13 September 2011

Launch of Suboxone Film - Sydney Olympic Site - August 2011

Product launch by Reckitt Benckiser - Suboxone Film 2mg and 8mg for opioid maintenance. Sydney Olympic site - Novotel 7pm Tuesday 23rd Aug 2011

Dramatis personae: Dr Mark Hardy (Chair); Mr Ruari Macdonald (Reckitt Benckiser); Prof Nicholas Lintzeris (Langton Centre); Mr Peter Muhleisen (Hunter NE area pharmacist); Ms Simone Cass (Consumer Representative).

Headings: Is combination buprenorphine best practice? Why is the film being marketed now? Is it bio-equivalent? No childhood poisonings in Oz. Prison diversion under postage stamps, etc. Pharmacists: unsung heroes of dependency treatments. Is dosing ‘films’ really faster? Were consumers consulted adequately?

## This was a rather unedifying event, proving, sadly, how much our field of medicine is now influenced by the pharmaceutical industry. It seemed as though not one person in the large assembly questioned the wisdom of swapping from one unproven mixed drug to another on the appointed day. And the recent appearance of a half-price ‘generic’ buprenorphine (at least in America) was not raised.

I personally do not prescribe combination buprenorphine at all so this launch was largely hypothetical in my case. I spoke to Dr Alex Wodak earlier in the day and was reassured to learn that he and his colleagues at St Vincent’s Hospital currently prefer to prescribe buprenorphine without naloxone and for the same reasons: a lack of good research evidence on equivalence, safety and effectiveness. My advice to doctors and pharmacists is to demand this evidence before prescribing any new drug. Products approved by the TGA and promoted by State health authorities are not automatically ‘best practice’ in the field.

The dinner guests were told that the new Suboxone SL ‘film’ was approved from September on condition that the tablets were withdrawn within two years because they are not bio-equivalent, the film being more highly soluble. It would be helpful to know what proven advantage the PBS committee found in this product that justifies the switch from the existing sublingual tablet. This is particularly the case since the ‘film’ formulation has been used as a vehicle to smuggle buprenorphine into prisons in the US on writing paper, under postage stamps and envelopes. It is important to justify any known disadvantages of a new formulation with the potential benefits, especially when a new drug effectively locks out generic competition. A more highly soluble product which dissolves more rapidly may also have a greater potential for intravenous use. An internet search can quickly confirm some of these harmful concerns, most notably injecting.

Even if one were to accept that naloxone reduces some diversion, the pure product is certainly the preferred medication during pregnancy … and probably also in women who may become pregnant … and also for inductions of new patients onto the drug.  The pure medication was used in the controlled research which supported buprenorphine treatment for addiction.  It was also the pure product which is used in France where widespread buprenorphine treatment started in 1995.  There are no serious moves, I understand, to use the combination drug in France, although it is a registered therapeutic product in the EU generally.  One wonders what the French know that we do not (or does ‘market saturation’ solve many of the problems found elsewhere?).  I cannot understand why, with its purported advantages, the company is not marketing a film version of the pure drug, even if just for pregnant patients. Such a form was supplied by the company to Strain et al. for their induction trial. The promise of unique identifiers on each sachet of the film as a means to detect and prevent diversion seems to have lapsed so ‘pill-counts’ and diversion tracing cannot be done. Yet another disappointment.

The evidence supporting reduced diversion with the combination tablets/films is scant anyway and lacks scientific rigour in my view.  Reports of the widespread injection use of the combination drug are legion and go back 20 years (‘The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand’. See below.).  If there is a disincentive to inject the combination drug, it is modest in degree and it can be little greater than that of buprenorphine alone in current users of heroin, morphine or methadone due to its well known ability to induce the extremely unpleasant ‘precipitated withdrawal reaction’. On the other hand, there is little or no aversive effect in those currently taking buprenorphine nor in those without a current tolerance, so these groups can inject either preparation with impunity. The latter may include some patients in detoxification facilities or prisons as well as opiate na├»ve individuals.  Furthermore, the evidence that is available indicates that the deterrent effects in persons who are actively using opioids may be associated with less safe injection practices (‘Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market’. See below.). 

