Prescribing Information and Adverse Events Reporting

Items

 

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.

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)

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

Presentation: ADYNOVI vials contain human coagulation factor VIII (rDNA), rurioctocog alfa pegol powder and solvent (2 or 5 ml sterilised water for injection). After reconstitution, nominally 250 IU/2 ml, 1000 IU/2 ml, and 2000 IU/5 ml per vial.

Indication: Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia A (congenital factor VIII deficiency).

Dosage and administration: Treatment should be under the supervision of a physician experienced in the treatment of haemophilia. The dose and duration of the substitution therapy depend on the severity of the factor VIII (FVIII) deficiency, on the location and extent of the bleeding and on the patient's clinical condition. For guidance on prophylactic and on-demand treatment dosing, please refer to the SmPC. Should be administered via the intravenous route at a maximum rate of 10 ml/min.

Contraindications: Hypersensitivity to the active substance, to the parent molecule octocog alfa or to any of the excipients. Known allergic reaction to mouse or hamster protein.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Hypersensitivity: Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADYNOVI. If symptoms occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. In case of shock, standard medical treatment for shock should be implemented. Inhibitors: Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with FVIII, including with ADYNOVI. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, management of such patients should be directed by physicians with experience in the care of haemophilia and FVIII inhibitors. All patients should be monitored for the development of inhibitors especially following any product switch, if plasma levels are not attained or if bleeding is not controlled with an appropriate dose. Immune tolerance induction (ITI): No clinical data for use of ADYNOVI in ITI are available. Cardiovascular events: In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk. Catheter-related complications: If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered. Excipient-related considerations: ADYNOVI contains up to 12.42 mg sodium per vial, equivalent to 0.62% of the World Health Organisation (WHO) recommended maximum daily intake of 2 g sodium for an adult. Depending on the body weight and posology, the patient could receive more than one vial. This should be taken into consideration by patients on a controlled sodium diet. It is strongly recommended that every time that ADYNOVI is administered to a patient, the name and batch number of ADYNOVI is recorded in order to maintain a link between the patient and the batch of ADYNOVI. Paediatric population: The listed warnings and precautions apply both to adults and children (12 to 18 years of age).

Interactions: None reported. 

Fertility, pregnancy and lactation: Based on the rare occurrence of haemophilia A in women, experience regarding the use of FVIII during pregnancy and breastfeeding is not available. Therefore, FVIII should be used during pregnancy and lactation only if clearly indicated.

Undesirable effects: Very common (≥1/10): Headache. Common (≥1/100 to <1/10): dizziness, diarrhoea, nausea, rash and urticaria. Uncommon (≥1/1000 to <1/100): FVIII inhibition (in previously treated patients), hypersensitivity, ocular hyperaemia, flushing, rash pruritic, eosinophil count increased and infusion related reaction. Not Known (cannot be estimated from the available data): anaphylactic reaction.

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

Legal classification: POM.

Marketing authorisation (MA) numbers: 250 IU/2ml: PLGB 34078/0020; 1000 IU/2ml: PLGB 34078/0017; 2000 IU/5ml: PLGB 34078/0019.

UK basic NHS price: 85p per IU.

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

PI approval code: pi-02883.

Date of preparation: January 2024. 

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

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 NORTHERN IRELAND

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

Presentation: ADYNOVI vials contain human coagulation factor VIII (rDNA), rurioctocog alfa pegol powder and solvent (2 or 5 ml sterilised water for injection). After reconstitution, nominally 250 IU/2ml, 1000 IU/2ml, and 2000 IU/5ml per vial.

Indication: Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia A (congenital factor VIII deficiency).

Dosage and administration: Treatment should be under the supervision of a physician experienced in the treatment of haemophilia. The dose and duration of the substitution therapy depend on the severity of the factor VIII (FVIII) deficiency, on the location and extent of the bleeding and on the patient's clinical condition. For guidance on prophylactic and on-demand treatment dosing, please refer to the SmPC. Should be administered via the intravenous route at a maximum rate of 10 ml/min.

Contraindications: Hypersensitivity to the active substance, to the parent molecule octocog alfa or to any of the excipients. Known allergic reaction to mouse or hamster protein.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Hypersensitivity: Allergic type hypersensitivity reactions, including anaphylaxis have been reported with ADYNOVI. If symptoms occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. In case of shock, standard medical treatment for shock should be implemented. Inhibitors: Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with FVIII, including with ADYNOVI. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. All patients should be monitored for the development of inhibitors especially following any product switch, if plasma levels are not attained or if bleeding is not controlled with an appropriate dose. Immune tolerance induction (ITI): No clinical data for use of ADYNOVI in ITI are available. Cardiovascular events: In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk. Catheter- related complications: If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered. Excipient-related considerations: ADYNOVI contains up to 12.42 mg sodium per vial, equivalent to 0.62% of the World Health Organisation (WHO) recommended maximum daily intake of 2 g sodium for an adult. Depending on the body weight and posology, the patient could receive more than one vial. This should be taken into consideration by patients on a controlled sodium diet. It is strongly recommended that every time that ADYNOVI is administered to a patient, the name and batch number of ADYNOVI is recorded in order to maintain a link between the patient and the batch of ADYNOVI. Paediatric population: The listed warnings and precautions apply both to adults and children (12 to 18 years of age). 

Interactions: None reported. 

Fertility, pregnancy and lactation: Based on the rare occurrence of haemophilia A in women, experience regarding the use of FVIII during pregnancy and breastfeeding is not available. Therefore, FVIII should be used during pregnancy and lactation only if clearly indicated.

Undesirable effects: Very common (≥1/10): Headache. Common (≥1/100 to <1/10): dizziness, diarrhoea, nausea, rash and urticaria. Uncommon (≥1/1000 to <1/100): FVIII inhibition (in previously treated patients), hypersensitivity, ocular hyperaemia, flushing, rash pruritic, eosinophil count increased and infusion related reaction. Not Known (cannot be estimated from the available data): anaphylactic reaction. 

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

Legal classification: POM. 

Marketing authorisation numbers: 250 IU/2ml: EU/1/17/1247/002; 1000 IU/2ml: EU/1/17/1247/010; 2000 IU/5ml: EU/1/17/1247/014. 

UK basic NHS price: 85p per IU. 

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

PI approval code: pi-02884.

Date of preparation: January 2024.

This medicinal product is subject to additional monitoring.

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.

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

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

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

Presentation: 1 vial of FEIBA 50 U/ml contains 500 U or 1000 U factor VIII inhibitor bypassing activity.

Indications: Treatment of spontaneous bleeding and cover of surgical interventions in haemophilia A patients with factor VIII inhibitors and in non-haemophiliacs with acquired factor VIII inhibitors. Prophylaxis in haemophilia A patients with high responding inhibitors and frequent joint bleeding.

Dosage and administration:  Treatment should be initiated and supervised by a physician experienced in the management of haemophilia. Posology: The dosage and duration of the therapy is dependent upon the severity of the disorder, the location and extent of the bleeding and the patient’s clinical condition. As a general guide a dose of 50 to 100 U of FEIBA per kg body weight is recommended, repeated every 6 – 12 hours depending on type of bleed and degree of response (for further information on dosage please refer to the SmPC). Dosage and frequency of administration should always be guided by the clinical efficacy in each individual case. FEIBA should be administered via the intravenous route at a maximum rate of 2 U/kg body weight per minute. A single dose of 100 U/kg body weight and a daily dose of 200 U/kg body weight should not be exceeded unless the severity of bleeding warrants and justifies the use of higher doses. Bleeding prophylaxis: For prevention of bleeding episodes during prophylaxis, dose 70 to 100 U/kg body weight every other day. Adjust dose based on the patient’s clinical response. Paediatrics: The experience in children under 6 years of age is limited; the same dose regimen as in adults should be adapted to the child's clinical condition. Monitoring: In case of inadequate response to treatment with the product, it is recommended that a platelet count be performed because a sufficient number of functionally intact platelets are considered to be necessary for the efficacy of the product. Results of routine coagulation tests may not correlate with clinical improvement – no direct monitoring is possible. Global haemostatic tests such as thromboelastogram (TEG) or thrombin generation assay (TGA) may be useful tools to monitor and optimise the treatment.

Contraindications: FEIBA must not be used in the following situations if therapeutic alternatives to FEIBA are available: Hypersensitivity to the active substance or to any of the excipients. Disseminated intravascular coagulation (DIC). Acute thrombosis or embolism (including myocardial infarction).

