Prescribing Information and Adverse Events Reporting

ADVATE (octocog alfa) powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR GREAT BRITAIN (ENGLAND, SCOTLAND, WALES)

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: ADVATE vials contain human coagulation factor VIII (rDNA) octocog alfa powder and solvent (5 ml or 2 ml sterilised water for injection). After reconstitution, nominally 250, 500, 1000, 1500, 2000 and 3000 IU per vial.

Indication: Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). ADVATE is indicated in all age groups.

Dosage and administration: Treatment should be initiated under the supervision of a physician experienced in thetreatment of haemophilia and with resuscitation support immediately available in case of anaphylaxis. In case of administration by a non-healthcare professional appropriate training is needed. Dosage and duration depend on the severity of the factor VIII (FVIII) deficiency, location and extent of bleeding and on the patient’s clinical condition (please refer to the SmPC guide for dosing and frequency of administration for on-demand treatment (bleeding episodes and surgery) and prophylaxis). Determination of plasma FVIII levels is also advised during treatment to guide dosing and frequency of repeated injections. For major surgical interventions, precise monitoring of the substitution therapy by means of plasma FVIII activity assay is indispensable. Should be administered via the intravenous route at a maximum rate 10 ml/min.

Contraindications: Hypersensitivity to the active substance or to any of the excipients or to mouse or hamster proteins.

Warnings and precautions: Hypersensitivity: Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Cease treatment and seek medical attention if such reactions occur. Caution advised during injection of ADVATE reconstituted in 2 ml solvent, especially in children (if hypersensitivity reactions occur there is less time to react by stopping the injection). Misapplication (intra-arterially or paravenously): May lead to mild, short-term injection site reactions. Inhibitors: The formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. All patients should be carefully monitored for the development of inhibitors. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to FVIII, this risk being highest within the first 20 exposure days. In patients with high levels of inhibitor, FVIII therapy may not be effective and other therapeutic options should be considered. Catheter-related complications in treatment: If central venous access device (CVAD) is required, risk of CVAD-related complications including local infections and catheter site thrombosis should be considered. Excipient-related considerations: After reconstitution this medicinal product contains 10 mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet. With each administration of ADVATE, the product name and batch number should be recorded. Paediatrics: The listed warnings and precautions apply to both adults and children.

Interactions: Not known.

Fertility, pregnancy and lactation: No data available, therefore FVIII should be used during pregnancy and lactation only if clearly indicated.

Undesirable effects: Very common (≥1/10): FVIII inhibition (PUPs, previously untreated patients). Common (≥1/100 to <1/10):Headache, pyrexia. Other serious undesirable effects: Uncommon (≥1/1,000 to <1/100): Post-procedural haemorrhage, lymphangitis, FVIII inhibition (PTPs, previously treated patients), syncope, haematoma, dyspnoea, peripheral oedema; Unknown frequency: Anaphylactic reaction, hypersensitivity.

Refer to the SmPC for details on full side effect profile and interactions.

Basic UK NHS cost: 71p per IU.

Legal classification: POM.

Marketing Authorisation (MA): 2 ml solvent: PLGB 06009/0028 (250 IU), PLGB 06009/0031 (500 IU); 5 ml solvent: PLGB 06009/0029 (250 IU), PLGB 06009/0032 (500 IU), PLGB 06009/0024 (1000 IU), PLGB 06009/0026 (1500 IU), PLGB 06009/0027 (2000 IU), PLGB 06009/0030 (3000 IU).

Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-01980.

Date of preparation: April 2022.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com

ADVATE (octocog alfa) powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: ADVATE vials contain human coagulation factor VIII (rDNA) octocog alfa powder and solvent (5 ml or 2 ml sterilised water for injection). After reconstitution, nominally 250, 500, 1000, 1500, 2000 and 3000 IU per vial.

Indication: Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). ADVATE is indicated in all age groups.

Dosage and administration: Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and with resuscitation support immediately available in case of anaphylaxis. In case of administration by a non-healthcare professional appropriate training is needed. Dosage and duration depend on the severity of the factor VIII (FVIII) deficiency, location and extent of bleeding and on the patient’s clinical condition (please refer to the SmPC guide for dosing and frequency of administration for on-demand treatment (bleeding episodes and surgery) and prophylaxis). Determination of plasma FVIII levels is also advised during treatment to guide dosing and frequency of repeated injections. For major surgical interventions, precise monitoring of the substitution therapy by means of plasma FVIII activity assay is indispensable. Should be administered via the intravenous route at a maximum rate 10 ml/min.

Contraindications: Hypersensitivity to the active substance or to any of the excipients or to mouse or hamster proteins.

Warnings and precautions: Hypersensitivity: Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Cease treatment and seek medical attention if such reactions occur. Caution advised during injection of ADVATE reconstituted in 2 ml solvent, especially in children (if hypersensitivity reactions occur there is less time to react by stopping the injection). Misapplication (intra-arterially or paravenously): May lead to mild, short-term injection site reactions. Inhibitors: The formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. All patients should be carefully monitored for the development of inhibitors. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to FVIII, this risk being highest within the first 20 exposure days. In patients with high levels of inhibitor, FVIII therapy may not be effective and other therapeutic options should be considered. Catheter-related complications in treatment: If central venous access device (CVAD) is required, risk of CVAD-related complications including local infections and catheter site thrombosis should be considered. Excipient-related considerations: After reconstitution this medicinal product contains 10 mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet. With each administration of ADVATE, the product name and batch number should be recorded. Paediatrics: The listed warnings and precautions apply to both adults and children.

