"The U.S. Food and Drug Administration today approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternat"...
The following serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Life Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Hypotensive Effect [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
In the randomized study, the most common adverse reactions with EMBEDA therapy were constipation, nausea, and somnolence. The most common adverse reactions leading to study discontinuation were nausea, constipation (sometimes severe), vomiting, fatigue, dizziness, pruritus, and somnolence.
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Short-Term Randomized Study
This study utilized an enriched enrollment with a randomized withdrawal design in which subjects were titrated to effect on open-label EMBEDA for up to 45 days. Once their pain was controlled, 344 of 547 subjects were randomized to either an active treatment with EMBEDA or were tapered off EMBEDA using a double-dummy design and placed on placebo. The maintenance Period was 12 weeks. Adverse reactions, reported in ≥ 2% of subjects in either the titration or maintenance phase of the 12-week study are presented in Table 1.
Table 1: Adverse Reactions Reported in ≥ 2%
of Subjects in the Randomized Study
|Constipation||165 (30%)||12 (7%)||7 (4%)|
|Nausea||106 (19%)||19 (11%)||11 (6%)|
|Somnolence||76 (14%)||2 (1%)||5 (3%)|
|Vomiting||46 (8%)||7 (4%)||2 (1%)|
|Dizziness||42 (8%)||2 (1%)||2 (1%)|
|Pruritus||34 (6%)||0||1 (1%)|
|Dry mouth||31 (6%)||3 (2%)||2 (1%)|
|Headache||22 (4%)||4 (2%)||2 (1%)|
|Fatigue||16 (3%)||1 (1%)||2 (1%)|
|Insomnia||7 (1%)||5 (3%)||4 (2%)|
|Diarrhea||6 (1%)||12 (7%)||12 (7%)|
|Abdominal pain upper||6 (1%)||4 (2%)||3 (2%)|
|Flushing||0||4 (2%)||1 (1%)|
Long-Term Open-Label Safety Study
In the long-term open-label safety study, 465 patients with chronic non-malignant pain were enrolled and 124 patients were treated for up to 1 year. The distributions of adverse events were similar to that of the randomized, controlled studies, and were consistent with the most common opioid-related adverse reactions. Adverse reactions reported in > 2.0% of subjects are presented in Table 2.
Table 2: Adverse Reactions
Reported by ≥ 2.0% of Subjects in Long-Term Safety Study
|Dry mouth||17 (4%)|
Adverse Reactions Observed in the Phase 2/3 Studies
Most common ( ≥ 10%): constipation, nausea, somnolence
Common ( ≥ 1% to < 10%): vomiting, headache, dizziness, pruritus, dry mouth, diarrhea, fatigue, insomnia, hyperhidrosis, anxiety, chills, abdominal pain, lethargy, edema peripheral, dyspepsia, anorexia, muscle spasms, depression, flatulence, restlessness, decreased appetite, irritability, stomach discomfort, tremor, arthralgia, hot flush, sedation
Less Common ( < 1%):
Eye disorders: vision blurred, orthostatic hypotension
Gastrointestinal disorders: abdominal distension, pancreatitis, abdominal discomfort, fecaloma, abdominal pain lower, abdominal tenderness
Hepatobiliary disorders: cholecystitis
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
Vascular disorders: hypotension, flushing
Anaphylaxis has been reported with ingredients contained in EMBEDA. Advise patients how to recognize such a reaction and when to seek medical attention.
Read the Embeda (morphine sulfate and naltrexone hydrochloride) Side Effects Center for a complete guide to possible side effects
Concomitant use of alcohol with EMBEDA can result in an increase of morphine plasma levels and potentially fatal overdose of morphine. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on EMBEDA therapy [see CLINICAL PHARMACOLOGY].
The concomitant use of EMBEDA with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and EMBEDA for signs of respiratory depression, sedation and hypotension.
Mixed Agonist/Antagonist And Partial Agonist Opioid Analgesics
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of EMBEDA and/or may precipitate withdrawal symptoms. Avoid the use of agonist/antagonist and partial agonist analgesics in patients receiving EMBEDA.
Opioids may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and EMBEDA for signs of respiratory depression that may be greater than otherwise expected.