Despite these disadvantages, I remain a great supporter of buprenorphine as a dependency treatment option. I first prescribed it (exceptionally) over 20 years ago ‘off-label’ to dependent patients.  The original combination product buprenorphine and naloxone was approved for maintenance prescription about 6 years ago in Australia.  We were strongly encouraged to prescribe it by each State and Territory Health Department.  There were also guidelines for unsupervised use in certain circumstances, based, we were told, on a single overseas study. However, close reading shows it mostly used supervised dosing and is of limited relevance to Australia (Fudala et al. 2003).  Apart from better results than with placebo (only in America or Russia could placebo be used in this context) this study showed a trend for better abstinence outcomes in those taking 16mg of pure buprenorphine compared with those taking the combination product (sixteen percent more clear urine tests in those on pure buprenorphine).  The trial was not sufficiently ‘powered’ to make this difference statistically significant.  Paradoxically, if pure buprenorphine had shown significant superiority, buprenorphine might have had a very different story in America. 

In the scramble to develop new guidelines for unsupervised use in 2006 (and contrary to its own long standing practice) the Royal Australasian College of Physicians accepted a six figure sum from the manufacturer/distributor to help ‘educate’ the profession. And this was using a combination drug which their chief dependency education officer Dr James Bell stated at the time was “therapeutically identical” to the pure product.  It was a shame such funds were not made available when the original product appeared on the market five years earlier when the original drug was introduced. 

We were told that in Australia the major complaint about Suboxone tablets was that they took too long to be absorbed.  Hence the company had developed the new film preparation as a response to this.  By contrast, Americans were told last year that the main reason for the company introducing the new ‘film’ preparation was the issue of childhood poisonings from Suboxone tablets (see Strain et al 2011, almost 1000 such reports annually by 2008 in America).  I was surprised to learn that despite these worrying statistics, buprenorphine is still sold by American pharmacies as loose tablets in regular pill bottles (albeit with child-resistant caps). Even paracetamol/acetaminophen is sold in blister packs in Australia and elsewhere to avoid this problem.

At the drug launch dinner the childhood poisonings were mentioned numerous times yet there have apparently been no cases in Australia to date.  Of itself, this would seem to be a lesson in public health safety. It would seem wrong-headed to address the dangers of existing tablets by introducing a new patented product rather than by promptly changing the loose packaging to blister packs. 

There was a warning from Professor Lintzeris that although he believed that most diversion of buprenorphine was of limited clinical significance, the treatment (Subutex) had been banned in Singapore and Finland after reported diversion and misuse.  He emphasised also that the use of unsupervised buprenorphine treatment could be at risk if patients were seen to divert medication.  Such treatment was introduced into France and America, and in a limited manner here in Australia, with almost no research base (see above).  The study which is quoted in the literature, Fudala et al., did not examine supervision in any rigorous way. Regarding diversion, the panel members seemed unaware of the New Zealand experience the early 1990s with Temgesic NX (buprenorphine 0.2mg plus naloxone 0.17 mg). This was another major lesson in public health policy which was published in D&A Dependence (Robinson et al, 1993).  In succession over a short period of time the pure drug and then combination buprenorphine were each withdrawn from the New Zealand market due to the wholesale abuse (the company states it was for ‘purely commercial reasons’).  

In question time Professor Kate Conigrave of Sydney University asked if the company proposed to make Suboxone in a 0.4mg size for patients who are detoxing or for finer dose titration.  Product manager Ruari McDonald answered in the negative.  He stated further that few if any other countries had 0.4mg Subutex and that Australian doctors were “lucky” that it was available.  To this Professor Lintzeris volunteered that he hardly ever finds the need for doses smaller than 2mg.  He told his fellow professorial colleague that at Langton Centre they did not use 0.4mg tablets much at all (meaning that they did use it, at least occasionally, I presume).  He said that one should not draw a false parallel between small reductions on methadone as this was just not necessary with buprenorphine – yet he did not explain this assertion or give any supporting references.  Furthermore, he contended that such a low-dose preparation would not have enough naloxone to deter injecting … although it was unclear how much naloxone he was referring to, 0.1, 0.17 or 0.34mg or other. Robinson reported that Temgesic NX, with over three times the proportion of naloxone than Suboxone, was nevertheless the most commonly injected drug by more than half of those applying for methadone treatment in Wellington in 1991.  This was one of the first reports of widespread injecting of a prescribed analgesic (see Quigley 1984; Strang 1985 for incident cases). 

