ACTRA ASM Derivation of an Occupational Exposure Limit for Methoxyflurane

Transcription

1 ACTRA ASM 2016 Derivation of an Occupational Exposure Limit for Methoxyflurane 1

2 Standard Setting Review dataset Choose critical adverse effect Choose critical study Define point of departure Select uncertainty factors Derive Occupational exposure limit 2

3 Introduction and Overview Presentation Glass bottle containing liquid form of methoxyflurane Dose limiting inhaler Activated Charcoal (AC) Chamber (optional) 3

4 Introduction and Overview INTERNAL FIBROUS PAD (to act as a wick) DILUTOR HOLE (enables two concentrations) OXYGEN INLET ONE-WAY VALVE (to prevent blow-back into wick) 4

5 Introduction and Overview Pharmacology Dramatically reduces pain scores by 50 80% Unique member of the volatile anaesthetics group which provides analgesia when inhaled in very low concentrations Primary site of action is in the central nervous system where inhibition of nerve transmission occurs at synapses; the sites at which neurotransmitters are released and exert their initial action in the body 5

6 Introduction and Overview 70 Anaesthesia ml dose Analgesia Anaesthesia Greater than 2.5 MAC hours of exposure required to cause reversible toxicity 1,2 Analgesia doses 3 6 ml dose Approximately MAC hours of exposure 3 Less than 25% of dose required to cause toxicity 6

7 Introduction and Overview Simple to give, safe, effective inhaled analgesia Given intermittently; patient controlled Initial breaths, or until onset of pain relief Rapid onset, effective for 7-10 minutes Patient decides on need for a further 6 breath supplement intermittently as needed Rapid recovery feel normal after maximum of 20 minutes, often much less 7

8 Introduction and Overview 30+ years and circa 4,000,000 doses of safe effective analgesic use Minimal minor side effects No requirement to withhold food or drink No need for premedication facilitates scheduling procedures Discharge at proceduralist discretion Improves patient outcomes 8

9 Data set Endpoints: Liver Kidney CNS Depression Developmental Toxicity (spontaneous abortion) 12 October

10 Introduction and Overview Properties (3, 4) Methoxyflurane [CAS ; MOF] 2,2-dichloro-1,1-difluoromethyl ether Clear, colourless, volatile liquid with a sweet fruity odour Stable, non-flammable and non-explosive in air or oxygen 10

11 Introduction and Overview Kinetics Complete and rapid absorption following inhalation Primarily distributed to blood, brain, liver and lungs Extensively metabolised20, 21, 22, % of MOF converted to metabolites Approximately 20% excreted as MOF in exhaled air 11

12 Introduction and Overview Kinetics (cont.) Metabolites include; Methoxydifluoroacetic acid, oxalic acid, chloride, inorganic fluoride, dichloroacetic acid Conclusion: At analgesic doses metabolites eliminated rapidly (within 24 hours) 24,25 12

13 Penthrox Safety Central Nervous System (CNS) No adverse non expected central nervous system effects or symptoms 24,26,27,29,30 Minor side effects not troublesome in most cases 31 Conclusion for Patients : Other than analgesia, CNS effects are transient and minor Conclusion for Operators : No adverse effects expected 13

14 Penthrox Toxicity Kidney Toxicity Nephrotoxicity thoroughly investigated in animals and humans 21,22,23,32 MOF nephrotoxicity is dose related MOF nephrotoxicity has a strong correlation with inorganic fluoride levels, no effects at 40 micromolar per litre 1 Serum fluoride levels need to be substantially elevated before kidney damage occurs 14

15 Penthrox Toxicity Kidney Toxicity (cont.) Conclusion Kidney Toxicity only occurs at doses greater than those achievable in current use 4 No adverse effects for Patients when used for analgesia No adverse effects for Operators when used for analgesia 15

16 Penthrox Toxicity Liver Toxicity Postulated immune system mediated mechanism of action 5,32 Rare, even at anaesthetic concentrations 5,32 Extremely rare in current uses 16 Conclusion Highly unlikely when used for analgesia 16

