The Effects of Ethanol on the Bioavailability of Oxymorphone Extended-Release Tablets and Oxymorphone Crush-Resistant Extended-Release Tablets

The Journal of Pain, Vol 13, No 1 (January), 2012: pp 90-99 Available online at www.sciencedirect.com

The Effects of Ethanol on the Bioavailability of Oxymorphone Extended-Release Tablets and Oxymorphone Crush-Resistant Extended-Release Tablets William D. Fiske,* Janet Jobes,* Qinfang Xiang,y Sou-Chan Chang,z and Irma H. Benedek* Departments of *Drug Metabolism and Pharmacokinetics, yQuantitative Science, and zPharmaceutical Development, Endo Pharmaceuticals Inc., Chadds Ford, Pennsylvania.

Abstract: Adverse events may occur with an extended-release (ER) opioid if tampering or coadministration with ethanol causes excessive exposure (dose dumping) to the opioid. The effects of ethanol on the in vitro dissolution and in vivo pharmacokinetics of oxymorphone ER and oxymorphone crushresistant formulation (CRF) were evaluated. In vitro dissolution rates were measured for oxymorphone ER 40-mg and oxymorphone CRF 40-mg tablets in aqueous solutions of 0 to 40% ethanol. In 2 in vivo, open-label, randomized, crossover studies, fasted healthy volunteers received single oral doses of oxymorphone ER 40 mg or oxymorphone CRF 40 mg with 240 mL of 0 to 40% ethanol. Naltrexone was used to minimize opioid effects. In the in vitro analyses, dissolution rates of oxymorphone ER and CRF were unaffected in aqueous solutions of #40% ethanol. Coadministration of oxymorphone ER or oxymorphone CRF with ethanol 20 and 40% increased oxymorphone peak plasma concentrations (Cmax) by 14 to 80% and reduced time to Cmax. For both formulations, oxymorphone area under the curve and terminal half-life were largely unaffected, but Cmax increased with ethanol dose. Neither oxymorphone formulation exhibited dose dumping in terms of overall exposure when coingested with ethanol. Perspective: Administering oxymorphone ER or oxymorphone CRF with 240 mL of #40% ethanol increased oxymorphone Cmax without dose dumping in terms of area under the curve. These results provide reassurance about the integrity of oxymorphone ER formulations with ethanol. Nonetheless, alcohol and opioids should never be combined because of the risk of respiratory depression. ª 2012 by the American Pain Society Key words: Bioavailability, dissolution, ethanol, opioid, oxymorphone, pharmacokinetics.

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xtended-release (ER) opioids are intended to produce stable plasma concentrations for 12 to 24 hours, reduce dosing frequency, minimize sleep interruptions for nighttime administration, and potentially promote patient adherence and improve tolerability compared with traditional opioid formulations.27,31 However, the large quantity of opioid in these tablets creates a potential risk of overdose if it is released Received May 3, 2011; Revised July 20, 2011; Accepted October 24, 2011. Endo Pharmaceuticals Inc, Chadds Ford, PA, is the sponsor of this research and the employer of all authors. Research facilities: Pharmaceutical Product Development, Inc. (Austin, TX) performed the clinical study of oxymorphone extended release; Clinical Pharmacology of Miami, Inc. (Miami, FL) conducted the clinical study of oxymorphone extendedrelease crush-resistant formulation; and analysis of laboratory samples was conducted at Pharmaceutical Product Development, Inc. (Middleton, WI) and Cetero Research (Houston, TX). Address reprint requests to Dr. Qinfang Xiang, Endo Pharmaceuticals Inc., 100 Endo Blvd., Chadds Ford, PA 19317. E-mail: Xiang.Qinfang@Endo. com 1526-5900/$36.00 ª 2012 by the American Pain Society doi:10.1016/j.jpain.2011.10.011

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precipitously because of accidental or intentional compromise of the ER mechanism. In 2005, Palladone (hydromorphone HCl ER; Purdue Pharma, Stamford, CT) capsules were withdrawn from the US market after pharmacokinetic (PK) data indicated that coadministration of hydromorphone ER and ethanol affected the ER mechanism of the capsules, resulting in dangerous increases in the peak plasma concentrations (Cmax) of hydromorphone, which could be lethal even in opioid-tolerant patients.30 Results of the study showed that coadministration of the lowest dosage strength capsule (12 mg) with 240 mL of 40% ethanol resulted in a mean 450% increase in Cmax compared with coadministration with water.32 Although the effect was generally more pronounced with increasing concentrations of ethanol, lower concentrations of ethanol may also have serious effects on the release of hydromorphone from hydromorphone ER in some individuals. Precipitous release of an ER opioid may also result from deliberate or accidental crushing of the tablet. A study of

