specialty [10%)::<1%): Eye disorders : vision blurred, orthostatic hypotension Gastrointestinal disorders : abdominal distension, pancreatitis, abdominal discomfort, fecaloma, abdominal pain lower, abdominal tenderness General disorders and administration site conditions : malaise, asthenia, feeling jittery, drug withdrawal syndrome Hepatobiliary disorders : cholecystitis Investigations : alanine aminotransferase increased, aspartate aminotransferase increased Musculoskeletal and connective tissue disorders : myalgia, muscular weakness Nervous system disorders : depressed level of consciousness, mental impairment, memory impairment, disturbance in attention, stupor, paresthesia, coordination abnormal Psychiatric disorders : disorientation, thinking abnormal, mental status changes, confusional state, euphoric mood, hallucination, abnormal dreams, mood swings, nervousness Renal and urinary disorders : urinary retention, dysuria Reproductive system and breast disorders : erectile dysfunction Respiratory, thoracic and mediastinal disorders : dyspnea, rhinorrhea Skin and subcutaneous tissue disorders : rash, piloerection, cold sweat, night sweats Vascular disorders : hypotension, flushing Postmarketing Experience The following adverse reactions have been identified during post-approval use of morphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Embeda. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ] . Drug Interactions Table 3 includes clinically significant drug interactions with Embeda. Table 3: Clinically Significant Drug Interactions with Embeda Alcohol Clinical Impact: Concomitant use of alcohol with Embeda can result in an increase of morphine plasma levels and potentially fatal overdose of morphine. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on Embeda therapy [see Warnings and Precautions (5.4) , Clinical Pharmacology (12.3) ] . Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Dosage and Administration (2.4) and Warnings and Precautions (5.4) ] . Examples: Benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Embeda if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6) ]. Intervention: Do not use Embeda in patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Embeda and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Opioids may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Embeda and/or muscle relaxant as necessary. Cimetidine Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Monitor patients for respiratory depression that may be greater than otherwise expected and decrease the dosage of Embeda and/or cimetidine as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Embeda is used concomitantly with anticholinergic drugs. P-Glycoprotein (PGP) Inhibitors Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure of morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Embeda and/or PGP-inhibitor as necessary. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3) ]. There are no available data with Embeda in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data ] . In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data ] . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 4% and 15 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Embeda is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Embeda, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Animal Data Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear. Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity. An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated. In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater. Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD). Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD). Lactation Risk Summary Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with extended-release morphine, including Embeda. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Embeda. Clinical Considerations Monitor infants exposed to Embeda through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Clinical Pharmacology (12.2) ] . In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [See Nonclinical Toxicology (13.1) ] . Pediatric Use The safety and efficacy of Embeda in patients less than 18 years of age have not been established. Geriatric Use Clinical studies of Embeda did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. The pharmacokinetics of Embeda have not been investigated in elderly patients (>65 years) although such patients were included in clinical studies. In a long-term open-label safety study, the pre-dose plasma morphine concentrations after dose normalization were similar for subjects> <65 years and those ≥65 years of age. Limited data are available on the pharmacokinetics of Embeda in geriatric patients [see Clinical Pharmacology (12.3) ]. Elderly patients (aged 65 years or older) may have increased sensitivity to Embeda. