Medicines for Symptom Management in Palliative Care

New Medicines Committee Briefing November 2012

Midazolam, glycopyrronium and alfentanil to be reviewed for use within: Primary Care  Secondary Care 

Symptom Management in Palliative Patients

Symptom Drugs Recommended Formulary Pack size Primary dose Status Care Cost / Pack Restlessness Midazolam 10 mg/2ml 2.5-5 mg PRN No 10 amps £7.20 Haloperidol 5 mg/ml 1.5-3 mg QDS Yes 5 amps £1.82 Levomepromazine 25 mg/ml 12.5-25 mg Yes 10 amps £20.13 Nausea and Metoclopramide 10mg/2ml 10mg TDS Yes 10 amps £2.62 vomiting Cyclizine 50mg/ml 50mg TDS Yes 5 amps £3.25 Levomepromazine 25 mg/ml 12.5-25 mg Yes 10 amps £20.13 Haloperidol 5 mg/ml 1.5-3 mg QDS Yes 5 amps £1.82 Respiratory Hyoscine butylbromide 20 mg QDS Yes 10 amps £2.23 tract 20 mg/ml secretions Hyoscine hydrobromide 400 mcg Yes 10 amps £32.44 400 mcg/ml Glycopyrronium 200 mcg/ml 200-400 mcg No 10 amps £5.40 Pain Diamorphine 5 mg 2.5-5 mg Yes 5 amps £12.75 Morphine 10 mg/ml 5-10 mg Yes 10 amps £9.36 Oxycodone 10 mg/ml 2.5-5 mg Yes 5 amps £8.00 Alfentanil 1 mg/2ml 300 mcg No 10 amps £2.90

Formulary application:

The Stoke-on-Trent and North Staffordshire Medicines Management Committee have requested that midazolam, alfentanil, and glycopyrronium be considered for inclusion in the North Staffordshire Joint Formulary for treatment of symptoms in palliative care. Consultant supporting application: Dr Claire Hookey (Palliative Care Consultant, Douglas McMillan Hospice).

1 Dr Hookey states that alfentanil is intended to be used as alternative in patients who are unable to tolerate other strong opioids particularly in renally impaired patients where other options like morphine and diamorphine are not advisable due to accumulation. Glycopyrronium would serve as an alternative to hyoscine butylbromide in the management of respiratory tract secretions, especially in patients where sedation or confusion is an issue. Midazolam, despite being commonly used in palliative care and being part of the standard UHNS palliative TTOs, is not currently on the formulary. The Douglas McMillan Hospice is working with primary care to ensure uniformity in the treatment received by patients irrespective of where they are seen throughout the local health economy. This will imply that the palliative TTOs used at UHNS will be similar to what patients receive in the community.

Introduction:1,2,3

The World Health Organization in 2002 stated that "palliative care is an approach that improves the quality of life for patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual." The National Consensus Guidelines for Palliative Care initially released in 2004 state the goals of palliative care are to prevent and relieve suffering and to support the best possible quality of life for patients and their families, regardless of the stage of the disease or the need for other therapies. Palliative care is both a philosophy of care and an organised, highly structured system for delivering care. Palliative care expands the traditional disease-modifying medical treatments to include the goals of enhancing quality of life for patient and family, optimising function, helping with the decision-making and providing opportunities for personal growth. Palliative care can be delivered concurrently with life-prolonging care or as the main focus of care. Palliative care is operationalised through effective management of pain and other distressing symptoms, while incorporating psychosocial and spiritual care according to patient and family needs, values, beliefs and culture. Palliative care:

provides relief from pain, shortness of breath, nausea, and other distressing symptoms;

affirms life and regards dying as a normal process;

intends neither to hasten nor to postpone death;

integrates the psychological and spiritual aspects of patient care;

offers a support system to help patients live as actively as possible;

offers a support system to help the family cope;

uses a team approach to address the needs of patients and their families;

will enhance quality of life;

is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy. Medications used for palliative patients are used differently than standard medications, based on established practices with varying degrees of evidence. Examples include the use of antipsychotic medications to treat nausea, anticonvulsants to treat pain, and morphine to treat dyspnea. Routes of administration may differ from acute or chronic care, as many patients lose the ability to swallow. A common alternative route of administration is subcutaneous, as it is less traumatic and less difficult to

