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TAPENTADOL

Comments to the World Health Organization (WHO; Expert Committee on Drug Dependence)

Tapentadol Critical Review Report 2014

Prepared by:

Grünenthal GmbH, Germany

Submitted by:

International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Switzerland

for the World Health Organization

22 May 2014

Grünenthal Comments to the

WHO (ECDD) Tapentadol Critical Review Report 2014

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LIST OF ABBREVIATIONS

Abbreviation Explanation ECDD Expert Committee on Drug Dependence ER* Extended release Nucynta® ER Brand name of tapentadol ER marketed in the US Q Quarter PR* Prolonged release RADARS® Researched Abuse, Diversion and Addiction-Related Surveillance RMP Risk management plan REMS Risk Evaluation and Mitigation Strategy UN United Nations URDD Unique recipients of dispensed drug US United States of America WHO World Health Organization

*For the extended release formulation of tapentadol, ER and PR are used interchangeably throughout the document

1 EXECUTIVE SUMMARY

The potential for abuse of tapentadol is described to be similar to that of pure, strong µ-opioid analgesics, such as morphine and hydromorphone. Tapentadol is still in the launch or post-launch phase in some countries and not yet commercially available in the majority of countries. It is currently only marketed in countries where sufficient national control measures providing the same control as for schedule I of the United Nations (UN) Single Convention on Narcotic Drugs are applied, a context under which low abuse has been observed. Considering future developments with increased market penetration, Grünenthal proposes international scheduling in schedule I of the UN Single Convention on Narcotic Drugs as a precautionary measure.

Appropriate scheduling right from the start is important to avoid a substantial abuse situation that is not easily controllable once present. Possible changes to the abuse situation expected at specific milestones should be considered. An expansion of market share and worldwide market penetration is expected as well as an increase in companies manufacturing and distributing tapentadol, possibly in countries where national control measures might not be in place. Therefore, sufficient international control mechanisms need to be in place to prevent a potential public health problem related to abuse of tapentadol.

1.1 Observed drug abuse rates and limitations The data presented in the WHO Tapentadol Critical Review Report 2014 (Section 13) reflect the abuse and dependence rates in the immediate post-marketing phase of tapentadol in the United States of America (US), however, the data presented are limited to the first 24 months following launch in the US (July 2009 through June 2011) and the immediate release formulation of tapentadol collected from the US RADARS® system. In the meantime, data are available up to the end of Q3 2013 including data on the prolonged release (PR) formulation (for further details see Grünenthal supplemental data for WHO 2014, Section 13, Comment 12). In the US, a country




where prescription opioid abuse constitutes a significant public health risk, tapentadol ER is only available as a tamper resistant formulation, to further minimize the widespread abuse of the ER formulations of opioids in the US.

As summarized in the WHO Tapentadol Critical Review Report 2014, tapentadol has been marketed since 2008 without significant events or signs of abuse. Although the abuse potential of tapentadol is comparable to other strong opioids currently scheduled in line with schedule I of the UN Single Convention on Narcotic Drugs such as hydromorphone, the abuse levels measured so far are still in the lower range compared to these compounds. However, tapentadol is not yet available worldwide and the market share specifically in the US is currently low in comparison to the substances with similar analgesic properties and considered to have similar abuse potential (e.g., morphine, oxycodone, hydromorphone), but expected to increase over the next years.

Considering tapentadol’s market penetration and risk minimization measures, the limited post-marketing evidence of drug abuse must be weighted together with non-clinical and clinical findings on abuse potential from the drug development program. Considering that the abuse of a new drug may develop slowly, the abuse of drugs with low population exposure, with infrequent abuse or non-serious medical consequences may not be detected in a timely manner (Canadian guideline [2007] of abuse liability for drugs with central nervous system activity). Therefore, sufficient mechanisms of control need to be in place, to prevent a potential public health problem related to abuse of tapentadol.

A program to collect data on abuse and dependence of tapentadol in comparison to other opioids is only established in the US (RADARS®). Similar systems have not been established in other countries. According to the recent US RADARS® system data, overall, tapentadol showed rates of events based on unique recipients of dispensed drug (URDD) that are in the lower range compared to classical strong opioids. However, quite high variability in the URDDs-corrected rates was observed for tapentadol over time. With regard to the observed pattern, “given the stability of the numerators, the variability of the URDD rates is likely driven by varying degrees of market penetration […]. This makes interpretation of the URDD rates difficult“ (Dart et al. 2012). Furthermore, abuse levels can only be meaningfully compared for compounds with similar control levels. A direct comparison between tapentadol and tramadol is misleading, as tramadol is currently not scheduled under the US Controlled Substances Act.

To minimize the risk of abuse, tapentadol is currently only marketed in countries where sufficient national control measures providing the same control as for schedule I of the UN Single Convention on Narcotic Drugs are applied by Grünenthal and partnering companies. Additionally, dedicated risk management plans (RMPs) and Risk Evaluation and Mitigation Strategy (REMS) are in place to appropriately mitigate the risk of abuse. A key objective is “To inform patients and healthcare professionals about the potential for abuse, misuse, overdose, and addiction to Nucynta® ER”. Elements of the REMS include specific prescriber training as well as a medication guide for the patients.

Considering future developments and increased market penetration, as a precautionary measure, Grünenthal proposes international scheduling in schedule I of the UN Single Convention on Narcotic Drugs.




1.2 Comment on Annex 1: Report on WHO Questionnaire for Review of

Psychoactive Substances for the 36th ECDD The data reported on harmful use in Annex 1 of the WHO report needs to be seen in context of market penetration as the absolute numbers per population may be misleading when comparing different opioids due to differences in the numbers of prescriptions. The low number of 0.6 emergency room visits due to intake of tapentadol per 100 000 population indicates a limited public health problem. This number is likely to be an underestimation compared to other opioids due to the lower market penetration of tapentadol.