17 Penthrox Toxicity Other Toxicity Animals study in mice investigating exposure at anaesthetic concentrations concluded that halogenated general anaesthetics do not pose a significant risk of cancer to humans 33 International Agency for Research on Cancer - no conclusive evidence for carcinogenicity (Group 3) 36 17

18 Penthrox Toxicity Other Toxicity (Cont.) Animal studies investigating the reproductive and developmental toxicity of MOF consistently show that MOF is neither teratogenic nor causes reproductive effects at subanaesthetic exposures which are not toxic to the mother 34,35 18

19 Key Study Kidney Clinical studies provided do not provide suitable data. Issues with historical studies extrapolation of dose Pivotal Study reference(s) Cousins MJ and Mazze RI (1973), Methoxyflurane nephrotoxicity, a study of dose response in man, JAMA 225(13) Study Population 26 healthy men scheduled for elective surgery (no age related information disclosed) Route of Exposure Inhalation via inhaler connected to anaesthetic vaporiser; anaesthesia was maintained with methoxyflurane or halothane supplemented by 50% nitrous oxide and 50% oxygen at a total gas flow of 6 litres/min. November 8,

20 Critical Effect Kidney Toxicity Dose response: Critical Effect(s) Cousins & Mazze found the mean threshold for toxicity to be approximately 2.5 MAC-hours. Subclinical toxicity was found to occur at exposures MAChours which resulted in: Peak serum fluoride ion concentration from µm Delayed return to preoperative urine osmolality Unresponsiveness to vasopressin administration This is equivalent to the lowest observed adverse effect level The study also found that patients receiving 2.0 MAC-hours or less methoxyflurane had peak serum fluoride ion concentrations <40 µm which was not associated with nephrotoxicity. 20

21 Dose Groups Cousins & Mazze 21

22 Converting MAC s to ppm is inherently difficult Exposure concentration and duration: Exposure Concentrations Group 2: 0.5 MAC methoxyflurane (800 ppm) Group3: 1.5 MAC methoxyflurane (2,400 ppm) Group4: 1.0 MAC methoxyflurane (1,600 ppm) Note group 1 is not considered here as the participants received halothane (control) instead of methoxyflurane. MAC is the minimum alveolar concentration to produce surgical anaesthesia in 50% of patients. According to Cousins & Mazze 1.0 MAC is equivalent to an end alveolar concentration of 0.16 vol % (1,600 ppm) methoxyflurane 3.8 +/- 0.5 hours (Exposures expressed as MAC-hours; range from 1 to 9 MAC-hours) Exposure Duration(s) MAC-hour is determined by multiplying the end alveolar anaesthetic concentration (%) by the duration of anaesthesia (h). Exposure duration of 3.8 h x MAC 0.5 (conc.) = 1.9 MAC-hour (approximately 2.0 MAC-hours) 2.0 MAC-hour is equivalent to approximately 192,000 ppm x min methoxyflurane (1,600 ppm x 120 min) 12 October

23 Extrapolated Dose Data 23

24 Preparing Concentration v Response dataset 24

25 Fig. 2. Dose-response data grouping. 1 The maximum dose (192,000 ppm min MOF) selected for benchmarking as there were no incidences recorded for Dose group 1. 2 Conservatively the lowest dose concentration (240,000 ppm min MOF) used for benchmarking for Dose g...

26 Derivation of MEL 26

27 Fig. 4. Estimate of Ambulance Officer Fluoride Concentration (red square) and Comparison to Measured Fluoride levels in Cousins and Mazze (1973) (Blue diamond). Using the best fit equation (power r2 of 0.7) of the curve from Cousins and Mazze (1973) the serum...

28 Fig. 5. Modelled vapour concentrations in ambulance patient compartment at intensive usage rate of 1 vial/h (top) or 2 vial/h (bottom) with AC Chamber. A volume of m3 and ACH of 46/h was assumed. Each peak represents a new vial being dispensed. The TWA (...

