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
and various forms of pain) should be at least as good as the efficacy of the oral
preparations.
Extrapolation of the safety of Caldolor on PK grounds is more problematic. Firstly, the
proposed maximum daily dose of Caldolor is higher than the dose that is approved in
Australia for oral ibuprofen. Secondly, the PK data still leave open the possibility that the
Cmax of Caldolor might be higher than that of Australian-registered oral ibuprofen
products, and the risk of some adverse effects could theoretically be related to peak
ibuprofen concentrations and not just AUC. These considerations mean that one cannot
infer the full safety profile of Caldolor on the basis of experience with Australianregistered
oral ibuprofen products. One might, of course, infer a safety profile on the basis
of experience with US-registered oral ibuprofen products (as reflected in the FDAapproved
PIs for those products). This, however, is not usually regarded as an acceptable
approach because the TGA does not have access to the original data and it is tantamount to
accepting a product for registration in Australia purely because it has been approved in
the USA.
The FDA noted that there is little experience with the use of oral ibuprofen in critically ill
patients - a clinical situation in which an IV preparation such as Caldolor is likely to be
used. Also, oral ibuprofen preparations are not specifically approved in Australia or the
USA for perioperative pain management, another use for which Caldolor is likely to be
promoted, given the studies that were conducted by the sponsor. The FDA was unwilling
to rely solely on bioequivalence data and insisted on clinical studies of Caldolor in these
situations, even though the issues mentioned above regarding the comparator in the
bioequivalence studies and the proposed maximum dose were not relevant to the FDA.
Those clinical studies have also been provided to the TGA.
While insufficient to infer that Caldor is safe for the proposed indications, the PK data, in
association with the tolerability study CPI-CL-006 (see Dosage Selection in Pivotal Studies
below) are sufficient to justify the choice of doses and the use of a 30 minute infusion in
the pivotal studies. They also showed that Caldolor injection needs to be diluted prior to
infusion to avoid an unacceptable incidence of infusion site pain.
The PK data indicate that the proposed alternative of rapid infusion of Caldolor over 5 to 7
minutes is not acceptable, due to the resultant doubling of Cmax with untested safety
consequences. Rapid infusion was also associated with a high incidence of infusion tie
pain, albeit mild.
The PK findings in CPI-CL-004 indicate that no change to the Caldolor dose interval is
required in critically ill patients. Although the PK data also show that ibuprofen
concentrations are approximately halved in critically ill patients for a given dose of
Caldolor, the lack of a positive dose response in critically ill patients and potential safety
concerns (most notably about adverse renal effects in patients with underlying fluid
balance abnormalities and compromised renal perfusion) argue against routinely
increasing the dose of Caldolor in patients who are critically ill.
Pharmacodynamics
The current submission did not include any clinical studies of the pharmacological effects
of ibuprofen but these are well known from studies of oral preparations and need not be
reiterated here.
Dose- or concentration-response relationship
In the current submission, plasma ibuprofen concentrations were measured in a large
majority of patients in the fever study CPI-CL-004 but no formal analysis of the
relationship between ibuprofen plasma concentration and temperature reduction was
Page 22 of 118