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
Reduced safety margins: Although IV studies with ibuprofen revealed no novel systemic
toxicity due to the change in route of administration, the safety margins for GI and renal
effects are not large (≤ 1), indicating potential risk of adverse effects on these organ
systems with treatment at the maximum daily dose. As such, although there are no
nonclinical objections to the proposed new dosage form and administration route, the
nominated MRHD of 3200 mg/day may pose a risk of target organ toxicity, and a reduction
in the MRHD may be warranted. These concerns may be alleviated by adequate clinical
safety data.
Local tolerance: Ibuprofen is a potential local irritant and haemolytic agent, and the
proposed mandatory dilution instructions are endorsed.
The safety of Caldolor in patients with renal impairment or history of GI ulceration will
need to be assessed from the clinical data.
Amendments to the draft PI document were also recommended.
IV. Clinical findings
Introduction
Initial formulation development efforts were based on an IV formulation that was
developed by Upjohn Inc. and used in clinical studies in the 1980's to 1995. That product
used sodium hydroxide to solubilise ibuprofen and adjust pH, hydrochloric acid to adjust
pH, glycine and sodium chloride. It had several undesirable characteristics, including a pH
of approximately 8.5, a considerable amount of sodium and a lengthy processing time. The
product was therefore reformulated with arginine, which allowed rapid dissolution of
ibuprofen at concentrations higher than 50 mg/mL without the use of sodium and a more
neutral pH of 7.2 to 7.8. The proposed products have a pH of 7.4, which is within the
normal physiological range (7.2 to 7.6).
The pivotal clinical trials used the arginine-containing formulation that is proposed for
registration in Australia. One supporting study (IND 32803) used the earlier Upjohn
formulation.
The clinical submission documented an abbreviated clinical development program of
pharmacokinetic, efficacy and safety studies.
Clinical data in the submission
The submission contained the following clinical information:
• Three pharmacokinetic (PK) studies. 2 PK studies compared the bioavailability of
Caldolor (various doses and infusion durations) and US-marketed oral ibuprofen
preparations. The third PK study was a substudy of one of the pivotal efficacy/safety
studies in patients with fever, in which ibuprofen pharmacokinetics were determined
in the first 94 patients. No comparison of Caldolor with an Australian registered oral
ibuprofen product was provided, nor was any evidence submitted to show that the USmarketed
products used in the PK studies were identical to, or bioequivalent to, an
Australian-registered product.
• 5 pivotal efficacy/safety studies (2 Fever, 3 Pain).
• 1 other efficacy/safety study (Fever).
• 1 tolerability study (healthy volunteers).
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