Interactions: Not known.

Fertility, pregnancy and lactation: No data available, therefore FVIII should be used during pregnancy and lactation only if clearly indicated.

Undesirable effects: Very common (≥1/10): FVIII inhibition (PUPs, previously untreated patients). Common (≥1/100 to <1/10): Headache, pyrexia. Other serious undesirable effects: Uncommon (≥1/1,000 to <1/100): Post-procedural haemorrhage, lymphangitis, FVIII inhibition (PTPs, previously treated patients), syncope, haematoma, dyspnoea, peripheral oedema; Unknown frequency: Anaphylactic reaction, hypersensitivity.

Refer to the SmPC for details on full side effect profile and interactions.

Basic UK NHS cost: 71p per IU.

Legal classification: POM.

Marketing authorisation numbers: 2 ml solvent: EU/1/03/271/007 (250 IU), EU/1/03/271/008 (500 IU); 5 ml solvent: EU/1/03/271/001 (250 IU), EU/1/03/271/002 (500 IU), EU/1/03/271/003 (1000 IU), EU/1/03/271/004 (1500 IU), EU/1/03/271/005 (2000 IU), EU/1/03/271/006 (3000 IU).

Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London W2 6BD, United Kingdom.

PI approval code: pi-01979.

Date of preparation: April 2022.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com

ADYNOVI®▼(rurioctocog alfa pegol) powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR GREAT BRITAIN (ENGLAND, SCOTLAND, WALES)

FEIBA (Factor VIII Inhibitor Bypassing Activity) 50 U/ml powder and solvent for solution for infusion

OBIZUR▼(susoctocog alfa) 500 U powder and solvent for solution for injection

VEYVONDI^®(vonicog alfa) 650 IU and 1300 IU powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR GREAT BRITAIN (ENGLAND, SCOTLAND, WALES)

Refer to the Summary of Product Characteristics (SmPC) before prescribing

Presentation: Each vial contains nominally 650 IU and 1300 IU vonicog alfa powder. After reconstitution with 5 mL or 10 mL, respectively, of solvent provided, VEYVONDI contains approximately 130 IU/mL of vonicog alfa.

Indication: VEYVONDI is indicated in adults (age 18 and older) with von Willebrand disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or not indicated, for the treatment of haemorrhage and surgical bleeding and prevention of surgical bleeding. VEYVONDI should not be used in the treatment of Haemophilia A.

Dosage and administration: Treatment of VWD should be supervised by a physician experienced in the treatment of haemostatic disorders. Dosage and frequency of administration must be individualised according to clinical judgement and based on the patient´s weight, type and severity of the bleeding episodes/surgical intervention and based on monitoring of appropriate clinical and laboratory measures. Dose based on body weight may require adjustment in underweight or overweight patients (refer to the SmPC for dosing calculations). Generally, 1 IU/kg of VEYVONDI raises the plasma VWF:RCo by 0.02 IU/mL (2%). If the patient’s baseline plasma FVIII:C level is <40% or is unknown and in all situations where a rapid correction of haemostasis should be achieved, it is necessary to administer a recombinant factor VIII (rFVIII) product with the first infusion of VEYVONDI, in order to achieve a haemostatic plasma level of FVIII:C. However, if an immediate rise in FVIII:C is not necessary, or if the baseline FVIII:C level is sufficient to ensure haemostasis, the physician may decide to omit the co-administration of rFVIII at the first infusion with VEYVONDI. In case of major bleeding events or major surgeries requiring repeated, frequent infusions, monitoring of FVIII:C levels is recommended, to decide if rFVIII is required for subsequent infusions to avoid excessive rise of FVIII:C. For guidance on the treatment of bleeding episodes (on-demand treatment) and prevention of bleeding / haemorrhage and treatment in case of elective surgery, please refer to the SmPC. VEYVONDI should be administered via the intravenous route up to a maximum rate of 4 mL/min. If any reaction, such as tachycardia, occurs that might be related to the administration of the product, the rate of infusion should be reduced or stopped as required by the clinical condition of the patient.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Known allergic reaction to mouse or hamster proteins.

Warnings and precautions: In actively bleeding patients it is recommended to co-administer a FVIII product with VEYVONDI as a first line treatment and depending on the FVIII activity levels. Traceability: Name and the batch number of the administered product should be clearly recorded. Hypersensitivity reactions: Hypersensitivity reactions (including anaphylaxis) have occurred. Patients should be closely monitored and carefully observed for any symptoms throughout the infusion period. If signs and symptoms occur, patients should immediately discontinue use of VEYVONDI and be provided with appropriate supportive care. VEYVONDI contains traces of mouse immunoglobulin and hamster proteins, and rFVIII. Thrombosis and embolism: There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels. Therefore, patients at risk have to be monitored for early signs of thrombosis, and prophylaxis measures against thromboembolism should be instituted according to current recommendations and standard of care. In patients requiring frequent doses of VEYVONDI in combination with rFVIII, FVIII:C activity should be monitored to avoid sustained excessive FVIII:C plasma levels, which may increase the risk of thrombotic events. Any FVIII that would be administered along with VEYVONDI should be a pure FVIII product. A combination with a FVIII product containing von Willebrand factor (VWF) would pose an additional risk of thrombotic events. Inhibitors: Patients with VWD, especially type 3, may develop neutralising antibodies (inhibitors) to VWF. If the expected plasma levels of VWF:RCo is not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of anti-VWF neutralising antibodies, von Willebrand factor therapy may not be effective and other therapeutic options should be considered to establish haemostasis. Patients who have high-titre binding antibodies (due to previous treatment with plasma-derived VWF) may require a higher dose to overcome the binding antibody effect and such patients could be managed clinically by administration of higher doses of VEYVONDI based on the PK data for each individual patient. Excipient-related considerations: VEYVONDI contains 5.2 mg sodium in each 650 IU vial or 10.4 mg sodium in each 1300 IU vial. To be taken into consideration by patients on a controlled sodium diet.

