Technology Evaluation
1.
Introduction
2.
Overview of the market
3.
Introduction to the
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compound Chemistry
5.
Pharmacodynamics
6.
Pharmacokinetics and metabolism
7.
Clinical efficacy
8.
Safety and tolerability
9.
Regulatory affairs Conclusion
11.
Expert opinion
Michael Soyka Privatklinik Meiringen, Meiringen, Switzerland
4.
10.
Buprenorphine--naloxone buccal soluble film for the treatment of opioid dependence: current update Introduction: Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine--naloxone film has been developed and introduced in the USA and Australia. Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine--naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer. Expert opinion: Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation. Keywords: buprenorphine, buprenorphine film, naloxone, opioid dependence, opioids, pharmacotherapy Expert Opin. Drug Deliv. [Early Online]
1.
Introduction
Substance use disorders are defined by a problematic pattern of substance use that leads to clinically significant impairment in different domains. According to the leading psychiatric classification systems international classfication of dieseases-10 and diagoistic and statistical manual (DSM)-IV, opioid dependence is a chronic medical disorder defined by a cluster of somatic, psychological and behavioral symptoms. Both classification systems list 11 symptoms for opioid use disorders. DSM-5 has given up the long-standing categorical distinction between abuse (or harmful use) and dependence and adopted a dimensional concept [1]. Substance use disorders are defined by a problematic pattern of substance use leading to clinically significant impairment in different domains. DSM-5 also specifies 11 symptoms; the presence of two to three symptoms indicates a mild disorder, the presence of four to five indicates a moderate and the presence of six or more indicates a severe disorder. 10.1517/17425247.2014.953479 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . . . .
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Novel buprenorphine--naloxone formulation is discussed. Buprenorphine--naloxone film’s efficacy in the treatment of opioid dependence is proven. Buprenorphine--naloxone film is approved and marketed in the USA and Australia. There are few pharmacological differences compared to the conventional sublingual tablet: similar dissolution time, dose and side effects. Some healthcare data indicate better retention rate with the novel film, but comparative studies with the conventional formulation are missing. Studies indicate that some patients prefer the novel tablet. Advantage of unit-dose packaging, that is, improvement in the ability to track a dose of medication is discussed. Buprenorphine--naloxone buccal soluble film is probably more child-resistant containment and has lower risk of diversion. Buprenorphine--naloxone film has less risk of intoxications.
This box summarizes key points contained in the article.
The nonmedical use of opioids, including heroin, represents a significant public health problem. Epidemiological studies indicate that the worldwide prevalence of opioid use disorders is about 0.4% in individuals aged 15 -- 64 years and that there are about 15.5 million opioid-dependent people worldwide [2,3]. In Europe, the average prevalence of problematic opioid use is estimated to be 3.6 -- 4.4 cases per 1000 people aged 15 -- 64 years [4]. This corresponds to approximately 1.35 million affected individuals in Europe. In the USA, the 12-month prevalence of drug abuse, in general, with and without dependence, is estimated at 5.7% [5]. Approximately 3.7 million individuals have used heroin at least once in their lives and 750,000 -- 1,000,000 individuals are currently heroin-dependent [6]. The World Health Organization (WHO) estimates that the burden of harm from opioid use is 11.2 million disability-adjusted life years (DALYs) [7]. The recent Global Burden of Disease study estimates the burden at 20.0 million DALYs for illicit drug dependence in general and 9.2 million for opioid dependence [8]. In addition, in the USA in particular, there is an epidemic of opioid prescription drug users and multiple deaths that are associated with an overdose of opioid pain killers, including many accidental poisonings in children [9,10]. The endogenous opioid endorphin system has been extensively studied over the past decades but the exact neurobiological mechanisms underlying opioid dependence, compulsive drug use and drug seeking are not entirely understood [11-13]. Three major classes of opioid receptors have been characterized -- mu, kappa and delta (µ, k and d) [14]. b-endorphins are endogenous ligands for µ and d receptors, enkephalins are endogenous ligands for d receptors and dynorphins are 2
predominantly but not exclusively endogenous ligands for k receptors [15]. The µ receptors mediate the analgesic and euphoric effects of opioids, respiratory depression and physical dependence. The opioid system is linked to other neurotransmitter systems and opioids modulate dopamine release in the mesolimbic system and nucleus accumbens via interaction with GABAergic neurons. The rewarding effects of opioids are mediated through dopamine release in the nucleus accumbens [16,17]. Neuroimaging studies, in particular positronemission tomography studies with opioid receptor ligands such as diprenorphine or carfentanil, have demonstrated the plasticity of the opioid receptor system [18] and the action of different drugs at the opioid receptor.
2.
Overview of the market
A number of psychosocial approaches and therapies with the goal of abstinence from opioids have proven efficacy in opioid dependence, but the overall abstinence rates are low and rarely exceed 20% [19]. Follow-up studies among opioiddependent individuals indicate a low abstinence rate and high mortality rate [11-13,20]. A review by Degenhardt et al. [21] of 58 prospective studies reporting mortality rates from opioid-dependent samples found an overall all-cause mortality of 2.09 per 100 person-years. Other studies estimate the mortality of untreated heroin dependence at 1 -- 3% per year and thus 13 times higher than that for the general population [22]. Termorshuizen et al. [20] reported follow-up data from a large sample of opioid users and found that at least 27% (probably 38%) of them had died within 20 years after starting regular drug use. Similar data (37.8% fatal outcome over 20 years) have been published for Norway, where an estimated standard mortality rate of 23.6 was reported [12], and other European studies [11]. The European Monitoring Centre for Drugs and Drug Addiction [4] concluded that problem drug users have a 10 to 20 times higher mortality risk than their peers. Maintenance treatment with full (methadone, recently morphine sulfate, heroin) or partial opioid agonists (buprenorphine) has proven efficacy in reducing opioid consumption, criminal behavior and psychosocial and medical morbidity, including rates of HIV and hepatitis B virus infections, as indicated by many studies and meta-analyses [23-26]. Over the past two decades, opioid maintenance treatment with methadone and buprenorphine has dramatically changed the therapeutic options for opioid-dependent individuals. It significantly reduces mortality rates compared to untreated heroin dependence [21] and numerous studies show that methadone increases retention rates and social functioning in opioid addicts [23,26-30]. Several long-term studies indicate that methadone and buprenorphine reduce opioid use and its associated harms [25,31]. However, particular and persistent concerns exist about diversion of buprenorphine and injecting of buprenorphine tablets [10,32-34].
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Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update
3.
Introduction to the compound
Search strategy methods This is an update of previous work [35]. Medline and PubMed were used for identifying relevant publications (buprenorphine film: 11 hits). In addition, the term ‘buprenorphine film’ was searched in the internet with the search engine Google and on the website of the National Institute on Drug Abuse (NIDA). The manufacturer Reckitt Benckiser was contacted for additional or unpublished material but it did not provide additional information. Finally, drug information on the following relevant websites was evaluated: www.drugs.com, www.suboxone.com, www.buprenorphine. samsha.gov.
