Trends and uptake of new formulations of controlled‐release oxycodone in Canada

Abstract Purpose This study investigated the impact of changing availability of tamper‐deterrent and non‐tamper‐deterrent oxycodone on prescribing patterns of controlled‐release oxycodone across Canada. Methods We conducted a population‐based, serial cross‐sectional study of controlled‐release oxycodone dispensing from community pharmacies across Canada between October 2007 and April 2016. We calculated rates of dispensing (tablets per 100 population) and reported the relative market share of generic non‐tamper‐deterrent controlled‐release oxycodone. All analyses were reported nationally and stratified by province. Results After the introduction of a tamper‐deterrent formulation, the national rate of controlled‐release oxycodone dispensing fell by 44.6% (from 26.4 to 14.6 tablets per 100 population from February 2012 to April 2016). Between December 2012 and July 2013, there was moderate uptake of generic non‐tamper‐deterrent controlled‐release oxycodone (968 452 tablets; 16.0% in July 2013), which appeared to have little impact on the overall rate of controlled‐release oxycodone dispensing in Canada. However, the uptake of generic non‐tamper‐deterrent oxycodone varied considerably by province. By April 2016, 55.0% of all controlled‐release oxycodone tablets dispensed in Quebec were for the generic formulation. Elsewhere in Canada, this prevalence was less than 30%, ranging between 1.6% (Prince Edward Island) and 26.9% (British Columbia) at the end of our study period. Conclusions The changing availability of tamper‐deterrent and non‐tamper‐deterrent formulations of controlled‐release oxycodone in Canada has had variable influence on the rate of use of these products across Canada. Future research should explore whether the availability of generic controlled‐release oxycodone has led to measurable changes in the safety of oxycodone use in Canada.

formulation of oxycodone in 1996. This was largely attributed to an intense marketing campaign by OxyContin's manufacturer, which promoted the use of controlled-release opioids for the treatment of chronic noncancer pain, with claims of minimal risk of addiction. 2,3 Over the subsequent decade, the addiction potential of controlled-release opioid formulations was realized, evidenced by an epidemic of prescription opioid misuse and related overdose deaths across North America. 1,[4][5][6] Since this time, policies have been introduced across Canada to address the rising use of oxycodone and its potential for misuse. These have included restricted access on some provincial drug programs and the introduction of safety warnings on product monographs. 7,8 In February 2012, the manufacturer of OxyContin introduced a tamperdeterrent formulation of controlled-release oxycodone (OxyNeo) across Canada and ceased production of their original product. 9 Although this new formulation does not protect against developing an opioid addiction or accidentally overdosing when ingesting the drug orally, it was designed to be more difficult to crush, chew, or dissolve thus introducing barriers to its misuse. 9 The introduction of this product coincided with restricted listing status of controlled-release oxycodone products on the public formularies in several provinces (Appendix S1). 7 In November 2012, the oxycodone prescribing landscape shifted again when the patent for OxyContin expired, and Health Canada approved generic forms of controlled-release oxycodone without tamper-deterrent properties. 10 In Australia, a similar decision to Canada was implemented in 2014. A published conference paper reported that the introduction of the tamper-deterrent form of oxycodone led to some switching to other opioids, but the authors found no discernible additional impact of the introduction of the generic products on opioid-switching patterns. 11 In contrast, in the United States, the Food and Drug Administration announced that it would not approve any forms of generic OxyContin because of concerns that the risks outweighed the benefits of this non-tamperdeterrent form of controlled-release oxycodone. 12 The approval of these drugs in Canada led to debate regarding the safety of reintroducing non-tamper-deterrent oxycodone to the market and decisions on the part of many Canadian provincial drug programs against listing the generic formulations on their formularies. [13][14][15] The generic long-acting forms of oxycodone are marketed in all Canadian provinces and can be prescribed by a registered medical practitioner (and in some provinces, a nurse practitioner) to any patient who is believed to need a controlled drug for pain relief. The prescription may be subject to special monitoring (eg, systems to avoid inappropriate "double doctoring," which vary by province) and the patient, and/or their insurer, is responsible for covering the dispensed drug price. For example, the cost of 100 tablets of 20-mg generic long-acting oxycodone is approximately $66 plus a pharmacist's professional fee. In Canada, the generic drug is covered by only 2 provincial public drug plans, Quebec and Nova Scotia (see Appendix S1), which have different levels of premiums, co-payment, and deductibles. In Quebec, patients can request a generic drug formulation from their pharmacist at time of dispensing unless their doctor has specified "no substitution" on their OxyNeo prescription, which would prevent the pharmacist from dispensing the generic non-tamper-deterrent formulation. In contrast, in Nova Scotia, pharmacists cannot substitute OxyNeo with generic controlled-release oxycodone.
Despite these changes, and the associated controversies, little is known about the uptake of OxyNeo and generic controlled-release oxycodone across the country. As policy-makers and drug regulators debate the role that tamper-deterrent opioid formulations can have in addressing opioid misuse and addiction, more information is needed to understand shifts in prescribing patterns when these drugs are reformulated. This study sought to determine the impact of changing availability of controlled-release oxycodone formulations on rates of dispensing across Canada.

