Environmental Risk Assessment Data Esomeprazole, Esomeprazole Sodium & Esomeprazole Magnesium/Omeprazole & Omeprazole Sodium

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1 Environmental Risk Assessment Data Esomeprazole, Esomeprazole Sodium & Esomeprazole Magnesium/Omeprazole & Omeprazole Sodium The data below refer both to esomeprazole and omeprazole, as esomeprazole is the S- enantiomer of the racemate omeprazole. In the absence of comprehensive environmental data for omeprazole, the more scientifically robust long-term data set for esomeprazole has been used to generate the Predicted No Effect (PNEC). These data are in accordance with the EU European Medicines Agency (EMA) guideline (Ref. 1). It is assumed that the same PNEC applies to omeprazole. Total sales of esomeprazole and omeprazole are included in the calculation of the Predicted Environmental (PEC), as a worst case. Esomeprazole and omeprazole are proton pump inhibitors (PPIs) for the treatment of acidrelated diseases. Esomeprazole is used in Nexium and Vimovo. Omeprazole is used in the following products: Gastroloc, Mopral, Omepral and Prilosec. After administration, esomeprazole and omeprazole are almost completely metabolised, with <1% found in urine as the parent compound. Approximately 80% of the metabolites are excreted by urine and approximately 20% via faeces. The two main excreted human metabolites are both excreted via urine, and are considerably less pharmacologically active than the parent compounds. Based on the physico-chemical and fate properties, esomeprazole and omeprazole are not predicted to be readily biodegraded during wastewater treatment. However, esomeprazole is rapidly degraded in aquatic sediment systems, which suggests that both compounds will be degraded in the aquatic environment. In addition, they are not predicted to bioaccumulate and are abiotically degraded under environmentally relevant conditions. The Predicted Environmental (PEC) / Predicted No Effect (PNEC) is 1.3 x 10-2, which means use of esomeprazole and omeprazole are not predicted to present a significant risk to the environment. Predicted Environmental (PEC) The PEC is based on the following data: PEC (µg/l) = (A*10 9 *(100-R))/(365*P*V*D*100) A (kg/year) = total patient consumption of esomeprazole and omeprazole (active moieties) in the European country with the highest combined per capita use in 2010 (Source: IMS Health) R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). For esomeprazole and omeprazole, it is assumed that R=0 as a worst case. P = number of inhabitants in the European country with the highest combined per capita use of esomeprazole and omeprazole in 2010 (Source: IMS Health) A/P = 9.7 x 10-4 kg/inhabitant V (L/day) = volume of wastewater per capita and day = 200 ( EMA default value) D = factor for dilution of waste water by surface water flow = 10 (EMA default value) (Note: The factor 10 9 in the equation above converts the quantity used from kg to μg) PEC = 1.3 µg/l (Note: Whilst esomeprazole and omeprazole are extensively metabolised, little is known about the ecotoxicity of the excreted metabolites. Hence, for the purpose of this calculation, May 2013

2 as a worst case, it is assumed that 100% of excreted metabolites have the same ecotoxicity as the parent compounds.) Predicted No Effect (PNEC) Long-term tests of esomeprazole have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The most sensitive species of these is the fathead minnow. Therefore, the PNEC is based on the results from the fathead minnow early life stage test, and an assessment factor of 10 is applied, in accordance with EMA guidance (Ref. 1). For the purpose of this risk assessment it is assumed that the same PNEC applies to omeprazole. PNEC = 1000/10 µg/l = 100 µg/l PEC/PNEC PEC = 1.3 µg/l PNEC = 100 µg/l PEC/PNEC = 1.3 x 10-2 The PEC/PNEC of 1.3 x 10-2 corresponds to the phrase Use of the substance has been considered to result in insignificant environmental risk in the scheme. Reference 1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, Ref EMEA/CPMP/SWP/4447/ /WC pdf Aquatic Toxicity Data - Esomeprazole LOEC - Based on Area under the Growth Curve Logarithmic Growth Rate LOEC - Based on Logarithmic Growth Rate Endpoint Species Common Method Time Result Area under the Growth Curve Selenastrum capri- Green Alga OECD h 3.9 mg/l cornutum) Green Alga OECD h 8.4 mg/l Green Alga OECD h 8.4 mg/l Green Alga OECD h 19 mg/l