The Reckitt Benckiser company earned my highest admiration ten years ago when, against the odds, it managed to have Subutex approved in Australia despite the unfortunate New Zealand experience. Happily for the manufacturer’s shareholders since 2000 they have managed to “evergreen” the exclusive market for the product on two further occasions. First this was done by using the naloxone combination and more recently with the ‘film’. In this way the company has turned a relatively cheap drug into a high profit line. I note that the Wikipedia entry reveals numerous commercial feats as well as some disturbing findings against the company along the way. I was interested to note that associates of this company have contributed to publications and conference events relating to supposed cardiac complications of methadone. Some of these omitted appropriate conflict statements (details on request). Large studies in France and Norway have now shown the reported cardiac complications of methadone to be vanishingly rare while at the same time highlighting the aging and complex nature of the medical problems faced by our patient population.

It is worrying that neither the manufacturer nor anyone else has performed controlled studies on the equivalence of Subutex and Suboxone. It is hard to understand why this was not required by the TGA before approval of the combination product. Evidence for the safety and effectiveness of combination buprenorphine cannot necessarily be extrapolated from the pure product. The need for more than 50% higher doses in an open-label study changing to the combination product by Bell and colleagues has never been corroborated (nor refuted).

A front page New York Times article recently reported the smuggling of Suboxone films into American jails (link below). When I asked about this none of the panel members admitted to knowing about it, despite its obvious relevance to the evening’s proceedings. Professor Lintzeris said that he recalled reading something about ‘crushed up tablets’ (not films at all, apparently) being made into paint in children's pictorial offerings to ‘daddy in jail’. According to the report, since the introduction of Suboxone film, prisoners’ mail in America is now vetted, delayed and in many cases, shredded. Envelopes and stamps are removed, and reportedly due to the widespread reported practice of smuggling buprenorphine films into jails. One prison governor was quoted saying the situation was a ‘crisis’. Lintzeris then changed the subject to advocating buprenorphine treatment in prison. This was a good point but only limited practical relevance to the serious problems described in the report. Professor Lintzeris then also told us that we needed to make a distinction between ‘true’ diversion where the drug was used by another party and the situation where the drug was used by the intended recipient which was ‘not really diversion’. These matters remain for debate. The film’s introduction into the US a year ago should be considered a research trial of sorts, and one which is already showing worrying outcomes from my reading (see also Pennsylvania Attorney General report below).

I wondered if I was the only one in the room to be questioning the use of Suboxone films in future. Two large Sydney clinics I contacted at the time did not generally dispense the combination drug at all. I will continue to prescribe pure buprenorphine in my practice and when necessary, in order to hasten dissolution and/or reduce diversion we will continue to ‘scrunch’ the tablets. It has not been explained why the company is not marketing a film version of the pure product, something the company has tested, see Strain et al below.

On the night nobody mentioned the need for pharmacists to keep yet more drug books (at least for the next two years). To my mind the community pharmacists remain the unsung heroes of dependency treatment in Australia. These caring professionals still mostly charge the same as they did in the 1980s for a service which is now more complex and in some ways hazardous. Instead of just one drug book (for methadone), they will now need up to nine such books!

We were all handed a glossy brochure on the new buprenorphine combination “film” stating: “Clinically Interchangeable with the Suboxone Tablet”. The text included a graph of a single dose comparison with a 6 day run-off axis. The first day (the only one that matters to those taking daily doses) blood levels were substantially higher in the film subjects (eg. 3.0 versus 2.25 ng/ml for peak). This single-dose study finding may be augmented in daily maintenance dosing, showing quite clearly that the film and tablet forms are not interchangeable at all with a very substantial 33% higher blood level for film when compared to the tablet (presumably not crushed). The prominent title statement would seem to be directly countered by the graph provided on the same page, showing (or, better expressed, almost concealing) a substantially higher area under the curve (AUC) in the first 16 hours. Knowledge of the raised blood levels may make a prudent doctor consider a lower dose for those changing to the film product, despite advice to keep the dose constant and only reduce it where necessary. The variability in response was stressed by all speakers at the launch. I invite Reckitt Benckiser to submit a comment to my blog explaining this and will gladly post the response as a service to readers.

