1 INDICATIONS AND USAGE COMBOGESIC IV is indicated in adults where an intravenous route of administration is considered clinically necessary for: • the relief of mild to moderate pain • the management of moderate to severe pain as an adjunct to opioid analgesics Limitations of Use COMBOGESIC IV is indicated for short-term use of five days or less.

COMBOGESIC IV is indicated in adults where an intravenous route of administration is considered clinically necessary for: • the relief of mild to moderate pain • the management of moderate to severe pain as an adjunct to opioid analgesics Limitations of Use COMBOGESIC IV is indicated for short-term use of five days or less.

6 ADVERSE REACTIONS The following clinically significant adverse reactions to ibuprofen or acetaminophen are described elsewhere in other sections of the labelling.

• Hepatotoxicity [see Warnings and Precautions (5.2) ] • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.3) ] • Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.4) ] • Hypertension [see Warnings and Precautions (5.5) ] • Heart Failure and Edema [see Warnings and Precautions (5.6) ] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.7) ] • Hypersensitivity and Anaphylactic Reactions [see Warnings and Precautions (5.8) ] • Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.9) ] • Serious Skin Reactions [see Warnings and Precautions (5.10) ] • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.11) ] • Hematologic Toxicity [see Warnings and Precautions (5.13) ] The most common adverse reactions (greater than or equal to 3%) are infusion site pain, nausea, constipation, dizziness, infusion site extravasation, vomiting, headache, somnolence.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.

at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical trials of COMBOGESIC IV have been conducted in patients with postoperative musculoskeletal pain and soft tissue pain models lasting between two to five days.

Two Phase 3 clinical trials have been conducted with COMBOGESIC IV to assess efficacy and safety after multiple doses.

In AFT-MXIV-07 participants were treated with COMBOGESIC IV, acetaminophen IV, ibuprofen IV or placebo for a treatment period of 48 hours.

In AFT-MXIV-11 participants were treated for between 48 hours and five days with COMBOGESIC IV.

The study population for AFT-MXIV-07 was comprised of adults aged 18 to 65 years, mean age: 42 years.

AFT-MXIV-11 included adults aged 19 – 87 years, mean age: 53 years.

Safety data for the first 48 hours of both studies was pooled.

Overall, 59.3% of the patients (N = 182/307) administered COMBOGESIC IV experienced one or more treatment-emergent adverse event (TEAE) during the first 48 hours of treatment, accounting for a total of 436 TEAEs (see Table 1).

The most common TEAEs were related to the infusion site (infusion site pain, infusion site extravasation), or affected the gastrointestinal (nausea, vomiting, constipation) or nervous (dizziness, headache, somnolence) systems.

Table 1: Common TEAEs (occurring in ≥ 3% of COMBOGESIC IV-treated participants) Adverse Reactions COMBOGESIC IV (N=307) % Acetaminophen (N=75) % Ibuprofen (N=76) % Placebo (N=50) % Gastrointestinal disorders Nausea 16.3 33.3 34.2 32.0 Vomiting 6.2 14.7 6.6 2.0 Constipation 7.2 5.3 5.3 8.0 Infusion Site Complications Infusion site pain 17.6 0.0 9.2 2.0 Infusion site extravasation 6.5 2.7 6.6 14.0 Nervous System Disorders Headache 5.5 6.7 6.6 20.0 Dizziness 7.2 9.3 9.2 18.0 Somnolence 3.9 8.0 7.9 6.0 Other skin and subcutaneous-related TEAEs (pruritis, hyperhidrosis) also affected around 2-3% of the study population, as did procedural nausea and polyuria.

AFT-MXIV-11 found no notable difference in the safety profile of COMBOGESIC IV in participants treated for 5 days compared to those treated for 48 hours.

Additionally, the safety profile was comparable between older participants (aged 65-75 years and >75 years) and younger participants (aged <65 years); the type and incidence of treatment-emergent adverse events was comparable, and the incidence of clinically significant shifts in laboratory tests (hematocrit 1.3% (n=3/228), hemoglobin 1.3% (n=3/228) and erythrocytes 0.9% (n=2/218), was low in participants over the age of 65.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of acetaminophen and ibuprofen.

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.

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).