2 REFERENCES

Dart RC, Cicero TJ, Surratt HL, Rosenblum A, Bartelson BB, Adams EH. Assessment of the abuse of tapentadol immediate release: the first 24 months. J Opioid Manag 2012; 8(6): 395-402.

Grünenthal GmbH. Supplemental data for World Health Organization (Expert Committee on Drug Dependence) Critical Review on drug dependence of tapentadol. 10 March 2014.

Health Canada. Health Products and Food Branch. Guidance Document. Clinical Assessment of Abuse Liability for Drugs with Central Nervous System Activity. December 2007

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CONFIDENTIAL No part of this document may be passed on, reproduced or published without written

permission of GRÜNENTHAL GmbH

TAPENTADOL

Supplemental data for World Health Organization (Expert Committee on Drug Dependence)

Critical Review on drug dependence of tapentadol

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Supplemental data for

WHO (ECDD) evaluation of drug dependence of tapentadol

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TABLE OF CONTENTS

List of abbreviations 3

1 Adverse reactions in humans 3

2 Dependence potential 6

3 Abuse Potential 9

4 Therapeutic applications, extent of therapeutic use and epidemiology of medical use 11

5 Marketing authorizations (as a medicine) 12

6 Non-medical use, abuse and dependence 12

7 Licit production, consumption and international trade 18

8 Illicit manufacture and traffic, and related information 19

9 Current international controls and their impact 19

10 Current and past national controls 19

11 Overall conclusion 20

12 References 21

LIST OF TABLES

Table 1: Animal models of drug dependence 7 Table 2: Animal models of drug dependence 10 Table 3: Annual worldwide volume figures and estimated patient exposure 18

LIST OF FIGURES

Figure 1: Mean total daily dose of tapentadol PR and mean pain scores (11-point NRS) over time for treatment completers (KF5503/24) 9 Figure 2: Postmarketing worldwide reporting rate of individual case reports of abuse with tapentadol 13 Figure 3: Drug diversion rates (per 1,000 URDD) 14 Figure 4: Poison Center opioid intentional exposure rates (per 1,000 URDD) 15 Figure 5: Opioid treatment program abuse rates (per 1,000 URDD) 16 Figure 6: Survey of key informants’ patients abuse rates (per 1,000 URDD) 17

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LIST OF ABBREVIATIONS

Abbreviation Explanation COWS Clinical Opioid Withdrawal Scale CR Controlled Release ER* Extended Release DPN Diabetic Peripheral Neuropathy FDA US Food and Drug Administration 5-HT 5-Hydroxytryptamin (Serotonin) IR Immediate-release MedDRA Medical Dictionary for Regulatory Activities NE Norepinephrine NRS Numerical Rating Scale PR* Prolonged-release RADARS® Researched Abuse, Diversion and Addiction-Related Surveillance REMS Risk Evaluation and Mitigation Strategy RMP Risk Management Plan TEAE Treatment-Emergent Adverse Event US United States of America URDD Unique Recipients of Dispensed Drug VAS Visual Analogue Scale WHO World Health Organization MOR μ-opioid receptor CYP cytochrome P

*For the extended release formulation of tapentadol, ER and PR are used interchangeably throughout the document

1 ADVERSE REACTIONS IN HUMANS

The adverse reaction profile of tapentadol is based on a broad clinical development program including ~14,000 patients/subjects and post-authorization experience with an estimated exposure of ~120 million Patient Treatment Days.

Safety in Phase II and Phase III trials of tapentadol IR Adverse drug reactions, the most common (≥10% subjects) being nausea, dizziness, vomiting, somnolence, and headache, were observed with tapentadol IR treatment in the dose range of 50 mg to 100 mg, and are as expected for a centrally-acting analgesic. Most adverse drug reactions reported with tapentadol IR were of mild or moderate intensity. Apart from withdrawal classified as mild in most cases, prolonged use of tapentadol IR (for up to 90 days) was not associated with a

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change in the safety profile of tapentadol IR. With prolonged use, the incidence of nausea and vomiting decreased with time, whereas constipation remained at the same level.

Tapentadol IR was well tolerated, with a safety profile similar to that of centrally acting analgesics with mu–opioid receptor agonist activity. Compared with oxycodone IR, the adverse event profile of tapentadol IR suggested a similar central nervous system tolerability and a better gastrointestinal tolerability (Hale et al. 2009).

Safety in Phase II and Phase III trials of tapentadol PR The most common adverse drug reactions (≥10% subjects) observed with tapentadol PR treatment in the dose range of 50 mg to 250 mg twice daily were nausea, dizziness, somnolence, headache, and constipation. These are as expected for a centrally-acting analgesic. In a randomized, placebo- and active-controlled study of tapentadol PR for the management of moderate to severe, chronic low back pain, the odds of experiencing constipation or the composite of nausea and/or vomiting was significantly lower with tapentadol PR than with oxycodone CR (p <0.001 for both comparisons) (Buynak et al. 2010). The incidence of the central nervous system (CNS)-related adverse event of dizziness was also significantly lower with tapentadol PR than with oxycodone CR (p <0.05) (Shapiro et al. 2009).

Most TEAEs reported with tapentadol PR are of mild or moderate intensity.

In a long-term safety trial (1 year, KF5503/24), the incidence of constipation for subjects on tapentadol PR was markedly lower than for oxycodone CR. The safety profile following exposure of up to 1 year was not qualitatively different to that following shorter exposure.

Based on pooled data from Phase II and Phase III multiple dose trials in non-cancer pain, 18% of the subjects on tapentadol PR discontinued due to TEAEs, primarily because of gastrointestinal events, general disorders, nervous system disorders, and skin disorders. This was markedly lower than with oxycodone CR (37%) and the difference was particularly notable in the titration period.