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3.1
Rationale for development of a new formulation for buprenorphine
3.2
Buprenorphine is a partial µ-opioid receptor agonist and k antagonist with a long half-life of 24 -- 42 h [36]. At clinical doses, buprenorphine occupies the µ-opioid receptor near maximum [37]. A receptor occupancy of 50 -- 60% is required to suppress withdrawal symptoms [38]. Buprenorphine is administered sublingually in opioid replacement therapy [39]. Buprenorphine sublingual tablets may require several minutes to fully dissolve and are used in avoiding extensive first-pass liver metabolism of buprenorphine after oral administration of buprenorphine. Nevertheless, buprenorphine effectively suppresses opioid withdrawal. Clinical studies that have compared methadone, primarily in moderate dosages (50 -- 60 mg), with buprenorphine (12 -- 16 mg) have generally found comparable efficacy of the two drugs [40-42], although some studies indicate a lower retention rate with buprenorphine [43]. For more detailed background information on the use of buprenorphine in opioid dependence, see Soyka et al. [30]. The usual dosages for maintenance therapy are 8 -- 16 (24) mg [44]. A possible advantage of buprenorphine is that cessation of treatment results in less severe withdrawal symptoms than cessation of methadone [25]. Another advantage over methadone is the lower cardiac risk of QT prolongation associated with buprenorphine [45]. Torsade de pointes has not been reported in buprenorphine [46]. Methadone but not buprenorphine blocks the cardiac potassium currents at clinically relevant concentrations [46]. In October 2002, the FDA approved buprenorphine for the treatment of addiction in the USA. Buprenorphine has been marketed in most European countries and the USA since 2000 for the treatment of opioid dependence. Like methadone, buprenorphine has an abuse potential and a substantial risk of diversion [26,36]. There have been persistent safety concerns about the increasing number of emergency department visits because of intoxications with opioid prescription drugs, including buprenorphine [47]. Specifically, the risk of exposure to buprenorphine appears to have increased in children [48]. For 2009, 1262 cases were recorded
by the American Association of Poison Control Centers. Although buprenorphine overdoses are generally well tolerated, children appear to be at risk for respiratory depression and CNS reactions [49]. In addition, the risk of diversion of the sublingual tablet form has been linked to difficulties in supervising its consumption [33]. A combination of buprenorphine with the opioid antagonist naloxone in a fixed 4:1 ratio was developed to avoid intravenous administration and diversion of buprenorphine. The bioavailability of naloxone after sublingual administration is too low to cause withdrawal symptoms [50]. However, naloxone has good parental bioavailability and therefore rapidly precipitates an opioid withdrawal syndrome if the combination buprenorphine--naloxone sublingual tablet is dissolved and injected [51]. The induction of an opioid withdrawal syndrome is thought to reduce the abuse potential of buprenorphine and improve its safety [52]. Although the combination of buprenorphine and naloxone may reduce intravenous misuse, it may not eliminate it [53]. Direct induction of buprenorphine--naloxone is generally considered to be easy and safe [54,55]. The buprenorphine--naloxone combination has been marketed for the treatment of opioid dependence since 2002. Buprenorphine and buprenorphine--naloxone are established first-line medications for the treatment of opioid dependence (see APA guidelines [6], WFSBP Guidelines [30], NSW Clinical Guidelines [56], British Association for Psychopharmacology guidelines [57], WHO guidelines [58], US Department of Health and Human Services guidelines [59], Canadian Agency for Drugs and Technologies in Health guidelines [60]); for reviews, see Mammen and Bell [53], Orman and Keating [36], Mauger et al. [61] and Yokell et al. [62]. In recent years, a buprenorphine--naloxone film was developed to address the above safety concerns and to improve retention in treatment, the bioavailability, absorption and dissolution time of buprenorphine and to reduce the risk of diversion [63]. The sublingual film was licensed in the USA in 2010 and in Australia in 2011 [64]. The film is produced in the same 2/0.5 and 8/2 mg doses as the tablets. The rationale for introducing the film was that it adheres to the sublingual mucosa quickly, is less easily removed and hence requires less time for supervised dosing and can be supplied in more tamper-proof unit packaging to limit consumption by children [64,65]. Other minor objectives for developing a film were to improve taste and obtain a formulation that may deter crushing and snorting. 4.
Chemistry
Buprenorphine is a semisynthetic derivative of thebaine. It is a mixed opioid agonist-antagonist that produces a less than maximal or partial agonist effect at the µ-opioid receptor and is an antagonist at the k-opioid receptor [36,53]. Steadystate drug concentrations for a 16 mg dose of buprenorphine are reached after 7 days [66]. Some data show a ceiling on the
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respiratory but not analgesic effect of buprenorphine [67]. Buprenorphine has a ceiling effect at the opioid receptor at dosages of about 32 mg resulting in a somewhat lower risk than methadone for fatal intoxications [30,68]. The ceiling effect means that partial agonists have maximal effects less than full agonists reaching a plateau with further increases being no more effective (see buprenorphine.samsha.gov). 5.
Pharmacodynamics
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No studies have been published on the pharmacodynamics of the novel film. 6.
Pharmacokinetics and metabolism
Distribution Buprenorphine is approximately 96% protein-bound, primarily to a and b globulin; naloxone is approximately 45% protein-bound, primarily to albumin. 6.1
Metabolism Buprenorphine is mainly metabolized by the CYP3A4 (60%) and CYP2D6 isoenzymes (30%) [70]. Buprenorphine undergoes Ndealkylation, predominantly via CYP3A4, to norbuprenorphine 4
Elimination The studies performed with the buprenorphine--naloxone film indicate that buprenorphine has a mean elimination plasma half-life ranging from 24 to 42 h and naloxone has a mean elimination plasma half-life ranging from 2 to 12 h. The elimination half-life of naloxone in plasma is about 30 min [77]. 6.3
In a previous review, the available data on the pharmacokinetic profile of the buprenorphine--naloxone film were given as provided by the manufacturer [35]. Pharmacology was studied in open-label studies comparing sublingual doses in healthy adult volunteers not using opioids (n = 16). Each administration was performed under a naltrexone block. Data indicate that the pharmacokinetics of the buprenorphine--naloxone sublingual film is similar to those of the sublingual tablet, although not all doses and dose combinations met bioequivalence criteria [69]. A single-dose, crossover pharmacokinetic study with buprenorphine 2 mg/naloxone 0.5 mg (n = 39) and 8/2 mg (n = 44) buprenorphine film and tablet showed a small, but not clinically relevant, increase in buprenorphine levels with the film. As expected, opioid agonist ceiling effects were observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 3, 8, 16 and 32 mg), placebo and a full agonist control at various doses. In each case, a dose was reached that produced no further effect [69]. The dissolution times of the buprenorphine--naloxone film were compared with those of the tablet in 42 healthy volunteers (buprenorphine--naloxone dose combinations: 2/0.5, 4/1, 8/2, 12/3 mg) and were found to be lower for the film than for the tablet at all dosages [69]. The pharmacokinetic parameters of buprenorphine, its active metabolite norbuprenorphine and naloxone after administration of the film were studied in randomized, crossover studies. The pharmacokinetics of the film is similar to the pharmacokinetics of the sublingual tablet.