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Thromboembolic events: Have occurred, including DIC, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. Some occurred with doses above 200 U/kg/day or in patients with other risk factors for thromboembolic events (including DIC, advanced atherosclerotic disease, crush injury or septicaemia). FEIBA should be used with particular caution in patients at risk of DIC, arterial or venous thrombosis. Thrombotic microangiopathy (TMA) has not been reported in FEIBA clinical studies. Cases of TMAs were reported in an emicizumab clinical trial where subjects received FEIBA as part of a treatment regimen for breakthrough bleeding. If treatment with FEIBA is considered required for patients receiving emicizumab, patients must be closely monitored. At the first signs or symptoms of thromboembolic events, the infusion should be stopped immediately, and appropriate diagnostic and therapeutic measures initiated. A single dose of 100 U/kg body weight and a daily dose of 200 U/kg body weight should not be exceeded. When used to stop bleeding, the product should be given only for as long as absolutely necessary to achieve the therapeutic goal. Allergic-type hypersensitivity reactions: FEIBA can precipitate allergic-type hypersensitivity reactions that have included, urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be severe and can be systemic (e.g. anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). At the first sign or symptom of an infusion/hypersensitivity reaction, FEIBA administration should be stopped and medical care initiated as appropriate. Measures to prevent transmission of infectious 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 nonenveloped 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). Appropriate vaccination (against hepatitis A and B) should be considered for patients in regular/repeated receipt of plasma-derived products. Discordant response to bypassing agents: Due to patient-specific factors the response to a bypassing agent can vary, in case of insufficient response to one bypassing agent, use of another agent should be considered. Anamnestic responses: Patients with inhibitors may result in an initial “anamnestic” rise in the inhibitor levels. Continuous administration of FEIBA may decrease the inhibitors over time. Interference with laboratory tests: High doses of FEIBA may result in misleading interpretation of positive results in serological testing. Sodium content: FEIBA contains approximately 4 mg sodium (calculated) per ml. To be taken into consideration in patients on a low sodium diet.

Interactions: No adequate and well-controlled studies of the combined or sequential use of FEIBA and recombinant factor VIIa (rFVIIa), antifibrinolytics or emicizumab have been conducted. The possibility of thromboembolic events should be considered when systemic antifibrinolytics are used. Therefore, antifibrinolytics and FEIBA should be administered at least 6 hours apart. In cases of concomitant rFVIIa use, a potential drug interaction may occur (potentially resulting in adverse events such as a thromboembolic event). Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab when FEIBA was used as part of a treatment regimen for breakthrough bleeding.

Fertility, pregnancy and lactation: There are no adequate data from the use of FEIBA in pregnant or lactating women.

Undesirable effects: Common (≥1/100 to <1/10): Hypersensitivity, headache, dizziness, hypotension, rash, and hepatitis B surface antibody positive. Other serious undesirable effects (unknown frequency): DIC, anamnestic response, anaphylactic reaction, embolic stroke, thrombotic stroke, cardiac infarction, arterial thrombosis, hypertension, thrombosis, venous thrombosis, bronchospasm, dyspnoea, pulmonary embolism, angioedema, pyrexia, tachycardia. Refer to the SmPC for details on full side effect profile and interactions.

UK basic NHS price: 50 U/ml powder/solvent: 500 U/10 ml – £390, 1000 U/20 ml – £780.

Legal classification: POM.

Marketing authorisation (MA) number: PL 34078/0003.

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

PI approval code: pi-02564.

Date of preparation: July 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. 

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

PRESCRIBING INFORMATION for NORTHERN IRELAND

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

Presentation: 1 vial of FEIBA 50 U/ml contains 500 U or 1000 U factor VIII inhibitor bypassing activity.

Indications: Treatment of spontaneous bleeding and cover of surgical interventions in haemophilia A patients with factor VIII inhibitors and in non-haemophiliacs with acquired factor VIII inhibitors. Prophylaxis in haemophilia A patients with high responding inhibitors and frequent joint bleeding.

Dosage and administration:  Treatment should be initiated and supervised by a physician experienced in the management of haemophilia. Posology: The dosage and duration of the therapy is dependent upon the severity of the disorder, the location and extent of the bleeding and the patient’s clinical condition. As a general guide a dose of 50 to 100 U of FEIBA per kg body weight is recommended, repeated every 6 – 12 hours depending on type of bleed and degree of response (for further information on dosage please refer to the SmPC). Dosage and frequency of administration should always be guided by the clinical efficacy in each individual case. FEIBA should be administered via the intravenous route at a maximum rate of 2 U/kg body weight per minute. A single dose of 100 U/kg body weight and a daily dose of 200 U/kg body weight should not be exceeded unless the severity of bleeding warrants and justifies the use of higher doses. Bleeding prophylaxis: For prevention of bleeding episodes during prophylaxis, dose 70 to 100 U/kg body weight every other day. Adjust dose based on the patient’s clinical response. Paediatrics: The experience in children under 6 years of age is limited; the same dose regimen as in adults should be adapted to the child's clinical condition. Monitoring: In case of inadequate response to treatment with the product, it is recommended that a platelet count be performed because a sufficient number of functionally intact platelets are considered to be necessary for the efficacy of the product. Results of routine coagulation tests may not correlate with clinical improvement – no direct monitoring is possible. Global haemostatic tests such as thromboelastogram (TEG) or thrombin generation assay (TGA) may be useful tools to monitor and optimise the treatment.

Contraindications: FEIBA must not be used in the following situations if therapeutic alternatives to FEIBA are available: Hypersensitivity to the active substance or to any of the excipients. Disseminated intravascular coagulation (DIC). Acute thrombosis or embolism (including myocardial infarction).

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Thromboembolic events: Have occurred, including DIC, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. Some occurred with doses above 200 U/kg/day or in patients with other risk factors for thromboembolic events (including DIC, advanced atherosclerotic disease, crush injury or septicaemia). FEIBA should be used with particular caution in patients at risk of DIC, arterial or venous thrombosis. Thrombotic microangiopathy (TMA) has not been reported in FEIBA clinical studies. Cases of TMAs were reported in an emicizumab clinical trial where subjects received FEIBA as part of a treatment regimen for breakthrough bleeding. If treatment with FEIBA is considered required for patients receiving emicizumab, patients must be closely monitored. At the first signs or symptoms of thromboembolic events, the infusion should be stopped immediately, and appropriate diagnostic and therapeutic measures initiated. A single dose of 100 U/kg body weight and a daily dose of 200 U/kg body weight should not be exceeded. When used to stop bleeding, the product should be given only for as long as absolutely necessary to achieve the therapeutic goal. Allergic-type hypersensitivity reactions: FEIBA can precipitate allergic-type hypersensitivity reactions that have included, urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be severe and can be systemic (e.g. anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). At the first sign or symptom of an infusion/hypersensitivity reaction, FEIBA administration should be stopped and medical care initiated as appropriate. Measures to prevent transmission of infectious 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 nonenveloped 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). Appropriate vaccination (against hepatitis A and B) should be considered for patients in regular/repeated receipt of plasma-derived products. Discordant response to bypassing agents: Due to patient-specific factors the response to a bypassing agent can vary, in case of insufficient response to one bypassing agent, use of another agent should be considered. Anamnestic responses: Patients with inhibitors may result in an initial “anamnestic” rise in the inhibitor levels. Continuous administration of FEIBA may decrease the inhibitors over time. Interference with laboratory tests: High doses of FEIBA may result in misleading interpretation of positive results in serological testing. Sodium content: FEIBA contains approximately 4 mg sodium (calculated) per ml. To be taken into consideration in patients on a low sodium diet.

Interactions: No adequate and well-controlled studies of the combined or sequential use of FEIBA and recombinant factor VIIa (rFVIIa), antifibrinolytics or emicizumab have been conducted. The possibility of thromboembolic events should be considered when systemic antifibrinolytics are used. Therefore, antifibrinolytics and FEIBA should be administered at least 6 hours apart. In cases of concomitant rFVIIa use, a potential drug interaction may occur (potentially resulting in adverse events such as a thromboembolic event). Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab when FEIBA was used as part of a treatment regimen for breakthrough bleeding.

Fertility, pregnancy and lactation: There are no adequate data from the use of FEIBA in pregnant or lactating women.

Undesirable effects: Common (≥1/100 to <1/10): Hypersensitivity, headache, dizziness, hypotension, rash, and hepatitis B surface antibody positive. Other serious undesirable effects (unknown frequency): DIC, anamnestic response, anaphylactic reaction, embolic stroke, thrombotic stroke, cardiac infarction, arterial thrombosis, hypertension, thrombosis, venous thrombosis, bronchospasm, dyspnoea, pulmonary embolism, angioedema, pyrexia, tachycardia. Refer to the SmPC for details on full side effect profile and interactions.