29 Fig. 6. Modelled MOF vapour concentrations in the TR, at intensive usage rates of 1(top) or 2 (bottom) vials/h with AC Chamber, assuming 32.4 m3 volume and 6 ACH. Each peak represents a new vial being dispensed. The TWA (0.74, 1.5 ppm) and peak concentrations...

30 Uncertainties Extrapolation from MAC to ppm Selection of dose groups Lack of d/r data on CNS effects Reliance on Cousins & Mazze - lack of d/r data on kidney toxicity in human or animal studies 30

31 Acknowledgements Antti Mikonnen Christin Down Sponsor Medical Developments International 31

32 References 1 Cousins, M. J. and Mazze, R. I. (1973). Methoxyflurane Toxicity A Study of Dose Response in Man. Journal of the American Medical Association. 225(13): Mazze, R. I. (1984). Fluorinated anaesthesia nephrotoxicity: An Update. Canadian Anaesthetists Society Journal. 31(3):S Medical Developments International. (2010). PENTHROX (methoxyflurane) Inhalation. Product Information, Version 6. Melbourne, Australia. 4 National Library of Medicine. (n.d.). ChemIDplus Advanced Methoxyflurane Fact Sheet. United States of America. Available from: (Accessed 12 April 2012). 5 Therapeutic Goods Administration. (2006). Safety of Methoxyflurane (Penthrox Inhalational Analgesic) nephrotoxicity and hepatotoxicity. Resolution No Woden, Australian Capital Territory, Australia. 6 Frangos, J. (2001). Health Based Risk Assessment for Ambulance Officers Exposed to Methoxyflurane. Toxikos Toxicology Consultants. Victoria, Australia. 7 National Occupational Health and Safety Commission. (2005). Exposure Standard Documentation. Australia. Available from: (Accessed 20 Mar 2012). 32

33 References 8 The National Institute for Occupational Safety and Health (NIOSH). (1977). Criteria for a Recommended Standard: Occupational Exposure to Waste Anesthetic Gases and Vapors. DHEW (NIOSH) Publication No Washington DC, United States of America. 9 Centre of Ambulance Services. (2009). COAS Clinical Practise Guidelines Emergency Medical Technician as amended from PHECC CPG 3 rd Edition. Dubai Corporation for Ambulance Services, Dubai, United Arab Emirates. 10 Chalgham, R. (24 October 2011). Abu Dhabi Police communication with Allan, G. 11 Hamad Medical Corporation. Ambulance Department Clinical Practise Guidelines. 12 Oxer, H. and Wilkes, G. J. (2007). Methoxyflurane is a safe, easy, effective analgesic for prehospital pain relief. St John Ambulance Western Australia, Australia. 13 Johnston, S., Wilkes, G., J., Thompson, J. A., Ziman, M. and Brightwell, R. (2011). Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emergency Medicine Journal. 28(1): Yakaitis, R. W. and Redding, J. S. (1970). Self-Administered Methoxyflurane. Anesthesia and Analgesia. 49(3):

34 References 15 Medical Developments International. (2012). Data on file. 16 Grindlay, J and Babl, F. E. (2009). Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emergency Medicine Australasia. 21: Gillis, M., Keirens, A., Steinkamm, C., Verbelen, J., Muysoms, W. and Reynders, N. (2008). The Use of Methoxyflurane (Penthrox) in the Emergency Department. Regional Anesthesia & Pain Medicine. 33(5): Buntine, P., Thom, O., Babl, F., Bailey, M. Bernard, S. (2007). Prehospital analgesia in adults using inhaled methoxyflurane. Emergency Medicine Australasia. 19: Jacobs, I. G. (2010). Health Effects of Patients Given Methoxyflurane in the Pre-Hospital Setting: A Data Linkage Study. The Open Emergency Medicine Journal. 2010(3): Yoshimura, N., Holaday, D.A. and Fiserova-Bergerova, V. (1976). Metabolism of methoxyflurane in man. Anesthesiology. 44(5) Mazze, R.I., Cousins, M.J. and Kosek, J.C. (1973). Strain differences in metabolism and susceptibility to the nephrotoxic effects of methoxyflurane in rats. Journal of Pharmacology and Experimental Therapeutics. 184(2):