Interactions: None known.

Fertility, pregnancy and lactation: Pregnancy: Experience in the treatment of pregnant or breast-feeding women is not available. VEYVONDI should be administered to pregnant women only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients. Breast-feeding: It is unknown whether VEYVONDI is excreted in human milk. VEYVONDI should be administered to lactating VWF-deficient women only if clearly indicated. Healthcare professionals should balance the potential risks and only prescribe VEYVONDI if needed. Fertility: The effects of VEYVONDI on fertility have not been established.

Undesirable effects: Very common (≥1/10): Headache. Common (≥1/100 to <1/10): Dizziness, vertigo, dysgeusia, tremor, tachycardia, deep venous thrombosis (serious), hypertension, hot flush, vomiting, nausea, pruritus generalised, chest discomfort, infusion site paraesthesia, electrocardiogram T wave inversion and heart rate increased. Other serious undesirable effects (unknown frequency): Anaphylactic reaction, infusion-related reaction (including tachycardia, flushing, rash, dyspnoea, blurred vision).

Refer to the SmPC for details on full side effect profile and interactions.

Legal classification: POM.

UK basic NHS price: 92p per IU.

Marketing authorisation numbers: 650 IU: PLGB 34078/0031; 1300 IU: PLGB 34078/0032.

Business Responsible for Sale and Supply: Takeda UK Ltd, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-02851.

Date of preparation: April 2024.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com

VEYVONDI^® (vonicog alfa) 650 IU and 1300 IU powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing

Presentation: Each vial contains nominally 650 IU and 1300 IU vonicog alfa powder. After reconstitution with 5 mL or 10 mL, respectively, of solvent provided, VEYVONDI contains approximately 130 IU/mL of vonicog alfa.

Indication: VEYVONDI is indicated in adults (age 18 and older) with von Willebrand disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or not indicated, for the treatment of haemorrhage and surgical bleeding and prevention of surgical bleeding. VEYVONDI should not be used in the treatment of Haemophilia A.

Dosage and administration: Treatment of VWD should be supervised by a physician experienced in the treatment of haemostatic disorders. Dosage and frequency of administration must be individualised according to clinical judgement and based on the patient´s weight, type and severity of the bleeding episodes/surgical intervention and based on monitoring of appropriate clinical and laboratory measures. Dose based on body weight may require adjustment in underweight or overweight patients (refer to the SmPC for dosing calculations). Generally, 1 IU/kg of VEYVONDI raises the plasma VWF:RCo by 0.02 IU/mL (2%). If the patient’s baseline plasma FVIII:C level is <40% or is unknown and in all situations where a rapid correction of haemostasis should be achieved, it is necessary to administer a recombinant factor VIII (rFVIII) product with the first infusion of VEYVONDI, in order to achieve a haemostatic plasma level of FVIII:C. However, if an immediate rise in FVIII:C is not necessary, or if the baseline FVIII:C level is sufficient to ensure haemostasis, the physician may decide to omit the coadministration of rFVIII at the first infusion with VEYVONDI. In case of major bleeding events or major surgeries requiring repeated, frequent infusions, monitoring of FVIII:C levels is recommended, to decide if rFVIII is required for subsequent infusions to avoid excessive rise of FVIII:C. For guidance on the treatment of bleeding episodes (on-demand treatment) and prevention of bleeding / haemorrhage and treatment in case of elective surgery, please refer to the SmPC. VEYVONDI should be administered via the intravenous route up to a maximum rate of 4 mL/min. If any reaction, such as tachycardia, occurs that might be related to the administration of the product, the rate of infusion should be reduced or stopped as required by the clinical condition of the patient.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Known allergic reaction to mouse or hamster proteins.

Warnings and precautions: In actively bleeding patients it is recommended to co-administer a FVIII product with VEYVONDI as a first line treatment and depending on the FVIII activity levels. Traceability: Name and the batch number of the administered product should be clearly recorded. Hypersensitivity reactions: Hypersensitivity reactions (including anaphylaxis) have occurred. Patients should be closely monitored and carefully observed for any symptoms throughout the infusion period. If signs and symptoms occur, patients should immediately discontinue use of VEYVONDI and be provided with appropriate supportive care. VEYVONDI contains traces of mouse immunoglobulin and hamster proteins, and rFVIII. Thrombosis and embolism: There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors for thrombosis including low ADAMTS13 levels. Therefore, patients at risk have to be monitored for early signs of thrombosis, and prophylaxis measures against thromboembolism should be instituted according to current recommendations and standard of care. In patients requiring frequent doses of VEYVONDI in combination with rFVIII, FVIII:C activity should be monitored to avoid sustained excessive FVIII:C plasma levels, which may increase the risk of thrombotic events. Any FVIII that would be administered along with VEYVONDI should be a pure FVIII product. A combination with a FVIII product containing von Willebrand factor (VWF) would pose an additional risk of thrombotic events. Inhibitors: Patients with VWD, especially type 3, may develop neutralising antibodies (inhibitors) to VWF. If the expected plasma levels of VWF:RCo is not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of anti-VWF neutralising antibodies, von Willebrand factor therapy may not be effective and other therapeutic options should be considered to establish haemostasis. Patients who have high-titre binding antibodies (due to previous treatment with plasma-derived VWF) may require a higher dose to overcome the binding antibody effect and such patients could be managed clinically by administration of higher doses of VEYVONDI based on the PK data for each individual patient. Excipient-related considerations: VEYVONDI contains 5.2 mg sodium in each 650 IU vial or 10.4 mg sodium in each 1300 IU vial. To be taken into consideration by patients on a controlled sodium diet.

