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
IV administration of 100 and 200 mg/kg/day ibuprofen to monkeys for 14 days caused
gastric and duodenal ulcers. However, administration of 300 mg/kg/day PO for 90 days
caused no GI tract (GIT) damage.
In conclusion, IV injection of ibuprofen resulted in previously documented systemic NSAID
toxicities. The main issue with the current submission was the potential for adverse local
tolerance with the proposed IV administration route.
Relative exposure
The proposed MRHD for IV ibuprofen (3200 mg/day) is 33% greater than the MRHD for
PO ibuprofen in Australia (2400 mg/day). The clinical exposure data indicate that the
plasma AUC was approximately 800 µg.h/mL at the 3200 mg/day IV dose and
approximately 600 µg.h/mL at the 2400 mg/day PO dose (Table 1) 2. Safety margins for
toxicities have been assessed using the increased clinical kinetic exposure derived from
the IV data compared to the toxicokinetic data from the animal studies.
In the repeat dose dog studies, systemic exposure (plasma AUC) was mostly less than
anticipated clinical exposure at the MRHD; exposure was similar to clinical exposure only
at the 45 mg/kg/day IV dose. However, given the presence of dose-limiting toxicities at
this dose, it is unlikely that further dose escalation in the dog studies would have been
feasible. GI effects were observed in repeat-dose toxicity studies at doses ranging from 5
to 45 mg/kg/day in dogs, at relative exposures of between 0.1 and 1.1 times the exposure
in humans receiving 3200 mg/day. The low relative exposures at which GI and renal
effects were observed in dogs may indicate that administration of 3200 mg/day IV
ibuprofen to humans could be associated with the risk of adverse GI and/or renal effects.
Although the elicited toxicities were dose-limiting, the effects were consistent with the
known adverse effects of clinical ibuprofen administration, and thus potentially clinically
relevant. It is noted that the Precautions section of the draft Product Information
document incorporates extensive warning statements in this regard, and the Dosage and
Administration section recommends using the lowest effective dose for the shortest
duration. The available nonclinical data supports the inclusion of such warning
statements.
2 The IV formulation would be expected to have greater bioavailability than PO formulations, although the
submitted clinical studies indicate ca 100% PO bioavailability.
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