2 maintain than intravenous access. Other routes of administration include sublingual, intramuscular and transdermal. Liverpool Care Pathway (LCP) is an integrated care pathway that is used at the bedside to drive up sustained quality of the dying in the last hours and days of life. It covers aspects of nursing care, medical care, and communication and gives detailed prescribing advice for common symptoms. It can be implemented in the different care settings: hospital, community, nursing home or hospice. Midazolam, glycopyrronium and alfentanil are already in use at UHNS in palliative patients. Midazolam is part of the standard palliative TTOs while alfentanil and glycopyrronium are listed as drugs commonly administered by continuous subcutaneous infusion in palliative care as shown below. Alfentanil has been recommended as alternative to morphine in UHNS Guideline for pain control in patients with iv access on critical care. Glycopyrronium is recommended as alternative in the UHNS guidelines for control of excessive respiratory secretions via iv or sc route on critical care.

Taken from UHNS Medical Guidelines4

GUIDELINES FOR PAIN CONTROL IN PATIENTS WITH IV ACCESS ON CRITICAL CARE5 (NOTE: if patient transferred to ward revert to generic symptom control flowchart) (Not to be sent to ward with IV infusion or IV drugs prescribed) Pain

Patient is in pain Patient’s pain is controlled

Is patient already on an IV opiate infusion? Is patient already on an IV opiate infusion? i.e. MORPHINE OR ALFENTANIL i.e. MORPHINE OR ALFENTANIL

YES NO YES NO

1. Give as required dose 1. Give as required dose 1. Continue IV opioid 1. Ensure as required of opioid within of morphine 2 – 5 mg IV infusion dose of morphine prescribed range: 2 – 5 mg IV is alfentanil 1 mg IV or 2. Commence morphine 2. Ensure as required prescribed morphine 2 – 5 mg IV 50 mg in 50 ml sodium dose prescribed of chloride 0.9% IV via an either, alfentanil 1 mg 2. Increase IV baseline infusion pump, at IV or morphine 2 – 5 mg infusion rate of opioid 5 – 10 mg/hr. IV. by 1 – 2 mg/hr as needed

SUPPORTIVE INFORMATION:

To convert from other strong opioids contact Palliative Care Team/Pharmacy for further advice & support as needed

If symptoms persist contact the Palliative Care Team (Ext 4087)

Anticipatory prescribing in this manner will ensure that in the last hours / days of life there is no delay responding to a symptom if it occurs

GUIDELINES FOR CONTROL OF EXCESSIVE RESPIRATORY SECRETIONS VIA IV or S/C ROUTE ON CRITICAL CARE5

(NOTE: if patient transfered to ward revert to generic symptom control flowchart) (Not to be sent to ward with IV infusion or IV drugs prescribed) Respiratory tract secretions

Present Absent

1. Ensure HYOSCINE BUTYLBROMIDE (BUSCOPAN) 20 mg IV or s/c as 1. Give HYOSCINE BUTYLBROMIDE required is prescribed (BUSCOPAN) 20 mg IV or s/c bolus injection

2. If two or more doses of HYOSCINE BUTYLBROMIDE (BUSCOPAN) required then consider syringe driver (20 – 40 mg HYOSCINE BUTYLBROMIDE made up to 24 ml with water for injection via s/c syringe driver over 24 hrs at 1 ml/hr)

SUPPORTIVE INFORMATION:

If symptoms persist contact the Palliative Care Team (Ext 4087)

Use of appropriate medication may reduce the need for suctioning

Glycopyrronium 400 micrograms IV or s/c may be used as an alternative

Anticipatory prescribing in this manner will ensure that in the last hours / days of life there is no delay responding to a symptom if it occurs.

