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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Prostin VR Sterile Solution.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains 500 micrograms (0.5 mg) alprostadil.

3 PHARMACEUTICAL FORM

Sterile solution for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Prostin VR is indicated to temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in infants who have congenital defects and who depend upon the patent ductus for survival. Such congenital heart defects include pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, co-arctation of the aorta, aortic stenosis, aortic atresia, mitral atresia, or transposition of the great vessels with or without other defects.

4.2 Posology and method of administration

For administration by intravenous drip or constant rate infusion pump.

In infants with lesions restricting pulmonary blood flow (blood is flowing through the ductus arteriosus from the aorta to the pulmonary artery), Prostin VR may be administered by continuous infusion through an umbilical artery catheter placed at or just above the junction of the descending aorta and the ductus arteriosus, or intravenously. Adverse effects have occurred with both routes of administration, but the types of reactions are different. A higher incidence of flushing has been associated with intra-arterial than with intravenous administration.

The infusion is generally initiated at a rate of 0.05 to 0.1 micrograms alprostadil per kilogram of body weight per minute. The most experience has been with 0.1 micrograms/kg/min. After a therapeutic response (an increase in pO₂ in neonates with restricted pulmonary blood flow or an increase in systemic blood pressure and blood pH in neonates with restricted systemic blood flow) has been obtained, the infusion rate should be reduced to the lowest possible dosage that will maintain the desired response.

Dilution Instructions: To prepare infusion solutions, dilute 1 ml of Prostin VR Sterile Solution with sterile 0.9% Sodium Chloride Intravenous Infusion or sterile 5% Dextrose Intravenous Infusion. If undiluted Prostin VR Sterile Solution comes in direct contact with a plastic container, plasticisers are leached from the sidewalls. The solution may turn hazy and the appearance of the container may change. Should this occur, the solution should be discarded and the plastic container should be replaced. This appears to be a concentration-dependent phenomenon. To minimise the possibility of haze formation, Prostin VR Sterile Solution should be added directly to the intravenous infusion solution, avoiding contact with the walls of plastic containers. Dilute to volumes appropriate for the delivery system available. Prepare fresh infusion solutions every 24 hours. Discard any solution more than 24 hours old.

PARTICULAR CARE SHOULD BE TAKEN IN CALCULATING AND PREPARING DILUTIONS OF PROSTIN VR.

4.3 Contraindications

Hypersensitivity to the active substance (alprostadil) or to any of the excipients.

4.4 Special warnings and precautions for use

Prostin VR should be administered only by well trained healthcare professionals and in facilities with immediate access to paediatric intensive care.

Apnoea may occur in about 10-12% of neonates with congenital heart defects treated with alprostadil (PGE1).There is some evidence that apnoea is dose related. Apnoea is most often seen in neonates weighing less than 2 kg at birth and usually appears during the first hour of drug infusion. Therefore Prostin VR Sterile Solution should be used where ventilatory assistance is immediately available.

Prostin VR Sterile Solution (alprostadil) should be infused for the shortest time and at the lowest dose which will produce the desired effects. The risk of long-term infusion of Prostin VR should be weighed against the possible benefits that critically ill infants may derive from its administration.

Pathologic studies of the ductus arteriosus and pulmonary arteries of infants treated with prostaglandin E1 have disclosed histologic changes related with the weakening effect upon these structures. The specificity or clinical relevance of these results is not known.

Cortical proliferation of the long bones has followed long-term infusions of alprostadil in infants and dogs. The proliferation in infants regressed after withdrawal of the drug.

Since prostaglandin E1 is a potent inhibitor of platelet aggregation; use Prostin VR Sterile Solution cautiously in neonates with histories of bleeding tendencies.

Alprostadil should not be used in neonates (or infants) with respiratory distress syndrome (hyaline membrane disease). A differential diagnosis should always be made between respiratory distress syndrome and cyanotic heart disease (restricted pulmonary blood flow). In the event that full diagnostic is not immediately available, the diagnosis should be based on the presence of cyanosis (pO2 less than 40 torr) and x-ray evidence of a restricted pulmonary blood flow.

Arterial pressure should be monitored by umbilical artery catheter, auscultation or with a Doppler transducer. Should arterial pressure fall significantly, the rate of infusion should be immediately decreased.

Weakening of ductus arteriosus wall and pulmonary artery has been reported, particularly during prolonged administration.

The administration of alprostadil to neonates may result in gastric outlet obstruction secondary to antral hyperplasia. This effect appears to be related to duration of therapy and cumulative dose of the drug. Neonates receiving alprostadil at recommended doses for more than 120 hours should be closely monitored for evidence of antral hyperplasia and gastric outlet obstruction.

In neonates (or infants) with decreased pulmonary blood flow, the oxygenation increase is inversely proportional to the previous pO2 values; ie, better responses are obtained in patients with low pO2 values (less than 40mmHg), whereas patients with high pO2 values (more than 40 mmHg) have usually a minimal response. In neonates (or infants) with decreased pulmonary blood flow, alprostadil efficacy is measured by monitoring blood oxygenation increase. In neonates (or infants) with decreased systemic blood flow the efficacy is determinated by monitoring the increase in systemic blood pressure and blood pH.