UK basic NHS price: 50 U/ml powder/solvent: 500 U/10 ml – £390, 1000 U/20 ml – £780.

Legal classification: POM.

Marketing authorisation (MA) number: PL 34078/0003.

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

PI approval code: pi-02565.

Date of preparation: July 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. 

FIRAZYR (icatibant) 30 mg solution for injection in pre-filled syringe

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

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

Presentation: Each pre-filled syringe of 3 ml contains icatibant acetate equivalent to 30 mg icatibant (10 mg/ml of icatibant).

Indication: Firazyr is indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older, with C1-esterase-inhibitor deficiency.

Dosage and administration: Firazyr is intended for use under the guidance of a healthcare professional. Posology: Adults: The recommended dose is a single subcutaneous injection of 30 mg. In the majority of cases a single injection is sufficient to treat an attack. In case of insufficient relief or recurrence of symptoms, a second injection can be administered after 6 hours. If the second injection produces insufficient relief or a recurrence of symptoms is observed, a third injection can be administered after a further 6 hours. No more than 3 injections should be administered in a 24 -hour period. In the clinical trials, not more than 8 injections per month have been administered. Children: The recommended dose is based on body weight in children and adolescents (aged 2 to 17 years), doses range from 10 to 30 mg, please refer to the SmPC for specific dosing. In the clinical trial, not more than 1 injection per HAE attack has been administered. No dosage regimen for children aged less than 2 years or weighing less than 12 kg can be recommended as the safety and efficacy in this paediatric group has not been established. Elderly: Limited information is available on patients older than 65 years of age. Elderly patients have been shown to have increased systemic exposure to icatibant. The relevance of this to the safety of Firazyr is unknown. Renal and hepatic impairment: No dosage adjustment is required. Method of administration: Firazyr injections are for subcutaneous administration, preferably in the abdominal area. They are for single use only, intended for use under the guidance of a healthcare professional. Injection should be given slowly due to the large volume to be administered.  Refer to the patient information leaflet for instructions for use. Caregiver/self-administration: The decision on initiating caregiver or self-administration of Firazyr should only be taken by a physician experienced in the diagnosis and treatment of HAE. Firazyr may be self-administered (in adults only) or administered by a caregiver only after training in subcutaneous injection technique by a healthcare professional.

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

Warnings and precautions: Laryngeal attacks: Patients with laryngeal attacks should be managed in an appropriate medical institution after injection until the physician considers discharge to be safe. Ischaemic heart disease: Under ischaemic conditions a deterioration of cardiac function and a decrease in coronary blood flow could theoretically arise from antagonism of bradykinin receptor type 2. Caution should therefore be observed in the administration of Firazyr to patients with acute ischaemic heart disease or unstable angina pectoris. Stroke: Although there is evidence to support a beneficial effect of B2 receptor blockade immediately following a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phase neuroprotective effects of bradykinin. Caution should be observed in the administration of icatibant to patients in the weeks following a stroke. Caregiver/self-administration: For patients who have never received Firazyr previously, the first treatment should be given in a medical institution or under the guidance of a physician. In case of insufficient relief or recurrence of symptoms after self-treatment or administration by a caregiver, it is recommended that the patient or caregiver should seek medical advice. For adults, subsequent doses required for the same attack should be given in a medical institution. There are no data on administering subsequent doses for the same attack in adolescents or children. Patients experiencing a laryngeal attack should always seek medical advice and be observed in a medical institution also after having taken the injection at home. Paediatric population: Limited experience with treatment of more than one HAE attack with Firazyr in the paediatric population.

Interactions: Interactions involving CYP450 are not expected. Co-administration of Firazyr with ACE inhibitors has not been studied. ACE inhibitors are contraindicated in HAE patients due to possible enhancement of bradykinin levels. Fertility, pregnancy and lactation: Firazyr should be used during pregnancy only if the potential benefit justifies the potential risk for the foetus (e.g., for treatment of potentially life-threatening laryngeal attacks). It is unknown whether icatibant is excreted in human breast milk but it is recommended that breast-feeding women should not breast-feed for 12 hours after treatment.

Effects on ability to drive and use machines: Firazyr has minor influence on the ability to drive or use machines. Patients should be advised not to drive or use machines if they feel tired or dizzy.

Undesirable effects: Very common (≥1/10): Injection site reactions (injection site bruising, injection site haematoma, injection site burning, injection site erythema, injection site hypoesthesia, injection site irritation, injection site numbness, injection site oedema, injection site pain, injection site pressure sensation, injection site pruritus, injection site swelling, injection site urticaria, and injection site warmth). Common (≥1/100 to <1/10): Dizziness, headache, nausea, rash, erythema, pruritus, pyrexia and increased transaminases. Refer to the SmPC for details on full side effect and interactions.

UK basic NHS price: Pack of one pre-filled syringe with one needle: £1395.00.

Legal category: POM.

Marketing authorisation number: PLGB 54937/0004.

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

PI approval code: pi-01945.

Date of preparation: March 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. 

 

FIRAZYR (icatibant) 30 mg solution for injection in pre-filled syringe

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

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

Presentation: Each pre-filled syringe of 3 ml contains icatibant acetate equivalent to 30 mg icatibant (10 mg/ml of icatibant).

Indication: Firazyr is indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older, with C1-esterase-inhibitor deficiency.

Dosage and administration: Firazyr is intended for use under the guidance of a healthcare professional. Posology: Adults: The recommended dose is a single subcutaneous injection of 30 mg. In the majority of cases a single injection is sufficient to treat an attack. In case of insufficient relief or recurrence of symptoms, a second injection can be administered after 6 hours. If the second injection produces insufficient relief or a recurrence of symptoms is observed, a third injection can be administered after a further 6 hours. No more than 3 injections should be administered in a 24 -hour period. In the clinical trials, not more than 8 injections per month have been administered. Children: The recommended dose is based on body weight in children and adolescents (aged 2 to 17 years), doses range from 10 to 30 mg, please refer to the SmPC for specific dosing. In the clinical trial, not more than 1 injection per HAE attack has been administered. No dosage regimen for children aged less than 2 years or weighing less than 12 kg can be recommended as the safety and efficacy in this paediatric group has not been established. Elderly: Limited information is available on patients older than 65 years of age. Elderly patients have been shown to have increased systemic exposure to icatibant. The relevance of this to the safety of Firazyr is unknown. Renal and hepatic impairment: No dosage adjustment is required. Method of administration: Firazyr injections are for subcutaneous administration, preferably in the abdominal area. They are for single use only, intended for use under the guidance of a healthcare professional. Injection should be given slowly due to the large volume to be administered.  Refer to the patient information leaflet for instructions for use. Caregiver/self-administration: The decision on initiating caregiver or self-administration of Firazyr should only be taken by a physician experienced in the diagnosis and treatment of HAE. Firazyr may be self-administered (in adults only) or administered by a caregiver only after training in subcutaneous injection technique by a healthcare professional.

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

Warnings and precautions: Laryngeal attacks: Patients with laryngeal attacks should be managed in an appropriate medical institution after injection until the physician considers discharge to be safe. Ischaemic heart disease: Under ischaemic conditions a deterioration of cardiac function and a decrease in coronary blood flow could theoretically arise from antagonism of bradykinin receptor type 2. Caution should therefore be observed in the administration of Firazyr to patients with acute ischaemic heart disease or unstable angina pectoris.
Stroke: Although there is evidence to support a beneficial effect of B2 receptor blockade immediately following a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phase neuroprotective effects of bradykinin. Caution should be observed in the administration of icatibant to patients in the weeks following a stroke. Caregiver/self-administration: For patients who have never received Firazyr previously, the first treatment should be given in a medical institution or under the guidance of a physician. In case of insufficient relief or recurrence of symptoms after self-treatment or administration by a caregiver, it is recommended that the patient or caregiver should seek medical advice. For adults, subsequent doses required for the same attack should be given in a medical institution. There are no data on administering subsequent doses for the same attack in adolescents or children. Patients experiencing a laryngeal attack should always seek medical advice and be observed in a medical institution also after having taken the injection at home. Paediatric population: Limited experience with treatment of more than one HAE attack with Firazyr in the paediatric population.

Interactions: Interactions involving CYP450 are not expected. Co-administration of Firazyr with ACE inhibitors has not been studied. ACE inhibitors are contraindicated in HAE patients due to possible enhancement of bradykinin levels.

Fertility, pregnancy and lactation: Firazyr should be used during pregnancy only if the potential benefit justifies the potential risk for the foetus (e.g., for treatment of potentially life-threatening laryngeal attacks). It is unknown whether icatibant is excreted in human breast milk but it is recommended that breast-feeding women should not breast-feed for 12 hours after treatment.