6.2
and glucuronidation. After sublingual absorption, buprenorphine is primarily converted and N-dealkylated to norbuprenorphine, an active metabolite, via CYP3A4 and to a lesser extent by CYP2C8 [71-73]. Buprenorphine and norbuprenorphine are further metabolized by uracil diphosphate-glucuronosyltransferases (UGTs), predominantly by UGT-1A3 and to a lesser extent by UGT-2B6 and -1A1 [74]. Neither buprenorphine nor methadone is major inducer or inhibitor of CYP450 enzymes but may compete with other drugs metabolized by these same pathways. Buprenorphine is a weak inhibitor of CYP3A4, but this effect does not occur with plasma concentrations achieved at clinically relevant doses [75,76].
Drug--drug interactions Drug interactions with buprenorphine can occur either through altered pharmacokinetics or as a result of pharmacodynamic interactions. Pharmacokinetic interactions can involve the inhibition or induction of hepatic CYP450 enzymes and effects on glucuronidation, on the function of the drug transporter, P-glycoprotein and on absorption of drugs [78,46]. CYP3A4 inhibitors such as ketoconazole or HIV protease inhibitors may increase buprenorphine plasma levels and CYP3A4 inducers may lower levels; dosage may have to be adjusted if symptoms of opioid withdrawal emerge [79]. Pharmacodynamic interactions are possible with other CNS depressants such as alcohol and other opioids and psychotropic drugs such as benzodiazepines, other hypnotics, antidepressants and antipsychotics that suppress respiration [46]. Drug--drug interactions can be expected to be the same for the buprenorphine--naloxone sublingual film as for the conventional sublingual tablet [46]. No special studies have been published on the film. 6.4
Switching from the conventional formulation Since the buprenorphine/naloxone film tablets are bioequivalent to the conventional sublingual formulation as indicated by pharmacokinetic studies, patients can be switched from tablets to film and vice versa (official FDA prescribing information, see www. drugs.com). 6.5
7.
Clinical efficacy
Strain et al. [80] studied the feasibility of induction with a buprenorphine--naloxone soluble film in a clinical setting and performed a randomized study comparing the ability of buprenorphine and buprenorphine--naloxone films to suppress
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Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update
spontaneous withdrawal in 34 opioid-dependent volunteers (18 in the buprenorphine, 16 in the buprenorphine--naloxone group), most of whom were intravenous heroin users but some of whom inhaled heroin. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Participants received either buprenorphine 16 mg or buprenorphine--naloxone film (16/4 mg) for a 3- to 5-day maintenance period. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score; secondary measures were pupillometry, a visual analog scale and subjective rating scales. The COWS score decreased significantly but there were no differences between the two groups. The most common adverse events were those consistent with opioid withdrawal. Four participants with high COWS scores (two in each group) dropped out. Four patients, again two in each group, had mild non-ulcerous irritations of the oral mucosa not present at baseline; in three of the four patients, the irritation was attributed to teeth grinding or dental decay. Strain et al. [80] interpreted the findings as supporting the use of buprenorphine and buprenorphine--naloxone films as safe and effective delivery methods for opioid induction. Further, they concluded that the new film will not precipitate opioid withdrawal when taken sublingually. The unit-dose packaging was seen as an advantage of the new formulation, because it improves the ability to track a dose of the medication and is also more child-resistant [80]. An Australian group, Lintzeris et al. [64], performed a randomized controlled clinical trial to compare the sublingual buprenorphine--naloxone tablets and film in regard to subjective dose effects and equivalence, trough plasma levels, adverse events, patient satisfaction, supervised dosing time and impact on treatment outcomes (substance use, psychosocial function) over a 31-day period. Ninety-two patients treated with the buprenorphine--naloxone tablets were recruited to this double-blind, double-dummy parallel group trial and randomized to either tablets or film. No dose changes were performed over a 3-day period. No significant differences were detected between film and tablets on subjective dose effects, trough plasma buprenorphine or norbuprenorphine levels, adverse events and treatment outcomes. More patients reported that the tablets were more likely to be accidentally swallowed (19%) compared to the film (5%). Buprenorphine--naloxone film took significantly less time to dissolve than tablets (173 vs 242 s, p = 0.007). Patient preference was higher for the film (61%) than for the tablets (23%). The authors concluded that the film and tablets are comparable in respect to dose equivalence and clinical outcomes, whereas the film shows improved dispensing times and higher patient ratings of satisfaction. Whether the novel film tablet can increase retention rate with buprenorphine--naloxone treatment is a crucial question and has not been addressed in head-to-head comparisons with the conventional formulation. There is some indirect evidence for a better outcome from a longitudinal, retrospective cohort
analysis [63]. This study analyzed data of a private US insurance claims database. Resource utilization and related costs were calculated over 6- and 12-month periods. Film and tablet groups included 2796 and 1510 patients. Mean prescribed doses were 14 mg in both groups Time to treatment discontinuation was significantly longer in the film group. In addition, the film group patients had more outpatient visits and lower probability to be hospitalized. This study cannot rule out bias due to differences in patient or prescriber profiles but suggests a better retention in patients on buprenorphine/naloxone film tablets compared to the conventional formulation. 8.
Safety and tolerability
As stated in Soyka [35], an unpublished 12-week, open-label safety and tolerability study of buprenorphine--naloxone film in 194 patients transferred to buprenorphine--naloxone film from the tablet (same initial dosage) indicated an overall good tolerability, with 28% treatment-emergent adverse events (TEAEs), mostly mild in intensity [69]. The most common TEAE related to the film was oral hypoesthesia, which was reported by two subjects (1%); it is unclear whether this effect was related to a lower dissolution time. The dose was adjusted in only one patient during the first 2 weeks and increased in 2% of the patients at any point during the study. The risk of diversion and injection of the novel buprenorphine--naloxone film was studied in Australia [81]. Surveys were conducted with people who inject drugs regularly and with opioid substitution clients (n = 543). Among the out-of-treatment patients, levels of injection for buprenorphine--naloxone film were comparable with those for methadone and buprenorphine tablet formulations. Among patients in maintenance treatment, recent injecting of one’s medication was similar among clients in all maintenance drugs. Weekly or more frequent injection of prescribed doses was reported by fewer buprenorphine--naloxone film patients (3%) than buprenorphine tablet clients (11%), but at levels similar to methadone and buprenorphine--naloxone tablets. These data do not indicate a significant benefit from the use of the novel film compared to conventional buprenorphine--naloxone formulations. The reduced risk of diversion of buprenorphine film could be the most relevant advantage of the new film. This risk of unintentional poisoning in children has only been addressed in few studies. This issue was studied by collecting and examining data from US addiction-related surveillance system poison centers. Lavonas et al. [9] reviewed 2380 cases of unintentional exposures to buprenorphine-containing products among children < 6 years, including four deaths (2009 -- 2012). Exposures to buprenorphine--naloxone film were significantly less frequent than exposure to buprenorphine tablets (rate ratio 3.5) and buprenorphine--naloxone tablets (rate ratio 8.8). The most frequent adverse events in all groups were lethargy, respiratory depression, miosis and vomiting. This large retrospective study gave robust evidence that exposure rates of tablet formulations, in the USA
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M. Soyka
typically dispensed in bottles containing 30-day supply, were much higher than the exposure rates of buprenorphinenaloxone film. These findings are in line with a study from the Utah Poison Control Center, which found that 94% of 179 buprenorphine exposures among children involved tablet rather than the film formulation [82]. The FDA states that the safety of buprenorphine--naloxone film is supported by clinical trials with buprenorphine and buprenorphine--naloxone sublingual tablets and an open-label study in 194 patients with the novel film (unpublished data, see Ref. [69]). Safety data on buprenorphine are available from clinical studies in over 3000 opioid-dependent subjects [69]. Few differences in the adverse event profile were noted between the buprenorphine--naloxone sublingual film and tablet and buprenorphine sublingual tablet. The most common adverse event (> 1%) associated with the novel film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome, hyperhidrosis and blurred vision. Both the sublingual tablet and film formulation have a bitter taste. A novel sublingual buprenorphine--naloxone formulation with a better taste has recently been tested in healthy volunteers but is not available yet [83]. 9.
