<p> Name of Trust / logo Memo – shortage of supply</p><p>To: From: Date: </p><p>Re: Remifentanil injection (all strengths)</p><p>Description of product affected Remifentanil is licensed as an analgesic agent for use during induction and/or maintenance of general anaesthesia, and for provision of analgesia and sedation in mechanically ventilated intensive care patients 18 years of age and over.1</p><p>Background</p><p>The shortage has partly arisen due to issues last year when GSK suspended manufacturing of the drug at its plant in Parma and partly due to shortages of active pharmaceutical ingredient. Also Pfizer/Hospira have discontinued their product and Teva is out of stock. Currently those companies holding stock or who are expecting further supplies will not have sufficient to cover current usage.</p><p>Alternative options </p><p>Alternative opioids include alfentanil and fentanyl2, which when administered parenterally in equivalent doses produce a similar analgesic effect to remifentanil, but pharmacokinetics, metabolism and side effects vary. The choice of agent therefore depends on the desired onset and duration of action and the potential adverse effects of the agent.2 Use of an alternative anaesthetic technique is another option.</p><p>Pharmacokinetic considerations</p><p>Remifentanil In contrast to other opioids which are metabolised in the liver, remifentanil undergoes rapid metabolism by nonspecific blood and tissue esterases;2 its effective biological half-life is 3-10 minutes1 and its short duration of action allows prolonged administration at high dosage, without accumulation, and with little risk of residual postoperative respiratory depression.3 Studies have suggested a better quality of sedation, hypnotic sparing effect and shorter time to extubation with remifentanil.2 </p><p>Fentanyl and alfentanil</p><p>The pharmacokinetic parameters reported for fentanyl are inconsistent, with estimates of apparent volume of distribution ranging from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in elderly) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose, and it may accumulate during prolonged infusion.2</p><p>Alfentanil is an analogue of fentanyl with around one-tenth of its potency and a shorter duration of action following a single dose. The pharmacokinetics of alfentanil can be described by a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90-111 minutes. Alfentanil has a small volume of distribution (between 0.4-1 L/kg). It is mainly metabolised in the liver. Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites.2</p><p>The initial doses of alfentanil or fentanyl are followed either by successive intravenous injections or by an intravenous infusion; prolonged infusions increase the duration of effect. Repeated intra-operative doses of alfentanil or fentanyl should be given with care since the resulting respiratory depression can persist postoperatively and occasionally it may become apparent for the first time postoperatively when monitoring of the patient might be less intensive.3</p><p>Management of current supply</p><p>Anaesthetists consulted state that there are certain situations where remifentanil's “unique” profile is crucial, but in other cases, alternative opioids or an alternative anaesthetic technique could be used. Therefore existing stock of remifentanil should be reserved for specific patient groups/procedures until full supplies resume. Anaesthetists should be consulted to identify situations where remifentanil is the preferred opioid and for advice on alternative treatment options/anaesthetic techniques should stock run out. If another opioid is used, medical and nursing staff should be made aware of the differences in dosing regimens as a result of differences in drug handling and pharmacokinetic profiles.</p><p>References</p><p>1. GlaxoSmithKline UK. Ultiva Injection. SPC; date of revision of text, 14 May 2015: https://www.medicines.org.uk/emc/medicine/14766 2. Sedation Committee of the Intensive Care Society United Kingdom. Intensive Care Society Review of Best Practice for Analgesia and Sedation in the Critical Care (June 2014): http://www.ics.ac.uk/AsiCommon/Controls/BSA/Downloader.aspx? iDocumentStorageKey=1c32a885-51fe-495b-a63f- 1335323db5da&iFileTypeCode=PDF&iFileName=Sedation%20for%20Patients %20in%20ICU 3. BNF (intraoperative analgesia) accessed via medicinescomplete on 07 June 2017</p><p>Acknowledgements</p><p> Franco Moscuzza, Director of Anaesthetics and Theatres, Guy’s and St Thomas’ NHS Foundation Trust  Eoin Sherry, Consultant anaesthetist, Guy’s and St Thomas’ NHS Foundation Trust  Ruth Wan, Expert Pharmacist, Perioperative, Critical Care and Pain, Guy’s and St Thomas’ NHS Foundation Trust</p><p>Original document prepared by: Yuet Wan, London and South East Regional Medicines Information, Guy’s and St Thomas’ NHS Foundation Trust (19 June 2017)</p><p>Document modified by: Name of individual at other centre using the product with modifications, centre, date</p><p>For all correspondence please contact: Name of person at base hospital where memo is circulated (i.e. NOT the original author at Guy’s and St Thomas’ NHS Foundation Trust</p><p>Disclaimer: The content of some of this memo is based on clinical opinion from practitioners. Users should bear this in mind in deciding whether to base their policy on this document. Individual trusts should ensure that procedures for unlicensed medicines are followed where a foreign import drug is required in the interim.</p>