Australian public assessment for Ibuprofen - Therapeutic Goods ...

AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1
Final 2 January 2013
Therapeutic Goods Administration
Infusion site pain was reported by 4 (33%) subjects during rapid infusion of Caldolor,
although it was mild in all cases. A more comprehensive assessment of infusion pain, for
example, using a visual analogue score (VAS), was not conducted and would not have been
meaningful in the absence of placebo control.
Systemic exposure to ibuprofen after an 800 mg dose of Caldolor, when infused over 5-7
minutes, was equivalent to exposure after a single US-marketed 800 mg tablet,
administered orally. The tmax of ibuprofen was much shorter after rapid IV administration
than after oral dosing or IV administration over 30 minutes (in CPI-CL-004) or 1 h (in CPI-
CL-001). This reduced tmax would probably translate into a faster onset of analgesia after
the first dose, and after subsequent doses if they are not given until pain recurs. This
would be clinically useful in a postoperative or other acute pain setting.
However, the Cmax of ibuprofen after rapid IV infusion was approximately doubled
compared to oral administration of the same dose. As noted in the sponsor’s Clinical
Overview, the clinical implication of these higher peak concentrations is not known.
Although there was no evidence of systemic toxicity in this small study, the potential for
an adverse effect of high peak concentrations in a patient population cannot be excluded.
The main clinical studies used a 30 minute infusion which provided reasonably rapid
onset of analgesia with lower peak ibuprofen concentrations (similar to those seen with to
oral dosing - see Table 7, below). In view of this consideration and the paucity of
tolerability data for the proposed rapid infusion, approval of the rapid infusion is not
recommended.
Table 7. Mean ibuprofen Cmax (μg/mL) after a single dose of IV Caldolor or US-marketed oral
ibuprofen preparations, according to infusion duration and study population.
Dose
(mg)
Healthy,
60 min
CPI-CL
-001
IV infusion (Caldolor) Oral
Critically
ill, 30 min
CPI-CL
-004
Noncritically
ill,
30 min
CPI-CL
-004
Healthy,
5-7 min
CPI-CL
-011
Healthy Healthy
CPI-CL
-001
100 - 8.2 14.5 - - -
200 19.3 11.5 22.9 - 24.7 -
400 39.2 25.7 49.1 - 42.9 -
CPI-CL
800 72.6 - - 120 81.0 63
Summary of pharmacokinetics
Systemic exposure to ibuprofen after IV administration of Caldolor was equivalent to
systemic exposure after oral administration of a matching dose of US-marketed ibuprofen
capsules and tablets. However, no comparison to an Australian-registered ibuprofen
product was submitted.
Ibuprofen Cmax and AUC were less than proportional to the dose after administration of IV
and oral ibuprofen.
-011
When Caldolor was infused over a period of 30 to 60 minutes, peak ibuprofen
concentrations were roughly comparable to those seen when the same dose was given
orally, although this is based on cross-study comparisons to US-marketed oral products.
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