Fiske et al prescription drug abusers entering a rehabilitation program found that 80% abused ER opioids by crushing or chewing to accelerate opioid release.23 To minimize this risk, pharmaceutical companies have been attempting to develop crush-resistant formulations or formulations that release an opioid antagonist or aversive component when crushed or chewed, exposing the user to sudden opioid withdrawal24 or adverse effects of the aversive component, respectively.18 It is important to ensure that such formulations are also resistant to the effects of ethanol so that abusers cannot use ethanol as an alternative means of facilitating rapid release of the opioid. Research suggests that opioid abuse sometimes occurs in conjunction with ethanol abuse.2,12,20 Oxymorphone ER (OPANA ER, Endo Pharmaceuticals Inc., Chadds Ford, PA) is an approved oral opioid formulation indicated for the chronic treatment of moderate to severe pain in opioid-naive and opioid-experienced patients requiring continuous, around-the-clock opioid treatment for an extended period. Oxymorphone ER, a semisynthetic opioid agonist, is effective in relieving chronic cancer and noncancer pain.11,13,19 The oxymorphone ER tablet consists of oxymorphone embedded in an agglomerated hydrophilic matrix that gradually releases oxymorphone as water penetrates the matrix, producing sustained oxymorphone plasma levels over a 12-hour dosing interval.21 A crush-resistant ER formulation (CRF) of oxymorphone (Endo Pharmaceuticals Inc.) has been developed with a hard polymer matrix (INTAC, Gru¨nenthal GmbH, Aachen, Germany) that differs in composition from the matrix used in oxymorphone ER. This new formulation has been shown to be bioequivalent to oxymorphone ER under fed and fasted conditions (Endo Pharmaceuticals Inc. EN3288-103, EN3288-104, and EN3288-105 Clinical Study Reports, 2010). Using designs similar to that used to evaluate hydromorphone ER and reported by the US Food and Drug Administration (FDA) in its Public Health Advisory,29 separate studies were conducted to evaluate the singledose bioavailability of oxymorphone ER 40-mg tablets and oxymorphone CRF 40-mg tablets when coadministered with graded concentrations of aqueous ethanol solutions under fasted conditions. It was hypothesized that the bioavailability of oxymorphone released from oxymorphone ER 40-mg tablets and oxymorphone CRF 40-mg tablets remains similar whether ingested with water or with aqueous solutions of up to 40% ethanol. Portions of this research were presented at the American Society for Clinical Pharmacology and Therapeutics Annual Meeting in 2007,9 the American Academy of Pain Medicine Annual Meeting in 2008,8 the American College of Clinical Pharmacy Annual Meeting in 2008,7 and the American Pain Society Annual Meeting in 2008.6

Methods In Vitro Dissolution Testing Dissolution testing on 12 tablets of 40 mg oxymorphone ER and 6 tablets of oxymorphone CRF was con-

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ducted using USP Apparatus II (paddle) at 50 rpm. Oxymorphone ER was tested in 500 mL of .1 N HCl at a temperature of 37 C 6 .5 C with 0, 4, 20, and 40% ethanol. Oxymorphone CRF was tested using the same apparatus in 900 mL of pH 4.5 phosphate buffer (simulating gastric fluid without pepsin) with 0, 5, and 40% ethanol. Dissolution samples were obtained at .5, 1, 2, 4, 8, 12 (both formulations), and 14 (oxymorphone CRF only) hours. Validated reverse-phase high-performance liquid chromatography methods with ultraviolet light detection at 230 nm were used for assay of dissolution samples.