Interactions: None known.

Fertility, pregnancy and lactation: Pregnancy: Experience in the treatment of pregnant or breast-feeding women is not available. VEYVONDI should be administered to pregnant women only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients. Breast-feeding: It is unknown whether VEYVONDI is excreted in human milk. VEYVONDI should be administered to lactating VWF-deficient women only if clearly indicated. Healthcare professionals should balance the potential risks and only prescribe VEYVONDI if needed. Fertility: The effects of VEYVONDI on fertility have not been established.

Undesirable effects: Very common (≥1/10): Headache. Common (≥1/100 to <1/10): Dizziness, vertigo, dysgeusia, tremor, tachycardia, deep venous thrombosis (serious), hypertension, hot flush, vomiting, nausea, pruritus generalised, chest discomfort, infusion site paraesthesia, electrocardiogram T wave inversion and heart rate increased. Other serious undesirable effects (unknown frequency): Anaphylactic reaction, infusion-related reaction (including tachycardia, flushing, rash, dyspnoea, blurred vision).

Refer to the SmPC for details on full side effect profile and interactions.

Legal classification: POM.

UK basic NHS price: 92p per IU.

Marketing authorisation numbers: 650 IU: EU/1/18/1298/001; 1300 IU: EU/1/18/1298/002.

Business Responsible for Sale and Supply: Takeda UK Ltd, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-02850.

Date of preparation: April 2024.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com

CEPROTIN (human protein C) 500 IU and 1000 IU powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR GREAT BRITAIN (ENGLAND, SCOTLAND, WALES)

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Ceprotin is prepared as a powder containing nominally 500 IU or 1000 IU human protein C per vial. The product reconstituted with 5 ml or 10 ml of Sterilised Water for Injections, respectively, contains approximately 100 IU/ml human protein C. Each pack also contains: one transfer needle and one filter needle.

Indications: Prophylaxis and treatment of purpura fulminans, coumarin induced skin necrosis and venous thrombotic events in patients with severe congenital protein C deficiency.

Dosage and administration: Initiate where monitoring of protein C activity is feasible and under supervision of a physician experienced in substitution therapy with coagulation factors/inhibitors. Allergic type hypersensitivity reactions are possible, administration should be made within reach of life-supporting facilities, in case acute and life-threatening allergic symptoms arise. Administer by intravenous injection – max. rate 2 ml/min. In children with body weight below 10 kg do not exceed 0.2 ml/kg/min. Where patient has no intravenous access, administer subcutaneously – dose adjustment may be required. Posology: Adjust dose on an individual basis – assess response based on laboratory assay results. Treatment of acute episodes and short-term prophylaxis (including invasive procedures): Initially, protein C activity of 100%(1 IU/ml) should be attained, then maintain levels above 25% for duration of treatment. Recommend an initial dose of 60 – 80 IU/kg body weight to determine recovery and half-life and measure protein C activity using chromogenic substrates to determine patient’s plasma level for protein C, before and during treatment with Ceprotin. If the response to CEPROTIN injection is satisfactory (measured by chromogenic assays), dosing may be gradually reduced to 12 hourly dosing ensuring trough protein C activity >25% (>0.25 IU/ml). In patients receiving prophylactic administration of protein C, higher trough levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma or surgical intervention). Long-term prophylaxis: A dose of 45 to 60 IU/kg every 12 hours is recommended. Measurement of the protein C activity should be performed to ensure trough levels of 25% or more. Dose or frequency of infusions should be adjusted accordingly. Combination treatment: For patients switched to permanent prophylaxis with oral anticoagulants initiate oral anticoagulant therapy with a low dose and discontinue protein C replacement until stable anticoagulation is achieved. At start of a combination treatment of anticoagulants (especially Vitamin K antagonists) with Protein C, stable activity levels of Protein C above 0.25 IU/ml (chromogenic) should be maintained before starting the anticoagulation. Careful monitoring of the international normalized ratio (INR) is recommended. In the combination of Protein C Concentrate and anticoagulants, a protein C trough level of about 10% or more is recommended to be maintained. Activated Protein C (APC) resistance: In patients with combined severe congenital protein C deficiency and with APC resistance, there are limited clinical data to support safety and efficacy of Ceprotin. Paediatrics: Dosing guidelines for adult subjects are considered valid for neonatal and paediatric patient population. Renal and/or hepatic impairment: Safety and efficacy of CEPROTIN in patients with renal and/or hepatic impairment have not been established. Patients with any of these conditions should be monitored more closely.

