VELETRI Powder for solution for infusion Ref.[9383] Active ingredients: Epoprostenol

The pH of the diluted “ready-to-use solution” decreases with dilution, and ranges from 12.0 for a concentration of 90,000 ng/mL, 11.7 for a concentration of 45,000 ng/mL to 11.0 for a concentration of 3,000 ng/mL. Therefore, peripheral intravenous use should be restricted to short duration only, using low concentrations.

Because of the high pH of the final infusion solutions, care should be taken to avoid extravasation during their administration and consequent risk of tissue damage.

The medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially sodium free.

VELETRI is a potent pulmonary and systemic vasodilator. The cardiovascular effects during infusion disappear within 30 min of the end of administration.

VELETRI is a potent inhibitor of platelet aggregation, therefore an increased risk for haemorrhagic complications should be considered, particularly for patients with other risk factors for bleeding (see section 4.5).

If excessive hypotension occurs during administration of VELETRI, the dose should be reduced or the infusion discontinued. Hypotension may be profound in overdose and may result in loss of consciousness (see section 4.9).

Blood pressure and heart rate should be monitored during administration of VELETRI.

VELETRI may either decrease or increase heart rate. The change is thought to depend on both the basal heart rate and the infusion rate of VELETRI administered.

The effects of VELETRI on heart rate may be masked by concomitant use of drugs which affect cardiovascular reflexes.

Extreme caution is advised in patients with coronary artery disease.

Elevated serum glucose levels have been reported (see section 4.8).

The solvent contains no preservative; consequently a vial should be used once only and then discarded

Pulmonary Arterial Hypertension

Some patients with pulmonary arterial hypertension have developed pulmonary oedema during dose-ranging, which may be associated with pulmonary veno-occlusive disease. VELETRI must not be used chronically in patients who develop pulmonary oedema during dose initiation (see section 4.3).

Abrupt withdrawal or interruption of infusion must be avoided, except in life-threatening situations. An abrupt interruption of therapy can induce a rebound of pulmonary arterial hypertension, resulting in dizziness, asthenia, increased dyspnoea, and may lead to death (see section 4.2).

VELETRI is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with VELETRI requires commitment by the patient to sterile drug reconstitution, drug administration, care of the permanent central venous catheter, and access to intense and ongoing patient education.

Aseptic conditions must be adhered to in preparing the drug and in the care of the catheter. Even brief interruptions in the delivery of VELETRI may result in rapid symptomatic deterioration. The decision to administer VELETRI for pulmonary arterial hypertension should be based upon the patient’s understanding that there is a high likelihood that therapy with VELETRI will be needed for prolonged periods, possibly years, and the patient’s ability to accept and care for a permanent i.v. catheter and infusion pump should be carefully considered.

Renal Dialysis

The hypotensive effect of VELETRI may be enhanced by the use of acetate buffer in the dialysis bath during renal dialysis.

During renal dialysis with VELETRI, it should be ensured that the cardiac output increases more than minimally so that delivery of oxygen to peripheral tissue is not diminished.

VELETRI is not a conventional anticoagulant. Epoprostenol has been successfully used instead of heparin in renal dialysis, but in a small proportion of dialyses clotting has developed in the dialysis circuit, requiring termination of dialysis. When epoprostenol is used alone, measurements such as activated whole blood clotting time may not be reliable.

When VELETRI is administered to patients receiving concomitant anticoagulants, standard anticoagulant monitoring is advisable.

The vasodilator effects of VELETRI may augment or be augmented by concomitant use of other vasodilators.

As reported with other prostaglandin analogues, VELETRI may reduce the thrombolytic efficacy of tissue plasminogen activator (t-PA) by increasing hepatic clearance of t-PA.

When NSAIDs or other drugs affecting platelet aggregation are used concomitantly, there is the potential for VELETRI to increase the risk of bleeding.

Patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with VELETRI, which – although transient – may be clinically significant in patients prone to digoxin toxicity.

Pregnancy

There is limited data from the use of epoprostenol in pregnant women.

Animal studies did not indicate harmful effects with respect to reproductive toxicity (see section 5.3).

Given the absence of alternative medicines, epoprostenol can be used in women who choose to continue their pregnancy, despite the known risk of pulmonary arterial hypertension during pregnancy.

Breast-feeding

It is unknown if epoprostenol or its metabolites are excreted in human milk. A risk to the breastfeeding child cannot be excluded. Breastfeeding should be discontinued during treatment with VELETRI.

Fertility

There are no data on the effects of epoprostenol on fertility in humans. Reproductive studies in animals have shown no effects on fertility (see section 5.3).

Pulmonary arterial hypertension and its therapeutic management may affect the ability to drive and operate machinery.

There are no data regarding the effect of VELETRI used in renal dialysis on the ability to drive or operate machinery.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as follows: very common ≥1/10 (≥10%); common ≥1/100 and <1/10 (≥1% and <10%); uncommon ≥1/1000 and <1/100 (≥0.1% and <1%); rare ≥1/10,000 and <1/1000 (≥0.01% and <0.1%); very rare <1/10,000 (<0.01%) and not known (cannot be estimated from the available data).

Infections and Infestations

Common: Sepsis, septicaemia (mostly related to delivery system for VELETRI)¹

Blood and Lymphatic System Disorders

Common: Decreased platelet count, bleeding at various sites (e.g. pulmonary, gastrointestinal, epistaxis, intracranial, post-procedural, retroperitoneal)

Unknown: Splenomegaly, Hypersplenism

Endocrine Disorders

Very rare: Hyperthyroidism

Psychiatric Disorders

Common: Anxiety, nervousness

Very rare: Agitation

Nervous System Disorders

Very common: Headache

Cardiac Disorders

Common: Tachycardia², bradycardia³

Not known: High output cardiac failure

Vascular Disorders

Very common: Facial flushing (seen even in the anaesthetised patient)

Common: Hypotension

Very rare: Pallor

Not known: Ascites

Respiratory, Thoracic and Mediastinal Disorders

Unknown: Pulmonary oedema

Gastrointestinal Disorders

Very common: Nausea, vomiting, diarrhoea

Common: Abdominal colic, sometimes reported as abdominal discomfort

Uncommon: Dry mouth

Skin and Subcutaneous Tissue Disorders

Common: Rash

Uncommon: Sweating

Musculoskeletal and Connective Tissue Disorders

Very common: Jaw pain

Common: Arthralgia

General Disorders and Administration Site Conditions

Very common: Pain (unspecified)

Common: Pain at the injection site*, chest pain

Rare: Local infection*

Very rare: Erythema over the infusion site*, occlusion of the long i.v. catheter*, lassitude, chest tightness

Investigations

Unknown: Blood glucose increased

* Associated with the delivery system for epoprostenol
¹ Catheter-related infections caused by organisms not always considered pathogenic (including micrococcus) have been reported.
² Tachycardia has been reported as a response to epoprostenol at doses of 5 ng/kg/min and below.
³ Bradycardia, sometimes accompanied by orthostatic hypotension, has occurred in healthy volunteers at doses of epoprostenol greater than 5 ng/kg/min. Bradycardia associated with a considerable fall in systolic and diastolic blood pressure has followed i.v. administration of a dose of epoprostenol equivalent to 30 ng/kg/min in healthy conscious volunteers.

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 at: 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.