Australian public assessment for Ibuprofen - Therapeutic Goods ...

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AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration (there is no conversion of S(+) ibuprofen to R(-) ibuprofen) 7. If the conversion of R(-) to S(+) ibuprofen were occurring presystemically (such as in the intestinal lumen or wall), then total ibuprofen concentrations would not be appropriate for comparing the pharmacokinetics of oral and IV formulations. However, a study using IV ibuprofen enantiomers has shown that the conversion of (R-) to (S+) ibuprofen occurs systemically rather than presystemically 8. Accordingly, the use of a non-stereospecific assay is acceptable. CPI-CL-001 CPI-CL-001 examined the pharmacokinetics and tolerability of single doses of ibuprofen 200, 400 and 800 mg administered IV (Caldolor) or orally (US- marketed ibuprofen capsules). The study enrolled 3 groups of 12 healthy adults aged 18 to 50 years, with 8 males and 4 females in each group; one group for each dose level. Subjects received the IV and oral formulations in a randomised, crossover fashion after an overnight fast, with a washout period of 7 days between doses. All doses of Caldolor were administered IV over 1 h. Initially, the undiluted 100 mg/mL solution was injected using a syringe pump and all subjects in the 200 mg dose group received Caldolor in this fashion. However, the first 3 subjects in both the 400 and 800 mg dose groups experienced administration site adverse events (AEs) such as irritation, pain and bruising. Because of this, subsequent doses of Caldolor were diluted in 500 mL (400 mg dose) or 600 mL (800 mg dose) of normal saline prior to administration. Total ibuprofen concentrations in plasma were measured in blood samples collected before and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after the start of the IV infusion, and before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after the oral dose. All 36 subjects were included in the pharmacokinetic analysis, the results of which are summarised in Table 2, below. Table 3 shows the results of the IV versus oral bioavailability comparison. Table 2. CPI-CL-001: Summary pharmacokinetic results (mean, CV%). Dose (mg) Route AUC last AUC inf C max t max t 1/2 (µg.h/mL) (µg.h/mL) μg/mL (h) (h) 200 IV 63.6 (20.7) 65.5 (21.5) 19.3 (16.0) 1.13 (20.3) 2.34 (12.4) Oral 68.0 (24.8) 69.9 (25.7) 24.7 (17.1) 0.65 (25.9) 2.33 ( 9.6) 400 IV 109.3 (26.4) 112.5 (29.2) 39.2 (15.5) 1.05 (15.8) 2.22 (20.1) Oral 108.3 (22.0) 110.9 (24.2) 42.9 (11.4) 0.55 (25.6) 2.23 (19.5) 800 IV 192.8 (18.5) 198.2 (20.0) 72.6 (13.2) 1.00 ( 0.0) 2.44 (12.9) Oral 212.1 (22.5) 218.8 (25.1) 81.0 (23.2) 0.85 (60.4) 2.48 (15.6) 7 Cheng H, Rogers JD, Demetriades JL, et al: Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharmaceutical Res 1994; 11:824-830. 8 National Heart Lung and Blood Institute. How is patent ductus arteriosus treated? http://www.nhlbi.nih.gov/health/dci/Diseases/pda/pda_treatments.html (accessed 26 April 2011). Page 16 of 118
AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration Table 3. CPI-CL-001: Bioavailability comparison of IV and oral ibuprofen (% ratio of LSmeans of log-transformed values [IV/Oral], 90%CI). Dose (mg) AUC last AUC inf C max 200 94.3 (84.2 - 105.6) 94.5 (84.3 - 105.9) 78.2 (70.0 - 87.4) 400 100.3 (92.7 - 108.5) 100.6 (93.0 - 108.8) 90.9 (83.8 - 98.7) 800 91.3 (86.9 - 96.1) 91.2 (86.5 - 96.2) 91.1 (83.1 - 99.7) The Cmax, AUClast and AUCinf of ibuprofen increased linearly with dose after IV and oral administration. All three parameters were also proportional to the dose after oral administration but after IV administration this was true only for Cmax. For AUClast and AUCinf after IV administration, the best-fit regression model was linear but included a constant in addition to the term for dose. Systemic exposure to ibuprofen was equivalent after IV and oral administration, with the 90% confidence intervals (CIs) for AUClast and AUCinf falling within the standard 80-125% bioequivalence limits at each dose level. The 1 h infusion produced Cmax values that were bioequivalent to oral administration for the 400 and 800 mg doses but lower for the 200 mg dose. The 1 h infusion period also led to a delayed the time to peak plasma concentration (tmax) compared to oral administration, which would presumably be accompanied by a delay in the onset of analgesia. The 1 h infusion duration does not match the 30 minute duration used in the efficacy/safety trials or the durations of 30 or 7 minutes that are proposed in the draft PI. These shorter durations would lead to higher Cmax values with a shorter tmax. The bioavailability comparisons were with a US-marketed oral capsule rather than an Australian-registered oral preparation. CPI-CL-004 CPI-CL-004 was a multicentre, randomised, double-blind, placebo controlled trial to evaluate the efficacy, safety and pharmacokinetics of ibuprofen injection in adult febrile patients. In brief, the study enrolled hospitalised patients with new-onset fever ≥ 101°F (38.3°C) who were randomised to receive Caldolor 100 mg, 200 mg, 400 mg or placebo (normal saline), administered IV over 30 minutes, every 4 h for 24 hs. Caldolor solution was diluted in 100 mL normal saline prior to infusion. Randomisation was stratified according to illness severity (critically or non-critically ill). Critically ill patients were defined as receiving vasopressor support for systemic hypotension and/or mechanical ventilation. Further details of the study design and population are covered later in this report. Blood was collected from the first 98 patients enrolled in the study at 0, 0.5, 1, 2, 3 and 4 h after the first dose and 0, 0.5, 1.5, 2, 4 and 6 h after the last (sixth) dose, for the determination of total ibuprofen concentrations in plasma. Ibuprofen Cmax, tmax, trough plasma concentration (Cmin), AUC0-4h and the half-life (t1/2) were determined after the first dose. Examination of plasma concentration at 0 h (C0h) and at 4 h (C4h) for the last dose when compared with C4h after the first dose allowed an assessment of whether steady state had been reached and the extent of drug accumulation. However, Cmax and AUC0-4h were not determined after the last dose, so steady-state values for these parameters were not available. Cmin and tmin were determined after the last dose but the values were irrelevant as they merely reflected the timing of the final sample 6 h after the dose (which did not correspond to the dosing interval in this study). Page 17 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 11 and 12: Carcinogenicity AusPAR Caldolor Ibu
Page 13 and 14: Nonclinical summary and conclusions
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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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