Effects on ability to drive and use machines: Firazyr has minor influence on the ability to drive or use machines. Patients should be advised not to drive or use machines if they feel tired or dizzy.

Undesirable effects: Very common (≥1/10): Injection site reactions (injection site bruising, injection site haematoma, injection site burning, injection site erythema, injection site hypoesthesia, injection site irritation, injection site numbness, injection site oedema, injection site pain, injection site pressure sensation, injection site pruritus, injection site swelling, injection site urticaria, and injection site warmth). Common (≥1/100 to <1/10): Dizziness, headache, nausea, rash, erythema, pruritus, pyrexia and increased transaminases. Refer to the SmPC for details on full side effect and interactions.

UK basic NHS price: Pack of one pre-filled syringe with one needle: £1395.00.

Legal category: POM.

Marketing authorisation number: EU/1/08/461/001.

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

PI approval code: pi-01946.

Date of preparation: March 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

HYQVIA®(Human normal immunoglobulin) 100 mg/ml solution for infusion for subcutaneous use 

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

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

Presentation: HyQvia is a dual vial unit consisting of one vial of 10% human normal immunoglobulin (IG) and one vial of recombinant human hyaluronidase (see the SmPC for details).

Indications: Replacement therapy in adults, children and adolescents (0-18 years) in: primary immunodeficiency syndromes with impaired antibody production; secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) or serum IgG level of <4 g/l. PSAF is a failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines.

Dosage and administration: For subcutaneous use only. Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. The product should be brought to room temperature before use. Inspect both vials for discolouration and particulate matter before administration. Do not use heating devices including microwaves. Do not shake or mix the components of the two vials. Suggested infusion site(s) are the middle to upper abdomen and thighs. The two components of the medicinal product must be administered sequentially through the same needle beginning with the recombinant human hyaluronidase followed by IG 10%. Please see the SmPC for infusion rates. The full contents of the recombinant human hyaluronidase vial should be administered regardless of whether the full contents of the IG 10% vial is administered. Longer needles may be used under medical supervision to prevent infusion site leakage. Home treatment should be initiated and monitored by a physician experienced in the guidance of patients for home treatment. Posology: Dose and dosage regimen may need to be individualised for each patient dependent on the response. Dose based on body weight may require adjustment in underweight or overweight patients. Patients naïve to IG therapy: The dose required to achieve a trough level of 6 g/l is approximately 0.4-0.8 g/kg body weight/month. The dosage interval to maintain steady state levels varies from 2-4 weeks. Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels (>6 g/l). At the initiation of therapy, it is recommended that the treatment intervals for the first infusions be gradually prolonged from a 1-week dose to up to a 3- or 4-week dose. Patients previously treated with IG administered intravenously (IV): For patients switching directly from IV IG, or who have had a previous IV dose of IG that can be referenced, the medicinal product should be administered at the same dose and at the same frequency as their previous IV IG treatment. Patients previously treated with IG administered subcutaneously: For patients currently being administered IG subcutaneously, the initial dose of HyQvia is the same as for subcutaneous treatment but may be adjusted to 3- or 4-week intervals. The first infusion of HyQvia should be given one week after the last treatment with the previous IG. Secondary immunodeficiencies: The recommended dose is 0.2-0.4 g/kg every three to four weeks. Trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections, an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection free. Children and adolescents (0-18 years): Follow adult dosage guidance

Contraindications: Hypersensitivity to any ingredient or human IG especially in patients with antibodies against IgA; systemic hypersensitivity to hyaluronidase or human recombinant hyaluronidase; HyQvia must not be given IV or intramuscularly.

Warnings and precautions: If HyQvia is accidentally administered into a blood vessel, patients could develop shock. The recommended infusion rate given in the SmPC should be adhered to. Infuse slowly and monitor closely throughout the infusion period, particularly patients starting therapy. Patients may require monitoring for up to 1 hour after administration. Manage infusion related events by slowing the infusion rate or stopping the infusion. Treatment will depend on the nature and severity of the adverse event. Patients should be reminded to report chronic inflammation and nodules which occur at the infusion site or other locations. For home treatment, patients should have the support of another responsible person in case of adverse reactions. Record treatment with HyQvia and batch number in patients’ notes. Hypersensitivity: Hypersensitivity reactions are possible in patients with anti-IgA antibodies who should only be treated with HyQvia if alternative treatments are not possible and under close medical supervision. In case of hypersensitivity, shock or anaphylactic-like reactions, discontinue the infusion immediately and treat the patient for shock. Rarely, human normal IG can induce a fall in blood pressure with anaphylactic reaction. In high-risk patients HyQvia should only be administered where supportive care is available for life threatening reactions. Patients should be informed of the early signs of anaphylaxis/ hypersensitivity. Pre-medication may be used as a preventative measure. Hypersensitivity to recombinant human hyaluronidase: Any suspicion of allergic or anaphylactic like reactions following recombinant human hyaluronidase administration requires immediate discontinuation of the infusion and standard medical treatment should be administered, if necessary. Immunogenicity of recombinant human hyaluronidase: Development of non-neutralising antibodies to the recombinant human hyaluronidase component has been reported in patients receiving HyQvia in clinical studies. Thromboembolism: Thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been observed with IG treatment and cannot be excluded with use of HyQvia. Ensure adequate hydration prior to treatment. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk. Patients should be informed about initial symptoms and advised to contact their physician immediately upon onset. Haemolytic anaemia: IG products contain antibodies to blood groups (e.g. A, B, D) which may act as haemolysins. Monitor for signs and symptoms of haemolysis. Acute renal failure: Severe renal adverse reactions have been reported in patients receiving IV IG. Aseptic meningitis syndrome: has been reported, symptoms usually begin within several hours to 2 days following treatment. Patients should be informed about initial symptoms. Discontinuation of IG treatment may result in remission within several days without sequelae. Transmissible agents: Infectious diseases due to the transmission of infective agents cannot be totally excluded. Sodium content: The recombinant human hyaluronidase component contains 4.03 mg sodium/mL. To be taken into consideration by patients on a controlled sodium diet. Traceability: The name and the batch number of the administered product should be clearly recorded.

Interactions: Live attenuated virus vaccines – postpone vaccination for 3 months after treatment with HyQvia. For measles vaccine, impairment may persist for up to 1 year, so check antibody status. Please see the SmPC for details.

Fertility, pregnancy and lactation: Safety during pregnancy has not been established and immunoglobulins are excreted into the milk, therefore use with caution in pregnant and breastfeeding mothers.

Effects on ability to drive and use machines: HyQvia has no or negligible influence on the ability to drive and use machines, e.g. dizziness. Please see the SmPC for details.

Undesirable effects: Very common (≥1/10 patients): Feeling hot, infusion site paraesthesia, infusion site pain (including discomfort, tenderness, groin pain). Common (≥1/100, <1/10 patients): Vomiting, nausea, abdominal pain (including abdominal upper and lower pain and tenderness), diarrhoea, infusion site erythema, infusion site swelling (including local swelling and oedema), infusion site pruritus (including vulvovaginal pruritus), pyrexia, asthenic conditions (including asthenia, fatigue, lethargy, malaise), myalgia, musculoskeletal chest pain, headache. Other serious undesirable effects (rare or unknown frequency): Direct Coombs’ test positive, meningitis aseptic. Refer to the SmPC for details on full side effect and interactions.

UK Basic NHS price: £69.00 per gram.

Legal classification: POM.

Marketing Authorisation (MA) number: PLGB 34078/0024.

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

PI approval code: pi-02373.

Date of preparation: February 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

HYQVIA®(Human normal immunoglobulin) 100 mg/ml solution for infusion for subcutaneous use 

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

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

Presentation: HyQvia is a dual vial unit consisting of one vial of 10% human normal immunoglobulin (IG) and one vial of recombinant human hyaluronidase (see the SmPC for details).

Indications: Replacement therapy in adults, children and adolescents (0 to 18 years) in: primary immunodeficiency syndromes (PID) with impaired antibody production; secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) or serum IgG level of <4 g/L. (PSAF is a failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines). Immunomodulatory therapy in adults, children and adolescents (0 to 18 years) in: Chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy after stabilization with Intravenous immunoglobulin (IVIg).