Regulatory affairs
The novel buprenorphine--naloxone film was approved by the FDA in August 2010 and in Australia in 2011. 10.
Conclusion
Both methadone and buprenorphine are well-established firstline medications in the treatment of opioid dependence [6,30]. Persisting safety concerns linked to the risk of intravenous use of buprenorphine and diversion stimulated the development of a buprenorphine--naloxone combination (ratio 4:1). The novel sublingual form of buprenorphine and naloxone may provide an even less divertible, more quickly administered and more childproof version than the conventional buprenorphine--naloxone tablet [84]. In its current forms, buprenorphine can only be administered sublingually, because of its poor bioavailability. The buprenorphine film appears to be a more convenient and preferred approach for patients [64]. Dissolution time and other pharmacodynamic variables may not differ much between the two forms, but soluble-film formulations can have unit-dose packaging, thereby improving the ability to track a dose of the medication. More importantly, the film formulation may reduce safety concerns and risk of diversion, which is particularly relevant in regard to the risk of intoxication in children. In the USA, the number of children exposed to buprenorphine has grown exponentially over the past decade [48]. Recent data indicate a lower risk of intoxications with the novel buprenorphine film in children [9,82]. 6
Few data on the new formulation have been published to date. The FDA recommends a target dose of the buprenorphine--naloxone sublingual film of 16/4 mg buprenorphine--naloxone as a single daily dose (range 4/1 -- 24/6 mg). Although there is no doubt concerning the general clinical efficacy of buprenorphine and consequently of the new buprenorphine film in opioid dependence and maintenance therapy, the relevant benefits of the pharmacology of the new formulation have yet to be established and demonstrated. Generally, the major risks of the novel formulation -respiratory and CNS depression, hepatic reactions, allergic reactions, precipitation of opioid withdrawal and neonatal withdrawal and so on -- are the same as for the sublingual tablet. The adverse event spectrum of the novel film is similar to that of the sublingual tablet and oral hypoesthesia appears to be the most common adverse event. The new film has not been studied in special subgroups such as pregnant or nursing women. The pharmacokinetics of the sublingual form and film appears to be similar, although unpublished pharmacokinetic data in healthy subjects suggest that absorption may be slightly higher with the buprenorphine--naloxone film than with the tablets. Therefore, patients switching from tablets to film should be monitored for overdose and, vice versa, patients switching from film to tablet should be monitored for opioid withdrawal. Few other published data are available to date. A recent study by Strain et al. [80] in opioid-dependent volunteers maintained on morphine who underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal showed that both buprenorphine and buprenorphine--naloxone soluble films suppress symptoms of opioid withdrawal. Strain et al. [80] concluded that both are safe and effective delivery methods for opioid induction. 11.
Expert opinion
Although buprenorphine is an established medication for the treatment of opioid dependence, the buprenorphine--naloxone soluble film is an interesting new formulation with some probable advantages over the conventional sublingual tablet. The key features of the pharmacological profile do not differ much from the tablet, although absorption may be somewhat faster with the film. Recent data indicate a clear patient preference for the film over the tablet. The mucoadhesion of the novel film may reduce risk of diversion [64]. The probably most important advantage, that is, a reduced risk for accidental intoxication especially in children, cannot be assessed in clinical studies but will have to be evaluated in pharmacoepidemiological studies in poison control centers and emergency rooms, among others. A risk evaluation and mitigation program is being implemented as part of the FDA requirements to ensure that the benefits of treatment with this medication outweigh the potential risks, particularly risk of accidental overdose, misuse and abuse.
Expert Opin. Drug Deliv. (2014) ()
Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update
Acknowledgment
Declaration of interest
The author thanks Jacquie Klesing, Board-certified editor in the Life Sciences (ELS), for editing assistance with the manuscript.
M Soyka has worked as a consultant and has received research grants from Reckitt Benckiser and Sanofi Pharma. No funding has been granted for preparation of this manuscript.
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Luscher C, Ungless MA. The mechanistic classification of addictive drugs. PLoS Med 2006;3(11):e437 Landmark paper on the molecular basis of addiction. Schreckenberger M, Klega A, Grunder G, et al. Opioid receptor PET reveals the psychobiologic correlates of reward processing. J Nucl Med 2008;49(8):1257-61
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Connock M, Juarez-Garcia A, Jowett S, et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess 2007;11(9):1-171.iii-iv Important review on opioid maintenance therapy.
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the risks and benefits. Expert Opin Drug Saf 2007;6:125-32 51.
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Doolittle B, Becker W. A case series of buprenorphine/naloxone treatment in a primary care practice. Subst Abus 2011;32:262-5
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New South Wales Department of Health. Opioid treatment program: Clinical guidelines for methadone and buprenorphine treatment. NSW Government, Sydney; 2011
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Lingford-Hughes AR, Welch S, Peters L, et al. BAP updated guidelines: evidencebased guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012;26:899-952
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Hanon S, Seewald RM, Yang F, et al. Ventricular arrhythmias in patients treated with methadone for opioid dependence. J Interv Card Electrophysiol 2010;28:19-22
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Orman JS, Keating GM. Buprenorphine/ naloxone: a review of its use in the treatment of opioid dependence. Drugs 2009;69:577-607 Comprehensive review.