These guidelines are produced according to local policy & procedure & you may want to alter them for local use and reference them accordingly

6 Midazolam:

Therapeutic class and mode of action: 6

Hypnotics and sedatives (benzodiazepine derivatives): Midazolam is a derivative of the imidazobenzodiazepine group. The pharmacological action is characterised by short duration because of rapid metabolic transformation. Midazolam has a sedative and sleep-inducing effect of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect. Indications:

Licensed indications:6

In adults as conscious sedation before and during diagnostic or therapeutic procedures with or without local anaesthesia.

As anaesthesia (Premedication before induction of anaesthesia, induction of anaesthesia, as a sedative component in combined anaesthesia) • As sedation in intensive care units In Palliative Care: Midazolam is used in general management of restlessness and agitation in the dying phase especially if anxiety/restlessness predominates.7 It can be given as sc injection or via syringe driver over 24 hrs. In advanced illness, confusion and terminal restlessness/agitation are common. Levomepromazine and haloperidol are also used especially if features of paranoia or psychosis are present. The main advantage of midazolam in palliative care is that it is water-soluble and compatible with most drugs commonly given by continuous subcutaneous infusion (CSCI) and it does not cause thrombophlebitis. In imminently dying patients, tolerance is not a practical problem.8 It also serves in patients whom persistent distressing hiccup is contributing to terminal restlessness at a time when sedation is acceptable to aid symptom relief.

Contraindication:6

Midazolam is contraindicated in patients with known hypersensitivity to benzodiazepines or to any excipient of the product and those with severe respiratory failure or acute respiratory depression.

Drug interactions:6

Midazolam is metabolised by CYP3A4. Inhibitors and inducers of CYP3A have the potential to respectively increase and decrease the plasma concentrations and, subsequently, the effects of midazolam thus requiring dose adjustments accordingly. After a single dose of iv midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. For more information please refer to the SPC.

7 Alfentanil

Therapeutic class and mode of action:9

Alfentanil is a selective mu receptor opioid antagonist similar to fentanyl but has a more rapid onset of action and a shorter half-life. It is mainly metabolised in the liver to inactive compounds hence can be used in renally impaired patients.10

Indications:

Licensed indication:9 Alfentanil is an analgesic supplement for use before and during anaesthesia. It is indicated for short procedures, outpatient surgery and procedures of medium and long duration when given as a bolus followed by supplemental doses or by continuous infusion. At very high doses, alfentanil 500 mcg/ml solution for injection may be used as an anaesthetic induction agent in ventilated patients. In Palliative Care:7 Alfentanil is used as suitable parental opioid in advanced renal disease. Many analgesics are excreted by the kidneys and any degree of renal impairment can reduce drug clearance, and therefore the dose of drug required. No opioid is completely safe in end-stage renal disease (ESRD). Alfentanil becomes a preferred choice as it is extensively metabolised in the liver. It can be given via sc injection and syringe driver. Its short duration of action limits its use for breakthrough analgesia. Fentanyl is another alternative but is only 90% metabolised in the liver and does not appear to accumulate significantly in renal failure. Alfentanil may be preferable if large dose volumes of fentanyl are required.

Contraindication: 9

Known hypersensitivity to the drug and other opioids. Obstructive airway disease or respiratory depression if not ventilating.

Concurrent administration with monoamine oxidase inhibitors or within 2 weeks of their discontinuation.

Drug interactions: 9

Monoamine oxidase (MAO) inhibitors may potentiate the effects of narcotics. It is not recommended to take alfentanil who have received MAO inhibitors within 14 days. Alfentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme. Available human pharmacokinetic data indicate that the metabolism of alfentanil may be inhibited by fluconazole, erythromycin, diltiazem and cimetidine (known cytochrome P450 3A4 enzyme inhibitors). For more information please refer to the SPC.

8 Glycopyrronium

Therapeutic class and mode of action:11

Glycopyrronium bromide is a quaternary ammonium antimuscarinic with peripheral effects similar to those of atropine. Peripheral antimuscarinic effects that are produced as the dose increases are: decreased production of secretions from the salivary, bronchial and sweat glands; dilatation of the pupils (mydriasis) and paralysis of accommodation (cyclopegia); increased heart rate; inhibition of micturition and reduction in gastrointestinal tone; inhibition of gastric acid secretion. Quaternary ammonium compounds are sparingly lipid soluble and do not readily pass lipid membranes such as the blood-brain barrier. Central effects are negligible.

