” they based their withdrawal of Suboxone tablets on was a single study RB had paid for itself. RB reportedly said the study demonstrated the risk factor for accidental ingestion was eight times higher in bottled tablets than for the individually packaged film. Yet its own data told a different story.

Compared to the more than 20,000 deaths in 2012 from prescription opiates and heroin, pediatric poisoning from Suboxone was far from a public health crisis. A preliminary study commissioned by Reckitt Benckiser found just 46 cases of serious injury or death out of more than 2,200 accidental pediatric exposures to Suboxone tablets between 2010 and 2012—which researchers described as not significantly different from poisonings from the film.

The FDA thought the RB study was inconclusive and did not demonstrate any difference in the safety profile or abuse potential of the two formulations. They said the study was poorly designed and conducted. “Reckitt’s own actions also undermine, to some extent, its claims with respect to the severity of this safety issue.” Despite the first report of pediatric death in June of 2010, RB continued marketing the tablets in multi-dose containers for two more years. And it continues to sell them throughout Europe, where Suboxone tablets are still under patent.

In June 2013 the FTC opened an investigation into whether Reckitt Benckiser abused public regulatory processes and fought for nearly two years to obtain more than 20,000 documents the company was fighting to withhold. That case is ongoing. In December of that year, federal agents raided Reckitt Benckiser’s West Virginia offices after the Department of Justice launched a criminal probe into the company’s Suboxone business. That investigation continues.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market to make room for a newly patented successor. A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month.

So it should come as no surprise that a lawsuit has been filed by 35 states and the District of Columbia alleging that Indivior violated antitrust laws by trying to extend its monopoly over Suboxone. Reporting for CNN, Susan Scutti said the lawsuit charges that Indivior/RB and MonoSol Rx “conspired to block generic competitors for Suboxone by switching the drug from a tablet to a dissolving film.” A September 23, 2016 press release on the Indivior website said: “The Company intends to continue to vigorously defend its position.”

The International-Dictionary.com said there are two meanings for the word “buzzard.” The first one is zoological, referring to a bird of prey of the hawk family. The second meaning is “a blockhead; a dunce.” A quote attributed to Goldsmith reads: “It is common, to a proverb, to call one who can not be taught, or who continues obstinately ignorant, a buzzard.” It seems to me that either sense can be applied to Reckitt Benckiser and Indivior.