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Embeda slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5) ] . This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Hepatic Impairment Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Embeda and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) ]. Renal Impairment Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Embeda and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) ]. Drug Abuse and Dependence Controlled Substance Embeda contains morphine, a Schedule II controlled substance. Abuse Embeda contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Embeda can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) ]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Embeda, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Embeda Embeda is for oral use only. Abuse of Embeda poses a risk of overdose and death. This risk is increased with concurrent abuse of Embeda with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved Embeda enhances drug release and increases the risk of overdose and death. The sequestered naltrexone hydrochloride in Embeda is intended to have no clinical effect when Embeda is taken as directed; however, if the capsules are crushed or chewed, up to 100% of the sequestered naltrexone HCl dose could be released, bioequivalent to an immediate-release (IR) naltrexone HCl oral solution of the same dose. In opioid-tolerant individuals, the absorption of naltrexone HCl may increase the risk of precipitating withdrawal. Due to the presence of talc as one of the excipients in Embeda, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies Embeda is formulated with a sequestered opioid antagonist, naltrexone HCl, which is released with manipulation by crushing. In Vitro Testing In vitro laboratory tests were performed to evaluate the effect of different physical and chemical conditions intended to defeat the extended-release formulation. When Embeda is crushed and mixed in a variety of solvents, both morphine sulfate and naltrexone hydrochloride are simultaneously extracted. Clinical Studies The abuse potential of Embeda when crushed was examined in three studies following administration by the oral (Studies 1 and 2) and intranasal (Study 3) routes. A fourth study was conducted with IV administration of simulated crushed Embeda (Study 4). These were randomized, double-blind, single dose, placebo and active-controlled, crossover studies in non-dependent recreational opioid users. Drug Liking in Studies 1 3 was measured on a bipolar 100-point Visual Analog Scale (VAS) where 0 represents maximum disliking, 50 represents a neutral response (neither like nor dislike), and 100 represents maximum liking. Drug Liking in Study 4 and Drug High in all studies was measured on a unipolar 100-point VAS where 0 represents no response and 100 represents maximum response. Response to whether the subject would take the study drug again was also measured in two studies (Study 2, Study 3) on a bipolar 100-point VAS where 0 represents the strongest negative response (e.g., 'definitely would not'), 50 represents a neutral response, and 100 represents the strongest positive response (e.g., 'definitely would'). The pharmacokinetics of morphine sulfate and naltrexone hydrochloride were also determined in these abuse potential studies. When Embeda was crushed and administered by the oral and intranasal routes, morphine and naltrexone were absorbed with similar median time-to-peak concentration (T max ) values of 1 hour following oral administration and approximately 36 minutes following intranasal administration. Oral Studies: Study 1 compared Embeda to IR morphine sulfate. In this study 32 subjects received four treatments: 120 mg/4.8 mg as intact Embeda capsules, 120 mg/4.8 mg as crushed Embeda in solution, 120 mg IR morphine in solution, and placebo. When Embeda was crushed and taken orally, the geometric mean ( SD) values for naltrexone C max and AUC inf were 1073 721 pg/mL and 3649 1868 pg hr/mL, respectively. The oral administration of crushed Embeda was associated with statistically significantly lower mean and median Drug Liking and Drug High scores compared with crushed IR morphine (as summarized in Table 4). Figure 1 (Study 1) demonstrates a comparison of Drug Liking for crushed Embeda compared to crushed IR morphine sulfate when given by the oral route in subjects who received both treatments. The Y-axis represents the percent of subjects attaining a percent reduction in Drug Liking with crushed Embeda vs. morphine greater than or equal to the value on the X-axis. Of the 32 subjects who completed the study, approximately 81% of subjects had some reduction in Drug Liking and Drug High with crushed Embeda compared to administration of IR morphine sulfate, while approximately 19% had no reduction in Drug Liking or in Drug High. At least a 30% and 50% reduction in Drug Liking with crushed Embeda compared to IR morphine was observed in 72% and 56% of subjects, respectively (summarized in Figure 1). At least a 30% and 50% reduction in Drug High with crushed Embeda was observed in 56% and 31% of subjects, respectively. Study 2 compared Embeda to ER morphine sulfate. In this study 36 subjects were randomized to receive three treatments in solution: 120 mg/4.8 mg as crushed Embeda capsules, 120 mg crushed ER morphine, and placebo. When