1. بسم الله الرحمن الرحیم

3. Methoxyflurane – Introduction It is first time introduced in USA in 1960 2,2 dichloro – 1,1 difluoro-ethyl methyl ether Fluorinated hydrocarbon Boiling Point: ~104°C Flash Point: 62.8°C Mildly pungent odour

4. History Methoxyflurane was introduced in the 1960’s Original use for general anaesthesia Single agent or in combination with N 2 O Excellent muscle relaxation with cardiac and respiratory stability Noted reduction in post-operative analgesics with Methoxyflurane ANAESTHETIC USE NOW A CONTRAINDICATION FOR Methoxyflurane

5. Methoxyflurane methabolites Almost 75% of Methoxyflurane methabolitis are methabolised by human body Methoxy difluroacetic acid Fluore ion Dichloro acetic acid

6. FDA Withdrawal of Methoxyflurane Methoxyflurane previous supplied in USA Indication included Anaesthesia and Analgesia (obstetrics/minor procedures) In 2005, FDA withdrew of Methoxyflurane due to Safety Concerns Previously withdrawn in USA by Abbott Laboratories in 2001 Commercial Reasons In public notice, FDA cited serious, irreversible and potentially fatal nephrotoxicity and hepatotoxicity

7. Nephrotoxicity From late 1960’s cases of renal toxicity associated with Methoxyflurane use reported Characterised by tubular necrosis within kidneys Believed to be due to oxalic acid and serum fluoride Metabolic Byproducts Study by Kharash 1 demonstrated that toxicity caused by metabolic by-products dichloroacetic acid and serum fluoride Nephrotoxicity specific to Methoxyflurane 1. Kharasch, E. D.,et al New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites. Anesthesiology, 2006: 105, 737-45

8. Nephrotoxicity Mazze and Cousin’s demonstrated renal damage to be Dose Related Large and Prolonged Anaesthetic doses cause toxicity Sub-clinical Renal Toxicity associated with > 2.5 MAC hours of use MAC: Minimum Alveolar Concentration Maximum analgesic dose (6mL): 0.59 MAC hours Less than ¼ of dose known to cause reversible damage! No reports of occurrence in Australia

10. Renal intoxication severity depends on blood Methoxyflurane and Fluore ion level

11. Hepatotoxicity Various reports of hepatic damage, including hepatitis with Methoxyflurane Use Rarely reports and predominantly with Anaesthetic use Considered idiosyncratic reaction by reviewers

13. Anaesthesia versus Analgesia Significant difference dose administered for Analgesic and Anaesthetic Use Anaesthetic Dose 40 – 60mL Analgesic Dose 3 – 6mL

14. Drug Regulatory Agency Evaluation Australian Regulatory Agency (TGA) reviewed safety of Methoxyflurane for Analgesic Use in 2006 Clinical Evaluator concluded: Risk of clinically important Nephrotoxicity relates the use of methoxyflurane in anaesthetic doses and is acceptably low when the drug is used for analgesia Hepatotoxicity is rare and does not appear to be more common with methoxyflurane than with other halogenated anaesthetic agents

15. present Methoxyflurane approved in 7 countries Australia, New Zealand, GCC, Moldova Predominantly used by Ambulance Service More than 2.5 million doses supplied in 30 years Excellent safety profile Common adverse effects include cough, drowsiness, nausea, dry throat

16. Summary Methoxyflurane associated Nephrotoxicity reported with Anaesthetic use of Methoxyflurane Nephrotoxicity is dose related Analgesic doses not reported to cause renal damage Independent Clinical Expert from Government Agency considers product safe for analgesic use

17. Dose linearity of inhaled fentanyl (FT) with comparative pharmacokinetics to transmucosal fentanyl (A) Background: Cancer patients frequently experience breakthrough pain which is a transitory flare of moderate or severe pain occurring on top of otherwise controlled, persistent pain. Fentanyl TAIFUN (FT), a novel breath-actuated dry powder inhaler is being developed for the treatment of breakthrough cancer pain in patients with ongoing opiate therapy. Methods: A randomized, open-label, crossover phase I study with 5 periods derived pharmacokinetics after fentanyl oromucosal (Actiq, A) and pulmonary (FT) administration in 30 healthy volunteers. Each single dose of study medication (200 mcg A; or 100, 200, 400 or 800 mcg FT) was administered following premedication with 50 mg of naltrexone with a minimum of 7 days between doses. Pharmacokinetic parameters were calculated from the plasma concentrations using a non-compartmental model. Results: The plasma concentrations of FT increased proportionally to the increasing dose and t 1/2 was independent of the dose. FT had a linear elimination phase. FT had a substantially faster absorption and higher peak fentanyl concentration (Cmax) than A. Median Tmax was 1 and 60 min for FT and A, respectively. Moreover, there was an 8-fold increase in bioavailability of fentanyl during the first 20 min when 200 mcg FT is compared to 200 mcg A. Conclusions: The plasma concentrations from FT increases proportionally to the increasing dose while t 1/2 is independent of the dose, and there is a linear elimination phase. Overall, FT is substantially more bioavailable than A during the important first 20–30 minutes after administration. Inhalation of FT allows an immediate and comparable availability of fentanyl suggesting potential for rapid pain relief.