Monoamine Oxidase Inhibitors (MAOIs)
The effects of morphine may be potentiated by MAOIs. Monitor patients on concurrent therapy with an MAOI and EMBEDA for increased respiratory and central nervous system depression. MAOIs have been reported to potentiate the effects of morphine anxiety, confusion, and significant depression of respiration or coma. EMBEDA should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
Cimetidine can potentiate morphine-induced respiratory depression. There is a report of confusion and severe respiratory depression when a patient undergoing hemodialysis was concurrently administered morphine and cimetidine. Monitor patients for respiratory depression when EMBEDA and cimetidine are used concurrently.
Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates.
Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when EMBEDA is used concurrently with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
P-gp inhibitors (e.g., quinidine) may increase the absorption/exposure of morphine by about two-fold. Monitor patients for signs of respiratory and CNS depression when P-gp inhibitors are used concurrently with EMBEDA.
Drug Abuse And Dependence
EMBEDA contains morphine, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. EMBEDA can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].
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, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the counter drug to get ”high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: 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 physical withdrawal.
“Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(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. Physicians 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 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 reduce 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 substances. Taking 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, 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.
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 (Tmax) values of 1 hour following oral administration and approximately 36 minutes following intranasal administration.
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 Cmax and AUCinf 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 3).
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 Cmax, AUC0-2h, and AUCinf 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 3).
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 3: Summary of Abuse
Potential Maximal Responses (Emax) with Oral Administration of Crushed EMBEDA
Compared to Crushed IR Morphine Sulfate (Study 1) or Crushed ER Morphine (Study
|VAS Scale (100 point)||Emax|
|Crushed EMBEDA (120 mg/4.8 mg)||Crushed Morphine (120 mg )|
|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)|
|* 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).
Emax = maximal response; ER = extended release; IR = immediate release; SE = standard error.
Figure 1: Percent Reduction
Profiles for Emax of Drug Liking VAS for EMBEDA vs. Morphine Following Oral
Administration in Studies 1 and 2.
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 Cmax, AUC0-2h, and AUCinf 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 4).
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 4: Summary of Abuse Potential
Maximal Responses (Emax) with Intranasal Administration of Crushed EMBEDA
Compared to Crushed ER Morphine Sulfate (Study 3)
|VAS Scale (100 point)||Emax|
|Crushed EMBEDA (30 mg/1.2 mg)||Crushed ER Morphine (30 mg)|
|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)|
|* 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). Emax = maximal response; ER = extended release; SE = standard error.
Figure 2: Percent Reduction
Profiles for Emax 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 in combination with 1.2 mg of IV naltrexone to simulate parenteral use of crushed EMBEDA. These doses were based on the assumption of the complete release of both morphine sulfate and naltrexone hydrochloride upon crushing EMBEDA. Intravenous administration of the combination of morphine sulfate and naltrexone hydrochloride was associated with statistically significantly lower mean and median Drug Liking and Drug High scores (median scores 34 and 23, respectively) compared with morphine alone (median scores 86 and 89, respectively). Three of the 26 subjects who completed the study had no reduction in Drug Liking and all the subjects showed some reduction in Drug High. Intravenous injection of crushed EMBEDA may result in serious injury and death due to a morphine overdose and may precipitate a severe withdrawal syndrome in opioid-dependent patients.
The in vitro and pharmacokinetic data demonstrate that crushing EMBEDA pellets results in the simultaneous release and rapid absorption of morphine sulfate and naltrexone hydrochloride. These data along with results from the oral and intranasal human abuse potential studies indicate that EMBEDA has properties that are expected to reduce abuse via the oral and intranasal route. However, abuse of EMBEDA by these routes is still possible.
Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of EMBEDA on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.
A human abuse potential study of intravenous morphine and naltrexone to simulate crushed EMBEDA demonstrated lower Drug Liking and Drug High compared with morphine alone. However, it is unknown whether these results with simulated crushed EMBEDA predict a reduction in abuse by the IV route until additional postmarketing data are available.
EMBEDA contains morphine sulfate, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal and illicit, including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. EMBEDA can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS and Drug Abuse and Dependence].
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
EMBEDA should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If EMBEDA is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations].
Read the Embeda Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/31/2014
This monograph has been modified to include the generic and brand name in many instances.
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