The profile of TEAEs was confirmed in 4 Phase IIIb trials in painful osteoarthritis or low back pain where tapentadol PR could be supplemented with tapentadol IR up to a total daily dose of 500 mg of tapentadol for up to 12 weeks (Steigerwald et al. 2012, Gálvez et al. 2013, Steigerwald et al. 2012a, Steigerwald et al. 2013).

Respiratory depression with tapentadol occurred rarely and had limited clinical relevance.

Drug withdrawal as an adverse event was reported with a relative frequency below 1% (uncommon). When systematically assessed by the Clinical Opiate Withdrawal Scale, more than 80% of the subjects had no withdrawal. Most cases were classified as mild and some as moderate in those subjects with withdrawal. No case was classified as moderately severe or severe. Accordingly, tapering of therapy is not required, but subjects should be cautioned about the possibility of experiencing withdrawal symptoms.

Safety experience from post-marketing data The safety profile of all tapentadol formulations emerging from post-marketing reports is in line with the clinical trial experience and has not lead to any major changes of the scientific knowledge.

The total cumulative post-authorization patient exposure to tapentadol IR and tapentadol PR since the first launch in Jul 2008 is ~120 million patient treatment days. Overall, the most frequently

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reported adverse drug reactions derived from spontaneous reports were (in descending order of frequency) nausea, drug ineffective, dizziness, headache, hallucination, and vomiting.

Interactions Pharmacokinetic interactions Patients with severe chronic pain may have comorbid conditions that necessitate the use of concomitant medications. Tapentadol is largely metabolized by phase 2 glucuronidation, a high capacity/low-affinity system that would not be inhibited at clinically relevant concentrations, suggesting a low potential for interactions related to phase 2 metabolism. Furthermore, tapentadol does not inhibit or induce cytochrome P450 enzymes, and tapentadol shows low plasma protein binding (~20%).Therefore, the occurrence of pharmacokinetic drug-drug interactions related to the cytochrome-P450 system or displacement from protein binding is unlikely (Palexia® SR summary of product characteristics). Tapentadol has no active metabolites and is not a prodrug that is activated by metabolism (Tzschentk et al. 2006), resulting in a reliable pharmacokinetic profile and an analgesic profile that is not altered by metabolic factors. Accordingly, results from 2 randomized, open-label, drug-drug interaction studies showed that when tapentadol was administered concomitantly with the commonly used non-opioid analgesics paracetamol, acetylsalicylic acid, and naproxen, no clinically relevant changes were observed in its pharmacokinetic properties (Smit et al. 2010). Results of other studies suggest no evidence of clinically relevant changes in the pharmacokinetic properties of tapentadol administered with metoclopramide, probenecid, or omeprazole.

Pharmacodynamic interactions A pooled analysis was performed of data from 11 randomized, placebo-controlled trials in which the safety and tolerability of tapentadol when used concomitantly with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) was evaluated. The TEAEs observed under these combination treatments were in line with those expected with tapentadol treatment alone taken into consideration the population studied and in addition no clinically relevant drug-drug interactions were identified. (Sanchez del Aguila, submitted).

The use of tapentadol concomitantly with analgesics and co-analgesics has been evaluated in a number of trials. The concomitant use of WHO step I analgesics and co-analgesics was permitted in 4 open-label, Phase IIIb trials of tapentadol PR in patients with low back pain with or without a neuropathic pain component (Steigerwald et al. 2012, Gálvez et al. 2013) or osteoarthritis knee pain (Steigerwald et al. 2012a, Steigerwald et al. 2013). Across all 4 trials, concomitant co-analgesics were taken by 14.3% to54.4% of patients and concomitant WHO step I analgesics were taken by 55.6% to 64.5% of patients. Despite the relatively high percentages of patients taking WHO step 1 analgesics or co-analgesics, the tolerability profile observed in these studies for tapentadol PR was generally good (Sanchez de Aguila, submitted).

In a double-blind trial in severe low back pain with a neuropathic component, tapentadol PR 500 mg was associated with comparable improvements in pain intensity to a combination of tapentadol PR 300 mg/pregabalin 300 mg, with improved central nervous system tolerability in the monotherapy arm but overall a favorable tolerability profile also for the combination (Baron et al, submitted).

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2 DEPENDENCE POTENTIAL

Animal studies Physical dependence/withdrawal The potential of tapentadol to produce physical dependence was examined in an acute mouse model

(PH405, PH542) and a chronic rat model (PH543) (Table 1). In the mouse model, withdrawal was precipitated by a high dose of naloxone after 2-day pretreatment with increasing doses of tapentadol or morphine. In the rat model, animals were pretreated for several weeks with either tapentadol or morphine, and withdrawal was induced by naloxone challenge (precipitated withdrawal) or by cessation of drug treatment (spontaneous withdrawal). In all experiments, tapentadol-treated animals showed signs of physical withdrawal. In all cases, however, tapentadol produced fewer withdrawal symptoms than morphine at equi-analgesic doses.

Tolerance To investigate the development of tolerance to tapentadol and cross-tolerance to morphine in the tail-flick test, female Sprague-Dawley rats were treated once daily with 21.5 mg/kg intraperitoneal tapentadol hydrochloride or an equi-analgesic dose of morphine hydrochloride (10 mg/kg intraperitoneal) (Table 1). Compared to morphine, for which complete tolerance (defined as an analgesic effect of less than 10% MPE) was observed after 21 days, tapentadol showed a delayed tolerance development with complete tolerance between Days 45 and 51. Tapentadol-tolerant rats showed complete cross-tolerance to morphine. On the other hand, in rats tolerant to morphine, tapentadol still showed an analgesic effect (PH526).

