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 In clinical practice, the option of varying the infusion site should be considered, in the event of an adverse local reaction and/or prolonged treatment. Haemocompatibility Ibuprofen solution up to 100 mg/mL did not induce blood flocculation in vitro at a 1:1 ratio between the drug solution and human plasma or serum. A similar study with human whole blood showed haemolysis (97%) of red blood cells at 100 mg/mL ibuprofen but not at 1.6 or 4 mg/mL. As no blood compatibility effects were detected at a concentration of 4 mg/mL, it is not expected that the diluted ibuprofen solution for infusion (4 mg/mL or less, as directed in the proposed PI) would pose haemolysis risks. It is noted that the “Precautions Haematological Effects” section of the proposed PI warns that infusion of Caldolor injection without dilution can cause haemolysis. The results of the local tolerance testing and the haemocompatibility studies, support the advice in the proposed PI regarding dilution prior to infusion. Paediatric use Caldolor is not proposed for paediatric use and no specific studies in juvenile animals were submitted. Other toxicities The genotoxic, carcinogenic, and reproductive and developmental toxicity potential of ibuprofen have been investigated previously. The sponsor has submitted published literature in support of safety statements proposed in the draft PI document. The studies support the PI safety statements. Impurities in drug substance and drug product Impurities A, J, N and F exceed the International Conference on Harmonisation (of technical requirements for registration of pharmaceuticals for human use) (ICH) guidance 4 threshold of 0.05% for a drug substance with a maximum daily dose of >2 g/day. However, the sponsor’s specifications for these impurities meet British Pharmacopiea (BP) requirements. All other (unspecified) impurities will be present at no more than (NMT) 0.05%, thereby complying with the ICH guidance document (and BP requirements). The proposed specifications for impurities in the drug product are within the TGA adopted EU guideline 5 qualification threshold (0.15% for a maximum daily dose of >2 g/day). Therefore, and given the long history of the oral ibuprofen products containing the drug substance impurities, the presence of the impurities was not considered a safety concern. 4 Guidance for industry. Q3A Impurities in New Drug Substances. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A _R2__Guideline.pdf 5 Note for Guidance on Impurities in New Drug Products. CPMP/ICH/2738/99. http://www.tga.gov.au/pdf/euguide/ich273899enrev2.pdf Page 12 of 118
Nonclinical summary and conclusions AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration • The maximum recommended human dose (MRHD) is 3200 mg/day in divided doses of 100-800 mg, this is 33% greater than the MRHD for PO ibuprofen (2400 mg/day). The IV formulation may also be expected to have greater bioavailability than PO formulations and therefore safety margins have been reduced. The draft Product Information (PI) document states that “after observing the response to initial therapy with Caldolor, the dose and frequency should be adjusted to suit an individual patient’s needs”; however, the Dosage and Administration section of the draft PI does not include a recommended maximum duration of treatment or guidance about switching to PO ibuprofen after a specific period of IV treatment. • The sponsor has provided a submission of bridging nonclinical studies. Toxicities observed were consistent with known ibuprofen toxicities, such as GI ulceration and renal inflammation. No additional systemic toxicities were observed. • In 28 day repeat-dose toxicity studies in dogs, ibuprofen caused GI effects (loose/liquid faeces) and mild renal inflammation after IV doses of between 5 and 45 mg/kg/day, associated with exposures (AUC) between 0.1 and 1.1 times the exposure expected in humans receiving the maximum daily dose. Pharmacokinetic studies in dogs indicated increased exposure with the IV route compared to the oral route. No sex differences or accumulation were observed. Local inflammation of the injection site was also observed, as well as thrombosis, oedema and erythema. • In a single-dose local tolerance study in rabbits, local irritation was observed after IV injection of 4, 20 and 100 mg/kg ibuprofen at respective concentrations of 4, 100 and 100 mg/mL. A dose of 4 mg/kg (4 mg/mL, the concentration proposed for clinical use) produced purple discoloration and the effect was more prominent at doses of 20 and 100 mg/kg, showing histopathological changes. Ibuprofen showed a local irritant effect at injection sites and must be diluted before clinical use. • In genotoxicity assessment, ibuprofen was negative in bacterial gene mutation (Ames) assays and weakly positive in the sister chromatid exchange (SCE) test in mouse bone marrow cells. • There was no evidence of carcinogenicity in mice administered ibuprofen 100 mg/kg/day PO for 80 weeks or in rats with 60 mg/kg/day PO for 104 weeks. • Oral/dietary reproductive toxicity studies in rats and rabbits were unremarkable, with no evidence of teratogenicity or impairment of fertility, apart from increased preimplantation loss in rabbits at a maternotoxic dose. • Haemolysis was observed when heparinised blood was mixed 1:1 with ibuprofen solution 100 mg/mL (but not 1.6 or 4 mg/mL). Flocculation was not seen at these concentrations. • The proposed specifications for impurities in the drug substance and the drug product comply with recommended TGA adopted EU guideline levels or with BP requirements. • Concomitant administration of ibuprofen and opioids may be anticipated but no interaction studies were submitted. Conclusions and recommendation The two major issues arising from the nonclinical evaluation are the reduced safety margins consequent to the increased MRHD and potential local reactions at the administration site. Page 13 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: Carcinogenicity AusPAR Caldolor Ibu
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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