McCance-Katz E. Drug-drug interactions in opioid therapy. 7th edition. PCM Healthcare Ltd; London: 2012
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Centers for Disease Control and Prevention (CDC). Emergency department visits involving nonmedical use of selected prescription drugs United States, 2004-2008. MMWR Morb Mortal Wkly Rep 2010;59:705-9
World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. World Health Organization, Geneva; 2009
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Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939 Substance Abuse and Mental Health Services Administration, Rockville, MD; 2004
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Greenwald MK, Johanson CE, Moody DE, et al. Effects of buprenorphine maintenance dose on muopioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology 2003;28(11):2000-7 Greenwald M, Johanson CE, Bueller J, et al. Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry 2007;61(1):101-10
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Boyer EW, McCance-Katz EF, Marcus S. Methadone and buprenorphine toxicity in children. Am J Addict 2010;19:89-95
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Hayes BD, Klein-Schwartz W, Doyon S. Toxicity of buprenorphine overdoses in children. Pediatrics 2008;121:e782-6
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van Dorp E, Yassen A, Dahan A. Naloxone treatment in opioid addiction:
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Mauger S, Fraser R, Gill K. Utilizing buprenorphine-naloxone to treat illicit and prescription-opioid dependence. Neuropsychiatr Dis Treat 2014;10:587-98 Yokell MA, Zaller ND, Green TC, et al. Buprenorphine and buprenorphine/ naloxone diversion, misuse, and illicit use: an international review. Curr Drug Abuse Rev 2011;4:28-41 Clay E, Khemiri A, Zah V, et al. Persistence and healthcare utilization associated with the use of buprenorphine/naloxone film and tablet formulation in adults with opioid dependence. J Med Econ 2014;6:6-11 Lintzeris N, Leung SY, Dunlop AJ, et al. A randomised controlled trial of sublingual buprenorphine-naloxone film versus tablets in the management of opioid dependence. Drug Alcohol Depend 2013;131:119-26
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Das NG, Das SK. Development of mucoadhesive dosage forms of buprenorphine for sublingual drug delivery. Drug Deliv 2004;11:89-95
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Moody DE, Slawson MH, Strain EC, et al. A liquid chromatographicelectrospray ionization-tandem mass spectrometric method for determination of buprenorphine, its metabolite, norbuprenorphine, and a coformulant, naloxone, that is suitable for in vivo and in vitro metabolism studies. Anal Biochem 2002;306:31-9
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Affiliation Michael Soyka1,2 MD 1 Ludwig Maximilian University, Department of Psychiatry, Munich, Germany 2 Privatklinik Meiringen, Postfach 612 CH -- 3860 Meiringen, Switzerland Tel: +41 33 972 82 95; Fax: +41 33 972 82 91; E-mail: [email protected]
9
1.
Introduction
2.
Overview of the market
3.
Introduction to the
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compound Chemistry
5.
Pharmacodynamics
6.
Pharmacokinetics and metabolism
7.
Clinical efficacy
8.
Safety and tolerability
9.
Regulatory affairs Conclusion
11.
Expert opinion
Michael Soyka Privatklinik Meiringen, Meiringen, Switzerland
4.
10.
Buprenorphine--naloxone buccal soluble film for the treatment of opioid dependence: current update Introduction: Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine--naloxone film has been developed and introduced in the USA and Australia. Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine--naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer. Expert opinion: Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation. Keywords: buprenorphine, buprenorphine film, naloxone, opioid dependence, opioids, pharmacotherapy Expert Opin. Drug Deliv. [Early Online]
1.
Introduction
Substance use disorders are defined by a problematic pattern of substance use that leads to clinically significant impairment in different domains. According to the leading psychiatric classification systems international classfication of dieseases-10 and diagoistic and statistical manual (DSM)-IV, opioid dependence is a chronic medical disorder defined by a cluster of somatic, psychological and behavioral symptoms. Both classification systems list 11 symptoms for opioid use disorders. DSM-5 has given up the long-standing categorical distinction between abuse (or harmful use) and dependence and adopted a dimensional concept [1]. Substance use disorders are defined by a problematic pattern of substance use leading to clinically significant impairment in different domains. DSM-5 also specifies 11 symptoms; the presence of two to three symptoms indicates a mild disorder, the presence of four to five indicates a moderate and the presence of six or more indicates a severe disorder. 10.1517/17425247.2014.953479 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
1
M. Soyka
Article highlights. . . . .
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.
. . .
.
Novel buprenorphine--naloxone formulation is discussed. Buprenorphine--naloxone film’s efficacy in the treatment of opioid dependence is proven. Buprenorphine--naloxone film is approved and marketed in the USA and Australia. There are few pharmacological differences compared to the conventional sublingual tablet: similar dissolution time, dose and side effects. Some healthcare data indicate better retention rate with the novel film, but comparative studies with the conventional formulation are missing. Studies indicate that some patients prefer the novel tablet. Advantage of unit-dose packaging, that is, improvement in the ability to track a dose of medication is discussed. Buprenorphine--naloxone buccal soluble film is probably more child-resistant containment and has lower risk of diversion. Buprenorphine--naloxone film has less risk of intoxications.
This box summarizes key points contained in the article.
The nonmedical use of opioids, including heroin, represents a significant public health problem. Epidemiological studies indicate that the worldwide prevalence of opioid use disorders is about 0.4% in individuals aged 15 -- 64 years and that there are about 15.5 million opioid-dependent people worldwide [2,3]. In Europe, the average prevalence of problematic opioid use is estimated to be 3.6 -- 4.4 cases per 1000 people aged 15 -- 64 years [4]. This corresponds to approximately 1.35 million affected individuals in Europe. In the USA, the 12-month prevalence of drug abuse, in general, with and without dependence, is estimated at 5.7% [5]. Approximately 3.7 million individuals have used heroin at least once in their lives and 750,000 -- 1,000,000 individuals are currently heroin-dependent [6]. The World Health Organization (WHO) estimates that the burden of harm from opioid use is 11.2 million disability-adjusted life years (DALYs) [7]. The recent Global Burden of Disease study estimates the burden at 20.0 million DALYs for illicit drug dependence in general and 9.2 million for opioid dependence [8]. In addition, in the USA in particular, there is an epidemic of opioid prescription drug users and multiple deaths that are associated with an overdose of opioid pain killers, including many accidental poisonings in children [9,10]. The endogenous opioid endorphin system has been extensively studied over the past decades but the exact neurobiological mechanisms underlying opioid dependence, compulsive drug use and drug seeking are not entirely understood [11-13]. Three major classes of opioid receptors have been characterized -- mu, kappa and delta (µ, k and d) [14]. b-endorphins are endogenous ligands for µ and d receptors, enkephalins are endogenous ligands for d receptors and dynorphins are 2
predominantly but not exclusively endogenous ligands for k receptors [15]. The µ receptors mediate the analgesic and euphoric effects of opioids, respiratory depression and physical dependence. The opioid system is linked to other neurotransmitter systems and opioids modulate dopamine release in the mesolimbic system and nucleus accumbens via interaction with GABAergic neurons. The rewarding effects of opioids are mediated through dopamine release in the nucleus accumbens [16,17]. Neuroimaging studies, in particular positronemission tomography studies with opioid receptor ligands such as diprenorphine or carfentanil, have demonstrated the plasticity of the opioid receptor system [18] and the action of different drugs at the opioid receptor.
2.