Tolerance development was also investigated in the chronic constriction injury model of mononeuropathic pain. Equi-analgesic doses of tapentadol hydrochloride (6.81 mg/kg intraperitoneal) and morphine (10 mg/kg intraperitoneal (PH522) or 6.81 mg/kg intraperitoneal (PH602) were administered daily to male Sprague-Dawley rats. As in the tail-flick model, tolerance developed more rapidly for morphine (complete tolerance [defined as lack of significant difference from control group] on Day 10) than for tapentadol (complete tolerance on Day 27 [PH522] or on Day 22 [PH602]).

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Table 1: Animal models of drug dependence

Model Species/ N/Sex

Tapentadol hydrochloride Dose (mg/kg)/

Route Results for tapentadol Physical dependence Withdrawal jumping (naloxone challenge, at 1, 1.5, 2 hours, PH405, PH542)

NMRI mouse/ 12/M

2.15 – 46.4/ i.p.

At equi-analgesic doses, withdrawal response was lower than that of morphine (0.215 - 100 mg/kg).

Withdrawal response for both tapentadol and morphine increased when interval between last

administration and naloxone challenge was reduced. Withdrawal after chronic treatment (naloxone, spontaneous withdrawal, PH543)

Wistar rat/ 12/M

4.64 – 31.6 (3× daily)/

s.c.

Naloxone-induced withdrawal: unlike morphine no weight loss, tremor or apoptosis; less frequent teeth

chattering and wet dog shaking than morphine. Spontaneous withdrawal: weight loss, hyperactivity,

and irritation less than with morphine. Opioid tolerance Tail flick (PH526) Sprague-Dawley

rat/ 10/F

21.5/ i.p.

Delayed tolerance (Days 45-51) compared to an equipotent dose of morphine (10 mg/kg; Day 21).

Bennett neuropathy (chronic constriction injury, PH522, PH602)

Sprague-Dawley rat/

10/M

6.81/ i.p.

Delayed tolerance (Days 27 or 22, respectively) compared to equipotent doses of morphine

(10 mg/kg or 6.81 mg/kg; Day 10).

F = female; M = male; i.p. = intraperitoneal; i.v. = intravenous; s.c. = subcutaneous. These studies specified doses using the hydrochloride salt weights. The base weights can be calculated using the conversion factor of 0.8585 mg base/mg salt.

Human data Drug dependence In a pooled analysis of Phase II and Phase III trials with tapentadol PR, the percentage of subjects treated with tapentadol PR with a TEAE that were included in the narrow scope of the Standardized MedDRA Queries (SMQ) drug abuse was 2 of 3613 (0.1%). For both of these subjects, the preferred term, “drug dependence” was reported. It is important to note that MedDRA terminology does not discriminate physical from psychological dependence that, for this analysis, the preferred term of drug dependence was searched within its narrow scope definition (i.e., a search with high specificity). Additionally, subjects with a history of substance abuse were excluded from these trials.

No adverse events with Preferred Term “drug abuse” or “drug dependence” were reported in two Phase III cancer pain trials.

Drug withdrawal The Clinical Opioid Withdrawal Scale (COWS) was used at cessation of treatment in Phase II and Phase III trials to systematically check for any cases of withdrawal that might otherwise not have been recognized as such by the subjects and/or the investigators (data on file). In the pooled

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analysis of Phase II and Phase III trials with tapentadol PR, subjects who were not treated with an opioid after cessation of trial medication and who were not enrolled into an open-label extension trial were assessed for opioid withdrawal using the COWS. Of these, 635 subjects of the tapentadol PR group were assessed between day 2 and day 4 (≥2 to <5) after discontinuing trial medication. There were 11.8% of subjects who had a COWS score category of mild withdrawal and 2.0% with a COWS score category of moderate withdrawal. Similar frequencies were seen for the 244 subjects assessed in the oxycodone CR group (mild: 13.5%, moderate: 1.6%). Assessments on Day 5 or later were available for 1145 subjects treated with tapentadol PR (mild: 5.1%, moderate: 0.3%) and for 447 subjects receiving oxycodone CR (mild: 10.7%; moderate: 2.0%).

Drug withdrawal as an adverse event was reported with a relative frequency below 1% (uncommon). When systematically assessed by the COWS, more than 80% of subjects had no withdrawal. Most cases were classified as mild and some as moderate withdrawal in subjects who had symptoms. No case was classified as moderately severe or severe.

Tolerance In the Phase III trials, KF5503/11 (Afilalo et al. 2010) and KF5503/12 in painful osteoarthritis and KF5503/23 (Buynak et al. 2010) in low back pain, a Maintenance Period of 12 weeks followed a 3-week titration to the optimal analgesic dose. The trials were designed to provide proof of efficacy for tapentadol PR 100 mg to 250 mg for a treatment period of 12 weeks. These trials show that pain relief for tapentadol PR was maintained at a constant level during the Maintenance Periods of the trials in chronic osteoarthritis pain and low back pain without a relevant increase in dose intake.

Additionally, a randomized withdrawal design trial in subjects with painful diabetic peripheral neuropathy (KF5503/36, Schwartz et al. 2011) demonstrated that pain relief was maintained over a 12 week period using fixed doses.

A long-term randomized open label and controlled safety trial (KF5503/24, Wild et al. 2010) was performed in subjects treated with either tapentadol PR or oxycodone CR for up to 1 year. Although the primary focus of this trial was on safety, efficacy data were also collected. This open-label trial provides supportive evidence for the maintenance of pain relief beyond 12 weeks and lasting at up to 1 year. A longitudinal analysis of both mean total daily dose and mean pain scores in subjects who completed 1 year of treatment showed stability for both parameters, suggesting that there was no development of tolerance to tapentadol PR. The mean total daily dose increased until ~4 weeks and there was only a slight increase until the end of the trial. The time course of average pain intensity scores demonstrated stable pain reduction with tapentadol PR (Figure 1).