Contraindications: Hypersensitivity to the active substance or excipients, or to mouse protein or heparin, except for control of life-threatening thrombotic complications.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Hypersensitivity: Risk of allergic reactions including anaphylaxis cannot be excluded. Renal and/or hepatic impairment: Due to the lack of experience in the treatment of patients with renal and/or hepatic impairment it is recommended to monitor such patients closely. Inhibitors: In patients with severe congenital protein C deficiency, antibodies inhibiting protein C may develop. Transmissible agents: Standard measures for safety of plasma products are employed but the risk of transmission of infective agents cannot be excluded. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women and for individuals with immunodeficiency or increased erythropoiesis. Vaccination (hepatitis A and B) for patients in regular/repeated receipt of human plasma-derived protein C should be considered. Heparin induced thrombocytopenia: Ceprotin may contain trace amounts of heparin and patients may experience heparin induced allergic reactions, including heparin induced thrombocytopenia (HIT). If HIT is suspected, number of thrombocytes should be determined immediately, and if necessary, stop therapy with Ceprotin. Concurrent anticoagulant medication: Bleeding episodes may occur.

Interactions: Interaction with Vitamin K antagonists: When starting patients on oral vitamin K antagonists (e.g., warfarin) a transient hypercoagulable state may arise due to the rapid suppression of protein C. When switching to oral anticoagulants, continue Ceprotin replacement until anticoagulation stabilises. Individuals with congenital protein C deficiency are particularly at risk for warfarin-induced skin necrosis.

Fertility, pregnancy and lactation: No clinical data on the use of Ceprotin in pregnant and lactating women. Therefore, the benefit of using Ceprotin during pregnancy or lactation must be judged against the risk for the mother and baby, and should be used only if clearly needed.

Undesirable effects: Rare (≥1/10,000 to <1/1,000): pruritus, rash, dizziness. Allergic type hypersensitivity reactions are possible. Restlessness, hyperhidrosis and injection site reaction have been reported postmarking, incidence unknown. Refer to the SmPC for details on full side effect profile and interactions. UK basic NHS price: 500 IU – £1000; 1000 IU – £2000. Legal Classification: POM. Marketing authorisation numbers: 500 IU: PLGB 06009/0034; 1000 IU: PLGB 06009/0033; Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-02443.

Date of preparation: April 2023.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com.

CEPROTIN (human protein C) 500 IU and 1000 IU powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Ceprotin is prepared as a powder containing nominally 500 IU or 1000 IU human protein C per vial. The product reconstituted with 5 ml or 10 ml of Sterilised Water for Injections, respectively, contains approximately 100 IU/ml human protein C. Each pack also contains: one transfer needle and one filter needle.

Indications: Prophylaxis and treatment of purpura fulminans, coumarin induced skin necrosis and venous thrombotic events in patients with severe congenital protein C deficiency.

Dosage and administration: Initiate where monitoring of protein C activity is feasible and under supervision of a physician experienced in substitution therapy with coagulation factors/inhibitors. Allergic type hypersensitivity reactions are possible, administration should be made within reach of life-supporting facilities, in case acute and life-threatening allergic symptoms arise. Administer by intravenous injection – max. rate 2 ml/min. In children with body weight below 10 kg do not exceed 0.2 ml/kg/min. Where patient has no intravenous access, administer subcutaneously – dose adjustment may be required. Posology: Adjust dose on an individual basis – assess response based on laboratory assay results. Treatment of acute episodes and short-term prophylaxis (including invasive procedures): Initially, protein C activity of 100%(1 IU/ml) should be attained then maintain levels above 25% for duration of treatment. Recommend an initial dose of 60 – 80 IU/kg body weight to determine recovery and half-life and measure protein C activity using chromogenic substrates to determine patient’s plasma level for protein C, before and during treatment with Ceprotin. If the response to CEPROTIN injection is satisfactory (measured by chromogenic assays), dosing may be gradually reduced to 12 hourly dosing ensuring trough protein C activity >25% (>0.25 IU/ml). In patients receiving prophylactic administration of protein C, higher trough levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma or surgical intervention). Long-term prophylaxis: A dose of 45 to 60 IU/kg every 12 hours is recommended. Measurement of the protein C activity should be performed to ensure trough levels of 25% or more. Dose or frequency of infusions should be adjusted accordingly. Combination treatment: For patients switched to permanent prophylaxis with oral anticoagulants initiate oral anticoagulant therapy with a low dose and discontinue protein C replacement until stable anticoagulation is achieved. At start of a combination treatment of anticoagulants (especially Vitamin K antagonists) with Protein C, stable activity levels of Protein C above 0.25 IU/ml (chromogenic) should be maintained before starting the anticoagulation. Careful monitoring of the international normalized ratio (INR) is recommended. In the combination of Protein C Concentrate and anticoagulants, a protein C trough level of about 10% or more is recommended to be maintained. Activated Protein C (APC) resistance: In patients with combined severe congenital protein C deficiency and with APC resistance, there are limited clinical data to support safety and efficacy of Ceprotin. Paediatrics: Dosing guidelines for adult subjects are considered valid for neonatal and paediatric patient population. Renal and/or hepatic impairment: Safety and efficacy of CEPROTIN in patients with renal and/or hepatic impairment have not been established. Patients with any of these conditions should be monitored more closely.

Contraindications: Hypersensitivity to the active substance or excipients, or to mouse protein or heparin, except for control of life-threatening thrombotic complications.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Hypersensitivity: Risk of allergic reactions including anaphylaxis cannot be excluded. Renal and/or hepatic impairment: Due to the lack of experience in the treatment of patients with renal and/or hepatic impairment it is recommended to monitor such patients closely. Inhibitors: In patients with severe congenital protein C deficiency, antibodies inhibiting protein C may develop. Transmissible agents: Standard measures for safety of plasma products are employed but the risk of transmission of infective agents cannot be excluded. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women and for individuals with immunodeficiency or increased erythropoiesis. Vaccination (hepatitis A and B) for patients in regular/repeated receipt of human plasma-derived protein C should be considered. Heparin induced thrombocytopenia: Ceprotin may contain trace amounts of heparin and patients may experience heparin induced allergic reactions, including heparin induced thrombocytopenia (HIT). If HIT is suspected, number of thrombocytes should be determined immediately, and if necessary, stop therapy with Ceprotin. Concurrent anticoagulant medication: Bleeding episodes may occur.

