Protamine sulphate LEO Pharma 1400 anti-heparin IU/ml solution for injection and infusion

Section 2:  updated in line with current QRD template
Section 4.2: updated in line with current QRD template, editorial changes, addition of safety and efficacy information in the paediatric population.
Section 4.3: updated in line with current QRD template

Section 4.4: Special warnings and precautions for use - updated in line with current data, editorial changes.

Administration of protamine sulphate can cause anaphylactic reactions and therefore facilities for resuscitation and treatment of shock should be available.

 

Administration of protamine sulphate, particularly when given too rapidly, may cause severe hypotension.

Risk factors for hypersensitivity (including anaphylactic reactions) to protamine sulphate:

•           Allergy to fish

•           Previous treatment with protamine insulin, protamine sulphate or protamine chloridecompounds

•           Infertility in men

•           Medical history of vasectomy (e.g. sterilisation)

Therefore if protamine sulphate is administered as a lifesaving measure to a patient with any of these conditions, the patient should be treated under closer surveillance.

Patients with known history of allergy to fish, patients who have been treated with protamine insulin, protamine sulphate or protamine chloride, infertile men and men who have had a vasectomy (e.g. sterilisation) may develop hypersensitivity (including anaphylactic reactions) to protamine sulphate and should therefore be treated with close surveillance.

 

Excessive dosage of protamine sulphate or when given in the absence of heparin or LMWH may induce prolonged the coagulation time sincebecause protamine sulphate in itself has anticoagulant activity.

 

RA rebound anticoagulant effect of heparin/LMWH with haemorrhage has been reported occasionally despite initial adequate heparin inhibition neutralisation by protamine sulphate.

This occurs more frequently in case of extra corporeal circulation in cardiovascular surgery, within 30 minutes to 18 hours after protamine sulphate administration. This rebound bleeding responds to further doses of protamine sulphate.  

Rebound bleeding may also occur when protamine sulphate is used to reverse subcutaneous heparin or LMWH, reflecting continuous release of heparin or LMWH from the subcutaneous injection sites which act as depots.

 

Patients undergoing prolonged procedures involving repeated doses of protamine sulphate should be subject to careful monitoring of clotting parameters, e.g. activated clotting time (ACT), and as thrombocytopenia due to extracorporeal circulation may be aggravated by protamine sulphate, platelet count should be monitored.

With heparin overdose, in the absence of overt haemorrhage, serious consideration should be given as to whether protamine sulphate should be used and the risk/benefit ratio should be considered for the individual patient. The relatively short half life for heparin (especially if given intravenously) and the potential risk of administering protamine sulphate must be considered in the assessment.

 

This medicinal product contains less than 1 mmol (23 mg) sodium per 5 ml, i.e. essentially ‘sodium-free’.

Section 4.6: Fertility, pregnancy and lactation - updated in line with current pharmacovigilance data and current QRD template.

Pregnancy

There are no or limited amount of data from the use of protamine sulphate in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity.

Protamine sulphate is not recommended during pregnancy and in woman of childbearing potential not using contraception, unless the clinical condition of the woman strongly requires treatment with protamine sulphate.

Pregnancy

There are no available data from the use of protamine sulphate in pregnant women.

No reproductive toxicological studies in animals have been carried out.

However, due to the necessity to treat, Protamine sulphate LEO Pharma should be used during pregnancy only when clearly necessary.

Breast-feeding

It is unknown whether protamine sulphate is excreted in human milk. A risk to the infants cannot be excluded. Breast-feeding should be discontinued during treatment with protamine sulphate.

Lactation

It is unknown whether protamine sulphate is excreted in breast milk. Due to the potential harmful effects on infants if breast fed, lactation is not recommended during treatment.

Fertility

There are no clinical or non-clinical studies with protamine sulphate regarding fertility.

Section 4.8: Undesirable effects - updated in line with current data and addition of suspected adverse reaction national reporting statement.

The frequency of adverse reactions is not known as this cannot be estimated from the available data.

The estimation of the frequency of undesirable effects is based on a pooled analysis of data from clinical trials and from spontaneous reporting.

The most serious and frequently reported adverse reactions are hypotension, pulmonary hypertension and anaphylactic reactions.

Undesirable effects are listed by MedDRA SOC.  and the individual undesirable effects are listed starting with the most frequently reported. Within each MedDRA SOCfrequency group, adverse reactions are presented in the order of decreasing seriousness.