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NRS = numerical rating scale; PR = prolonged-release Source: PAI-3007/ KF24/ Fig 8 Figure 1: Mean total daily dose of tapentadol PR and mean pain scores (11-point NRS) over

time for treatment completers (KF5503/24)

3 ABUSE POTENTIAL

Animal studies Drug discrimination The discriminative stimulus properties of tapentadol hydrochloride at intraperitoneal doses of 1.0 to 10.0 mg/kg were evaluated in 2 groups of Long-Evans rats (PH532). One group was trained to discriminate morphine from saline, and the other was trained to discriminate d-amphetamine from saline. Tapentadol showed a dose-dependent, full generalization to a morphine hydrochloride (3.16 mg/kg) training cue; however, it did not produce an amphetamine-appropriate response. Morphine also showed a dose-dependent, full generalization to the morphine cue. These findings demonstrate that tapentadol is perceived as morphine-like, but lacks psychomotor stimulus properties as associated with amphetamine.

Reward and reinforcement (conditioned place preference and self-administration) The rewarding effects of tapentadol were evaluated in the conditioned place preference paradigm in rats after intraperitoneal administration (PH495). Tapentadol hydrochloride was administered at doses of 1.0 to 68.1 mg/kg. Morphine served as the reference compound. Tapentadol hydrochloride produced a conditioned place preference from 2.15 mg/kg onwards with no clear dose dependency. The lowest-observed-effect-level was 1.47 mg/kg for morphine. The conditioned place preference effect of all compounds was antagonized by naloxone. In contrast to morphine (4.64 mg/kg), no

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locomotor sensitization (increase in locomotion) was associated with any dose of tapentadol hydrochloride during the conditioning experiment.

The reinforcing properties of tapentadol were investigated in intravenous self-administration experiments in Rhesus monkeys (PH397/A). The monkeys were trained to self-administer morphine sulfate (0.03 mg/kg/infusion). Tapentadol hydrochloride in the dose range of 0.01 to 0.3 mg/kg/infusion dose-dependently maintained self-administration behavior in morphine sulfate experienced monkeys.

Table 2: Animal models of drug dependence

Model Species/ N/Sex

Tapentadol hydrochloride Dose (mg/kg)/

Route Results for tapentadol Reward Conditioned place preference (PH495)

Sprague-Dawley rat/

8/M

1.0 – 68.1/ i.p.

Non-dose-dependent conditioned place preference, antagonized by naloxone.

Locomotor sensitization only seen with morphine.

Reinforcement Intravenous self-administration (PH397/A)

Rhesus monkey/

3/M

0.01 – 0.3/ i.v.

Dose-dependent maintenance of self-administration in morphine-experienced animals.

Drug discrimination (PH532)

Long-Evans rat/

10/M

1.0 – 10.0/ i.p.

Dose-dependent, naloxone-sensitive generalization to morphine but not to amphetamine.

F = female; M = male; i.p. = intraperitoneal; i.v. = intravenous; s.c. = subcutaneous. These studies specified doses using the hydrochloride salt weights. The base weights can be calculated using the conversion factor of 0.8585 mg base/mg salt.

Human data A single-dose, double-blind, double-dummy, placebo-controlled, randomized, crossover Phase I trial was performed to evaluate the abuse liability of tapentadol (HP5503/14). The trial was conducted in 40 opiate-experienced, non-dependent subjects who used opioids recreationally. Tapentadol IR (50, 100 and 200 mg) was compared with hydromorphone IR (4, 8 and 16 mg). Hydromorphone was selected because it is a µ-opioid analgesic under international control in accordance with schedule I of the UN Single Convention on Narcotic Drugs and has similar pharmacokinetic properties to tapentadol. The dosage selection was based on equi-analgesic potency conversion factors for hydromorphone, morphine and tapentadol in various animal models.

The mean peak scores on a 100 mm visual analogue scale (VAS)for “Overall Drug Liking” at 24 hours post dose increased in a dose-related manner after administration of tapentadol IR (from 59.1 to 73.0 mm) and hydromorphone IR (from 60.6 to 71.4 mm); after placebo, the mean peak score was 48.8 mm. Statistically significant differences (p <0.05) were demonstrated between each tapentadol IR or hydromorphone IR dose and placebo and a similar dose-response relationship was observed between tapentadol IR and hydromorphone IR.

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Other secondary endpoints measured in this study corroborated these findings, suggesting that tapentadol might be associated with similar drug liking as currently marketed, controlled prescription opioids in recreational non-dependent drug users.

The results of this dedicated clinical abuse liability trial demonstrated that tapentadol has rewarding properties for subjects who use opioids on a recreational basis.

In other large clinical trials with tapentadol, actual abuse or drug dependency were uncommonly reported as an adverse event. However, it has to be taken into account that all these trial protocols excluded individuals with a history of substance abuse.

Tapentadol has similar ‘good effects’ as other µ-opioid agonists, measured as ‘drug liking’, which was shown to be comparable to hydromorphone. Also, tapentadol shows better tolerability in comparison to oxycodone, which can be seen as a surrogate for less ‘bad effects’ in drug abuse. Overall, this supports the assessment of abuse potential similar to classical strong opioids like oxycodone or hydromorphone.

4 THERAPEUTIC APPLICATIONS, EXTENT OF THERAPEUTIC USE AND EPIDEMIOLOGY OF MEDICAL USE

Discontinuation rates were lower in subjects on tapentadol than subjects on oxycodone based on data from the pooled analysis of 3 similarly designed, randomized, double-blind, phase III studies on about 3000 patients (2 trials in osteoarthritis pain, one in low back pain) (Lange et al. 2010) mainly due to an improved tolerability profile. A favorable gastrointestinal tolerability profile has also been demonstrated for elderly patients (≥75 years of age) in a post-hoc analysis of the quoted pooled data which showed significantly lower incidences of gastrointestinal treatment-emergent adverse events (TEAEs) and gastrointestinal TEAE-related discontinuations with tapentadol PR compared with oxycodone CR (P <0.05 for both comparisons, Sanchez del Aguila, submitted.)

