PROSULF 10MG/ML SOLUTION FOR INJECTION

PACKAGE LEAFLET: INFORMATION FOR THE USER

to protamine sulphate or any of the other ingredients in the injection (see list under What Protamine Sulphate Injection contains in section 6 of this leaflet). Special care is needed if you: are allergic to fish, because you may also be allergic to Protamine Sulphate Injection as protamine sulphate comes from fish have ever had heart surgery are an insulin dependent diabetic because Protamine Sulphate Injection may cause problems if you have previously used protamine insulin are a man and you have had a vasectomy or are infertile. If you are undergoing a long operation, where repeated doses of Protamine Sulphate Injection are necessary, you may occasionally experience bleeding up to 18 hours after your operation, which will stop when you are given further doses of Protamine Sulphate Injection.
If any of the above apply to you, speak to your doctor or nurse before Protamine Sulphate Injection is given to you.

Protamine Sulphate 10mg/ml Solution for Injection
Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again while you are receiving your treatment. - If you have any further questions, please ask your doctor or nurse. - This medicine has been prescribed for you. The contents of your vial of Protamine Sulphate 10mg/ml Solution for Injection should not be shared with other patients. The name of your medicine is Protamine Sulphate 10mg/ml Solution for Injection. In the rest of this leaflet it is called Protamine Sulphate Injection. In this leaflet: 1. What Protamine Sulphate Injection is and what it is used for 2. Before you are given Protamine Sulphate Injection 3. How Protamine Sulphate Injection should be given 4. Possible side effects 5. How to store Protamine Sulphate Injection 6. Further information



Taking other medicines Please tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including those medicines obtained without a prescription. Pregnancy and breast-feeding You should let your doctor know if you are pregnant or are breast-feeding before Protamine Sulphate Injection is administered. Driving and using machines Protamine Sulphate Injection has not been reported to affect ability to drive or operate machines. Important information about the sodium content of Protamine Sulphate Injection Protamine Sulphate Injection contains less than 1mmol sodium (23mg) per 10mg/ml dose, it is essentially sodium-free.

1. WHAT PROTAMINE SULPHATE INJECTION IS AND WHAT IT IS USED FOR
The name of your medicine is Protamine Sulphate Injection. The active ingredient in Protamine Sulphate Injection is protamine sulphate. How does your medicine work? Protamine Sulphate Injection contains protamine sulphate which is a heparin antidote which neutralises the anti blood-clotting effect of heparin and prevents it from thinning the blood too much. It is used before surgery, after kidney dialysis, after open - heart surgery, if you bleed during heparin treatment or if too much heparin has been given to you by accident.

3. HOW PROTAMINE SULPHATE INJECTION SHOULD BE GIVEN
Protamine Sulphate Injection is not recommended for use in children (persons aged 12 years or younger). Blood clotting tests should be carried out to check on the effects of Protamine Sulphate Injection to see if you need further doses. Protamine Sulphate Injection should be given slowly by infusing into a vein over a period of about ten minutes. The dose of Protamine Sulphate Injection you will be given depends on the amount and type of heparin to be neutralised, the way the heparin was given to you,

2. BEFORE YOU ARE GIVEN PROTAMINE SULPHATE INJECTION
Protamine Sulphate Injection should only be given as an antidote to heparin. It is not suitable for use as an antidote to other medicines that are used to thin the blood that are taken by mouth. Protamine Sulphate Injection should not be used if you have ever had a reaction or been told that you are allergic

SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Protamine Sulphate 10mg/ml Solution for Injection