Dosage and administration: Therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency/CIDP. The medicinal product should be administered via the subcutaneous (SC) route only, do not administer intravenously (see SmPC). The dose and dose regimens are dependent on the indication. The dose may need to be individualized for each patient dependent on the pharmacokinetic (PK) and clinical response. Dose based on bodyweight may require adjustment in underweight or overweight patients. Posology: Replacement therapy in PID; Patients naïve to immunoglobulin therapy: The dose required to achieve a trough level of 6 g/L is of the order of 0.4 to 0.8 g/kg body weight per month. The dose interval to maintain steady-state levels varies from 2-to-4 weeks. Patients previously treated with Intravenous immunoglobulin (IVIg): For patients switching directly from IVIg, or who have a previous IVIg dose that can be referenced, the medicinal product should be administered at the same dose and at the same frequency as their previous IVIg treatment. If patients were previously on a 3 week dosing regimen, increasing the interval to 4 weeks can be accomplished by administering the same weekly equivalents. Patients previously treated with subcutaneous immunoglobulin (SCIg): The initial dose of the medicinal product is the same as for SCIg treatment but may be adjusted to 3 or 4 weeks interval. The first infusion should be given one week after the last treatment with the previous immunoglobulin. Replacement therapy in SID: The recommended dose is 0.2 to 0.4 g/kg every 3 to 4 weeks. Replacement therapy in PID & SID: IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections, an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection free. Immunomodulatory therapy in CIDP: Before initiating therapy, the weekly equivalent dose should be calculated by dividing the planned dose by the planned dose interval in weeks. The typical dosing interval range for HyQvia is 3 to 4 weeks. The recommended subcutaneous dose is 0.3 to 2.4 g/kg body weight per month, administered in 1-or 2-sessions over 1-or 2-days. The patient’s clinical response should be the primary consideration in dose adjustment. In clinical deterioration, the dose may be increased to the recommended maximum of 2.4 g/kg monthly. If the patient is clinically stable, periodic dose reductions may be needed to observe whether the patient still needs IG therapy. A titration schedule that permits gradual dose increase over time (ramp-up) is recommended to ensure the patient’s tolerability until the full dose is reached (see SmPC). Patients must be on stable doses (see SmPC) of IVIg. Before initiating therapy with the medicinal product, the weekly equivalent dose should be calculated by dividing the last IVIg dose by the IVIg dose interval in weeks. The starting dose and dosing frequency are the same as the patient’s previous IVIg treatment. The typical dosing interval for HyQvia is 4-weeks. (see SmPC). Paediatric population: Replacement therapy: The dosing schedule for children and adolescents (0 to 18 years) is the same as for adults. The dosing is based on body weight and adjusted to the clinical outcome (see SmPC). Immunomodulatory therapy: The dosing schedule for children and adolescents (0 to 18 years) is the same as for adults. The dosing is based on the calculated weekly equivalent dose and adjusted to the clinical outcome (see SmPC).

Contraindications: HyQvia must not be given intravenously or intramuscularly. Hypersensitivity to the active substance (IgG) or to any of the excipients listed in the SmPC. Hypersensitivity to human immunoglobulins, especially in very rare cases of IgA deficiency when the patient has antibodies against IgA. Known systemic hypersensitivity to hyaluronidase or rHuPH20.

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. Precautions for use: If HyQvia is accidentally administered into a blood vessel, patients could develop shock (see SmPC). Hypersensitivity to IG 10%: True hypersensitivity reactions are rare. They can particularly occur in patients with anti IgA antibodies who should be treated with particular caution. Patients with anti IgA antibodies, in whom treatment with SCIg products remains the only option, should be treated with HyQvia only under close medical supervision. Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin (see SmPC). Hypersensitivity to rHuPH20: Any suspicion of allergic or anaphylactic like reactions following rHuPH20 administration requires immediate discontinuation of the infusion and standard medical treatment should be administered, if necessary. Immunogenicity of rHuPH20: Development of non- neutralizing antibodies and neutralizing antibodies to the rHuPH20 component has been reported in patients receiving HyQvia in clinical studies. The potential exists for such antibodies to cross react with endogenous hyaluronidase, which is known to be expressed in the adult male testes, epididymis, and sperm. It is unknown whether these antibodies may have any clinical significance in humans (see SmPC). Thromboembolism: Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Patients should be sufficiently hydrated before using immunoglobulins. Caution should be exercised in patients with pre-existing risk factors for thromboembolic events (see SmPC). Haemolytic anaemia: Immunoglobulin product recipients should be monitored for clinical signs and symptoms of haemolysis (see SmPC). Aseptic meningitis syndrome (AMS): Has been reported to occur in association with IVIg and SCIg treatment; the symptoms usually begin within several hours to 2 days following immunoglobulin treatment. Patients should be informed about the first symptoms which encompass severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting. Discontinuation of immunoglobulin treatment may result in remission of AMS within several days without sequelae (see SmPC). Interference with serological testing: After infusion of immunoglobulins, the transitory rise of the various passively transferred antibodies in the patient’s blood may result in misleading positive results in serological testing (see SmPC). Transmissible agents: When medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens (see SmPC). Sodium content: The IG 10% component is essentially sodium-free. The rHuPH20 contains varying amounts (mg) of sodium per vial which is equivalent to 0.25 to 3% of the WHO recommended maximum daily intake of 2 g sodium for an adult (see SmPC). Paediatric population: The warnings and precautions apply both to adults and children.

Interactions: Live attenuated virus vaccines: Immunoglobulin administration may impair for a period of at least 6-weeks and up to 3-months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3-months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked. Paediatric population: The interactions apply both to adults and children.

Fertility, pregnancy and lactation: Pregnancy: The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical studies and therefore should only be given with caution to pregnant women and breast feeding mothers. Breast-feeding: Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry. Fertility: There are currently no clinical safety data for this medicinal product on fertility available.

Effects on ability to drive and use machines: The ability to drive and operate machines may be impaired by some adverse reactions e.g., dizziness (see SmPC) associated with this medicinal product. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Undesirable effects: Very common (≥1/10 patients): Headache, Blood pressure increased and Hypertension, Nausea, Abdominal pain, Abdominal pain lower, Abdominal pain upper and Abdominal tenderness, Diarrhea, Vomiting, Arthralgia, Local reactions (Total); Infusion site discomfort, Infusion site pain, Injection site pain, Puncture site pain and Tenderness, Infusion site erythema and Injection site erythema, Infusion site oedema, Injection site oedema, Infusion site swelling, Injection site swelling and Swelling (local), Infusion site pruritus, Injection site pruritus, Puncture site pruritus and Vulvovaginal pruritus, Feeling hot and Pyrexia, Asthenia, Fatigue, Lethargy and Malaise. Common (≥1/100, <1/10 patients)Dizziness, Migraine, Tremor, Paraesthesia Sinus tachycardia and Tachycardia, Hypotension, Dyspnoea, Abdominal distension, Erythema, Pruritus, Rash, Rash erythematous, Rash macular, Rash maculo-papular and Rash popular, Urticaria, Myalgia, Limb discomfort and Pain in extremity, Back pain, Musculoskeletal chest pain, Groin pain, Hemosiderinuria, Infusion related reaction, Infusion site bruising, Injection site bruising, Infusion site haematoma, Injection site haematoma, Infusion site haemorrhage and Vessel puncture site bruise, Infusion site reaction, Injection site reaction and Puncture site reaction, Infusion site mass, Injection site mass and Infusion site nodule, Infusion site discoloration, Infusion site rash and Injection site rash, Infusion site induration and Injection site induration, Infusion site warmth, Infusion site paraesthesia and Injection site paraesthesia, Infusion site inflammation, Chills, Oedema, Oedema peripheral and Swelling (systemic), Localised oedema, Peripheral swelling and Skin oedema, Gravitational oedema, Oedema genital, Scrotal swelling and Vulvovaginal swelling, Hyperhidrosis, Coombs direct test positive and Coombs test positive. Other serious undesirable effects: meningitis aseptic, acute renal failure, cerebrovascular accident and ischaemic stroke.

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

UK Basic NHS price: £69.00 per gram.

Legal classification: POM.

Marketing Authorisation (MA) numbers: 2.5g EU/1/13/840/001, 5g EU/1/13/840/002, 10g EU/1/13/840/003, 20g EU/1/13/840/004, 30g EU/1/13/840/005.

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

PI approval code: pi-02959.

Date of preparation: February 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

KIOVIG Human normal immunoglobulin (IVIg) 10% (100mg/ml) solution for infusion

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

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

Presentation: One ml contains 100 mg of human normal immunoglobulin (purity of at least 98% IgG). Each vial of 10 ml, 25 ml, 50 ml, 100 ml, 200 ml, and 300 ml contains: 1 g, 2.5 g, 5 g, 10 g, 20 g, and 30 g of human normal immunoglobulin, respectively.