In addition to trials in non-cancer pain, the efficacy of tapentadol PR was demonstrated for the treatment of cancer pain in an 8-week Phase III randomized withdrawal trial in which tapentadol PR was statistically significantly superior to placebo in the number of treatment responders. During the Titration Phase, when tapentadol PR (100 mg to 250 mg twice daily) and morphine PR (40 mg to 100 mg twice daily) could be compared without selection bias, tapentadol PR was shown to be non-inferior to morphine PR and to be associated with better gastrointestinal tolerability than morphine PR (Kress et al. 2012).

In a double-blind trial in severe low back pain with a neuropathic component, tapentadol PR 500 mg was associated with comparable improvements in pain intensity to a combination of tapentadol PR 300 mg/pregabalin 300 mg, with improved central nervous system tolerability in the monotherapy arm but overall a favorable tolerability profile also for the combination (Baron et al, submitted).

A further trial in diabetic peripheral neuropathic pain (Vinik et al. 2012) has been performed confirming the findings of Schwartz et al. 2011 as a basis for the DPN pain indication in the US.

Please note, the publication of Steigerwald et al. 2012 (cited in the draft report) refers to subjects with low back pain with or without a neuropathic component and not diabetic peripheral neuropathy.

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Hale et al. 2009 was a safety trial in chronic low back pain and knee or hip osteoarthritis.

5 MARKETING AUTHORIZATIONS (AS A MEDICINE)

Grünenthal GmbH, Aachen, is the originator of tapentadol and holds marketing authorizations in European Union countries, Australia, and selected Latin American countries.

Tapentadol is marketed under the trade names Palexia®, Yantil®, Palexias®, and Palexis®. In the US the product is marketed under the trade name Nucynta® by Janssen Pharmaceuticals Inc.

Tapentadol was first approved in the US on 20 Nov 2008, the international birth date (IBD).

In total, the product is authorized in 37 countries, namely Australia, Austria, Belgium, Bulgaria, Canada, Chile, Colombia, Cyprus, the Czech Republic, Denmark, Ecuador, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Mexico, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and US.

In the US it is indicated for the treatment of moderate to severe acute pain in patients 18 years of age or older, for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time, and for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

In the EU it is indicated for the relief of moderate to severe acute pain in adults and for the management of severe chronic pain in adults, which can be adequately managed with opioid analgesics.

Please note that Johnson & Johnson Pharmaceutical Research & Development is now called Janssen Research and Development.

6 NON-MEDICAL USE, ABUSE AND DEPENDENCE

Based on the publication by Dart 2014, cited above, it has to be taken into account that abuse levels can only be meaningfully compared for compounds with similar control levels. A direct comparison between tapentadol and tramadol is misleading, as tramadol is currently not scheduled under the US Controlled Substances Act, although this substance is listed as Schedule IV in 10 US states including Kentucky in 2008 and Arkansas in 2007, as well as by the US military. In contrast, tapentadol is classified as schedule II substance under the US Controlled Substances Act, in line with schedule I of the United Nations Single Convention on Narcotic Drugs.

Data from Grünenthal’s Global Drug Safety Database Grünenthal performed a search in its Global Drug Safety database for reports related to abuse/addiction where tapentadol was a suspected drug. The Data Lock Point for inclusion was 31 Dec 2013.

Figure 2 shows the number of abuse/addiction reports in relation to estimated patient exposure from 2009 to 2013 for tapentadol. Reporting rates were calculated as the ratio of the number of reports in the Grünenthal Global Drug Safety database per million patient treatment days (PTD) (source: sales

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data from GRT and Ortho-McNeil-Janssen Pharmaceuticals, Inc. licenses, as displayed in the comment to Section 15).

Figure 2: Postmarketing worldwide reporting rate of individual case reports of abuse with

tapentadol

The increase in the reporting rate in 2012 can be explained by the addition of a solicited data collection program (NAVIPPRO®) from the United States.

This data shows that the reporting rates of abuse/addiction for tapentadol increased over time, peaked 2012, and are 2.5 reports per Million PTDs in 2013 on a global level.

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Researched Abuse Diversion and Addiction Related Surveillance (RADARS®) The Researched Abuse Diversion and Addiction Related Surveillance (RADARS®) System is designed to provide timely surveillance and monitoring data to characterize prescription drug abuse, misuse and diversion in the US.

The below presented data from the RADARS® system have to be interpreted in the context that tapentadol is marketed as a drug under national control (Controlled Substance Schedule II). In the US the formulation of tapentadol in use is a tamper resistant formulation. The comparators used in the figures (oxycodone, hydromorphone, morphine and fentanyl) have all the same scheduling status in the US as tapentadol.

Drug Diversion Program Data The Drug Diversion Program is conducted by the Center for Research on Substance Use & Health Disparities at Nova Southeastern University to determine the rates of diversion of selected prescription opioids based on case information obtained from a nationwide sample of police and regulatory agencies. Figure 3 shows the current data for tapentadol oxycodone, hydromorphone, morphine and fentanyl based on the number of unique recipients of dispensed drug (URDD) thus putting it into perspective regarding different market shares of the drugs.

Figure 3: Drug diversion rates (per 1,000 URDD)

When rank ordered with oxycodone, hydromorphone, morphine and fentanyl, the rates for tapentadol were among the lowest on an URDD basis.

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Poison Center Network This program is conducted at the Rocky Mountain Poison and Drug Center (RMPDC) to compile information concerning targeted prescription pain medications associated with cases reported to the center and at least 40 other regional poison centers. Figure 4 showed the current data for tapentadol, oxycodone, hydromorphone, morphine and fentanyl.