Overview of the market
A number of psychosocial approaches and therapies with the goal of abstinence from opioids have proven efficacy in opioid dependence, but the overall abstinence rates are low and rarely exceed 20% [19]. Follow-up studies among opioiddependent individuals indicate a low abstinence rate and high mortality rate [11-13,20]. A review by Degenhardt et al. [21] of 58 prospective studies reporting mortality rates from opioid-dependent samples found an overall all-cause mortality of 2.09 per 100 person-years. Other studies estimate the mortality of untreated heroin dependence at 1 -- 3% per year and thus 13 times higher than that for the general population [22]. Termorshuizen et al. [20] reported follow-up data from a large sample of opioid users and found that at least 27% (probably 38%) of them had died within 20 years after starting regular drug use. Similar data (37.8% fatal outcome over 20 years) have been published for Norway, where an estimated standard mortality rate of 23.6 was reported [12], and other European studies [11]. The European Monitoring Centre for Drugs and Drug Addiction [4] concluded that problem drug users have a 10 to 20 times higher mortality risk than their peers. Maintenance treatment with full (methadone, recently morphine sulfate, heroin) or partial opioid agonists (buprenorphine) has proven efficacy in reducing opioid consumption, criminal behavior and psychosocial and medical morbidity, including rates of HIV and hepatitis B virus infections, as indicated by many studies and meta-analyses [23-26]. Over the past two decades, opioid maintenance treatment with methadone and buprenorphine has dramatically changed the therapeutic options for opioid-dependent individuals. It significantly reduces mortality rates compared to untreated heroin dependence [21] and numerous studies show that methadone increases retention rates and social functioning in opioid addicts [23,26-30]. Several long-term studies indicate that methadone and buprenorphine reduce opioid use and its associated harms [25,31]. However, particular and persistent concerns exist about diversion of buprenorphine and injecting of buprenorphine tablets [10,32-34].
Expert Opin. Drug Deliv. (2014) ()
Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update
3.
Introduction to the compound
Search strategy methods This is an update of previous work [35]. Medline and PubMed were used for identifying relevant publications (buprenorphine film: 11 hits). In addition, the term ‘buprenorphine film’ was searched in the internet with the search engine Google and on the website of the National Institute on Drug Abuse (NIDA). The manufacturer Reckitt Benckiser was contacted for additional or unpublished material but it did not provide additional information. Finally, drug information on the following relevant websites was evaluated: www.drugs.com, www.suboxone.com, www.buprenorphine. samsha.gov.
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3.1
Rationale for development of a new formulation for buprenorphine
3.2
Buprenorphine is a partial µ-opioid receptor agonist and k antagonist with a long half-life of 24 -- 42 h [36]. At clinical doses, buprenorphine occupies the µ-opioid receptor near maximum [37]. A receptor occupancy of 50 -- 60% is required to suppress withdrawal symptoms [38]. Buprenorphine is administered sublingually in opioid replacement therapy [39]. Buprenorphine sublingual tablets may require several minutes to fully dissolve and are used in avoiding extensive first-pass liver metabolism of buprenorphine after oral administration of buprenorphine. Nevertheless, buprenorphine effectively suppresses opioid withdrawal. Clinical studies that have compared methadone, primarily in moderate dosages (50 -- 60 mg), with buprenorphine (12 -- 16 mg) have generally found comparable efficacy of the two drugs [40-42], although some studies indicate a lower retention rate with buprenorphine [43]. For more detailed background information on the use of buprenorphine in opioid dependence, see Soyka et al. [30]. The usual dosages for maintenance therapy are 8 -- 16 (24) mg [44]. A possible advantage of buprenorphine is that cessation of treatment results in less severe withdrawal symptoms than cessation of methadone [25]. Another advantage over methadone is the lower cardiac risk of QT prolongation associated with buprenorphine [45]. Torsade de pointes has not been reported in buprenorphine [46]. Methadone but not buprenorphine blocks the cardiac potassium currents at clinically relevant concentrations [46]. In October 2002, the FDA approved buprenorphine for the treatment of addiction in the USA. Buprenorphine has been marketed in most European countries and the USA since 2000 for the treatment of opioid dependence. Like methadone, buprenorphine has an abuse potential and a substantial risk of diversion [26,36]. There have been persistent safety concerns about the increasing number of emergency department visits because of intoxications with opioid prescription drugs, including buprenorphine [47]. Specifically, the risk of exposure to buprenorphine appears to have increased in children [48]. For 2009, 1262 cases were recorded
by the American Association of Poison Control Centers. Although buprenorphine overdoses are generally well tolerated, children appear to be at risk for respiratory depression and CNS reactions [49]. In addition, the risk of diversion of the sublingual tablet form has been linked to difficulties in supervising its consumption [33]. A combination of buprenorphine with the opioid antagonist naloxone in a fixed 4:1 ratio was developed to avoid intravenous administration and diversion of buprenorphine. The bioavailability of naloxone after sublingual administration is too low to cause withdrawal symptoms [50]. However, naloxone has good parental bioavailability and therefore rapidly precipitates an opioid withdrawal syndrome if the combination buprenorphine--naloxone sublingual tablet is dissolved and injected [51]. The induction of an opioid withdrawal syndrome is thought to reduce the abuse potential of buprenorphine and improve its safety [52]. Although the combination of buprenorphine and naloxone may reduce intravenous misuse, it may not eliminate it [53]. Direct induction of buprenorphine--naloxone is generally considered to be easy and safe [54,55]. The buprenorphine--naloxone combination has been marketed for the treatment of opioid dependence since 2002. Buprenorphine and buprenorphine--naloxone are established first-line medications for the treatment of opioid dependence (see APA guidelines [6], WFSBP Guidelines [30], NSW Clinical Guidelines [56], British Association for Psychopharmacology guidelines [57], WHO guidelines [58], US Department of Health and Human Services guidelines [59], Canadian Agency for Drugs and Technologies in Health guidelines [60]); for reviews, see Mammen and Bell [53], Orman and Keating [36], Mauger et al. [61] and Yokell et al. [62]. In recent years, a buprenorphine--naloxone film was developed to address the above safety concerns and to improve retention in treatment, the bioavailability, absorption and dissolution time of buprenorphine and to reduce the risk of diversion [63]. The sublingual film was licensed in the USA in 2010 and in Australia in 2011 [64]. The film is produced in the same 2/0.5 and 8/2 mg doses as the tablets. The rationale for introducing the film was that it adheres to the sublingual mucosa quickly, is less easily removed and hence requires less time for supervised dosing and can be supplied in more tamper-proof unit packaging to limit consumption by children [64,65]. Other minor objectives for developing a film were to improve taste and obtain a formulation that may deter crushing and snorting. 4.
Chemistry
Buprenorphine is a semisynthetic derivative of thebaine. It is a mixed opioid agonist-antagonist that produces a less than maximal or partial agonist effect at the µ-opioid receptor and is an antagonist at the k-opioid receptor [36,53]. Steadystate drug concentrations for a 16 mg dose of buprenorphine are reached after 7 days [66]. Some data show a ceiling on the
Expert Opin. Drug Deliv. (2014) ()
3
M. Soyka
respiratory but not analgesic effect of buprenorphine [67]. Buprenorphine has a ceiling effect at the opioid receptor at dosages of about 32 mg resulting in a somewhat lower risk than methadone for fatal intoxications [30,68]. The ceiling effect means that partial agonists have maximal effects less than full agonists reaching a plateau with further increases being no more effective (see buprenorphine.samsha.gov). 5.
Pharmacodynamics
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No studies have been published on the pharmacodynamics of the novel film. 6.