Indications: Replacement therapy in adults, and children and adolescents (0 - 18 years) in: primary immunodeficiency (PID) syndromes with impaired antibody production; secondary immunodeficiencies (SID) in patients suffering from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) or serum IgG level ofin patients suffering from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) or serum IgG level of <4 g/l. Immunomodulation in adults, and children and adolescents (0 - 18 years) in: primary immune thrombocytopenia (ITP) in patients at high risk of bleeding or prior to surgery to correct the platelet count; Guillain-Barré syndrome (GBS); Kawasaki disease (KD) in conjunction with acetylsalicylic acid; chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); multifocal motor neuropathy (MMN).

Dosage and administration: Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Administration: Administer by IV infusion at an initial rate of 0.5 ml/kg body weight (BW)/hr for 30 minutes. If well tolerated, rate may gradually be increased up to a maximum of 6 ml/kg BW/hr. If dilution is required, 5% glucose solution is recommended. Posology: Dose and dosage regimen is dependent on the indication and body weight, consult the SmPC for full details. A typical starting dose for replacement therapy in PID: 0.4 - 0.8 g/kg BW followed by 0.2 - 0.8 g/kg BW every 3 - 4 weeks to obtain IgG trough levels of at least 5 - 6 g/L. SID: 0.2 – 0.4 g/kg every 3 - 4 weeks. ITP: 0.8 - 1.0 g/kg BW on day one repeated once within 3 days or 0.4 g/kg BW daily for 2 - 5 days. The treatment can be repeated if relapse occurs. GBS: 0.4 g/kg BW/day over 5 days (possible repeat of dosing in case of relapse). KD: 2.0 g/kg BW as a single dose, in conjunction with acetylsalicylic acid. CIDP: starting dose 2 g/kg BW divided over 2 - 5 consecutive days; maintenance dose 1 g/kg BW over 1 - 2 consecutive every 3 weeks. MMN: starting dose 2 g/kg BW given over 2 - 5 consecutive days; maintenance dose 1 g/kg BW every 2 to 4 weeks, or 2 g/kg BW every 4 to 8 weeks over 2 - 5 days. Paediatrics: Same dose as for adults because posology for each indication is given by BW and adjusted to clinical outcome of the above-mentioned conditions.

Contraindications: Hypersensitivity to the active substance or to any of the excipients or to human immunoglobulins, especially in patients with antibodies against IgA. Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA containing product can result in anaphylaxis.

Warnings and precautions: Infusion reaction: Infuse slowly (0.5 ml/kg BW/hr) to begin with and monitor patient closely to ensure tolerance. Treat infusion-related events by slowing the infusion rate or stopping the infusion. Ensure adequate hydration, monitor urine output and serum creatinine. In case of shock, standard medical treatment for shock should be implemented. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. IVIg discontinuation should be considered in case of renal impairment. In patients at risk of acute renal failure, IVIg should be administered at the minimum rate of infusion and dose practicable. Avoid concomitant loop diuretics. If dilution of Kiovig is required for diabetic patients, use of 5% glucose solution for dilution should be reconsidered. Thus, dosing should be carefully calculated for this population. Hypersensitivity reactions are possible in patients with anti-IgA antibodies. IVIg has been associated with thrombotic events. Use with caution in obese patients and those with pre-existing risk factors for thrombotic events. Hyperproteinaemia, increased serum viscosity and subsequent relative pseudohyponatremia may occur whilst treatment for true hyponatremia and may lead to a further increase in serum viscosity and a possible predisposition to thromboembolic events. Transfusion-related acute lung injury (TRALI), aseptic meningitis syndrome (AMS), haemolytic anaemia and neutropenia/ leukopenia have been reported in patients treated with IVIg. IVIg recipients should be monitored for symptoms of haemolysis. Interference with serological testing may occur. Infectious diseases due to the transmission of infective agents cannot be totally excluded. To improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Paediatric patients may be more susceptible to volume overload.

Interactions: Live attenuated viruses: Postpone vaccination for 3 months after treatment with Kiovig. For measles vaccine, check antibody status as efficacy of vaccine may be impaired for up to 1 year after administration of immunoglobulins. Blood glucose: Dilution with 5% glucose may result in increased blood glucose levels. Loop diuretics: Avoid concomitant use of loop diuretics.

Fertility, pregnancy and lactation: IVIg products have been shown to cross the placenta, increasingly during the third trimester and immunoglobulins are excreted into breast milk. The safety of this medicinal product for use in human pregnancy has not been established and therefore it should only be given with caution to pregnant women and breastfeeding mothers.

Effects on ability to drive and use machines: The ability may be impaired by some adverse reactions associated with Kiovig. If adverse reactions occur, patients should wait for these to resolve before driving or operating machines.

Undesirable effects: Very common (≥1/10): Headache, hypertension, nausea, rash, local reactions (e.g. infusion site pain/swelling/reaction/pruritus), pyrexia and fatigue. Common (≥1/100, <1/10): Bronchitis, nasopharyngitis, anaemia, lymphadenopathy, decreased appetite, insomnia, anxiety, dizziness, migraine, paraesthesia, hypoesthesia, conjunctivitis, tachycardia, flushing, cough, rhinorrhoea, asthma, nasal congestion, oropharyngeal pain, dyspnoea, diarrhoea, vomiting, abdominal pain, dyspepsia, contusion, pruritus, urticaria, dermatitis, erythema, back pain, arthralgia, pain in extremity, myalgia, muscle spasms, muscular weakness, chills, oedema, influenza-like illness, chest discomfort, chest pain, asthenia, malaise, rigors. Other serious undesirable effects: Haemolysis, anaphylactic shock/reaction, transient ischaemic attack, cerebral vascular accident, myocardial infarction, deep vein thrombosis, pulmonary embolism, pulmonary oedema, direct Coombs test positive, transfusion-related acute lung injury, kidney infection, reversible aseptic meningitis and transient cutaneous reactions (including cutaneous lupus erythematosus).Overdose: Overdose may lead to fluid overload and hyperviscosity particularly in at-risk patients (elderly, or those with cardiac or renal impairment). Children with KD are at high risk especially due to underlying cardiac compromise so dose and rate of administration should be carefully controlled.

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

UK basic NHS price: £69.00 per gram

Legal classification: POM.

Marketing Authorisation number: PLGB 06009/0035.

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

PI approval code: pi-02377.

Date of preparation: February 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

KIOVIG Human normal immunoglobulin (IVIg) 10% (100mg/ml) solution for infusion

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

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

Presentation: One ml contains 100 mg of human normal immunoglobulin (purity of at least 98% IgG). Each vial of 10 ml, 25 ml, 50 ml, 100 ml, 200 ml, and 300 ml contains: 1 g, 2.5 g, 5 g, 10 g, 20 g, and 30 g of human normal immunoglobulin, respectively.

Indications: Replacement therapy in adults, and children and adolescents (0 - 18 years) in: primary immunodeficiency (PID) syndromes with impaired antibody production; secondary immunodeficiencies (SID) in patients suffering from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) or serum IgG level of <4g/l. Immunomodulation in adults, and children and adolescents (0 - 18 years) in: primary immune thrombocytopenia (ITP) in patients at high risk of bleeding or prior to surgery to correct the platelet count; Guillain-Barré syndrome (GBS); Kawasaki disease (KD) in conjunction with acetylsalicylic acid; chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); multifocal motor neuropathy (MMN).

Dosage and administration: Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Administration: Administer by IV infusion at an initial rate of 0.5 ml/kg body weight (BW)/hr for 30 minutes. If well tolerated, rate may gradually be increased up to a maximum of 6 ml/kg BW/hr. If dilution is required, 5% glucose solution is recommended. Posology: Dose and dosage regimen is dependent on the indication and bodyweight, consult the SmPC for full details. A typical starting dose for replacement therapy in PID: 0.4 - 0.8 g/kg BW followed by 0.2 - 0.8 g/kg BW every 3 - 4 weeks to obtain IgG trough levels of at least 5 - 6 g/L. SID: 0.2 – 0.4 g/kg every 3 - 4 weeks. ITP: 0.8 - 1.0 g/kg BW on day one repeated once within 3 days or 0.4 g/kg BW daily for 2 - 5 days. The treatment can be repeated if relapse occurs. GBS: 0.4 g/kg BW/day over 5 days (possible repeat of dosing in case of relapse). KD: 2.0 g/kg BW as a single dose, in conjunction with acetylsalicylic acid. CIDP: starting dose 2 g/kg BW divided over 2 - 5 consecutive days; maintenance dose 1 g/kg BW over 1 - 2 consecutive every 3 weeks. MMN: starting dose 2 g/kg BW given over 2 - 5 consecutive days; maintenance dose 1 g/kg BW every 2 to 4 weeks, or 2 g/kg BW every 4 to 8 weeks over 2 - 5 days. Paediatrics: Same dose as for adults because posology for each indication is given by BW and adjusted to clinical outcome of the above-mentioned conditions.