In Vivo Pharmacokinetic Study Design and Treatment Oxymorphone ER was evaluated in a single-center (Pharmaceutical Product Development Inc., Austin, TX), open-label, randomized, 4-period, 4-sequence crossover study (study 1) enrolling healthy volunteers (Fig 1A). The 40-mg dose is the highest-strength single-dosage tablet available; therefore, this dose was chosen to maximize the single-dose exposure to oxymorphone in this study. Oxymorphone CRF was evaluated in a single-center (Clinical Pharmacology of Miami, Inc., Miami, FL), open-label, randomized, single-dose, 3-period, 6-sequence crossover study (study 2; Fig 1B). In study 1, subjects were randomized to receive a single oral dose of oxymorphone ER 40 mg coadministered with each of 3 ethanol solutions or water over 4 separate periods, with each period separated by at least 7 days. The 4 aqueous solutions evaluated were 240 mL of 40% ethanol (Tito’s Handmade Vodka, Austin, TX; 80 proof, diluted for lower concentrations), corresponding to 5.4 standard drinks; 240 mL of 20% ethanol, corresponding to 2.7 standard drinks; 240 mL of 4% ethanol, corresponding to .5 standard drinks; and 240 mL of water (0% ethanol). In study 2, subjects received single oral doses of oxymorphone CRF 40 mg coadministered with 1 of 2 ethanol solutions or water in 3 separate periods separated by at least 7 days. The aqueous solutions used were 240 mL of 40% ethanol (Absolut Vodka, Ahus, Sweden; 80 proof, diluted for lower concentrations), 240 mL of 20% ethanol, and 240 mL of water (0% ethanol). Ethanol 4% was not studied for oxymorphone CRF. In each study, subjects swallowed the oxymorphone ER or CRF tablet with their initial ingestion of ethanol solution and were to ingest the remaining solution as quickly as possible. If the entire 240 mL of solution could not be ingested before scheduled PK sample collection time points, samples were drawn anyway and the subject continued drinking the remainder of the solution. The time at which subjects finished the entire 240 mL of solution was recorded. Subjects were confined to the clinical research facility beginning the evening before the start of dosing until 48 hours after dosing for each treatment period. The study medication was administered after an overnight fast ($8 hours), and subjects remained fasting for $4 hours after dosing. Water was permitted ad libitum throughout the study except for 1 hour before until

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Ethanol and Bioavailability of Oxymorphone ER

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Figure 1. CONSORT diagram for study 1 (A) and study 2 (B). CRF, crush-resistant formulation; ER, extended release. 1 hour after dosing. Subjects were administered naltrexone 50 mg (Barr Pharmaceuticals, Inc., Woodcliff, NJ) approximately 12 hours and 2 hours before, and 12 hours after the administration of oxymorphone ER in each treatment period to minimize the potential for significant opioid-related adverse events (AEs). Subjects who were dehydrated and vomiting were to receive electrolyte solutions.

Subjects Eligible subjects included healthy (as determined by medical history, physical examination, 12-lead electrocardiogram, and clinical laboratory examinations) men and women aged 22 through 45 years. Women must have been using a medically acceptable form of contraception for at least 1 month before dosing with study drug, and those of childbearing potential must have had a negative pregnancy test within 24 hours before the start of the study. Other inclusion criteria were a history of moderate ethanol consumption defined as 7 to 21 drinks per week for at least the past year (defined as 1.5 oz of liquor, 12 oz of beer, or 5 oz of wine), a body mass index $18.5 kg/m2 and <33 kg/m2, and a body weight of at least 68 kg for women and 57 kg for men. Exclusion criteria included known hypersensitivity or allergy to oxymorphone, other opioids, naltrexone, or ethanol; women who were pregnant or breast-feeding; any disease or condition that might have compromised the cardiovascular, hematologic, endocrine, renal, hepatic, gastrointestinal, or central nervous system or interfered with the absorption, distribution, metabolism, and excretion of study drugs; positive screening for hepatitis B; receipt of an investigational drug within

30 days before the start of the study or within 60 days for an investigational drug with an elimination half-life greater than 15 days; use of a drug therapy known to alter hepatic drug metabolism within 30 days before the start of the study; and a positive drug screen for ethanol and substances of abuse (eg, benzodiazepines, barbiturates, cocaine, and opiates). Both studies received institutional review board approval, and all subjects reviewed and signed an informed consent form before participation in the study. The studies were conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practices, and FDA regulations.

Measurements and Statistical Analyses for the In Vitro Study Percentage of dissolved oxymorphone was determined at each time point and percentage dissolved versus time profiles were generated. No formal statistical analyses were performed.

Measurements and Statistical Analyses for the In Vivo Study Blood samples (7 mL each in K3 [study 1] or K2 [study 2] ethylenediaminetetraacetic acid tubes) were collected from each subject at time 0 (predose) and .25, .5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 hours after administration of each oxymorphone ER 40-mg or CRF 40-mg tablet. The plasma fraction was separated by centrifugation (1500 g, 10 minutes, 48 C), and all plasma samples were stored at 70 C within 1 hour after collection until analyzed. Plasma concentrations of