Embeda was crushed and taken orally, the geometric mean ( SD) values for naltrexone C max , AUC 0 2h , and AUC inf were 824 469 pg/mL, 1121 561 pg hr/mL, and 2984 1388 pg hr/mL, respectively. The oral administration of crushed Embeda was associated with statistically significantly lower mean and median Drug Liking, Drug High, and Take Drug Again scores compared with crushed ER morphine (summarized in Table 4). Figure 1 (Study 2) demonstrates a comparison of maximum Drug Liking for crushed Embeda compared to crushed ER morphine in subjects who received both treatments. Of the 33 subjects who completed the study, approximately 85% of subjects had some reduction in Drug Liking with crushed Embeda compared to administration of crushed ER morphine sulfate, while approximately 15% had no reduction in Drug Liking. Similarly, 100% of subjects showed some reduction in Drug High with crushed Embeda compared to crushed ER morphine. At least a 30% and 50% reduction in Drug Liking with crushed Embeda compared to crushed ER morphine was observed in 76% and 52% of subjects, respectively (summarized in Figure 1). At least a 30% and 50% reduction in Drug High with crushed Embeda was observed in 79% and 64% of subjects, respectively. Table 4. Summary of Abuse Potential Maximal Responses (E max) with Oral Administration of Crushed Embeda Compared to Crushed IR Morphine Sulfate (Study 1) or Crushed ER Morphine (Study 2) VAS Scale (100 point) E max Crushed Embeda (120 mg/4.8 mg) Crushed Morphine (120 mg ) E max = maximal response; ER = extended release; IR = immediate release; SE = standard error. * Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response). † Presented on a unipolar 100-point VAS scale (0=no response, 100=maximum response). Study 1 Immediate Release Drug Liking * Mean (SE) 68.1 (3.1) 89.5 (2.2) Median (range) 62 (50 100) 93 (57 100) Drug High † Mean (SE) 54.7 (6.1) 90.2 (2.1) Median (range) 64 (0 100) 97 (61 100) Study 2 Extended Release Drug Liking * Mean (SE) 65.2 (2.0) 80.6 (2.3) Median (range) 65 (51 100) 81 (50 100) Drug High † Mean (SE) 29.2 (3.6) 64.1 (3.3) Median (range) 27 (0 78) 63 (28 100) Take Drug Again * Mean (SE) 58.0 (3.8) 70.6 (4.3) Median (range) 58 (9 100) 75 (12 100) Figure 1: Percent Reduction Profiles for E max of Drug Liking VAS for Embeda vs. Morphine Following Oral Administration in Studies 1 and 2. Intranasal Study: Study 3 compared intranasal administration of crushed Embeda to crushed ER morphine sulfate. In this study, 33 subjects were randomized to receive three treatments: 30 mg/1.2 mg as crushed Embeda, 30 mg crushed ER morphine, and crushed placebo. When Embeda was crushed and taken intranasally, the geometric mean ( SD) values for naltrexone C max , AUC 0 2h , and AUC inf were 1441 411 pg/mL, 1722 441 pg hr/mL and 3228 846 pg hr/mL, respectively. Intranasal administration of crushed Embeda was associated with statistically significantly lower mean and median Drug Liking, Drug High, and Take Drug Again scores compared with crushed ER morphine (summarized in Table 5). Figure 2 demonstrates a comparison of maximum Drug Liking for intranasal administration of crushed Embeda compared to crushed ER morphine in subjects who received both treatments. Of the 27 subjects who completed the study, approximately 78% of subjects had some reduction in Drug Liking with crushed Embeda compared to administration of crushed ER morphine sulfate, while approximately 22% had no reduction in Drug Liking. Similarly, approximately 70% of subjects showed some reduction in Drug High with crushed Embeda compared to crushed ER morphine and approximately 30% of subjects had no reduction in Drug High. At least a 30% and 50% reduction in Drug Liking with crushed Embeda compared to crushed ER morphine was observed in 63% and 59% of subjects, respectively (summarized in Figure 2). At least a 30% and 50% reduction in Drug High with crushed Embeda was observed in 59% and 37% of subjects, respectively. Table 5. Summary of Abuse Potential Maximal Responses (E max) with Intranasal Administration of Crushed Embeda Compared to Crushed ER Morphine Sulfate (Study 3) VAS Scale (100 point) E max Crushed Embeda (30 mg/1.2 mg) Crushed ER Morphine (30 mg) E max = maximal response; ER = extended release; SE = standard error. * Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response). † Presented on a unipolar 100-point VAS scale (0=no response, 100=maximum response). Drug Liking * Mean (SE) 69.0 (3.5) 88.4 (3.2) Median (range) 66 (50 100) 100 (51 100) Drug High † Mean (SE) 48.6 (7.8) 84.4 (3.8) Median (range) 51 (-39 100) 100 (42 100) Take Drug Again * Mean (SE) 59.1 (5.4) 87.0 (4.0) Median (range) 56 (0 100) 100 (12 100) Figure 2: Percent Reduction Profiles for E max of Drug Liking VAS for Embeda vs. Morphine Following Intranasal Administration in Study 3. Simulated IV Study: Study 4, a randomized double-blind, placebo-controlled, three-way cross-over trial in 28 non-dependent recreational opioid users, was performed using 30 mg of intravenous (IV) morphine sulfate alone and 30 mg of IV morphine sulfate smart move
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