Regulatory Decision Summary for Combogesic IV

This New Drug Submission was submitted to seek approval for Combogesic IV, a combination of ibuprofen (3 milligrams per millilitre [mg/mL]) and acetaminophen (10 mg/mL) in a solution formulation. The sponsor was seeking indications for the treatment of mild to moderate pain, management of moderate to severe pain as an adjunct to opioid analgesics, as well as for the reduction of fever, when the intravenous route of administration is the only suitable option. Upon review, only the indications for mild to moderate pain and moderate to severe pain as an adjunct to opioid analgesics were granted.

This New Drug Submission included a selection of nonclinical and clinical studies to support the use of Combogesic IV as an intravenous agent to reduce mild to moderate pain, and to reduce moderate to severe pain as an adjunct to opioids where an intravenous route of administration is considered clinically necessary and/or when other routes of administration are not possible.

One Phase III, pivotal, active and placebo-controlled, randomized, double-blind clinical trial and one open-label, supportive trial were conducted to assess the safety and efficacy of Combogesic IV in postoperative musculoskeletal pain and soft tissue pain management.

The pivotal trial assessed the effect of placebo, acetaminophen alone, ibuprophen alone, or Combogesic IV as an adjunct to opioids for the treatment of moderate to severe pain after bunionectomy. The study results showed a statistically significant reduction in pain intensity, which was deemed clinically meaningful according to established standards. Pain was measured using the Visual Analogue Scale (VAS), and the primary efficacy endpoint was the time-adjusted summed pain intensity difference (SPID) from baseline over 48 hours (time-adjusted SPID48). To account for the impact of rescue medication on pain scores, a sensitivity analysis was conducted using the “last value prior to rescue carried forward 2 hours” (Rescue Observation Carried Forward [ROCF]). The change from baseline in pain scores was superior for Combogesic IV (36.68 millimetres [mm] ± 2.22 standard error [SE]) to those for placebo (17.49 mm ± 2.72 SE), ibuprofen (24.57 mm ± 2.21 SE) and acetaminophen (19.32 mm ± 2.22 SE). Heterogeneity in the data between the two study sites as well as uncertainties regarding some data handling in the sensitivity analyses were noted; however, the results of the primary analysis as well as several sensitivity analyses all revealed a consistent statistically significant effect of Combogesic IV compared to placebo as well as the monotherapies, providing confidence to the efficacy of Combogesic IV for this indication.

The indication for mild to moderate pain was supported with data from the pivotal trials as well as data from the market authorization of Combogesic (oral combination formulation). Clinical pharmacokinetic studies were used to bridge the data from the IV Combogesic formulation to the oral Combogesic for which there is already an approved indication for mild to moderate pain. The safety of Combogesic IV for this indication was supported using data from the pivotal and open-label Combogesic IV studies.

No severe or unexpected adverse events were reported in the pivotal trial. There were two reports of serious adverse events leading to discontinuation in the supportive open label trial, however they were assessed as unlikely (hypotension) and not related (intestinal obstruction) to the study drug. Based on the known safety profiles of acetaminophen and ibuprofen, adverse effects are likely in eventual practice and wide spread use, especially when given in high doses and to vulnerable patients; however, the safety profile and the risks factors for experiencing serious adverse events with these two drugs are well known. Safety language commensurate with the risks and uncertainties, including standard class labelling, was included in the Product Monograph.

The toxicology studies submitted were sufficient and given the known toxicology profiles of these two drugs, no unexpected safety signals were detected. A repeat-dose study in rats suggested an acceptable safety level at 100/30 milligrams per kilogram per day (mg/kg/day), which provides an adequate safety margin for short term human use. Studies on its local effects showed that it did not cause irritation even when leaked into the local tissue and there was no evidence of adverse effects on the integrity of blood cells or on platelet function.

The sponsor did not assess the effects of Combogesic IV for the treatment of fever in either the pivotal or supportive trials. While there are a small number of studies in the literature that investigated combination of acetaminophen and ibuprofen for treatment of fever, mainly in pediatrics, these trials employed different dosing regimens and lacked sufficient detail for a regulatory review. Of note, the oral, over-the-counter (OTC) formulation of this combination (Combogesic) does have an approved indication for fever; however, this was primarily based on literature and clinical opinion. Given the lack of data regarding the effects of Combogesic IV on fever, and the use of literature to support the indication for the OTC formulation, there was insufficient data within this submission to assess the safety and efficacy of Combogesic IV for this indication. The sponsor was requested to remove this indication and they accepted.

In the first review of the Chemistry and Manufacturing section of the submission it was identified that the leachables study did not comply with United States Pharmacopeia (USP) general chapter and therefore did not permit an assessment of identified leachables with respect to safety limits and toxicological evaluation thereof over the proposed 24-month shelf life. This led to the recommendation of issuing a Notice of Non-Compliance (NON) on April 14, 2023. These issues were addressed and found to be acceptable in the response to NON.

Taken together, Combogesic IV has a favourable clinical profile of benefit-harm-uncertainty when used by health care professionals in a hospital setting. Therefore, a Notice of Compliance was recommended.

For further details about Combogesic IV, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.