Contraindications: Hypersensitivity to the active substance or to any of the excipients or to human immunoglobulins, especially in patients with antibodies against IgA. Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA containing product can result in anaphylaxis.

Warnings and precautions: Infusion reaction: Infuse slowly (0.5 ml/kg BW/hr) to begin with and monitor patient closely to ensure tolerance. Treat infusion-related events by slowing the infusion rate or stopping the infusion. Ensure adequate hydration, monitor urine output and serum creatinine. In case of shock, standard medical treatment for shock should be implemented. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. IVIg discontinuation should be considered in case of renal impairment. In patients at risk of acute renal failure, IVIg should be administered at the minimum rate of infusion and dose practicable. Avoid concomitant loop diuretics. If dilution of Kiovig is required for diabetic patients, use of 5% glucose solution for dilution should be reconsidered. Paediatric patients may be more susceptible to volume overload. Thus, dosing should be carefully calculated for this population. Hypersensitivity reactions are possible in patients with anti-IgA antibodies. IVIg has been associated with thrombotic events. Use with caution in obese patients and those with pre-existing risk factors for thrombotic events. Hyperproteinaemia, increased serum viscosity and subsequent relative pseudohyponatremia may occur whilst treatment for true hyponatremia and may lead to a further increase in serum viscosity and a possible predisposition to thromboembolic events. Transfusion-related acute lung injury (TRALI), aseptic meningitis syndrome (AMS), haemolytic anaemia and neutropenia/ leukopenia have been reported in patients treated with IVIg. IVIg recipients should be monitored for symptoms of haemolysis. Interference with serological testing may occur. Infectious diseases due to the transmission of infective agents cannot be totally excluded. To improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Interactions: Live attenuated viruses: Postpone vaccination for 3 months after treatment with Kiovig. For measles vaccine, check antibody status as efficacy of vaccine may be impaired for up to 1 year after administration of immunoglobulins. Blood glucose: Dilution with 5% glucose may result in increased blood glucose levels. Loop diuretics: Avoid concomitant use of loop diuretics.

Fertility, pregnancy and lactation: IVIg products have been shown to cross the placenta, increasingly during the third trimester and immunoglobulins are excreted into breast milk. The safety of this medicinal product for use in human pregnancy has not been established and therefore it should only be given with caution to pregnant women and breastfeeding mothers.

Effects on ability to drive and use machines: The ability may be impaired by some adverse reactions associated with Kiovig. If adverse reactions occur, patients should wait for these to resolve before driving or operating machines.

Undesirable effects: Very common (≥1/10): Headache, hypertension, nausea, rash, local reactions (e.g. infusion site pain/swelling/ reaction/pruritus), pyrexia and fatigue. Common (≥1/100, <1/10): Bronchitis, nasopharyngitis, anaemia, lymphadenopathy, decreased appetite, insomnia, anxiety, dizziness, migraine, paraesthesia, hypoesthesia, conjunctivitis, tachycardia, flushing, cough, rhinorrhoea, asthma, nasal congestion, oropharyngeal pain, dyspnoea, diarrhoea, vomiting, abdominal pain, dyspepsia, contusion, pruritus, urticaria, dermatitis, erythema, back pain, arthralgia, pain in extremity, myalgia, muscle spasms, muscular weakness, chills, oedema, influenza-like illness, chest discomfort, chest pain, asthenia, malaise, rigors.Other serious undesirable effects: Haemolysis, anaphylactic shock/reaction, transient ischaemic attack, cerebral vascular accident, myocardial infarction, deep vein thrombosis, pulmonary embolism, pulmonary oedema, direct Coombs test positive, transfusion-related acute lung injury, kidney infection, reversible aseptic meningitis and transient cutaneous reactions (including cutaneous lupus erythematosus). Overdose: Overdose may lead to fluid overload and hyperviscosity particularly in at-risk patients (elderly, or those with cardiac or renal impairment). Children with KD are at high risk especially due to underlying cardiac compromise so dose and rate of administration should be carefully controlled.

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

UK basic NHS price: £69.00 per gram

Legal classification: POM.

Marketing Authorisation number: EU/1/05/329/001-6.

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

PI approval code: pi-02378.

Date of preparation: February 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

OBIZUR(susoctocog alfa) 500 U 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: 500 U of B domain deleted antihaemophilic factor VIII (rDNA), porcine sequence, susoctocog alfa powder in a vial and solvent in pre-filled syringe (1 ml water for injection). 

Indication:Treatment of bleeding episodes in patients with acquired haemophilia caused by antibodies to factor VIII. OBIZUR is indicated in adults.

Dosage and administration:Treatment with OBIZUR should be under the supervision of a physician experienced in the treatment of haemophilia. Treatment monitoring: The product is for in-patient administration only. Requires clinical supervision of the bleeding status of the patient. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. When using aPTT-based one-stage clotting assay results can be significantly affected by both the type of aPTT reagent and the reference standard. Also, there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. Posology: The dose, frequency, and duration of the therapy with OBIZUR depend on the location, extent and severity of the bleeding episode, target factor FVIII (FVIII) activity, and on the patient´s clinical condition. The recommended initial dose is 200 U/kg body weight, given by intravenous injection - titrate subsequent doses based on clinical response and to maintain target FVIII trough activity. Monitor FVIII activity and clinical condition 30 minutes after the first injection and 3 hours after administering OBIZUR. Monitor FVIII activity immediately prior to and 30 minutes after subsequent doses. If testing of anti-rpFVIII antibodies is negative at baseline, a dose lower than the recommended 200 U/kg may be used as the initial treatment dose. Clinical response should be closely monitored as dosing below 200 U/kg has been associated with a lack of efficacy.  Refer to the SmPC guide for dosing and frequency of administration. The total volume of reconstituted OBIZUR should be administered via the intravenous route at a rate of 1 to 2 mL per minute.

Contraindications: Hypersensitivity to the active substance, hamster protein, or to any of the excipients. Congenital haemophilia A with inhibitors (CHAWI).

Warnings and precautions: Dosing: Initial dosing below the recommended 200 U/kg has been associated with lack of efficacy. Traceability: Name and the batch number of the administered medicinal product should be clearly recorded. Hypersensitivity: Allergic-type hypersensitivity reactions are possible with OBIZUR. The medicinal product contains trace amounts of hamster proteins. Cease treatment and seek medical attention if such reactions occur. Inhibitors: It is recommended to test for anti-rpFVIII antibodies prior to initiation of treatment.
Treatment may be started at physician’s discretion prior to receiving the result of this test. Treatment decisions can be further supported by monitoring FVIII levels. Inhibitory antibodies against porcine FVIII were detected before and after exposure to OBIZUR. Inhibitor titres of up to 29 Bethesda units were recorded at baseline yet patients responded positively to OBIZUR. Lack of efficacy could be due to inhibitory antibodies to OBIZUR.  It is recommended that treatment should be based on clinical judgement and not based on detection of inhibitory antibodies by the Bethesda assay. Anamnestic reactions with rise in human FVIII and/or porcine FVIII inhibitors have also been reported. These anamnestic rises may result in lack of efficacy. There is a lack of clinical information on the development of inhibitory antibodies to OBIZUR following repeated administration. Therefore, OBIZUR must only be administered when considered clinically necessary. Cardiovascular events: In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk. Thromboembolic Events: High and sustained FVIII activity in blood may predispose to thromboembolic events.  Those with pre-existing cardiovascular disease and the elderly are at particular risk. Treatment Monitoring: FVIII activity determined by the chromogenic assay is generally lower than FVIII activity determined by the one stage clotting assay. Measurement of FVIII activity must always be carried out using the same assay methodology on any one patient. The one stage assay is recommended. Sodium content: OBIZUR contains 4.6 mg sodium in 1 mL of reconstituted solution in each vial. Multiple vials must be taken per dose.

Interactions: None reported.

Fertility, pregnancy and lactation: No clinical experience in pregnant or lactating women, therefore OBIZUR should only be used during pregnancy and lactation, if clearly indicated.  

Undesirable effects: Very common (≥1/10): Anamnestic reaction; Common (≥1/100 to <1/10): Positive test for inhibitory antibodies against porcine FVIII. Other serious undesirable effects: Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) are possible and may progress to severe anaphylaxis (including shock). Refer to the SmPC for details on full side effect profile and interactions.

Basic UK NHS Cost: £2.29 per IU.

Legal Category: POM.

Marketing authorisation (MA) number: PLGB  34078/0025.

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

PI approval code: pi-02113.

Date of preparation: September 2022.

This medicinal product is subject to additional monitoring.