Interactions: Interaction with Vitamin K antagonists: When starting patients on oral vitamin K antagonists (e.g., warfarin) a transient hypercoagulable state may arise due to the rapid suppression of protein C. When switching to oral anticoagulants, continue Ceprotin replacement until anticoagulation stabilises. Individuals with congenital protein C deficiency are particularly at risk for warfarin-induced skin necrosis.

Fertility, pregnancy and lactation: No clinical data on the use of Ceprotin in pregnant and lactating women. Therefore, the benefit of using Ceprotin during pregnancy or lactation must be judged against the risk for the mother and baby, and should be used only if clearly needed.

Undesirable effects: Rare (≥1/10,000 to <1/1,000): pruritus, rash, dizziness. Allergic type hypersensitivity reactions are possible. Restlessness, hyperhidrosis and injection site reaction have been reported postmarking, incidence unknown. Refer to the SmPC for details on full side effect profile and interactions. UK basic NHS price: 500 IU – £1000; 1000 IU – £2000. Legal Classification: POM. Marketing authorisation numbers: 500 IU: EU/1/01/190/001; 1000 IU: EU/1/01/190/002.

Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-02444.

Date of preparation: April 2023.

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com.

PROTHROMPLEX TOTAL (human prothrombin complex) 500 IU powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR GREAT BRITAIN (ENGLAND, SCOTLAND, WALES)

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: The total protein content per vial is 250 – 625 mg. The specific activity of the product is at least 0.6 IU/mg, in relation to the factor IX activity. One vial contains at least 333 IU protein C co-purified with the blood coagulation factors.

Indications: Treatment of bleeding and perioperative prophylaxis of bleeding in acquired deficiency of prothrombin complex coagulation factors, such as a deficiency caused by treatment with vitamin K antagonists or in case of overdose with vitamin K antagonists, when rapid correction of the deficiency is required. Treatment and perioperative prophylaxis of haemorrhages in congenital deficiency of vitamin K-dependent coagulation factors, when purified specific coagulation factor concentrate is not available. Prothromplex TOTAL is indicated in adults. There are insufficient paediatric data to recommend the administration of Prothromplex TOTAL in children.

Dosage and administration: Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders. Posology: The dosage and duration of the substitution therapy depend on the severity of the coagulation disorder, on the location and extent of the bleeding and on the patient’s clinical condition. Dosage and frequency of administration should be calculated on an individual patient basis. Dosage intervals must be adjusted to the different circulating half-lives of the various coagulation factors in the prothrombin complex (refer to SmPC). Individual dosage requirements can only be identified on the basis of regular determinations of the individual plasma levels of the coagulation factors of interest or on the global test of the prothrombin complex level (e.g., Quick’s time value, INR, prothrombin time) and continuous monitoring of the patient’s clinical condition. In case of major surgical interventions precise monitoring of the substitution therapy by means of coagulation assays is essential (specific coagulation factor assays and/or global tests for prothrombin complex levels). Maximum single dose: In order to correct the INR, it is not necessary to exceed the dose of 50 IU/kg. If the severity of bleeding requires a higher dose, the risk/benefit has to be evaluated by the treating physician. Paediatric population: The safety and efficacy in paediatric patients have not been established in clinical trials. Method of administration: To be administered via the intravenous route slowly. It is recommended not to administer more than 2 ml per minute (60 IU/min). For instructions on reconstitution of the medicinal product before administration, please refer to the SmPC.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Known allergy to heparin or history of heparin-induced thrombocytopenia.