3 Endpoint Species Common Method Time Result E r C50 - Based on Logarithmic Growth Rate Green Alga OECD h 85 mg/l E b C50 - Based on Area under the Growth Curve NOEC - Overall,3 NOEC Overall,5 LOEC - Overall, 6 NOEC - Overall, 6 EC50 - Based on Green Alga OECD h 19 mg/l Daphnia magna Giant Water Flea OECD d 10 mg/l Chironomus riparius Midge OECD d 400 mg/kg dry weight Pimephales promelas Fathead Minnow OECD d 3.2 mg/l Pimephales Fathead OECD d 1.0 mg/l promelas Minnow - - OECD h >100 mg/l Note OECD h 100 mg/l Note 7 Environmental Fate Data - Esomeprazole Endpoint Method Test Substance Time Result Partition Coefficient Octanol Water OECD and 20 mg/l - Log Dow = ph 5 Partition Coefficient Octanol Water OECD and 20 mg/l - Log Dow = ph 7 Partition Coefficient Octanol Water OECD and 20 mg/l - Log Dow = ph 9 Percentage Biodegradation 0.42 mg/l Note 6 95 d <2 % Mineralisation Percentage Biodegradation 0.42 mg/l Note 6 with high organic matter with low organic matter 95 d <2 % Mineralisation d in total system d in total system

4 Endpoint Method Test Substance with high organic matter with low organic matter Time Result d in water compartment d in water compartment Physical Chemistry Data - Esomeprazole Endpoint Method Test Substance Adsorption OPPTS mg/l Coefficient Note 6 Solubility Water Note 8 Note 8 Note 8 Result K d (Adsorption) = mg/l - pka(1) = 4 (Pyridinium ion) - pka(2) = 8.8 (Benzimidazole) : Data from studies on esomeprazole sodium. : Results are expressed as mean measured concentrations. Note 3: The population relevant endpoints measured were survival, fecundity and adult length. : s were confirmed by analysis, and results expressed as nominal. : The population relevant endpoints measured were total number of emerged adult insects, sex ratio and replicate mean plus individual emergence times (development rates). Note 6: The population relevant endpoints measured were hatch, survival, length and dry weight. Note 7: Results are expressed as nominal concentrations. Note 8: This study predates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines. Aquatic Toxicity Data - Omeprazole Endpoint Species Common E b C50 - Based on Biomass E r C50 - Based on Growth Rate Biomass Selenastrum capricornutum) Method Time Result Green Alga OECD h 30.1 mg/l Green Alga OECD h >75.9 mg/l Green Alga OECD h <1.81 mg/l

5 Endpoint Species Common Method Time Result Growth Rate Green Alga OECD h 1.81 mg/l Immobilisation EC50 - Based on Immobilisation LC50 Mortality LOEC - Based on Mortality EC50 - Based on Daphnia magna Daphnia magna Danio rerio Brachydanio rerio) Danio rerio B. rerio) Danio rerio B. rerio) Giant Water Flea Giant Water Flea OECD h 50 mg/l Note 3 OECD h >100 mg/l Note 3 Zebra Fish OECD h 41.9 mg/l Zebra Fish OECD h 23.2 mg/l Zebra Fish OECD h 67.2 mg/l - - OECD h 100 mg/l - - OECD h >100 mg/l Environmental Fate Data - Omeprazole Endpoint Method Test Substance Time Result Distribution Coefficient Octanol Water - - Log D = 2.24 Degradation Half-life Degradation Half-life Percentage Biodegradation ThOD In aqueous solution - T1/2 = o C, ph 7 In aqueous solution - T1/2 = o C, ph 7 OECD 301C 100 mg/l 24 d 0 % ThOD go 2 /g

6 Physical Chemistry Data - Omeprazole Endpoint Test Conditions Result Solubility Water 22 o C 130 mg/l pka(1 )= 4 (Pyridinium ion) pka(2) = 8.8 (Benzimidazole ion) : Data from studies on omeprazole sodium. : Results are expressed as mean measured concentrations. Note 3: s were confirmed by analysis, and results expressed as nominal. : Data from studies on omeprazole. : This study predates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines.