684Fm.3 Iloprost Infusion Protocol

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684FM.3 ILOPROST INFUSION PROTOCOL Introduction Iloprost is licensed in the UK only for use in primary pulmonary hypertension and has recently been licensed for Raynaud’s phenomenon and peripheral arterial occlusive disease. This protocol defines how iloprost should be administered to patients.

Mode of Action Iloprost is a synthetic prostacyclin analogue which is a normal product of vascular endothelial cells. It is a potent vasodilator and inhibitor of platelet aggregation.

Availability The hospital pharmacy routinely holds enough stock for a single course of treatment.

Indications 1. Treatment of patients with severe disabling Raynaud’s phenomenon1 unresponsive to other therapies for the prevention of ischaemic pain, peripheral ulcers, necrosis of fingers and toes in order to prevent patients proceeding to amputation. 2. Treatment of patients with severe peripheral arterial occlusive disease, particularly those at risk of amputation and in whom surgery or angioplasty is either not possible or is delayed. 3. Treatment of advanced thromboangiitis obliterans (Buerger’s disease) with critical limb ischaemia in cases where revascularisation is not indicated.

Contraindications 1. Hypersensitivity to iloprost or to any of the excipients. 2. Pregnancy, lactation. 3. Conditions where the effects of iloprost on platelets might increase the risk of haemorrhage (e.g. active peptic ulcers, trauma, intracranial haemorrhage, inherited bleeding tendency). 4. Severe coronary heart disease or unstable angina; myocardial infarction within the last six months; decompensated cardiac failure if not under close medical supervision; severe arrhythmias; suspected pulmonary congestion; cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last 3 months. 5. Pulmonary hypertension due to venous occlusive disease. 6. Congenital or acquired cardiac valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension.

Warnings and Precautions 1. Iloprost should not be initiated in patients with systolic blood pressure lower than 85 mmHg. Orthostatic hypotension can occur in patients getting up from lying to an upright position after the end of administration. 2. Renal failure and liver cirrhosis – use half of the recommended dose. A cautious initial dose titration using dose intervals of at least 3 hours is recommended. 3. Patients with acute pulmonary infections, chronic obstructive pulmonary disease and severe asthma should be carefully monitored. 4. Surgery should not be delayed in patients requiring urgent amputation (e.g. in infected gangrene). 5. Patients should be strongly advised to stop smoking. 6. Currently no experience in children and adolescents is available. Iloprost should not be used in patients below 18 years of age. 7. The paravascular infusion (extravasation) of undiluted iloprost can lead to local changes at the injection site. 8. Oral ingestion and contact with mucous membranes must be avoided. On contact with the skin, iloprost may provoke long-lasting but painless erythema. Guideline 684FM.3 1 of 6 Uncontrolled if printed

Side Effects Common: Facial flushing, headache, hypotension, tachycardia, nausea, nausea and vomiting, cramping abdominal pain, diarrhoea, sweating, jaw and shin pain, bleeding events, chest discomfort. Less common: Malaise, sensation of warmth, weakness, dizziness, fever. Rare: Pain in affected limb, hypersensitivity, thrombocytopenia, bronchospasm, wheezing, dysgeusia, tremor, hypoglycaemia, anxiety.

Drug Interactions 1. Iloprost may have additive antihypertensive effects in patients also taking:  Β-blockers  Calcium antagonists  ACE inhibitors  Angiotensin II receptor antagonists If significant hypotension occurs, reduce the infusion rate of iloprost. 2. Iloprost may increase the risk of bleeding with:  Antiplatelets (for example aspirin, non-steroidal anti-inflammatories, inhibitors of glycoprotein IIb/IIIa and phosphodiesterase inhibitors)  Heparin  Warfarin or other coumarin type anticoagulant drugs  Direct thrombin inhibitors  Non-vitamin K antagonist oral anticoagulants (NOACs), for example apixaban, dabigatran, rivaroxaban Stop the infusion if bleeding occurs.

Administration: Iloprost may be administered by one of three schedules:  3-day schedule2 (for the treatment of Raynaud’s/scleroderma as an inpatient)  5-day schedule3 (for the treatment of Raynaud’s/scleroderma as a day-case outpatient)  Continuous infusion schedule4 (for the treatment of patients with active/extensive digital ulcers, digit threatening ischaemia or for patients who cannot tolerate higher rates of iloprost infusion)

Guideline 684FM.3 2 of 6 Uncontrolled if printed 3 Day Iloprost Infusion Schedule

Prior to treatment:  Weigh the patient  Measure patient’s baseline pulse and blood pressure

Pre-medication (given 1 hour prior to start of iloprost infusion):  Paracetamol 1000 mg orally  Metoclopramide 10 mg orally (or domperidone 10 mg orally in patients at risk of extrapyramidal side effects)

Dose: 100 micrograms (1 ml) iloprost in 49 ml sodium chloride 0.9% or glucose 5% (in a 50 ml syringe). Concentration = 2 micrograms/ml (2000 nanograms/ml).