Figure 4: Poison Center opioid intentional exposure rates (per 1,000 URDD)


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Opioid Treatment Program (OTP) The American Association for the Treatment of Opioid Dependence (AATOD) and the National Development and Research Institutes (NDRI) are working collaboratively to determine the prevalence of prescription opioid abuse among admissions to opioid treatment programs (OTPs) nationally, including methadone maintenance centers, and focusing on the states with the highest risk. Figure 5 showed the current data for tapentadol oxycodone, hydromorphone, morphine and fentanyl.

Figure 5: Opioid treatment program abuse rates (per 1,000 URDD)


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Survey of Key Informants’ Patients Program This program is conducted through the Washington University (WU) School of Medicine to ascertain the number of people nationwide who might be abusing specific opioids and to describe the general characteristics of the abuse patterns. Figure 6 showed the current data for tapentadol oxycodone, hydromorphone, morphine and fentanyl.

Figure 6: Survey of key informants’ patients abuse rates (per 1,000 URDD)


Overall, tapentadol showed rates of events based on URDD, which are in the lower range compared to classical strong opioids.

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Conclusion Although the abuse potential of tapentadol is assessed to be high and comparable to hydromorphone the abuse levels measured so far are still in the lower range compared to classical strong opioids. This has to be seen in light of the facts, that

• Tapentadol is only marketed in countries where sufficient national control measures are applied.

• Dedicated Risk Management Plan (RMP) and Risk Evaluation and Mitigation Strategy (REMS) are in place to appropriately mitigate the risk of abuse. A key objective is “To inform patients and healthcare professionals about the potential for abuse, misuse, overdose, and addiction to Nucynta® ER”. Elements of the REMS include specific prescriber training as well as a medication guide for the patients.

• Tapentadol is not available worldwide and the market share specifically in the US is currently low in comparison to the substances with similar analgesic properties and abuse potential (e.g. morphine, oxycodone, hydromorphone), but expected to increase over the next years. Therefore, sufficient mechanisms of control need to be in place, to prevent a public health problem related to abuse of tapentadol.

• In the US, a country where prescription opioid abuse constitutes a significant public health risk, tapentadol ER is only available as a tamper resistant formulation, to further minimize the widespread abuse of the ER formulations of opioids in the US.

7 LICIT PRODUCTION, CONSUMPTION AND INTERNATIONAL TRADE

Table 3 provides an overview of the worldwide volume figures and estimated patient exposure of tapentadol for Grünenthal and partner company (Janssen). The increase in volume figures has to be seen in the light of still ongoing launch activities.

Table 3: Annual worldwide volume figures and estimated patient exposure

Year

2009 2010 2011 2012 2013 Total (kg) 1172.7 3103.15 7215.91 11232.39 12541.76 Million PTD based on DDD (280 mg)

4.2 11.1 25.8 40.1 44.8

PTD = patient treatment days; DDD = defined daily dose.

Additional data on sales of tapentadol Please note that companies in China and India are not license partners of Grünenthal GmbH or its license partners.

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8 ILLICIT MANUFACTURE AND TRAFFIC, AND RELATED INFORMATION

However, the lack of availability of precursors of tapentadol as a commodity items, as well as the complexity of the downstream chemical synthesis would make the illicit synthesis of tapentadol very difficult.

9 CURRENT INTERNATIONAL CONTROLS AND THEIR IMPACT

Considering the high abuse potential of tapentadol, placing tapentadol under schedule I of the United Nations Single Convention on Narcotic Drugs would ensure minimization of the risk of abuse whilst providing sufficient availability for medical and scientific purposes.

10 CURRENT AND PAST NATIONAL CONTROLS

Grünenthal proactively addressed national controls in all countries where marketing authorizations have been sought and requested that national control measures should be undertaken in accordance with schedule I of the United Nations Single Convention on Narcotic Drugs to help minimize the risks of abuse and diversion.

In the meantime, 37 countries have finalized their scheduling procedures of tapentadol (summary available on request). Although each country has its national scheduling system with its own naming convention for respective schedules, tapentadol was always included in a schedule providing the same control as for schedule I of the United Nations Single Convention on Narcotic Drugs prior to marketing.

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11 OVERALL CONCLUSION

Since tapentadol has prominent µ-opioid agonist activity, a thorough investigation of tapentadol, both non-clinical and clinical, was undertaken to fully characterize it with respect to reinforcing and rewarding properties, physical dependence and tolerance development. The potential for abuse of tapentadol was found to similar to that of µ-opioid analgesics, such as morphine and hydromorphone.

Therefore, Grünenthal proactively requested appropriate control measures in accordance with schedule I of the United Nations Single Convention on Narcotic Drugs in all countries where marketing authorizations have been sought. This was done to ensure an appropriate balance of minimizing the risks of abuse and diversion while still permitting sufficient availability for medical purposes.

The post-marketing data show that, despite the increasing availability of tapentadol, the abuse and diversion levels of tapentadol are in the lower range of classical strong opioids. These data have to be interpreted in the context that

• Tapentadol is only marketed in countries where sufficient national control measures are applied.

• Dedicated RMP and REMS are in place to appropriately mitigate the risk of abuse. A key objective is “To inform patients and healthcare professionals about the potential for abuse, misuse, overdose, and addiction to Nucynta® ER”. Elements of the REMS include specific prescriber training as well as a medication guide for the patients

• Tapentadol is not available worldwide and the market share specifically in the US is currently low in comparison to the substances with similar analgesic properties and abuse potential (e.g. morphine, oxycodone, hydromorphone), but expected to increase over the next years. Therefore, sufficient mechanisms of control need to be in place, to prevent a public health problem related to abuse of tapentadol.

• In the US, a country where prescription opioid abuse constitutes a significant public health risk, tapentadol ER is only available as a tamper resistant formulation, to further minimize the widespread abuse of the ER formulations of opioids in the US.

Overall, the available data support the conclusion that tapentadol should be placed under international control in accordance with schedule I of the United Nations Single Convention on Narcotic Drugs.