4.5 Interaction with other medicinal products and other forms of interaction

No drug interactions have been reported to occur between Prostin VR and the standard therapy employed in neonates with congenital heart defects. Standard therapy includes antibiotics, such as penicillin or gentamicin; vasopressors, such as dopamine or isoproterenol; cardiac glycosides; and diuretics, such as furosemide.

4.6    Fertility, pregnancy and lactation

Not applicable.

4.7    Effects on ability to drive and use machines

Not applicable.

4.8    Undesirable effects

The most frequent adverse reactions observed with Prostin VR infusion in neonates with ductal-dependent congenital heart defects are related to the drug's known pharmacological effects.

The following undesirable effects have been observed and reported during treatment with alprostadil (436 neonates treated) with the following frequencies: 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).

System Organ Class	Frequency	Undesirable effects
Nervous system disorders	Common	Seizures
Cardiac disorders	Common	Bradycardia, hypotension, tachycardia
Respiratory, thoracic and medicinal disorders	Very common	Apnoea
Gastrointestinal disorders	Common	Diarrhoea
	Uncommon	Obstruction gastric, gastric mucosal hypertrophy

Musculoskeletal and connective tissue disorders	Uncommon	Exostosis
Vascular disorders	Uncommon	Vascular fragility
General disorders and administration site conditions	Very common	Transient pyrexia
	Common	Cutaneous vasodilatation (flushing)*
*This is the only adverse event directly re		lated to the route of administration,

being more frequent with intra-arterial administration.

The relationship of the following adverse events, in decreasing frequency, to the drug is unknown: sepsis, cardiac arrest, disseminated intravascular coagulation, hypokalaemia, and oedema.

4.9 Overdose

Apnoea, bradycardia, pyrexia, hypotension and flushing may be signs of drug overdose. If apnoea or bradycardia occur, the infusion should be discontinued and the appropriate medical treatment initiated. Caution should be used if the infusion is restarted. If pyrexia or hypotension occur, the infusion rate should be reduced until these symptoms subside. Flushing is usually attributed to incorrect intra-arterial catheter placement and is usually alleviated by repositioning the tip of the catheter.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Prostaglandins are potent vasoactive derivatives of arachadonic acid that exert vasomotor, metabolic and cellular effects on the pulmonary and coronary circulation. The E series of prostaglandins produces vasodilation of the systemic and coronary circulation in most species: these prostaglandins have been used for maintaining the patency of the ductus arteriosus in children.

Doses lower than 0.05 microgram/kg/min (as low as 0.005 microgram/kg/min) alprostadil have been used successfully in neonates, specifically when transport of the infant is necessary. No comparative trials exist and the efficacy and safety of this approach when compared to initiating dosing according to section 4.2 is currently unclear.

5.2 Pharmacokinetic properties

Based on studies in several animal species, intravenous or arterially administered prostaglandin E₁ is very rapidly metabolised and distributed throughout the entire body, with the exception of the CNS, where distribution, though detectable, is markedly reduced. The primary organisms for metabolism and inactivation of prostaglandin E₁ are probably the lung, liver and kidney which remove and metabolise 40-95% of the prostaglandin E₁ in a single pass through the organ. A number of other tissues possess lesser, but significant, capacity to metabolise prostaglandin E₁. The predominant metabolites found in plasma, 15-oxo-prostaglandin E₁ and 13,14-dihydro-15 oxo-prostaglandin E₁ are extensively metabolised by P and co-oxidation prior to excretion, primarily by the kidney. Few urinary metabolites of prostaglandin E₁ have been characterised, but are widely believed to be analogous to those reported in detail for prostaglandin E₂ and prostaglandin F₂ . Excretion is essentially complete within 24 hours after dosing, with no intact prostaglandin E₁ being found in urine and no evidence of tissue retention of prostaglandin E₁ or metabolites. In three species, rat, rabbit and lamb, the prostaglandin metabolising activity of lung from near-term fetal animals has been shown to be at least as effective as that of adults.

5.3 Preclinical safety data

Long-term carcinogenicity and fertility studies have not been done. The Ames and Alkaline Elution assays reveal no potential for mutagenesis

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Dehydrated ethanol

Incompatibilities

Diluted solutions of Prostin VR should be infused from glass or hard plastic containers, or PVC infusion bags. If undiluted Prostin VR Sterile Solution comes in direct contact with a plastic container, plasticisers are leached from the sidewalls. This appears to be a concentration-dependent phenomenon.

6.3    Shelf life

Three years.

6.4    Special precautions for storage

Store in a refrigerator.

6.5    Nature and contents of container

Glass ampoule, containing 1 ml solution.

6.6    Special precautions for disposal

Diluted solutions should be used within 24 hours.

7    MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 0032/0083

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of Grant: 23 July 1981

10    DATE OF REVISION OF THE TEXT

07/04/2014