| METHODS
We conducted a population-based, serial cross-sectional study of con-

KEY POINTS
• The introduction of a tamper-deterrent formulation was associated with a 44.6% reduction in overall dispensing of controlled release oxycodone.
• There was moderate uptake of generic, nontamper-deterrent oxycodone; however, this did not lead to an expansion in the overall prescribing rate of controlled-release oxycodone.
• By 2016, 1 in 5 tablets for controlled-release oxycodone that were dispensed in Canada were for a generic, nontamper-deterrent form.
period. This was calculated as the total number of generic controlledrelease oxycodone tablets dispensed divided by the total number of controlled-release oxycodone tablets dispensed nationally and stratified by province.

| RESULTS
A total of 780.2 million tablets for controlled-release oxycodone were dispensed across Canada over the study period, the majority of which  (Figures 2 and 3).
The uptake of generic controlled-release oxycodone varied considerably across Canada, with a range of 1.6% to 55.0% across the

| DISCUSSION
In this repeated cross-sectional study of controlled-release oxycodone dispensing patterns across Canada, we found reductions in the rate of dispensing of this drug after the introduction of a tamper-deterrent formulation in February 2012. We observed no obvious "rebound" in national oxycodone dispensing after the introduction of generic nontamper-deterrent products later in the same year. However, we did   Our study also suggests that the listing status of generic controlledrelease oxycodone had a significant impact on the uptake of these products. This is most apparent in Quebec where both brand (OxyNeo) and generic controlled-release oxycodone are listed similarly on the drug formulary, with interchangeability and application of lowest prices in effect. This listing creates a financial incentive for the generic form of this drug to be dispensed, which may have led to the high degree of controlled-release oxycodone dispensed in the province being for this non-tamper-deterrent form. Similarly, in British Columbia, the provincial drug formulary reimbursed the generic form until February 2015 when it was announced that the PharmaCare program would no longer cover these products. 18

| Strengths and limitations
The core strength of this study is our ability to report changes in the dispensing patterns of all controlled-release oxycodone prescriptions dispensed over more than 8 years across Canada at the national and provincial level. However, several limitations warrant emphasis. First, we did not have access to patient-level data and, therefore, could not determine the degree to which generic controlled-release oxycodone tablets were clustered at the individual level or rates of initiation of these products. Second, the Compuscript database only captures prescriptions dispensed from community pharmacies and, therefore, cannot comment on patterns of hospital use of controlled-release oxycodone. Finally, we are not able to distinguish between publicly and privately funded (ie, cash paid or privately insured) prescriptions.
However, given that generic forms of controlled-release oxycodone are generally not covered by public drug programs, this should have limited impact on our interpretation of these results.

| CONCLUSIONS
Changes to the availability and listing status of generic and brand name formulations of controlled-release oxycodone have led to important changes in both the rate of use of these products across Canada and the relative market share of non-tamper-deterrent opioids. Importantly, although the introduction of a tamper-deterrent formulation in early 2012 led to considerable reductions in the rate of controlled-release oxycodone dispensing, the marketing of generic non-tamper-deterrent formulations later that year did not lead to any subsequent expansion of the market. By 2016, 1 in 5 tablets for controlled-release oxycodone that were dispensed in Canada were for a generic, non-tamper-deterrent form, and in several provinces, this was likely paid for by private insurers or cash payments. The geographic variation in uptake of these products suggests that provincial drug reimbursement policies-including restrictions on access through public drug formularies-has influenced these trends. In Canada, there was sufficient uptake of generic nontamper-deterrent formulations of oxycodone to justify further research to determine if this has led to measurable changes in the safety of oxycodone use in Canada. This is important as drug regulators from around the world consider the role of tamper-deterrent opioid formulations in addressing the opioid crisis and seek to understand how patent expiration and generic non-tamper-deterrent alternatives will impact the prescribed opioid environment.