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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

Adverse Reaction Titration Maintenance
EMBEDA
(N=547)
n (%)
EMBEDA
(N=171)
n (%)
Placebo
(N=173)
n (%)
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

Adverse Reaction EMBEDA
(N=465)
n (%)
Constipation 145 (31%)
Nausea 103 (22%)
Vomiting 37 (8%)
Somnolence 34 (7%)
Headache 32 (7%)
Pruritus 26 (6%)
Fatigue 19 (4%)
Dizziness 19 (4%)
Dry mouth 17 (4%)
Hyperhidrosis 16 (3%)
Insomnia 13 (3%)
Diarrhea 10 (2%)
Anxiety 10 (2%)

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

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

Anaphylaxis has been reported with ingredients contained in EMBEDA. Advise patients how to recognize such a reaction and when to seek medical attention.