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12 REFERENCES

Animal studies PH397/A. Evaluation of CG5503 (BN 200) for antinociceptive activity and abuse potential in the rhesus monkey. Grünenthal R&D, 2000.

PH405. Naloxone precipitated withdrawal jumping in the mouse after repeated intraperitoneal application of BN 200. Grünenthal R&D, 2000.

PH495. Effects of BN 200 in conditioned place preference, and antagonism by naloxone, after i.p. application in rats. Grünenthal R&D, 2001.

PH522. Analysis of tolerance development and cross-tolerance after chronic i.p.-administration of BN 200 and reference compounds in a rat model of peripheral mononeuropathy. Grünenthal R&D, 2002.

PH526. Report on tolerance development and cross-tolerance after chronic i.p.-administration of CG5503 (BN 200) and the reference compounds morphine and tramadol in the tail-flick test in rats. Grünenthal R&D, 2002.

PH532. Discriminative stimulus effects of BN 200 in rats after i.p. administration. Grünenthal R&D, 2003.

PH542. Naloxone precipitated withdrawal jumping in the mouse at different time points after pre-treatment with CG5503 (BN 200). Grünenthal R&D, 2003.

PH543. Evaluation of the physical dependence potential in the naloxone-precipitated and non-precipitated withdrawal test after chronic subcutaneous administration in the rat – Comparison of CG5503 (BN200) with morphine. Grünenthal R&D, 2004.

PH602. Analysis of tolerance development after chronic i.p.-administration of CG5503 and the reference compound morphine in a rat model of peripheral mononeuropathy. Grünenthal R&D, 2005.

Human trials HP5503/14: A Single-Center, Single-Dose, Double-Blind, Double-Dummy, Placebo-Controlled, Randomized Cross-Over Study to Evaluate the Abuse Potential of Three Doses of CG5503 Compared to Immediate Release Hydromorphone in Opiate-Experienced Non-Dependent Subjects (R331333-PAI-1007).

KF5503/11: A Randomized Double-Blind, Placebo- and Active-Control, Parallel-Arm, Phase 3 Study With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee (R331333-PAI-3008).

KF5503/12: A Randomized Double-Blind, Placebo- and Active-Control, Parallel-Arm, Phase 3 Study With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee (R331333-PAI-3009).

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KF5503/23: A Randomized Double-Blind, Placebo- and Active-Control, Parallel-Arm, Phase 3 Study With Controlled Adjustment of Dose to Evaluate the Efficacy and Safety of Tapentadol Extended-Release (ER) in Subjects With Moderate to Severe Chronic Low Back Pain (R331333-PAI-3011).

KF5503/24: A One-Year, Randomized, Open-Label, Parallel-Arm, Phase 3 Long-Term Safety Study, With Controlled Adjustment of Dose, of Multiple Doses of Tapentadol Extended-Release (ER) and Oxycodone Controlled-Release (CR) in Subjects With Chronic Pain

KF5503/35: A randomized, double-blind, parallel-arm, placebo- and comparator-controlled trial of the efficacy and safety of multiple doses of immediate-release (IR) CG5503 for post-operative pain following abdominal hysterectomy.

KF5503/36: A Randomized-Withdrawal Phase 3 Study Evaluating the Safety and Efficacy of Tapentadol Extended-Release (ER) in Subjects With Painful Diabetic Peripheral Neuropathy (DPN) (R331333-PAI-3015).

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Buynak R, Shapiro DY, Okamoto A, Van Hove I, Rauschkolb C, Steup A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010; 11: 1787–804.

Daniels S, Casson E, Stegmann JU, Oh C, Okamoto A, Rauschkolb C, Upmalis D. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin 2009; 25(3): 1551-61.

Daniels SE, Upmalis D, Okamoto A, Lange C, Haeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin 2009a; 25: 765-76.

Dart RC, Bartelson BB, Adams EH. Non-medical use of tapentadol immediate release by college students. Clin J Pain 2014.

Dart RC, Cicero TJ, Surratt HL, Rosenblum A, Bartelson BB, Adams EH. Assessment of the abuse of tapentadol immediate release: the first 24 months. J Opioid Manag 2012; 8(6): 395-402.

Etropolski M, Kelly K, Okamoto A, Rauschkolb C. Comparable efficacy and superior gastrointestinal tolerability (nausea, vomiting, constipation) of tapentadol compared with oxycodone hydrochloride. Adv Ther 2011; 28(5): 401-417.

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Etropolski MS, Okamoto A, Shapiro DY, Rauschkolb C. Dose conversion between tapentadol immediate and extended release for low back pain. Pain Physician 2010; 13(1): 61-70.

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Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin 2009; 25(9): 1095-104.

Hartrick C, Van Hove I, Stegmann JU, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther 2009; 31(2): 260-71

Hartrick CT, Rodríguez Hernandez JR Tapentadol for pain: a treatment evaluation. Expert Opin Pharmacother 2012; 13(2): 283-6.

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Imanaka K, Tominaga Y, Etropolski M, van Hove I, Ohsaka M, Wanibe M, et al. Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Curr Med Res Opin 2013; 29(10): 1399-409.

Jeong ID, Camilleri M, Shin A, Iturrino J, Boldingh A, Busciglio I, et al. A randomised, placebo-controlled trial comparing the effects of tapentadol and oxycodone on gastrointestinal and colonic transit in healthy humans. Aliment Pharmacol Ther 2012; 35(9): 1088-96.

Kemp W, Schlueter S, Smalley E. Death due to apparent intravenous injection of tapentadol. J Forensic Sci 2013; 58(1): 288-91.

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Shapiro DY, Buynak R, Okamoto A, van Hove I, Lange C, Etropolski M. Gastrointestinal tolerability of tapentadol extended release (ER) in patients with chronic low back pain: results of a randomized, double-blind, active- and placebo-controlled phase 3 study. Amer. Acad. Phys. Med and Rehab. 2009; 1: S124.

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