Pharmacokinetics and metabolism
Distribution Buprenorphine is approximately 96% protein-bound, primarily to a and b globulin; naloxone is approximately 45% protein-bound, primarily to albumin. 6.1
Metabolism Buprenorphine is mainly metabolized by the CYP3A4 (60%) and CYP2D6 isoenzymes (30%) [70]. Buprenorphine undergoes Ndealkylation, predominantly via CYP3A4, to norbuprenorphine 4
Elimination The studies performed with the buprenorphine--naloxone film indicate that buprenorphine has a mean elimination plasma half-life ranging from 24 to 42 h and naloxone has a mean elimination plasma half-life ranging from 2 to 12 h. The elimination half-life of naloxone in plasma is about 30 min [77]. 6.3
In a previous review, the available data on the pharmacokinetic profile of the buprenorphine--naloxone film were given as provided by the manufacturer [35]. Pharmacology was studied in open-label studies comparing sublingual doses in healthy adult volunteers not using opioids (n = 16). Each administration was performed under a naltrexone block. Data indicate that the pharmacokinetics of the buprenorphine--naloxone sublingual film is similar to those of the sublingual tablet, although not all doses and dose combinations met bioequivalence criteria [69]. A single-dose, crossover pharmacokinetic study with buprenorphine 2 mg/naloxone 0.5 mg (n = 39) and 8/2 mg (n = 44) buprenorphine film and tablet showed a small, but not clinically relevant, increase in buprenorphine levels with the film. As expected, opioid agonist ceiling effects were observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 3, 8, 16 and 32 mg), placebo and a full agonist control at various doses. In each case, a dose was reached that produced no further effect [69]. The dissolution times of the buprenorphine--naloxone film were compared with those of the tablet in 42 healthy volunteers (buprenorphine--naloxone dose combinations: 2/0.5, 4/1, 8/2, 12/3 mg) and were found to be lower for the film than for the tablet at all dosages [69]. The pharmacokinetic parameters of buprenorphine, its active metabolite norbuprenorphine and naloxone after administration of the film were studied in randomized, crossover studies. The pharmacokinetics of the film is similar to the pharmacokinetics of the sublingual tablet.
6.2
and glucuronidation. After sublingual absorption, buprenorphine is primarily converted and N-dealkylated to norbuprenorphine, an active metabolite, via CYP3A4 and to a lesser extent by CYP2C8 [71-73]. Buprenorphine and norbuprenorphine are further metabolized by uracil diphosphate-glucuronosyltransferases (UGTs), predominantly by UGT-1A3 and to a lesser extent by UGT-2B6 and -1A1 [74]. Neither buprenorphine nor methadone is major inducer or inhibitor of CYP450 enzymes but may compete with other drugs metabolized by these same pathways. Buprenorphine is a weak inhibitor of CYP3A4, but this effect does not occur with plasma concentrations achieved at clinically relevant doses [75,76].
Drug--drug interactions Drug interactions with buprenorphine can occur either through altered pharmacokinetics or as a result of pharmacodynamic interactions. Pharmacokinetic interactions can involve the inhibition or induction of hepatic CYP450 enzymes and effects on glucuronidation, on the function of the drug transporter, P-glycoprotein and on absorption of drugs [78,46]. CYP3A4 inhibitors such as ketoconazole or HIV protease inhibitors may increase buprenorphine plasma levels and CYP3A4 inducers may lower levels; dosage may have to be adjusted if symptoms of opioid withdrawal emerge [79]. Pharmacodynamic interactions are possible with other CNS depressants such as alcohol and other opioids and psychotropic drugs such as benzodiazepines, other hypnotics, antidepressants and antipsychotics that suppress respiration [46]. Drug--drug interactions can be expected to be the same for the buprenorphine--naloxone sublingual film as for the conventional sublingual tablet [46]. No special studies have been published on the film. 6.4
Switching from the conventional formulation Since the buprenorphine/naloxone film tablets are bioequivalent to the conventional sublingual formulation as indicated by pharmacokinetic studies, patients can be switched from tablets to film and vice versa (official FDA prescribing information, see www. drugs.com). 6.5
7.
Clinical efficacy
Strain et al. [80] studied the feasibility of induction with a buprenorphine--naloxone soluble film in a clinical setting and performed a randomized study comparing the ability of buprenorphine and buprenorphine--naloxone films to suppress
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Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update
spontaneous withdrawal in 34 opioid-dependent volunteers (18 in the buprenorphine, 16 in the buprenorphine--naloxone group), most of whom were intravenous heroin users but some of whom inhaled heroin. Participants were maintained on morphine and underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal. Participants received either buprenorphine 16 mg or buprenorphine--naloxone film (16/4 mg) for a 3- to 5-day maintenance period. The primary outcome measure was the Clinical Opiate Withdrawal Scale (COWS) score; secondary measures were pupillometry, a visual analog scale and subjective rating scales. The COWS score decreased significantly but there were no differences between the two groups. The most common adverse events were those consistent with opioid withdrawal. Four participants with high COWS scores (two in each group) dropped out. Four patients, again two in each group, had mild non-ulcerous irritations of the oral mucosa not present at baseline; in three of the four patients, the irritation was attributed to teeth grinding or dental decay. Strain et al. [80] interpreted the findings as supporting the use of buprenorphine and buprenorphine--naloxone films as safe and effective delivery methods for opioid induction. Further, they concluded that the new film will not precipitate opioid withdrawal when taken sublingually. The unit-dose packaging was seen as an advantage of the new formulation, because it improves the ability to track a dose of the medication and is also more child-resistant [80]. An Australian group, Lintzeris et al. [64], performed a randomized controlled clinical trial to compare the sublingual buprenorphine--naloxone tablets and film in regard to subjective dose effects and equivalence, trough plasma levels, adverse events, patient satisfaction, supervised dosing time and impact on treatment outcomes (substance use, psychosocial function) over a 31-day period. Ninety-two patients treated with the buprenorphine--naloxone tablets were recruited to this double-blind, double-dummy parallel group trial and randomized to either tablets or film. No dose changes were performed over a 3-day period. No significant differences were detected between film and tablets on subjective dose effects, trough plasma buprenorphine or norbuprenorphine levels, adverse events and treatment outcomes. More patients reported that the tablets were more likely to be accidentally swallowed (19%) compared to the film (5%). Buprenorphine--naloxone film took significantly less time to dissolve than tablets (173 vs 242 s, p = 0.007). Patient preference was higher for the film (61%) than for the tablets (23%). The authors concluded that the film and tablets are comparable in respect to dose equivalence and clinical outcomes, whereas the film shows improved dispensing times and higher patient ratings of satisfaction. Whether the novel film tablet can increase retention rate with buprenorphine--naloxone treatment is a crucial question and has not been addressed in head-to-head comparisons with the conventional formulation. There is some indirect evidence for a better outcome from a longitudinal, retrospective cohort
analysis [63]. This study analyzed data of a private US insurance claims database. Resource utilization and related costs were calculated over 6- and 12-month periods. Film and tablet groups included 2796 and 1510 patients. Mean prescribed doses were 14 mg in both groups Time to treatment discontinuation was significantly longer in the film group. In addition, the film group patients had more outpatient visits and lower probability to be hospitalized. This study cannot rule out bias due to differences in patient or prescriber profiles but suggests a better retention in patients on buprenorphine/naloxone film tablets compared to the conventional formulation. 8.