In the reversal of UF heparin following cardiopulmonary bypass, either a standard dose of protamine may be given, as above, or the dose may be titrated according to the activated clotting time. Patients should be carefully monitored using either the activated partial thromboplastin time or the activated clotting time, carried out 5-15 minutes after protamine sulphate administration. Further doses may be needed because protamine is cleared from the blood more rapidly than heparin. Neutralisation of low molecular weight (LMW) heparins: A dose of 1mg per 100 units is usually recommended but the manufacturer's own guidelines should be consulted. The anti-Xa activity of LMW heparins may not be completely reversible with protamine sulphate and may persist for up to 24 hours after administration. The longer half-life of LMW heparins (approximately twice that of UF heparin) should also be borne in mind when estimating the dose of protamine sulphate required in relation to the time which has elapsed since the last heparin dose. Theoretically, the dose of protamine sulphate should be halved when one half-life has elapsed since the last LMW heparin dose. Intermittent injections or continuous infusion of protamine sulphate have been recommended for the neutralisation of LMW heparin following subcutaneous administration, as there may be continuing absorption from the subcutaneous depot. Patients should be carefully monitored. Further doses may be needed because protamine is cleared from the blood more rapidly than heparin, especially low molecular weight heparin. Elderly: There is no current evidence for alteration of the recommended dose. Children: Safety and efficacy in children have not been established. Not recommended. 4.3 Contraindications None known. 4.4 Special warnings and precautions for use Too rapid administration of protamine sulphate may cause severe hypotension and anaphylactoid reactions. Facilities for resuscitation and treatment of shock should be available. Protamine sulphate is not suitable for reversing the effects of oral anticoagulants. Caution should be observed when administering protamine sulphate to patients who may be at increased risk of allergic reaction to protamine. These patients include those who have previously undergone procedures such as coronary angioplasty or cardio-pulmonary by-pass which may include use of protamine, diabetics who

2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Protamine Sulphate 10mg/ml.

3 PHARMACEUTICAL FORM
Solution for injection A clear, colourless solution.

4 CLINICAL PARTICULARS
4.1 Therapeutic indications Protamine sulphate is used to counteract the anticoagulant effect of heparin: before surgery; after renal dialysis; after open-heart surgery; if excessive bleeding occurs and when an overdose has inadvertently been given. 4.2 Posology and method of administration Adults: Protamine Sulphate Injection should be administered by slow intravenous injection over a period of about 10 minutes. No more than 50mg of protamine sulphate should be given in any one dose. The dose is dependent on the amount and type of heparin to be neutralised, its route of administration and the time elapsed since it was last given, since heparin is continuously being excreted. Ideally, the dose required to neutralise the action of heparin should be guided by blood coagulation studies or calculated from a protamine neutralisation test. In gross excess, protamine itself acts as an anticoagulant. Neutralisation of unfractionated (UF) heparins: 1mg of protamine sulphate will usually neutralise at least 100 international units of mucous heparin or 80 units of lung heparin. The dose of protamine sulphate should be reduced if more than 15 minutes have elapsed since intravenous injection. For example, if 30-60 minutes have elapsed since heparin was injected intravenously, 0.5-0.75mg protamine sulphate per 100 units of mucous heparin is recommended. If two hours or more have elapsed, 0.25-0.375mg per 100 units of mucous heparin should be administered. If the patient is receiving an intravenous infusion of heparin, the infusion should be stopped and 25-50mg of protamine sulphate given by slow intravenous injection. If heparin was administered subcutaneously, 1mg protamine sulphate should be given per 100 units of mucous heparin - 25-50mg by slow intravenous injection and the balance by intravenous infusion over 8-16 hours.

and the amount of time that has passed since your last heparin injection. No more than 50 milligrams protamine sulphate should be given to you in one dose. Your doctor will decide the dose that is best for you. If you do not understand, or are in any doubt, ask your doctor or nurse. If you think you have missed a dose If you think that an injection has been missed, speak to your doctor or nurse. If you think you have been given too much Protamine Sulphate Injection If you think you have been given too much Protamine Sulphate Injection, speak to your doctor or nurse. Signs of an overdose include hypotension (a lowering of blood pressure), an abnormally slow heart rate, a shortness of breath, excessive/unexplained bleeding and/or bruising, feeling sick, being sick, a feeling of weakness or facial flushing and/or a feeling of warmth.

expiry date on the label has passed. The expiry date refers to the last day of that month. Protamine Sulphate Injection should not be used if it is discoloured or has gone cloudy. The injection should be stored between 15C and 25C in the package or container in which it was dispensed. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION
What Protamine Sulphate Injection contains The active ingredient in Protamine Sulphate Injection is protamine sulphate.The injection comes in one strength of 10mg/ml. Other ingredients in Protamine Sulphate Injection injection are sodium chloride, water for injections and trace amounts of hydrochloric acid and sodium hydroxide. What Protamine Sulphate Injection looks like and contents of the pack Protamine Sulphate Injection is a clear and colourless solution for injection. It is available in packs of 10 glass ampoules. Each ampoule contains 5ml of solution. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK. Manufacturer: CP Pharmaceuticals Ltd, Ash Road North, Wrexham, LL13 9UF, UK. Other formats To listen to or request a copy of this information in Braille, large print or audio please call, free of charge: 0800 198 5000 (UK only) Please be ready to give the following information: Product Name Protamine Sulphate 10mg/ml Solution for Injection Reference Number 29831/0180