Fiske et al oxymorphone (study 1 and study 2) and 6-OH-oxymorphone (study 2 only) were determined using a modified validated liquid chromatography tandem mass spectrometry assay, as it was in a previous PK study of oxymorphone ER.1 The lower limit of quantitation was 10 pg/mL in study 1 and 25 pg/mL in study 2. The concentration of ethanol in plasma was not measured. PK parameters were estimated by standard noncompartmental analysis. The observed Cmax and time to Cmax (tmax) were obtained from the plasma concentration profile for each subject. Area under the plasma concentration versus time curve (AUC) from time 0 to the last quantifiable concentration (AUC0–t) was calculated using the linear trapezoidal rule. The extrapolated AUC from time 0 to infinity (AUC0–inf) was calculated as AUC0–t 1 Ct/lz (Ct = last measured plasma concentration; lz = terminal rate constant). For subject demographic and baseline characteristics, descriptive statistics were generated for continuous variables, and the number and percentage of subjects were generated for categorical variables (sex, race, and age group). Descriptive statistics were derived for plasma concentrations and PK parameter estimates. Based on FDA guidelines,30 PK data were excluded from the period(s) in which subjects experienced emesis within 12 hours of dosing. The primary assessment was to determine the effect of graded concentrations of aqueous ethanolic solutions on the relative bioavailability of oxymorphone measured as Cmax and AUC values. The relative bioavailability was assessed as point estimates and 90% CIs. CIs for the geometric mean ratios of the values of AUC0–t, AUC0–inf, and Cmax of each treatment (ie, 40, 20, and 4% ethanol) were compared with the reference treatment (0% ethanol). A conclusion of no effect of ethanol was made if the 90% CIs for the ratios of Cmax and AUC values (AUC0–t and AUC0–inf) for treatment with ethanol (relative to reference) were within .80 and 1.25. For tmax, the HodgeLehmann method was used to calculate the 90% CIs for the median difference of interest (ie, medians for each ethanol treatment corrected for the median for the reference). The relative bioavailability of oxymorphone was assessed using an analysis of variance with fixed effects for sequence, period, and treatment, and a random effect for subject nested within sequence performed on the natural logarithms of AUC0–t, AUC0–inf, and Cmax. All descriptive and inferential statistical analyses were performed using the SAS/STAT system (version 8.2 [study 1] and version 9.2 [study 2], SAS Institute Inc, Cary, NC).

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in each treatment period at the following times: before opioid administration and at 6, 12, 24, and 48 hours after administration. In study 2, pulse, respiration rate, and blood pressure also were measured in each treatment period at the following times: before opioid administration and at 1, 2, 3, 4, 8, 12, 24, and 48 hours after opioid administration.

Results In Vitro Dissolution Testing Oxymorphone Extended Release The percentage dissolved versus time profiles of oxymorphone ER for each of 4 media are shown in Fig 2. Mean percentage of oxymorphone dissolved over time in 4% ethanol was similar to 0% ethanol (ie, .1 N HCl) over the 12 hours of testing. The media with higher concentrations of ethanol showed slower dissolution rates than the 4 and 0% ethanol media, with 40% ethanol showing the slowest dissolution rate.

Oxymorphone Crush-Resistant Formulation The percentage dissolved versus time profile of oxymorphone CRF when exposed to 40% ethanol is presented in Fig 3. The in vitro dissolution rate for the oxymorphone CRF 40-mg tablet in 5 and 40% ethanol solutions was not increased relative to the 0% ethanol medium. Similar to oxymorphone ER, 40% ethanol in the medium tended to slow dissolution of oxymorphone CRF, confirming that ethanol did not accelerate release of oxymorphone from the oxymorphone CRF tablet. At 2 hours, the mean (SD) percentage of oxymorphone CRF 40 mg that was dissolved in 40% ethanol was 44% (1.3%). After 14 hours, the entire dose was dissolved.

In Vivo Pharmacokinetic Interaction Studies Demographics and Disposition of Subjects Thirty subjects were enrolled in study 1 and randomized to receive oxymorphone ER; 25 completed all 4 study periods, and 5 discontinued the study (1 because of an AE [pruritus and rash]; Fig 1A). More than half of

Safety Assessments Safety was monitored with AE reporting throughout the study periods, clinical laboratory evaluations, vital sign assessment, and physical examination. In study 1 and study 2, routine vital signs (heart rate, respiration rate, blood pressures, and oral body temperature) were measured at screening, at check-in to the research facility for each treatment period, and at study completion (or discontinuation from the study). In study 1, heart rate, respiration rate, and blood pressure also were measured

Figure 2. Mean dissolution profiles of 40-mg oxymorphone ER tablets in .1 N HCl and ethanol solutions. ER, extended release; HCl, hydrochloride.

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Figure 3. Mean dissolution profiles of 40-mg oxymorphone CRF tablets in 900 mL of pH 4.5 phosphate buffer and ethanol solutions. CRF, crush-resistant formulation; HCl, hydrochloride.

the enrolled subjects were men (60%) and white (53%), and the mean age was 31 years; the mean body mass index (BMI) was 28 kg/m2. All 30 subjects were included in the safety evaluation (Fig 1A). Per FDA guidelines,30 15 subjects who experienced emesis within 12 hours of dosing were excluded from the PK analyses. Twenty-two subjects were enrolled in study 2 and 20 were randomized to receive oxymorphone CRF. Sixteen subjects completed all 3 treatment periods (Fig 1B). Three subjects discontinued owing to treatmentemergent AEs (vomiting), and 1 was lost to follow-up. Most subjects were men (86%) and more than half were white (82%). The mean age was 35 years and the mean BMI was 27 kg/m2. All 22 subjects were included in the safety population, and the 16 subjects who completed the study and 1 who received a single dose of oxymorphone CRF with 20% ethanol and another dose with water were included in the PK analyses (Fig 1B).