This same glossy hand-out states that “Suboxone Film dissolves faster than Suboxone Tablet”. It was disappointing that the company provided evidence for slightly faster dissolution times but omitted to state just how much longer it takes for the staff to open the tough little packets to reveal and then administer the flimsy films. I tried with the placebo and took 35 seconds to open one while the experienced nurse who ran one of the trials told me that she had got it down to about 15 seconds. And the pack does not always open as designed, sometimes needing scissors and therefore taking even longer. Most patients will need more than one pack and someone taking 22mg, for example, would need 5 (2x8mg and 3x2mg). One example quoted was that 2mg dissolved one minute faster (6 versus 7 minutes), yet to open the packs needed before administration could mean little is gained in staff and patient time. Advice that one does not need to observe the patient for so long due to adherence of the film is not based on evidence and remains to be demonstrated to be safe and effective, just like the preparation itself (at least in comparison to pure buprenorphine). Crushing tablets may be just as useful when time is limited or when dealing with challenging circumstances such as in the prison system.

In an early presentation we were told of the comprehensive post marketing survey published recently by Briony Larance et al. in D&A Dependence (n=440). It was perhaps the most important slide of the night although its significance was not emphasised by the speaker at the time. It demonstrated the enormous misuse of buprenorphine as published when compared to methadone. They showed that no less than one in eight supposedly “supervised” doses of buprenorphine (12%) were taken out of the dispensary compared with 1% for methadone(!). They also showed that buprenorphine patients consistently showed about double the rate of injecting drugs when compared with those on methadone. While there was less injecting of the combination drug, this finding is confounded because at the time it may have been used more widely unsupervised for those who were already more stable patients and therefore may be less likely to inject anyway. Clearly a proportion of these buprenorphine patients would be doing better on methadone … but this was neither the time nor the place.

Ms Cass spoke eloquently from a consumer perspective about communications, involvement with health professionals and ‘vulnerability’. While she and others had made out that consumer representation was a novel endeavour and it was not usual in other fields, my understanding is that it is now much more widespread than it was. Such moves are still inadequate and consumer involvement can always be improved. However, such input made an early start in Australia before many other countries and now there are respected voices from individuals, State and Federal organisations of several persuasions, which is as it should be. One of the earliest and most prominent is Family Drug Support which enjoys widespread respect in the Australian community (there is nothing remotely comparable in the United States according to my sources). NUAA and AVIL representatives were also at this meeting.


Despite the usual modern practice, there were no conflict statements given by the speakers which would seem to be a fault.


Comments by Andrew Byrne ..

Conflict statement: Reckitt Benckiser paid for my dinner but I paid my own train fare to Homebush Bay from Kings Cross. Reckitt Benckiser has sponsored refreshments and data projector for our post-graduate Concord study group.

References:
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6

Larance B, Degenhardt L, Lintzeris N, Bell J, Winstock A, Dietze P, Mattick R, Ali R, Horyniak D. Post-marketing surveillance of buprenorphine-naloxone in Australia: Diversion, injection and adherence with supervised dosing. Drug and Alcohol Dependence 2011 In press.

Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Fudala PJ, Bridge TP, Herbert S, et al. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Am J Drug Alcohol Abuse 2009 Feb 12;1:1-5

Quigley AJ, Bredemeyer DE, Seow SS. A case of buprenorphine abuse. Medical Journal of Australia 1984 140:425-426

Strang J. Abuse of buprenorphine. Lancet. 1985 Sep 28;2(8457):725

Goodnough A. When Children’s Scribbles Hide a Prison Drug. New York Times 27 May 2011 page A1. http://www.nytimes.com/2011/05/27/us/27smuggle.html

Click here Full Pennsylvania report.

HARRISBURG Acting Attorney General Bill Ryan noted that Suboxone, a Schedule III prescription narcotic used to treat heroin addiction, was commonly produced in pill form, but now is being manufactured in thin film like strips very similar to the popular breath freshening strips. … charges [were announced] against eleven suspects, including five inmates, who allegedly smuggled prescription narcotics into the Carbon County Correctional Facility via the inmates’ incoming mail. The investigation, known as ‘Operation Postage Stamp’ began in January 2011 after the Warden at the Carbon County Correctional Facility intercepted three letters containing a Suboxone underneath the letters’ stamps.

http://en.wikipedia.org/wiki/Bart_Becht

http://en.wikipedia.org/wiki/Reckitt_Benckiser