Australian public assessment for Ibuprofen - Therapeutic Goods ...

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Study details, species, treatment duration CPI-CL-001, human healthy volunteers, IV (60 min infusion) or PO n=12/group CPI-CL-011, human healthy volunteers, IV (5-7 min infusion), or PO n=12/group CPI-CL-004, hospitalized adult febrile patients, IV (30 min infusion) n=30- 31/group Dose (mg/kg/day), Route 200 mg, IV 400 mg, IV 800 mg, IV 200 mg, PO 400 mg, PO 800 mg, PO AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Day Sex AUC (µg∙h/mL) 27 ♂ 1 1 1 1 1 1 ♀ NA NA NA NA NA NA 163 165 65.5 112.5 198.2 69.9 110.9 218.8 Therapeutic Goods Administration AUC (µg∙h/mL) extrapolated to 3200 mg dose NA NA 1048 900 792.8 838.8^ 665.4^ 656.4^ 800 mg, IV 1 NA 196 784 NA 800 mg, PO 1 NA 196 588^ NA 100 mg, IV 1 NA 22.3 & 713.6 NA 200 mg, IV 1 NA 32.6 & 521.6 NA 400 mg, IV 1 NA 70.6 & 564.8 NA * = animal AUC compared with human AUC of 788.4 µg∙h/mL (mean of studies CPI-CL-001 and CPI-CL-011, bolded; Clinical study data obtained from Clinical Study Reports); ^ = extrapolated to 2400 mg dose (daily MRHD for PO ibuprofen); & = AUC0-4h; The relative exposure would be only slightly higher if animal exposure was compared with exposure in febrile humans. Toxicity in combination with other drugs The sponsor did not submit any studies which addressed the potential toxicity of ibuprofen when used in combination with other drugs. The potential for toxicity due to interactions between ibuprofen and opioids was not examined in nonclinical studies. Genotoxicity Studies performed in 1986 and 1997 were submitted as part of the application in order to address the genotoxic potential of ibuprofen. Ibuprofen was negative in the Ames test (with and without metabolic activation) and the sister chromatid exchange (SCE) test in bone marrow cells of mice gave a weak positive response. No genotoxicity concerns were found that were specific to the new formulation or the new route of administration. Relative exposure 0.2 0.2 NA NA NA NA NA NA Page 10 of 118
Carcinogenicity AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration Ibuprofen was not carcinogenic to mice after administration of 100 mg/kg/day for 80 weeks, or to rats after administration of 60 mg/kg/day for 104 weeks. These (1970) studies were not GLP-compliant and did not incorporate toxicokinetic measurements. No carcinogenic potential was found that was specific to the new formulation or the new route of administration. Reproductive toxicity One study from 1969 was submitted, investigating embryofetal development in rats and rabbits (PO dosing) and fertility in rats (dietary dosing). Rabbits treated throughout gestation had interruption of early pregnancy (increased pre-implantation losses). There was no evidence of treatment-related malformations in rabbits or rats following treatment during gestation (including the period of organogenesis) at respective doses up to 60 and 180 mg/kg/day PO, which was sufficient to induce GI lesions and reduce growth. Although this is a very early, non-GLP-compliant study lacking exposure data, it found no evidence of teratogenicity. The rat fertility component of the study was also unremarkable. It is not expected that the new formulation or the new route of administration will change the reproductive toxicity profile of ibuprofen. Local tolerance A local tolerance study in rabbit marginal ear veins showed signs of dose/concentration related local irritancy around the vein at single IV doses of 1.6, 4, 20 and 100 mg/kg. The vehicle alone contributed to the local irritation. There were only minimal effects at the lowest dose/concentration (1.6 mg/kg, 1.6 mg/mL), namely increased small vessel congestion, while delayed slight mottling/discolouration was seen with 4 mg/kg (4 mg/mL). Higher doses/concentrations (20-100 mg/kg, 100 mg/mL) elicited more severe reactions (profound discolouration and necrosis). The animal data suggest that 4 mg/mL may be the maximal concentration which could be used without risk of adverse local effects. It is noted that the “Dosage and Administration Preparation and Administration” section of the proposed PI recommends dilution of Caldolor to a final concentration of 4 mg/mL or less. In the single dose local tolerance study, repeated observations of the animals and the injection sites should have been performed during the 48-96 h following the drug administration (according to TGA adopted (with amendment) European Union (EU) Guideline) 3. Rabbits were sacrificed 1 or 24 h after the single IV dose. The reversibility of the effects was also not studied. Studies assessing the local tolerance of paravenous tissues were not performed with the ibuprofen formulation, which may have been useful to evaluate its local toxicity in sites which might come into contact through accidental exposure. The draft PI does not discuss the potential for adverse infusion site reactions or recommend a maximal duration of treatment and therefore it is difficult to compare the results of this single-dose irritancy study in rabbits with the proposed human use. If repeated/prolonged therapy is envisaged this study may be considered inadequate but appropriate clinical data could overcome this deficiency. Local swelling and inflammation were observed in dogs from all groups receiving repeated doses of ibuprofen IV (15-45 mg/kg/day in divided doses) or control, indicative of irritancy from ibuprofen and/or the vehicle used. Microscopic changes indicative of inflammation were also found in the injected veins. The local effects were not exacerbated by increasing doses. 3 Note for guidance on the non-clinical local tolerance testing of medicinal products. CPMP/SWP/2145/00. http://www.tga.gov.au/pdf/euguide/swp214500en.pdf Page 11 of 118
Page 1 and 2: Australian Public Assessment Report
Page 3 and 4: Contents AusPAR Caldolor Ibuprofen
Page 5 and 6: AusPAR Caldolor Ibuprofen Phebra Pt
Page 9: AusPAR Caldolor Ibuprofen Phebra Pt
Page 13 and 14: Nonclinical summary and conclusions
Page 31 and 32: Time to afebrility (temp
Page 39 and 40: Table 12. CPI-CL-006: Patient dispo
Page 41 and 42: Other efficacy studies IND 32803 Au
Page 49 and 50: Baseline data AusPAR Caldolor Ibupr
Page 57 and 58: Dose-response and non-pivotal effic
Page 59 and 60: Combined indications AusPAR Caldolo
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AusPAR Caldolor Ibuprofen Phebra Pt
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IVIb = Caldolor. AusPAR Caldolor Ib
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Table 37. IND 32803 (Sepsis syndrom
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Pivotal studies AusPAR Caldolor Ibu
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Pharmacovigilance plan AusPAR Caldo
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Table 44. Other efficacy outcomes.
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Caldolor is indicated for the reduc
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