35 References 22 Kharasch, E.D., Schroeder, J.L., Liggitt, H.D., Park, S.B., Whittington, D. and Sheffels, P. (2006). New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway. Anesthesiology. 105(4): Kharasch, E.D., Schroeder, J.L., Liggitt, H.D., Ensign, D. and Whittington, D. (2006). New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites. Anesthesiology. 105(4): Corbett, T.H. and Ball, G.L. (1971). Chronic exposure to methoxyflurane a possible occupational hazard to anesthesiologists. Anesthesiology. 34(6): Strum, D.P., Eger EI 2nd, Unadkat, J.D., Johnson, B.H. and Carpenter, R.L. (1991). Age affects the pharmacokinetics of inhaled anesthetics in humans. Anesthesia and Analgesia. 73(3): Dahlgren, B.E. and Goodrich, B.H. (1976). Changes in kidney and liver function after methoxyflurane (penthrane) anaesthesia. British Journal of Anaesthesia. 48(2): Dahlgren, B.E. (1977). Influence of methoxyflurane-nitrous oxide analgesia during childbirth on renal and hepatic function. British Journal of Anaesthesia. 49(12):

36 References 28 Abdullah, W. A., Sheta, S. A., and Nooh, N. S. (2011). Inhaled methoxyflurane (Penthrox) sedation for third molar extraction: a comparison to nitrous oxide sedation. Australian Dental Journal. 56(3): Dahlgren, B.E. (1979). Fluoride concentrations in urine of delivery ward personnel following exposure to low concentrations of methoxyflurane. Journal of Occupational Medicine. 21(9): Mazze, R.I., Trudell, J.R. and Cousins, M.J. (1971). Methoxyflurane metabolism and renal dysfunction: Clinical correlations in man. Anesthesiology. 35(3): Gilman, A.G., Goodman, L.S., Gilman, A., Meyer, S.E. and Melmon, K.L. (1980). Chapter 13 and Chapter 14. Goodman and Gilman s The Pharmacological Basis of Therapeutics, 6 th edition. McGraw Hill, United States of America. 32 Kenna, J.G. and Jones, R.M. (1995). The organ toxicity of inhaled anesthetics. Anesthesia and Analgesia. 81(6 Suppl):S Eger II, E.I. White, A.E, Brown, C.L, Biava, C.G, Corbett, T.H. and Stevens, W.C. (1978) A test of the carcinogenicity of enflurane, isoflurane, halothane, methoxyflurane and nitrous oxide in mice. Anesthesia and Analgesia. 57(6):

37 References 34 Pope, W.D., Halsey, M.J., Lansdown, A.B., Simmonds, A. and Bateman, P.E. (1978). Fetotoxicity in rats following chronic exposure to halothane, nitrous oxide, or methoxyflurane, Anesthesiology. 48(1): Wharton, R.S., Mazze, R.I., Baden, J.M., Hitt, B.A. and Dooley, J.R. (1978). Fertility, reproduction and postnatal survival in mice chronically exposed to halothane. Anesthesiology. 48(3): International Agency for Research on Cancer. (1987). Overall evaluations of carcinogenicity, Anaesthetics, volatile. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42 Supplement Pollard, T. (1990). Relative Addiction Potential of Major Centrally-Active Drugs and Drug Classes Inhalants and Anaesthetics. Addiction Potential of Abused Drugs and Drug Classes. Editors; Erickson, I., Carlton K., Javors, M., A., Morgan, W, Stimmel, B. Haworth Press. 37

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44 Fig. 1. Dose response data adapted from Cousins and Mazze (1973).

45 Fig. 3. Benchmark dose modelling results (using US EPA BMDS Wizard).