4. POSSIBLE SIDE EFFECTS
Like many medicines, Protamine Sulphate Injection may cause side-effects in some patients, particularly when it is first given. These include: slowing of the pulse low blood pressure (you may feel dizzy or faint or you may black out) high blood pressure shortness of breath flushing and a feeling of warmth in the body back pain feeling sick being sick tiredness Rarely, allergic reactions occur resulting in breathing difficulties or a rash. This can sometimes be more serious with fainting and collapse, swelling of the lips and face, and a blue discoloration of the lips and tongue. The doctor treating you will be ready to treat these effects if they occur. If you experience any other side-effects or feel that the medicine is affecting you badly, tell your doctor or nurse immediately.

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5. HOW TO STORE PROTAMINE SULPHATE INJECTION
Keep out of the reach and sight of children. Protamine Sulphate Injection should not be used if the

have been treated with protamine insulin, patients allergic to fish and men who have had a vasectomy or are infertile and may have antibodies to protamine. Patients undergoing prolonged procedures involving repeated doses of protamine should be subject to careful monitoring of clotting parameters. A rebound bleeding effect may occur up to 18 hours post-operatively which responds to further doses of protamine. 4.5 Interaction with other medicinal products and other forms of interaction None known. 4.6 Pregnancy and lactation As with most drugs, to be used only if clearly indicated in pregnancy and with caution during lactation. 4.7 Effects on ability to drive and to use machinery None. 4.8 Undesirable effects Blood and lymphatic system disorders: anticoagulant effect (when used at doses in excess of that required to neutralise the anticoagulant effect of heparin). Immune system disorders: Hypersensitivity reactions, including angioedema anaphylactoid reactions and fatal anaphylaxis, have been reported. Cardiac disorders: bradycardia Vascular disorders: sudden fall in blood pressure, pulmonary and systemic hypertension, transitory flushing and a feeling of warmth, severe, acute pulmonary vasoconstriction with cardiovascular collapse Respiratory, thoracic and mediastinal disorders: Dyspnoea. There have been rare instances of noncardiogenic pulmonary oedema with prolonged hypotension, with significant morbidity and mortality. Gastrointestinal disorders: nausea and vomiting Musculoskeletal and connective tissue disorders: back pain General disorders and administration site conditions: lassitude 4.9 Overdose Symptoms:- Protamine has weak anticoagulating properties and if given in the absence of heparin, or at doses in excess of those required to neutralise the anticoagulant effect of heparin, exerts its own anticoagulant effect. Hypotension, bradycardia, dyspnoea nausea, vomiting, lassitude, transitory flushing and/ or a sensation of warmth may also occur. Treatment:- Includes monitoring of coagulation tests, respiratory ventilation and symptomatic treatment. If bleeding is a problem, fresh frozen plasma or fresh whole blood should be given.

5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties Although protamine is a potent antidote for heparin, its precise mechanism of action is unknown. However, when the strongly basic protamine combines with the strongly acid heparin, a stable salt is formed lacking in anticoagulant activity. 1mg of protamine sulphate neutralises between 80 and 120 units of heparin. However, methods of standardisation and the use of heparin from different sources (mucosal, lung) may produce different responses to protamine. 5.2 Pharmacokinetic properties The onset of action of protamine occurs within five minutes following intravenous administration. The fate of the protamine-heparin complex is unknown, but it may be partially degraded, thus freeing heparin. 5.3 Preclinical safety data No data are available. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium Chloride Hydrochloric Acid 3M Sodium Hydroxide 3M Water for Injections 6.2 Incompatibilities Protamine sulphate is incompatible with certain antibiotics, including several cephalosporins and penicillin. 6.3 Shelf life 48 months 6.4 Special precautions for storage Store between 15C and 25C. 6.5 Nature and contents of container 5ml and 10ml neutral type 1 hydrolytic glass ampoules in pack sizes of 10 ampoules in cartons. 6.6 Special precautions for disposal Not applicable.

7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK

8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0180

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27 June 2007

10 DATE OF REVISION OF THE TEXT
August 2010. 104376/2