Rate: According to weight (see table below).  Commence infusion at 0.5 nanograms/kg/min.  Increase rate by 0.5 nanograms/kg/min every 30 minutes until a maximum dose of 2.0 nanograms/kg/min is reached (or highest tolerated dose up to this maximum).

Body weight Dose (nanograms/kg/min) (kg) 0.5 1.0 1.5 2.0 Infusion rate (ml/hr) 40 0.6 1.2 1.8 2.4 50 0.8 1.5 2.3 3 60 0.9 1.8 2.7 3.6 70 1.1 2.1 3.2 4.2 80 1.2 2.4 3.6 4.8 90 1.4 2.7 4.1 5.4 100 1.5 3 4.5 6 110 1.7 3.3 5 6.6

Duration: Over 10 hours for 3 consecutive days.

Repeated: Every 3 - 6 months depending on patient need.

If side effects become intolerable reduce dose by 0.5 nanograms/kg/min.

Monitoring:  Blood pressure and pulse every 30 minutes for first hour, then hourly and one hour after completion of infusion.  Document the infusion rate on the observation chart together with the observations.

Guideline 684FM.3 3 of 6 Uncontrolled if printed 5 Day Iloprost Infusion Schedule

Prior to treatment:  Weigh the patient  Measure patient’s baseline pulse and blood pressure

Dose: 100 micrograms (1 ml) iloprost in 49 ml sodium chloride 0.9% or glucose 5% (in a 50 ml syringe). Concentration = 2 micrograms/ml (2000 nanograms/ml).

Duration: Over 6 hours for 5 consecutive days.

Repeated: Every 3 - 6 months depending on patient need.

If side effects become intolerable reduce dose by 0.5 nanograms/kg/min.

Guideline 684FM.3 4 of 6 Uncontrolled if printed Continuous Iloprost Infusion Schedule

Prior to treatment:  Weigh the patient  Measure patient’s baseline pulse and blood pressure

Pre-medication (given 1 hour prior to start of iloprost infusion):  Paracetamol 1000 mg orally, can be repeated 6 hourly  Metoclopramide 10 mg orally, can be repeated 8 hourly (or domperidone 10 mg in patients at risk of extrapyramidal side effects)

Dose: 100 micrograms (1 ml) iloprost in 49 ml sodium chloride 0.9% or glucose 5% (in a 50 ml syringe). Concentration = 2 micrograms/ml (2000 nanograms/ml).

Rate: Start the infusion at 0.9 ml/hour. The infusion rate may be increased if clinically indicated according to patient’s tolerance and haemodynamic stability. The usual maximum tolerated rate is up to 4 ml/hr. The infusion is usually continued for 5 to 14 days as clinically indicated. Longer durations may be required in scleroderma renal crisis or severe ischaemia or digital ulcers. Higher rates can be used for patients who have extensive ulceration to improve blood flow to the affected areas. Increase the infusion rate gradually as tolerated by the patient.

Duration: Continuously over 24 hours for as many days as required.

Repeated: Every 3 - 6 months depending on patient need. If side effects become intolerable reduce dose by 0.5 nanograms/kg/min. Side-effects: Patients commonly experience hypotension, headache, nausea, flushing and can experience bone pain (shin and jaw).

Guideline 684FM.3 5 of 6 Uncontrolled if printed References: 1. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR) Ann Rheum Dis 2009;68:620-628. 2. Otylia Kowal-Bielecka1et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017;76:1327 – 1339 3. Denton P et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology 2016;55:1906 - 1910 4. Royal Free Hospital Rheumatology Department “Iloprost for Peripheral Vascular Disease, March 2012. 5. Pope J et al. Iloprost and cisaprost for Raynauds phenomenon in progressive systemic sclerosis (review). The Cochrane Collaboration 2009. 6. McHugh et al. Infusion of iloprost, a prostaglandin, for treatment of Raynauds phenomenon in systemic sclerosis. Annals of the Rheumatic Diseases 1988; 47: 43 – 47. 7. NICE 2013. Critical limb ischaemia in peripheral vascular disease: intravenous iloprost [ESUOM24]. London: NICE 8. Data sheet for Ilomedin® (New Zealand). Available on: https://medsafe.govt.nz/profs/Datasheet/i/Ilomedininf.pdf. Date of preparation 19 March 2012 [Accessed 22/02/2019]

See also: Guideline 6 Policy for Consent to Examination or Treatment Guideline 222 Adult and Paediatric Injectables Guide

Title of Guideline Iloprost Infusion Protocol Guideline Number 684FM Version 3 Effective Date July 2019 Review Date July 2022 Original Version Published January 2008 Approvals: Clinical Guidelines Subgroup 19th June 2019 Author/s Rheumatology Consultants SDU(s)/Department(s) responsible Rheumatology for updating the guideline Uploaded to Intranet 5th July 2019 Buckinghamshire Healthcare NHS Trust

Guideline 684FM.3 6 of 6 Uncontrolled if printed