Very common (≥1/10)
Common (≥1/100 and < 1/10)
Uncommon (≥1/1,000 and <1/100)
Rare (≥1/10,000 and <1/1,000)
Very rare (<1/10,000)Gastrointestinal disorders

Vomiting

Immune system disorders

Anaphylactic reaction (incl. anaphylactic shock, even fatal)

Hypersensitivity

Musculoskeletal and connective tissue disorders

Back pain

Respiratory, thoracic and mediastinal disorders

Pulmonary hypertension

Vascular disorders

Hypotension (incl. blood pressure decreased)*

Haemorrhage

Gastrointestinal disorders
Rare (≥1/10,000 and <1/1,000)	Vomiting
Immune system disorders
Rare (≥1/10,000 and <1/1,000)	Anaphylactic reaction (incl. anaphylactic shock, even fatal)
Very rare (<1/10,000)	Hypersensitivity
Musculoskeletal and connective tissue disorders
Rare (≥1/10,000 and <1/1,000)	Back pain
Respiratory, thoracic and mediastinal disorders
Common (≥1/100 and < 1/10)	Pulmonary hypertension
Vascular disorders
Common (≥1/100 and < 1/10)	Hypotension (incl. blood pressure decreased)*
Rare (≥1/10,000 and <1/1,000)	Haemorrhage

*Some of the reported hypotensive events may have anaphylactic background

 

Descriptions of selected adverse reactions
Hypersensitivity including immune-mediated allergic reactions (see section 4.4 for potential risk factors).  

 

Symptoms like urticarial or other skin rashes, peripheral vasodilation, dyspnoea or angioedema have been observed and more severe reactions include bronchospasm, hypotension with cardiac and circulatory changes, loss of consciousness and cramps. Fatal anaphylactic shock has been seen after protamine administration.

 

Prolonged hypotension accompanied by bradycardia, cyanosis, stupor, syncope, loss of consciousness or transient cardiac asystole.

 

Too rapid administration may cause hypotension (transient or severe) or bradycardia and increase the risk for anaphylactic reaction.

 

Mild events such as feeling of warmth, flushing and hypotension are commonly reported following protamine sulphate administration.

Severe systemic reactions such as pulmonary hypertension, non-cardiogenic pulmonary oedema, and severe hypotension are rarely reported.

Exact incidences cannot be given:

 

Immune System Disorders:

Hypersensitivity reactions including hypotension, dyspnoea, bronchospasm, flushing, urticaria, angioedema, anaphylactic shock (see section 4.4 for potential risk factors).

 

For potential risk factors for hypersensitivity reactions, see section 4.4.

 

Vascular and Cardiac Disorders:

Prolonged hypotension, accompanied by bradycardia, cyanosis, stupor, syncope, loss of consciousness or momentary cardiac standstill.

Too rapid administration of protamine may cause severe hypotension or bradycardia.

 

Haemorrhage (see section 4.4 and section 4.9)

 

Respiratory, Thoracic and Mediastinal Disorders:

Pulmonary arterial hypertension

 

Gastrointestinal Disorders:

Nausea and Vomiting

General Disorders and Administration Site Conditions:

Back pain, feeling of warmth

Paediatric population
The observed safety profile is similar in children and adults.

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  HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Section 4.9:  Overdose - editorial changes and update to treatment options in the event of overdose.

Clinical Effect of Overdose:

Overdose may cause  bleedinghaemorrhage, as protamine sulphate in itself has an weak anticoagulant effect. Furthermore, in volunteers with very high doses of protamine sulphate (800 mg/70 kg) typical signs of histamine release were observed in a dose-dependent way such as: itching, flushingperipheral vasodilation, fatigue, malaise, nausea/vomiting, headache, hyperventilation and temperature elevation.

 

Treatment of Overdose:

In the event of bleeding haemorrhage due to protamine sulphate overdose, administration of the product should be discontinued. To determine that the pProtamine sulphate is contributing to the bleeding, the heparin titration test with protamine sulphate and the determination of plasma thrombin time are commonly used in this setting. For severe haemorrhage, transfusion of whole blood or fresh frozen plasma or other intervention may also be required. Hypotensive patients may require additional intravenous fluids, oxygen, epinephrineadrenaline, dobutamine or dopamine.

Section 6.4: updated in line with current QRD template.

Section 6.6: SPC section heading updated in line with current QRD template.

Section 10: Date of revision of text updated to October 2014

Date of revision of the text has changed from September 2010 to November 2010

Section 2: Editorial change only
Section 4.4: Editorial change only
Section 4.5: Editorial change only
Section 5.1: Editorial change only
Section 6.3: Addition of text: 'When diluted for administration as a slow intravenous infusion the mixture should be used immediately'.
Section 9: Date updated as a result of renewal
Section 10: Date updated as a result of revision of the text

Legal Category amended to new classification 'Product subject to prescription which may not be renewed (A)'