Pharmacokinetics Oxymorphone Extended Release Oxymorphone plasma concentration versus time profiles for oxymorphone ER administered with each of the 4 ethanol concentrations are shown in Fig 4. Mean oxymorphone concentrations for the 4% ethanol treatment were similar to those for the 0% ethanol treatment

Figure 4. Mean oxymorphone plasma concentration versus time profiles after administration of oxymorphone ER with ethanol. ER, extended release.

Ethanol and Bioavailability of Oxymorphone ER over the first 12 hours after ethanol and oxymorphone ER coadministration. Secondary peaks in mean oxymorphone plasma concentrations were seen at 5 hours after coadministration of oxymorphone ER with 4 and 0% ethanol and at 12 hours after all treatments. Although mean oxymorphone plasma concentrations were higher between .5 and 6 hours after coadministration with 40% ethanol, these levels declined rapidly after 6 hours and were lower than the other 3 treatments at 8 to 12 hours. All curves were superimposable from 16 to 48 hours after dosing. Coadministration of oxymorphone ER with 4, 20, or 40% ethanol did not substantially alter oxymorphone AUC0–t, AUC0–inf, or tmax but did increase the oxymorphone Cmax (Table 1). The 90% CIs were contained within .80 and 1.25 for Cmax with 4% ethanol and for both AUC0–t and AUC0–inf for coadministration of oxymorphone ER with all 3 ethanol concentrations. The geometric mean ratios showed that Cmax was 70 and 31% higher when oxymorphone ER was coadministered with 40 and 20% ethanol, respectively, compared with water (Table 2).

Oxymorphone Crush-Resistant Formulation Mean oxymorphone concentration versus time profiles for oxymorphone CRF with each ethanol solution are plotted in Fig 5. For .5 to 6 hours after dosing, mean oxymorphone concentrations were highest when oxymorphone CRF was administered with 40% ethanol, lowest when administered with water, and intermediate when administered with 20% ethanol. Beginning at 8 hours postdose, mean oxymorphone concentrations were similar with 20 and 40% ethanol and slightly higher with water. Mean oxymorphone concentrations reached a plateau 2 to 5 hours after dosing with 40% ethanol and 2 to 10 hours after dosing with 20% ethanol or water. There were no substantial effects of 20% ethanol on any PK parameter compared with water. As with oxymorphone ER, coadministration of oxymorphone CRF with 40% ethanol had little effect on the AUC0–t, AUC0–inf, or tmax of oxymorphone but did increase the oxymorphone Cmax (Table 3). Cmax was higher and tmax was earlier when oxymorphone CRF was administered with 40% ethanol compared with administration with 20% ethanol or water. Mean oxymorphone concentrations for the 3 treatments were indistinguishable after 16 hours (Fig 5). For all parameters except Cmax, the 90% CIs when oxymorphone CRF was coadministered with 20% ethanol were within .80 and 1.25 of the values for coadministration with water. When oxymorphone CRF was coadministered with 40% ethanol, 90% CIs were outside the upper limit of 1.25 of the values for coadministration with water for AUC0–t, AUC0–inf, and Cmax. Geometric mean ratios showed that both AUC0–t and AUC0–inf were 14 to 15% higher when oxymorphone CRF was coadministered with 40% ethanol and 5% lower when coadministered with 20% ethanol compared with oxymorphone CRF coadministration with water. Geometric mean ratios for Cmax when oxymorphone CRF was coadministered with 40 and 20% ethanol were 80

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Mean (SD) Oxymorphone PK Parameters After Administration of Oxymorphone ER With 0 to 40% Aqueous Ethanol

Table 1.

