ILOPROST Concentrate for solution for infusion Ref.[9900] Active ingredients: Iloprost

Special warnings

Surgery should not be delayed in patients requiring urgent amputation (e.g. in cases of infected gangrene).

Patients who are smokers should be strongly advised to stop smoking.

In patients with renal insufficiency requiring dialysis or severe hepatic impairment, it should be taken into account that iloprost plasma levels may be increased due to less elimination of the product (see section 5.2). In these patients, cautious initial titration with dose reduction (see section 4.2) and close clinical monitoring are required.

In patients with low blood pressure care should be taken to avoid further hypotension.

Also, patients with significant heart disease should be closely monitored.

The possibility of orthostatic hypotension should be considered in patients getting up from the lying to an upright position after the end of administration.

For patients with a cerebrovascular event, a careful benefit-risk assessment should be undertaken (see also section 4.3 risk of haemorrhage, intracranial haemorrhage).

This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per dose.

Special precautions

Accidental infusion of undiluted iloprost may result in local changes at the injection site. Therefore a dedicated intravenous cannula should be placed for the infusion of iloprost and the patency of the line should be checked during infusion.

Oral ingestion and contact with the mucous membranes should be avoided. On contact with the skin, iloprost may cause long-lasting but painless erythema. Suitable precautions should therefore be taken to avoid iloprost contact with the skin. In the event of such contact, the affected area should be washed immediately with copious amounts of water or saline.

Iloprost may increase the anti-hypertensive activity of β-blockers, calcium antagonists, vasodilators and ACE inhibitors. In case of significant hypotension, this can be corrected by dose reduction of iloprost.

Because iloprost inhibits platelet aggregation, concomitant use with oral anticoagulants, and/or heparin and related molecules (coumarin-type anticoagulants), and/or thrombolytics and/or other inhibitors of platelet aggregation (such as acetylsalicylic acid, ticlopidine, clopidogrel, and/or anti IIB/IIIA) may increase the risk of bleeding. The possible increase in haemorrhagic risk should be taken into account by maintaining close clinical monitoring. If this occurs, iloprost administration should be stopped.

Iloprost infusions do not affect the pharmacokinetics of multiple oral doses of digoxin.

Pregnancy

Iloprost 100 micrograms/ml Concentrate for solution for infusion is contraindicated during pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception during treatment. There are no or limited amount of data from the use of iloprost in pregnant women.

Studies in animals have shown embryotoxicity in rats but not in rabbits and monkey (see section 5.3).

Breast-feeding

Iloprost 100 micrograms/ml Concentrate for solution for infusion is contraindicated during breast-feeding (see section 4.3). It is unknown whether iloprost is excreted in human milk.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Iloprost 100 micrograms/ml Concentrate for solution for infusion therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data available.

Iloprost has major influence on the ability to drive and use machines for patients experiencing hypotensive symptoms such as dizziness.

Care should be exercised during initiation of therapy until any effects on the individual have been determined.

a. Summary of safety profile

The overall safety profile of iloprost is based on data from post-marketing surveillance as well as on pooled clinical trial data. The raw incidence was based on the cumulative database of 3325 patients having received iloprost either in controlled or uncontrolled clinical trials or in a compassionate use program from generally elderly and multimorbid patients with peripheral arterial occlusive disease (PAOD) in advanced stages III and IV, and patients with thromboangiitis obliterans (TAO); for details see Table 1.

The most common observed adverse events (≥10%) in patients receiving iloprost in clinical trials are headache, flushing, nausea, vomiting and hyperhidrosis. These undesirable effects are likely to occur during the dose titration at the start of treatment to identify the best tolerable dose for the individual patient. Usually these undesirable effects resolve with dose reduction.

Overall, the most severe undesirable effects (life-threatening or fatal) in patients receiving iloprost are cerebrovascular stroke, myocardial infarction, pulmonary embolism, cardiac failure, convulsion, hypotension, tachycardia, asthma, angina pectoris, dyspnoea, and pulmonary oedema.

Another group of side effects is related to the local infusion site reactions. For example, infusion site redness and infusion site pain may occur or a cutaneous vasodilation may give rise to a linear erythema above the infusion vein.

b. Tabular list of adverse reactions

Adverse reactions observed after use of iloprost 100 micrograms/1 ml are listed in the table below. They are classified by system organ class (MedDRA version 19.0). The most appropriate MedDRA term has been selected to describe a certain reaction and its synonyms and associated conditions.

Adverse reactions from clinical studies are classified by their frequency.

The following categories are used for stating the frequency of adverse reactions: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Table 1. Adverse reactions reported during clinical studies or observed in post-marketing experience in patients treated with iloprost 100micrograms/ml:

Blood and lymphatic system disorders

Uncommon: Thrombocytopenia

Immune system disorders

Uncommon: Hypersensitivity

Metabolism and nutrition disorders

Common: Decreased appetite

Psychiatric disorders

Common: Bradypsychia, Confusional state

Uncommon: Anxiety, Depression, Hallucination

Nervous system disorders

Very common: Headache

Common: Dizziness/Vertigo, Paraesthesia/Palpitations/Hyperaesthesia/Burning sensation, Restlessness/drowsiness

Uncommon: Convulsion*, Syncope, Tremor, Migraine

Eye disorders

Uncommon: Vision blurred, Eye irritation, Eye pain

Cardiac disorders

Common: Tachycardia*, Bradycardia, Angina pectoris*

Uncommon: Myocardial infarction*, Cardiac failure*, Arrhythmia/Extrasystoles*,

Vascular disorders

Very common: Flushing

Common: Hypotension*, Blood pressure increased

Uncommon: Cerebrovascular event*/Cerebral ischaemia, pulmonary embolism*, Deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea*

Uncommon: Asthma*, Pulmonary oedema*

Rare: Cough

Gastrointestinal disorders

Very common: Nausea, Vomiting

Common: Diarrhoea, Abdominal discomfort/Abdominal pain

Uncommon: Diarrhoea haemorrhagic, Rectal haemorrhage, Dyspepsia, Rectal tenesmus, Constipation, Dysphagia, Dry mouth/Dysgeusia

Rare: Proctitis

Hepatobiliary disorders

Uncommon: Hepatic impairment

Skin and subcutaneous tissue disorders

Very common: Hyperhidrosis

Uncommon: Pruritus

Musculoskeletal and connective tissue disorders

Common: Pain in jaw/Trismus, Myalgia/Arthralgia

Uncommon: Tetany/Muscle spasms

Renal and urinary disorders

Uncommon: Kidney pain, Dysuria

General disorders and administration site conditions

Common: Pain, Pyrexia/Body temperature increased, Feeling hot, Asthenia, Chills, Thirst, Infusion site reactions (infusion site erythema, infusion site pain, infusion site phlebitis)

* life threatening and/or fatal cases have been reported

Iloprost may cause angina pectoris, especially in patients with coronary artery disease.

The risk of bleeding is increased in patients when inhibitors of platelet aggregation, heparin or coumarin-type anticoagulants are given concomitantly.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.