Safety and tolerability
As stated in Soyka [35], an unpublished 12-week, open-label safety and tolerability study of buprenorphine--naloxone film in 194 patients transferred to buprenorphine--naloxone film from the tablet (same initial dosage) indicated an overall good tolerability, with 28% treatment-emergent adverse events (TEAEs), mostly mild in intensity [69]. The most common TEAE related to the film was oral hypoesthesia, which was reported by two subjects (1%); it is unclear whether this effect was related to a lower dissolution time. The dose was adjusted in only one patient during the first 2 weeks and increased in 2% of the patients at any point during the study. The risk of diversion and injection of the novel buprenorphine--naloxone film was studied in Australia [81]. Surveys were conducted with people who inject drugs regularly and with opioid substitution clients (n = 543). Among the out-of-treatment patients, levels of injection for buprenorphine--naloxone film were comparable with those for methadone and buprenorphine tablet formulations. Among patients in maintenance treatment, recent injecting of one’s medication was similar among clients in all maintenance drugs. Weekly or more frequent injection of prescribed doses was reported by fewer buprenorphine--naloxone film patients (3%) than buprenorphine tablet clients (11%), but at levels similar to methadone and buprenorphine--naloxone tablets. These data do not indicate a significant benefit from the use of the novel film compared to conventional buprenorphine--naloxone formulations. The reduced risk of diversion of buprenorphine film could be the most relevant advantage of the new film. This risk of unintentional poisoning in children has only been addressed in few studies. This issue was studied by collecting and examining data from US addiction-related surveillance system poison centers. Lavonas et al. [9] reviewed 2380 cases of unintentional exposures to buprenorphine-containing products among children < 6 years, including four deaths (2009 -- 2012). Exposures to buprenorphine--naloxone film were significantly less frequent than exposure to buprenorphine tablets (rate ratio 3.5) and buprenorphine--naloxone tablets (rate ratio 8.8). The most frequent adverse events in all groups were lethargy, respiratory depression, miosis and vomiting. This large retrospective study gave robust evidence that exposure rates of tablet formulations, in the USA
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M. Soyka
typically dispensed in bottles containing 30-day supply, were much higher than the exposure rates of buprenorphinenaloxone film. These findings are in line with a study from the Utah Poison Control Center, which found that 94% of 179 buprenorphine exposures among children involved tablet rather than the film formulation [82]. The FDA states that the safety of buprenorphine--naloxone film is supported by clinical trials with buprenorphine and buprenorphine--naloxone sublingual tablets and an open-label study in 194 patients with the novel film (unpublished data, see Ref. [69]). Safety data on buprenorphine are available from clinical studies in over 3000 opioid-dependent subjects [69]. Few differences in the adverse event profile were noted between the buprenorphine--naloxone sublingual film and tablet and buprenorphine sublingual tablet. The most common adverse event (> 1%) associated with the novel film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome, hyperhidrosis and blurred vision. Both the sublingual tablet and film formulation have a bitter taste. A novel sublingual buprenorphine--naloxone formulation with a better taste has recently been tested in healthy volunteers but is not available yet [83]. 9.
Regulatory affairs
The novel buprenorphine--naloxone film was approved by the FDA in August 2010 and in Australia in 2011. 10.
Conclusion
Both methadone and buprenorphine are well-established firstline medications in the treatment of opioid dependence [6,30]. Persisting safety concerns linked to the risk of intravenous use of buprenorphine and diversion stimulated the development of a buprenorphine--naloxone combination (ratio 4:1). The novel sublingual form of buprenorphine and naloxone may provide an even less divertible, more quickly administered and more childproof version than the conventional buprenorphine--naloxone tablet [84]. In its current forms, buprenorphine can only be administered sublingually, because of its poor bioavailability. The buprenorphine film appears to be a more convenient and preferred approach for patients [64]. Dissolution time and other pharmacodynamic variables may not differ much between the two forms, but soluble-film formulations can have unit-dose packaging, thereby improving the ability to track a dose of the medication. More importantly, the film formulation may reduce safety concerns and risk of diversion, which is particularly relevant in regard to the risk of intoxication in children. In the USA, the number of children exposed to buprenorphine has grown exponentially over the past decade [48]. Recent data indicate a lower risk of intoxications with the novel buprenorphine film in children [9,82]. 6
Few data on the new formulation have been published to date. The FDA recommends a target dose of the buprenorphine--naloxone sublingual film of 16/4 mg buprenorphine--naloxone as a single daily dose (range 4/1 -- 24/6 mg). Although there is no doubt concerning the general clinical efficacy of buprenorphine and consequently of the new buprenorphine film in opioid dependence and maintenance therapy, the relevant benefits of the pharmacology of the new formulation have yet to be established and demonstrated. Generally, the major risks of the novel formulation -respiratory and CNS depression, hepatic reactions, allergic reactions, precipitation of opioid withdrawal and neonatal withdrawal and so on -- are the same as for the sublingual tablet. The adverse event spectrum of the novel film is similar to that of the sublingual tablet and oral hypoesthesia appears to be the most common adverse event. The new film has not been studied in special subgroups such as pregnant or nursing women. The pharmacokinetics of the sublingual form and film appears to be similar, although unpublished pharmacokinetic data in healthy subjects suggest that absorption may be slightly higher with the buprenorphine--naloxone film than with the tablets. Therefore, patients switching from tablets to film should be monitored for overdose and, vice versa, patients switching from film to tablet should be monitored for opioid withdrawal. Few other published data are available to date. A recent study by Strain et al. [80] in opioid-dependent volunteers maintained on morphine who underwent challenge sessions to confirm sensitivity to naloxone-induced opioid withdrawal showed that both buprenorphine and buprenorphine--naloxone soluble films suppress symptoms of opioid withdrawal. Strain et al. [80] concluded that both are safe and effective delivery methods for opioid induction. 11.
Expert opinion
Although buprenorphine is an established medication for the treatment of opioid dependence, the buprenorphine--naloxone soluble film is an interesting new formulation with some probable advantages over the conventional sublingual tablet. The key features of the pharmacological profile do not differ much from the tablet, although absorption may be somewhat faster with the film. Recent data indicate a clear patient preference for the film over the tablet. The mucoadhesion of the novel film may reduce risk of diversion [64]. The probably most important advantage, that is, a reduced risk for accidental intoxication especially in children, cannot be assessed in clinical studies but will have to be evaluated in pharmacoepidemiological studies in poison control centers and emergency rooms, among others. A risk evaluation and mitigation program is being implemented as part of the FDA requirements to ensure that the benefits of treatment with this medication outweigh the potential risks, particularly risk of accidental overdose, misuse and abuse.
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Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update
Acknowledgment
Declaration of interest
The author thanks Jacquie Klesing, Board-certified editor in the Life Sciences (ELS), for editing assistance with the manuscript.
M Soyka has worked as a consultant and has received research grants from Reckitt Benckiser and Sanofi Pharma. No funding has been granted for preparation of this manuscript.
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Affiliation Michael Soyka1,2 MD 1 Ludwig Maximilian University, Department of Psychiatry, Munich, Germany 2 Privatklinik Meiringen, Postfach 612 CH -- 3860 Meiringen, Switzerland Tel: +41 33 972 82 95; Fax: +41 33 972 82 91; E-mail: [email protected]
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