ETHANOL CONCENTRATION PARAMETER, MEAN (SD) No. of subjects No. analyzed* Cmax, ng/mL AUC0–t, ng∙h/mL AUC0–inf, ng∙h/mL t½, h tmax,y h

40%

20%

4%

0%

25 15 3.92 (1.67) 36.38 (12.44) 39.97z (13.60) 11.3z (3.5) 1.5 (.756.0)

25 20 3.09 (1.15) 35.39 (11.50) 36.89 (12.36) 9.9 (3.2) 1.5 (.758.0)

25 25 2.56 (1.04) 35.15 (12.53) 37.55x (13.45) 10.4x (4.1) 3.0 (1.012.0)

25 25 2.37 (.87) 33.35 (11.86) 36.03x (11.39) 10.7x (4.7) 2.0 (.512.0)

Abbreviations: PK, pharmacokinetic; ER, extended release; Cmax, maximum plasma concentration; AUC0–t, area under the concentration versus time curve from time 0 to the last quantifiable concentration; AUC0–inf, area under the concentration versus time curve from time 0 to infinity; t½, terminal half-life; tmax, time to maximum plasma concentration. *PK data were excluded from 10 subjects in the 40% ethanol group and 5 subjects in the 20% ethanol group because of emesis that occurred within 12 hours of dosing. PK data were excluded from these subjects based on US Food and Drug Administration guidelines.30 yMedian and range reported for tmax. zn = 13. xn = 24.

and 14% higher, respectively, compared with coadministration with water (Table 4).

Safety Oxymorphone Extended Release No AEs were considered severe in intensity by the investigator. The most frequent AE was vomiting, which occurred more frequently during treatment with 40% ethanol (38% of subjects) compared with 20 and 4% ethanol solutions (21 and 4% of subjects, respectively). Other AEs that occurred in more than 2 subjects during a particular treatment included headache (15, 14, 11, and 8% of subjects during treatment with 40, 20, 4, and 0% ethanol, respectively), nausea (15, 0, 4, and 4%), and dizziness (4, 11, 7, and 0%). The overall incidence of AEs was highest during treatment with the 40 and 20% ethanol solutions (54 and 43%, respectively) relative to the incidence with 4% ethanol (21%) and water (20%). Other than vomiting, which was considered

moderate in severity, all AEs were considered mild in intensity by the investigator. The 1 subject who discontinued because of an AE experienced generalized pruritus and macular rash, as well as a burning sensation on the face, after administration of naltrexone. These AEs were considered mild in intensity and not related to the study medication; they resolved spontaneously at 1.5 hours (pruritus, rash) and 7 hours (burning sensation) after onset. There were no serious or unexpected AEs in this study. No clinically important effects of study treatments were observed on blood pressures, respiration rates, physical examination findings, and clinical laboratory results. Mean heart rate was increased at 6 and 12 hours after dosing in proportion to the amount of ethanol consumed, but the pattern was no longer evident at 24 and 48 hours.

Oxymorphone Crush-Resistant Formulation As with oxymorphone ER, no severe AEs after administration of oxymorphone CRF were reported. The most

Table 2. Geometric Mean Ratios Versus Water and 90% CIs for Oxymorphone After Administration of Oxymorphone ER With 4 to 40% Aqueous Ethanol PARAMETER, GEOMETRIC MEAN RATIO (90% CI) No. of subjects No. analyzed* Cmax AUC0–t AUC0–inf

ETHANOL CONCENTRATION 40%

20%

4%

25 15 1.70 (1.48–1.97) 1.13 (1.03–1.24) 1.13y (1.03–1.24)

25 20 1.31 (1.15–1.49) 1.04 (.95–1.13) 1.01 (.93–1.09)

25 25 1.07 (.95–1.21) 1.06 (.97–1.14) 1.02z (.95–1.10)

Abbreviations: ER, extended release; Cmax, maximum plasma concentration; AUC0-t, area under the concentration versus time curve from time 0 to the last quantifiable concentration; AUC0-inf, area under the concentration versus time curve from time 0 to infinity. *PK data were excluded from 10 subjects in the 40% ethanol group and 5 subjects in the 20% ethanol group because of emesis that occurred within 12 hours of dosing. PK data were excluded from these subjects based on US Food and Drug Administration guidelines.30 yn = 13. zn = 24.

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Geometric Mean Ratios Versus Water and 90% CIs for Oxymorphone After Administration of Oxymorphone CRF With 20 to 40% Aqueous Ethanol

Table 4.

ETHANOL CONCENTRATION PARAMETER, GEOMETRIC MEAN RATIO (90% CI)

Figure 5. Mean oxymorphone plasma concentration versus time profiles after administration of oxymorphone crushresistant formulation with ethanol. frequent AE was vomiting, which occurred exclusively when oxymorphone CRF was coadministered with 40% ethanol (21% of subjects). Other AEs reported in more than 2 subjects after 1 of the 3 treatments included nausea (16, 6, and 0% of subjects during treatment with 40, 20, and 0% ethanol, respectively), headache (16, 0, and 0%), dizziness (16, 0, and 0%), somnolence (16, 6, and 6%), and feeling hot (11, 12, and 0%). All AEs were considered mild in intensity. Five different subjects each experienced a single event of somnolence, 3 during coadministration of oxymorphone CRF with 40% ethanol (durations of 3 hours, 7 hours 10 minutes, and 8 hours), 1 with 20% ethanol (duration of 2 hours 20 minutes), and 1 with water (duration of 1 hour). Overall, the incidence of AEs increased in proportion to the amount of alcohol consumed but not in proportion to systemic exposure to oxymorphone and 6-OH-oxymorphone. All AEs resolved without intervention. Three subjects discontinued treatment owing to vomiting that was considered possibly related to study treatment; all had taken oxymorphone CRF with 40% ethanol. No serious AEs were reported. No clinically important effects of study