Warnings and precautions: Traceability: In order to improve the traceability of biological medicinal products, the name, and the batch number of the administered product should be clearly recorded. The advice of a specialist experienced in the management of coagulation disorders should be sought. In patients with acquired deficiency of the vitamin K-dependent coagulation factors (e.g., as induced by treatment with vitamin K antagonists) Prothromplex TOTAL should only be used when rapid correction of the prothrombin complex levels is necessary, such as major bleeding or emergency surgery. In other cases, reduction of the dose of vitamin K antagonist and/or administration of vitamin K is usually sufficient. Patients receiving a vitamin K antagonist may have an underlying hypercoagulable state and infusion of human prothrombin complex may exacerbate this. In congenital deficiency of any vitamin K-dependent factors, specific coagulation factor product should be used when available. Allergic-type hypersensitivity reactions including anaphylactic reactions and anaphylactic shock have been reported with Prothromplex TOTAL. If allergic or anaphylactic-type reactions occur, the injection/infusion should be stopped immediately. In the case of shock standard medical treatment for shock should be implemented. Thromboembolism, DIC, Fibrinolysis: There is a risk of thrombosis and disseminated intravascular coagulation (DIC) when patients, with either congenital or acquired deficiency are treated with human prothrombin complex concentrates, including Prothromplex TOTAL, particularly with repeated dosing. Arterial and venous thromboembolic events including myocardial infarction, cerebrovascular accident (e.g., stroke), pulmonary embolism as well as DIC have been reported with Prothromplex TOTAL. The risk may be higher in treatment of isolated F VII deficiency, since the other vitamin K-dependent coagulation factors, with longer half-lives, may accumulate to levels considerably higher than normal. Patients given human prothrombin complex concentrates should be observed closely for signs and symptoms of intravascular coagulation or thrombosis. Because of the risk of thromboembolic complications, particularly close monitoring should be exercised when administering prothrombin complex concentrates to: patients with a history of coronary heart disease, patients with liver disease, pre- or post-operative patients, neonates, or other patients at risk of thromboembolic events or disseminated intravascular coagulation. In each of these situations, the potential benefit of treatment should be weighed against the risk of these complications. Virus safety: Standard measures to prevent infections which can be transmitted by medicinal products made from human blood or plasma include donor selection, testing of individual donations and plasma pools for specific infection markers and the execution of effective manufacturing steps to inactivate/remove viruses. Nevertheless, when medicinal products prepared from human blood or plasma are administered, infectious diseases due to transmission of infective agents cannot be totally excluded. This also applies to unknown or emerging viruses or other pathogens. The measures taken are considered effective for enveloped viruses such as HIV, HBV, and HCV as well as against the non-enveloped HAV virus. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., haemolytic anaemia). It is strongly recommended that every time that Prothromplex TOTAL is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product. When a medicinal product prepared from human blood or plasma is administered regularly/repeatedly, appropriate vaccinations (hepatitis A and B) must be considered. Sodium content: This medicinal product contains 68 mg sodium per vial or 0.14 mg sodium per International Unit equivalent to 3.4 % of the WHO recommended maximum daily intake of 2g sodium for an adult. Heparin: May cause allergic reactions and reduced blood cell counts, which may affect the blood clotting system. Patients with a history of heparin-induced allergic reactions should avoid the use of heparin-containing medicines. Paediatric population: There are insufficient data to recommend the administration of Prothromplex TOTAL in children.

Interactions: Human prothrombin complex products neutralize the effect of vitamin K antagonist treatment. No interaction studies have been performed. Interference with biological testing: When performing clotting tests, which are sensitive to heparin in patients receiving high doses of human prothrombin complex, the heparin as a constituent of the administered product must be taken into account.

Fertility, pregnancy and lactation: The effects of Prothromplex TOTAL on fertility have not been established in controlled clinical trials. The safety of human prothrombin complex for use in human pregnancy and during lactation has not been established. There are no adequate data from the use of Prothromplex TOTAL in pregnant or lactating women. Animal studies are not suitable to assess the safety with respect to pregnancy, embryonal/foetal development, parturition, or postnatal development. Therefore, Prothromplex TOTAL should be used during pregnancy and lactation only if clearly indicated. Refer to the SmPC for information on the risk of Parvovirus B19 infection in pregnant women.

Undesirable effects: Common (≥1/100 to <1/10): Disseminated intravascular coagulation inhibitors to one or more of the prothrombin complex factors (factors II, VII, IX, X), Anaphylactic shock, Anaphylactic reaction, Hypersensitivity, Cerebrovascular accident, Headache, Heart failure, Acute myocardial infarction, Tachycardia, Arterial thrombosis, Venous thrombosis, Hypotension, Flushing, Pulmonary embolism, Dyspnoea, Wheezing, Vomiting, Nausea, Urticaria, Rash erythematous, Pruritus, Nephrotic syndrome and Pyrexia.

Refer to the SmPC for details on full side effect profile and interactions.

UK basic NHS price: £255.00 per vial.

Legal Classification: POM. Marketing authorisation (MA) numbers: PL 34078/0037.

Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-02715

Date of preparation: September 2023

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events should also be reported to Takeda UK Ltd at: AE.GBR-IRL@takeda.com.

PROTHROMPLEX TOTAL (human prothrombin complex) 500 IU powder and solvent for solution for injection

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: The total protein content per vial is 250 – 625 mg. The specific activity of the product is at least 0.6 IU/mg, in relation to the factor IX activity. One vial contains at least 333 IU protein C co-purified with the blood coagulation factors.

Indications: Treatment of bleeding and perioperative prophylaxis of bleeding in acquired deficiency of prothrombin complex coagulation factors, such as a deficiency caused by treatment with vitamin K antagonists or in case of overdose with vitamin K antagonists, when rapid correction of the deficiency is required. Treatment and perioperative prophylaxis of haemorrhages in congenital deficiency of vitamin K-dependent coagulation factors, when purified specific coagulation factor concentrate is not available. Prothromplex TOTAL is indicated in adults. There are insufficient paediatric data to recommend the administration of Prothromplex TOTAL in children.

Dosage and administration: Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders. Posology: The dosage and duration of the substitution therapy depend on the severity of the coagulation disorder, on the location and extent of the bleeding and on the patient’s clinical condition. Dosage and frequency of administration should be calculated on an individual patient basis. Dosage intervals must be adjusted to the different circulating half-lives of the various coagulation factors in the prothrombin complex (refer to SmPC). Individual dosage requirements can only be identified on the basis of regular determinations of the individual plasma levels of the coagulation factors of interest or on the global test of the prothrombin complex level (e.g., Quick’s time value, INR, prothrombin time) and continuous monitoring of the patient’s clinical condition. In case of major surgical interventions precise monitoring of the substitution therapy by means of coagulation assays is essential (specific coagulation factor assays and/or global tests for prothrombin complex levels). Maximum single dose: In order to correct the INR, it is not necessary to exceed the dose of 50 IU/kg. If the severity of bleeding requires a higher dose, the risk/benefit has to be evaluated by the treating physician. Paediatric population: The safety and efficacy in paediatric patients have not been established in clinical trials. Method of administration: To be administered via the intravenous route slowly. It is recommended not to administer more than 2 ml per minute (60 IU/min). For instructions on reconstitution of the medicinal product before administration, please refer to the SmPC.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Known allergy to heparin or history of heparin-induced thrombocytopenia.