Indications:

Licensed indication:11

To protect against the peripheral muscarinic actions of anticholinesterases such as neostigmine and pyridostigmine, used to reverse residual neuromuscular blockade by non-depolarising muscle relaxants.

As a pre-operative antimuscarinic agent to reduce salivary, tracheobronchial and pharyngeal secretions and to reduce the acidity of the gastric contents.

As a pre-operative or intra-operative antimuscarinic to attenuate or prevent intra-operative bradycardia associated with the use of suxamethonium or due to cardiac vagal reflexes.

In Palliative Care: Dying patients may be unable to cough effectively or swallow which can lead to retained secretions in the upper respiratory tract. It is an established clinical practice to use anticholinergic drugs to try to reduce the accumulation of further secretions.7 Glycopyrronium bromide is used as an alternative to hyoscine butylbromide in the management of respiratory secretions. They are preferred options as they do not usually cause drowsiness, confusion and paradoxical excitation since they do not cross the blood-brain barrier.7 The onset of action of glycopyrronium bromide occurs within one minute, with peak activity at around 5 minutes11 and this makes it a more reliable method of controlling symptom at this critical time. Although it is excreted via kidney, it can still be used in renally impaired patients by using 50% dose.7

Contraindication: 11

Patients with angle-closure glaucoma, myasthenia, paralytic ileus, pyloric stenosis and prostatic enlargement.

Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrronium should be avoided in patients with a prolonged QT interval.

Drug interaction: 11

Concomitant use of two or more antimuscarinic drugs can increase side-effects such as dry mouth, urine retention and constipation. Concomitant use can also lead to confusion in the elderly. Anticholinergic agents may delay absorption of other medication given concomitantly. Concurrent administration of anticholingergics and corticosteroids may result in increased intraocular pressure. Concurrent use of anticholinergic agents with slow-dissolving tablets of digoxin may cause increased serum digoxin levels. For more information please refer to the SPC.

References:

1 World Health Organisation (WHO) Definition of Palliative Care. Accessed via http://www.who.int/cancer/palliative.

2 The National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Quality Palliative Care. Second Edition.2004

3 Liverpool Care Pathway. Access via http://www.liv.ac.uk/mcpcil/liverpool-care-pathway.

4 The Bedside Clinical Guidelines Partnership. UHNS Medical Guidelines 2012-2013.

5 UHNS Critical Care Liverpool Care Pathway for the dying patients Version 12/March 2011.

6 Hypnovel® 10mg/2ml solution for injection. Summary of Product Characteristics. Roche Products Limited. Accessed www.medicines.org.uk 12/10/12

7 West Midlands Palliative Care Physicians, Palliative care, Guidelines for the use of drugs in symptom control, Revised Jan 2012, 5th Edition 2012

8 Twycross R, Wilcock A. 2011 Palliative Care Formulary (PCF4) Edition 4th Nottingham: Palliativedrugs.com

9 Alfentanil 5 mg/ml solution for injection. Summary of Product Characteristics. Hameln pharmaceuticals ltd. Last updated on the eMC: 25/07/2011. Accessed via www.medicines.org.uk

10 Watson M, Lucas C, Hoy A, Wells J 2009 Oxford Handbook of Palliative Care. Edition: 2nd New York: Oxford University Press

11 Glycopyrronium bromide 200 micrograms/ml injection. Summary of product Characteristics. Accord Healthcare Limited. Accessed via http://www.medicines.org.uk

Produced by:

Sr. Maria Chidiamara Njoku Athenais Djossous Primary Care/Secondary Care Interface Pharmacist Rotational Specialist Pharmacist University Hospital of North Staffordshire Telephone: 01782 674541 e-mail: [email protected]

Produced for use within the NHS. Not to be reproduced for commercial purposes.