Mean (SD) Oxymorphone Pharmacokinetic Parameters After Administration of Oxymorphone CRF With 0 to 40% Aqueous Ethanol

Table 3.

ETHANOL CONCENTRATION PARAMETER, MEAN (SD)

40%

20%

0%

No. of subjects No. analyzed Cmax, ng/mL AUC0–t, ng∙h/mL AUC0–inf, ng∙h/mL t½, h tmax, h*

14 14 3.9 (2.3) 35.6 (14.1) 35.6 (13.9) 9.2 (2.3) 2.0 (.5–6.0)

17 17 2.3 (1.1) 28.4 (8.8) 30.0 (9.0) 9.8 (2.6) 5.0 (.5–12.0)

17 17 2.0 (.7) 30.0 (9.2) 31.6 (9.9) 10.7 (3.5) 5.0 (.8–12.0)

Abbreviations: CRF, crush-resistant formulation; Cmax, maximum plasma concentration; AUC0-t, area under the concentration versus time curve from time 0 to the last quantifiable concentration; AUC0-inf, area under the concentration versus time curve from time 0 to infinity; t½, terminal half-life; tmax, time to maximum plasma concentration. *Median and range reported for tmax.

No. of subjects No. analyzed Cmax AUC0–t AUC0–inf

40%

20%

14 14 1.80 (1.49–2.16) 1.15 (1.01–1.32) 1.14 (.99–1.31)

17 17 1.14 (.96–1.35) 0.95 (.84–1.08) 0.95 (.84–1.08)

Abbreviations: CRF, crush-resistant formulation; Cmax, maximum plasma concentration; AUC0-t, area under the concentration versus time curve from time 0 to the last quantifiable concentration; AUC0-inf, area under the concentration versus time curve from time 0 to infinity.

treatments were observed in blood pressure, respiration rate, heart rate, physical examination findings, and clinical laboratory results.

Discussion Extended-release opioids are a valuable component of the chronic pain management armamentarium but are associated with risks of accidental overdose and abuse. Stability of the extended-release mechanism when combined with ethanol is an important safety concern. In 2 studies, we sought to determine whether administration of oxymorphone ER or CRF with ethanol alters the PK of either formulation in a clinically meaningful way. In particular, we wanted to confirm that ethanol does not cause excessive exposure (dose dumping) to oxymorphone from oxymorphone ER or CRF tablets. In vitro dissolution studies demonstrated that ethanol at concentrations #40% does not cause premature release of oxymorphone from either tablet formulation; in fact, the dissolution rates of oxymorphone ER and CRF tablets in 40% ethanol were slower than the dissolution rates observed in water. Because of the complexity of living systems, in vitro results do not always reliably predict in vivo observations. For oxymorphone ER and CRF, coadministration with ethanol had measureable effects on PK parameters compared with coadministration with water. The lowest concentration and quantity of ethanol administered (240 mL of 4% ethanol; studied only with oxymorphone ER) was intended to model modest ethanol consumption, whereas the highest concentration (240 mL of 40% ethanol) modeled serious ethanol abuse. The AUC was virtually unchanged in subjects after oxymorphone ER was coadministered with 240 mL of 40, 20, or 4% ethanol, indicating that overall oxymorphone exposure was similar under each treatment condition. However, although mean Cmax was unchanged by 4% ethanol compared with water, coadministration of oxymorphone ER 40 mg with 240 mL of 20% ethanol, and to a greater extent 40% ethanol, under fasted