Warnings and precautions: Traceability: In order to improve the traceability of biological medicinal products, the name, and the batch number of the administered product should be clearly recorded. The advice of a specialist experienced in the management of coagulation disorders should be sought. In patients with acquired deficiency of the vitamin K-dependent coagulation factors (e.g., as induced by treatment with vitamin K antagonists) Prothromplex TOTAL should only be used when rapid correction of the prothrombin complex levels is necessary, such as major bleeding or emergency surgery. In other cases, reduction of the dose of vitamin K antagonist and/or administration of vitamin K is usually sufficient. Patients receiving a vitamin K antagonist may have an underlying hypercoagulable state and infusion of human prothrombin complex may exacerbate this. In congenital deficiency of any vitamin K-dependent factors, specific coagulation factor product should be used when available. Allergic-type hypersensitivity reactions including anaphylactic reactions and anaphylactic shock have been reported with Prothromplex TOTAL. If allergic or anaphylactic-type reactions occur, the injection/infusion should be stopped immediately. In the case of shock standard medical treatment for shock should be implemented. Thromboembolism, DIC, Fibrinolysis: There is a risk of thrombosis and disseminated intravascular coagulation (DIC) when patients, with either congenital or acquired deficiency are treated with human prothrombin complex concentrates, including Prothromplex TOTAL, particularly with repeated dosing. Arterial and venous thromboembolic events including myocardial infarction, cerebrovascular accident (e.g., stroke), pulmonary embolism as well as DIC have been reported with Prothromplex TOTAL. The risk may be higher in treatment of isolated F VII deficiency, since the other vitamin K-dependent coagulation factors, with longer half-lives, may accumulate to levels considerably higher than normal. Patients given human prothrombin complex concentrates should be observed closely for signs and symptoms of intravascular coagulation or thrombosis. Because of the risk of thromboembolic complications, particularly close monitoring should be exercised when administering prothrombin complex concentrates to: patients with a history of coronary heart disease, patients with liver disease, pre- or post-operative patients, neonates, or other patients at risk of thromboembolic events or disseminated intravascular coagulation. In each of these situations, the potential benefit of treatment should be weighed against the risk of these complications. Virus safety: Standard measures to prevent infections which can be transmitted by medicinal products made from human blood or plasma include donor selection, testing of individual donations and plasma pools for specific infection markers and the execution of effective manufacturing steps to inactivate/remove viruses. Nevertheless, when medicinal products prepared from human blood or plasma are administered, infectious diseases due to transmission of infective agents cannot be totally excluded. This also applies to unknown or emerging viruses or other pathogens. The measures taken are considered effective for enveloped viruses such as HIV, HBV, and HCV as well as against the non-enveloped HAV virus. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., haemolytic anaemia). It is strongly recommended that every time that Prothromplex TOTAL is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product. When a medicinal product prepared from human blood or plasma is administered regularly/repeatedly, appropriate vaccinations (hepatitis A and B) must be considered. Sodium content: This medicinal product contains 68 mg sodium per vial or 0.14 mg sodium per International Unit equivalent to 3.4 % of the WHO recommended maximum daily intake of 2g sodium for an adult. Heparin: May cause allergic reactions and reduced blood cell counts, which may affect the blood clotting system. Patients with a history of heparin-induced allergic reactions should avoid the use of heparin-containing medicines. Paediatric population: There are insufficient data to recommend the administration of Prothromplex TOTAL in children.

Interactions: Human prothrombin complex products neutralize the effect of vitamin K antagonist treatment. No interaction studies have been performed. Interference with biological testing: When performing clotting tests, which are sensitive to heparin in patients receiving high doses of human prothrombin complex, the heparin as a constituent of the administered product must be taken into account.

Fertility, pregnancy and lactation: The effects of Prothromplex TOTAL on fertility have not been established in controlled clinical trials. The safety of human prothrombin complex for use in human pregnancy and during lactation has not been established. There are no adequate data from the use of Prothromplex TOTAL in pregnant or lactating women. Animal studies are not suitable to assess the safety with respect to pregnancy, embryonal/foetal development, parturition, or postnatal development. Therefore, Prothromplex TOTAL should be used during pregnancy and lactation only if clearly indicated. Refer to the SmPC for information on the risk of Parvovirus B19 infection in pregnant women.

Undesirable effects: Common (≥1/100 to <1/10): Disseminated intravascular coagulation inhibitors to one or more of the prothrombin complex factors (factors II, VII, IX, X), Anaphylactic shock, Anaphylactic reaction, Hypersensitivity, Cerebrovascular accident, Headache, Heart failure, Acute myocardial infarction, Tachycardia, Arterial thrombosis, Venous thrombosis, Hypotension, Flushing, Pulmonary embolism, Dyspnoea, Wheezing, Vomiting, Nausea, Urticaria, Rash erythematous, Pruritus, Nephrotic syndrome and Pyrexia.

Refer to the SmPC for details on full side effect profile and interactions.

UK basic NHS price: £255.00 per vial.

Legal Classification: POM. Marketing authorisation (MA) numbers: PL 34078/0037.

Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London, W2 6BD, United Kingdom.

PI approval code: pi-02716

Date of preparation: September 2023

Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events should also be reported to Takeda UK Ltd at: AE.GBR-IRL@takeda.com.