Fiske et al conditions increased the Cmax by 31 and 70%, respectively, compared with water. Similarly, coadministration of oxymorphone CRF with 20 and 40% ethanol increased mean Cmax by 14 and 80%, respectively, compared with water, but had little effect on oxymorphone AUC, indicating that total exposure remained relatively unchanged. The maximum mean effects of ethanol, compared with water, on AUC and Cmax were slightly more variable with oxymorphone ER than with oxymorphone CRF; however, results from the separate studies may not be directly comparable and the differences between the 2 formulations were not clinically significant. Collectively, these results suggest that modest ethanol consumption is unlikely to produce clinically meaningful effects in patients taking oxymorphone ER or oxymorphone CRF but that moderate ethanol use or ethanol abuse may produce maximum oxymorphone exposure in individual patients that is meaningfully increased and occurs more rapidly (ie, greater Cmax and smaller tmax), without changing overall exposure (ie, stable AUC). A similar pattern for AUC and Cmax has been seen when other opioids are taken with ethanol under fasting conditions; for 40% ethanol, these include hydromorphone prolonged release (AUC increased 26%, but Cmax increased 453% [tmax not reported]),32 OROS hydromorphone (AUC increased 2%, but Cmax increased 28% and tmax decreased by 4 hours),25 morphine sulfate and naltrexone hydrochloride extended release (AUC decreased by 3%, but Cmax increased 100% and tmax decreased by 5 hours),15 morphine sulfate extended release (AUC decreased 11%, but Cmax increased 2% and tmax was unchanged).14 Potential mechanisms for the influence of ethanol on PK parameters for oxymorphone ER and CRF are not known, but in vitro studies suggest that they do not involve deterioration of the oxymorphone ER or CRF matrix by ethanol. The rate of gastric emptying is known to be delayed by both ethanol and a high-fat meal, which could influence the systemic availability of the drug.10,26 Effects on Cmax similar to those of ethanol were observed when oxymorphone ER 40-mg tablets were administered with a high-fat meal.6 Although there was an approximately 50% increase in Cmax in subjects fed a high-fat meal compared with fasted subjects, AUC was relatively unchanged.6 Thus, a common mechanism may account for the increased Cmax in subjects administered ethanol or a high-fat meal with the oxymorphone ER formulation. Consistent with this, the pattern of greater effects on Cmax than on AUC was not seen when oxycodone sustained release was taken with 40% ethanol by fed subjects; instead, both parameters increased to a small and similar degree (AUC, 18%; Cmax, 14%; tmax was unchanged).3 The clinical relevance of the transitory increases in absorption and whether there is any pharmacodynamic interaction have not been determined. However, because of the potential for increased plasma levels, patients must not consume alcoholic beverages or prescription or nonprescription medications containing ethanol while taking oxymorphone ER or CRF.21 In these studies,

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subject safety was carefully monitored in the environment of a controlled testing center; outside such a supervised setting, patients taking oxymorphone ER or CRF with alcohol could be at greater risk of serious complications; for example, emesis that could lead to asphyxiation in the sedated state. Moreover, oxymorphone ER, oxymorphone CRF, and other ER opioids carry warnings against ethanol use because of the potential additive depressive effects on the central nervous system.4,5,16,22,28 Based on these results, it is not possible to characterize the extent to which the additive effects of opioid and ethanol might compromise safety and tolerability in clinical practice. In our studies, the observed AEs resulting from concomitant administration of graded concentrations of ethanol with oxymorphone ER 40-mg tablets and oxymorphone CRF 40-mg tablets would be expected to occur with the quantities of ethanol administered alone and to increase in frequency with increasing concentration of ethanol. Although the kind of AEs observed (eg, vomiting, nausea, headache, dizziness) were similar to those reported for other opioids,17 the administration of naltrexone in this study was intended to minimize opioid-related AEs, and the increased frequency of AEs with increasing ethanol concentration would suggest that ethanol was the more influential factor in producing these AEs. In clinical practice, however, elevated opioid concentrations in the absence of naltrexone would likely be accompanied by increased occurrence of opioid-related AEs, and patients with both increased opioid exposure and significant blood ethanol levels might reasonably be expected to be at increased risk of significant or even dangerous AEs. Patients should therefore be advised to take the warnings on opioid labeling very seriously. In summary, there is an interaction between ethanol and oxymorphone ER or oxymorphone CRF 40-mg tablets when coadministered to healthy subjects. The ethanol effect was manifested by an ethanol concentration–dependent increase in Cmax, whereas AUC was unchanged. Increased systemic exposure to oxymorphone was greatest in the presence of excessive levels of ethanol (40%), which models serious ethanol abuse, but its clinical importance is not known. For oxymorphone ER, the increase was comparable to the effect of a high-fat meal on oxymorphone ER but appeared unrelated to ethanol-mediated deterioration of the formulation.

Acknowledgments The authors thank Gabriela Photivihok-Achenbach and Paula Allen for their contributions to the conduct of the in vivo studies. Jeffrey Coleman, MA, and Robert Gatley, MD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA) provided editorial support for this manuscript with funding from Endo Pharmaceuticals. The crush-resistant formulation technology was developed by and is the property of € nenthal, Aachen, Germany. Endo holds an excluGru sive license for use of the technology with Opana ER.

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