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

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

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

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

Presentation: 500 U of B domain deleted antihaemophilic factor VIII (rDNA), porcine sequence, susoctocog alfa powder in a vial and solvent in pre-filled syringe (1 ml water for injection).

Indication: Treatment of bleeding episodes in patients with acquired haemophilia caused by antibodies to factor VIII. OBIZUR is indicated in adults.

Dosage and administration: Treatment with OBIZUR should be under the supervision of a physician experienced in the treatment of haemophilia. Treatment monitoring: The product is for in-patient administration only. Requires clinical supervision of the bleeding status of the patient. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. When using aPTT-based one-stage clotting assay results can be significantly affected by both the type of aPTT reagent and the reference standard. Also, there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. Posology: The dose, frequency, and duration of the therapy with OBIZUR depend on the location, extent and severity of the bleeding episode, target factor FVIII (FVIII) activity, and on the patient´s clinical condition. The recommended initial dose is 200 U/kg body weight, given by intravenous injection - titrate subsequent doses based on clinical response and to maintain target FVIII trough activity. Monitor FVIII activity and clinical condition 30 minutes after the first injection and 3 hours after administering OBIZUR. Monitor FVIII activity immediately prior to and 30 minutes after subsequent doses. If testing of anti-rpFVIII antibodies is negative at baseline, a dose lower than the recommended 200 U/kg may be used as the initial treatment dose. Clinical response should be closely monitored as dosing below 200 U/kg has been associated with a lack of efficacy. Refer to the SmPC guide for dosing and frequency of administration. The total volume of reconstituted OBIZUR should be administered via the intravenous route at a rate of 1 to 2 mL per minute. 

Contraindications: Hypersensitivity to the active substance, hamster protein, or to any of the excipients. Congenital haemophilia A with inhibitors (CHAWI).

Warnings and precautions: Dosing: Initial dosing below the recommended 200 U/kg has been associated with lack of efficacy. Traceability: Name and the batch number of the administered medicinal product should be clearly recorded. Hypersensitivity: Allergic type hypersensitivity reactions are possible with OBIZUR. The medicinal product contains trace amounts of hamster proteins. Cease treatment and seek medical attention if such reactions occur. Inhibitors: It is recommended to test for anti-rpFVIII antibodies prior to initiation of treatment. Treatment may be started at physician’s discretion prior to receiving the result of this test. Treatment decisions can be further supported by monitoring FVIII levels. Inhibitory antibodies against porcine FVIII were detected before and after exposure to OBIZUR. Inhibitor titres of up to 29 Bethesda units were recorded at baseline yet patients responded positively to OBIZUR. Lack of efficacy could be due to inhibitory antibodies to OBIZUR.  It is recommended that treatment should be based on clinical judgement and not based on detection of inhibitory antibodies by the Bethesda assay. Anamnestic reactions with rise in human FVIII and/or porcine FVIII inhibitors have also been reported. These anamnestic rises may result in lack of efficacy. There is a lack of clinical information on the development of inhibitory antibodies to OBIZUR following repeated administration. Therefore, OBIZUR must only be administered when considered clinically necessary. Cardiovascular events: In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk. Thromboembolic Events: High and sustained FVIII activity in blood may predispose to thromboembolic events.  Those with pre-existing cardiovascular disease and the elderly are at particular risk. Treatment Monitoring: FVIII activity determined by the chromogenic assay is generally lower than FVIII activity determined by the one stage clotting assay. Measurement of FVIII activity must always be carried out using the same assay methodology on any one patient. The one stage assay is recommended. Sodium content: OBIZUR contains 4.6 mg sodium in 1 mL of reconstituted solution in each vial. Multiple vials must be taken per dose.

Interactions: None reported. 

Fertility, pregnancy and lactation: No clinical experience in pregnant or lactating women, therefore OBIZUR should only be used during pregnancy and lactation, if clearly indicated. 

Undesirable effects: Very common (≥1/10): Anamnestic reaction; Common (≥1/100 to <1/10): Positive test for inhibitory antibodies against porcine FVIII. Other serious undesirable effects: Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) are possible and may progress to severe anaphylaxis (including shock). Refer to the SmPC for details on full side effect profile and interactions. 

Basic UK NHS Cost: £2.29 per IU.

Legal Category: POM.

Marketing authorisation numbers: EU/1/15/1035/001-003.

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

PI approval code: pi-02027.

Date of preparation: July 2022. 

This medicinal product is subject to additional monitoring.

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

VPRIV® (velaglucerase alfa) 400 units powder for solution for infusion

PRESCRIBING INFORMATION FOR GREAT BRITAIN (ENGLAND, SCOTLAND, WALES) AND NORTHERN IRELAND.

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

Presentation: Each vial contains 400 Units of velaglucerase alfa. Powder for solution for infusion. After reconstitution, the solution contains 100 Units of velaglucerase alfa per ml.

Indication: VPRIV is indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease.

Dosage and administration: VPRIV requires reconstitution and dilution, and is intended for intravenous infusion only over 60 minutes. VPRIV is for single-use only and must be administered through a 0.2 or 0.22 μm filter. VPRIV should be administered under the supervision of a physician experienced in the management of Gaucher disease. Appropriate medical support, including adequately trained personnel in emergency measures, should be readily available when velaglucerase alfa is administered. If anaphylactic or other acute reactions occur, discontinue the infusion and initiate appropriate medical treatment. Home administration, under the supervision of a healthcare professional, may be considered for patients who have received at least three infusions and are tolerating their infusions well. Posology: 60 Units/kg administered every other week as a 60-minute intravenous infusion. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 Units/kg every other week. Patients currently treated with imiglucerase enzyme replacement therapy for type 1 Gaucher disease may be switched to VPRIV, using the same dose and frequency.Renal or hepatic impairment: No dosage adjustment is recommended in patients with renal or hepatic impairment based on current knowledge of the pharmacokinetics and pharmacodynamics of velaglucerase alfa. Elderly (≥65 years old): Elderly patients may be treated with the same dose range (15 to 60 Units/kg EOW) as other adult patients. Paediatric population: Twenty of the 94 patients who received velaglucerase alfa during clinical studies were in children and adolescents age range (4 to 17 years). The safety and efficacy profiles were similar between paediatric and adult patients. The safety and efficacy of velaglucerase alfa in children below the age of 4 years have not yet been established, no data are available.

Contraindications: Severe allergic reaction to the active substance or to any of the excipients.

Warnings and precautions: Hypersensitivity: Hypersensitivity reactions, including symptoms consistent with anaphylaxis have been reported in patients in clinical studies and in post-marketing experience. Infusion-related reactions were the most commonly observed adverse reactions in patients treated in clinical studies and often appear as a hypersensitivity reaction. The most frequently reported symptoms of hypersensitivity include: nausea, rash, dyspnoea, back pain, chest discomfort (including chest tightness), urticaria, arthralgia, and headache. In treatment naïve subjects the majority of infusion-related reactions occurred during the first six months of treatment. The management of infusion-related reactions should be based on the severity of the reaction and include slowing the infusion rate; treatment with medication such as antihistamines; antipyretics and/or corticosteroids; and/or stopping and resuming treatment with increased infusion time. Due to the risk for hypersensitivity reactions including anaphylaxis, adequately trained persons in emergency measures should be readily available when velaglucerase alfa is administered. If anaphylactic or other acute reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment. For patients developing anaphylaxis in a home setting, consider continuing treatment in a clinical setting. Use velaglucerase alfa or other enzyme replacement therapy with caution in patients who have exhibited symptoms of hypersensitivity. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in cases where symptomatic treatment was required. Immunogenicity: Antibodies may play a role in treatment-related reactions found with the use of velaglucerase alfa. To further evaluate the relationship, in cases of severe infusion-related reactions and in cases of lack or loss of effect, patients should be tested for the presence of antibodies and the results reported to the company. In clinical trials, one of 94 (1%) patients developed IgG-class antibodies to velaglucerase alfa. In this one event, the antibodies were determined to be neutralising in an in vitro assay. No infusion-related reactions were reported for this patient. No patients developed IgE antibodies to velaglucerase alfa. During a post-marketing extension study, one patient developed IgG antibodies to VPRIV. In addition, a few events of positive neutralising antibodies and lack of effect were reported post-marketing. Sodium: This medicinal product contains 12.15 mg sodium per vial equivalent to 0.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Interactions: No interaction studies have been performed.

Fertility, pregnancy and lactation: Patients with Gaucher disease who become pregnant may experience increased disease activity during pregnancy and the puerperium. A risk-benefit assessment is required for women who are considering pregnancy. There are no or limited amount of data from the use of velaglucerase alfa in pregnant women. Close monitoring of the pregnancy and clinical manifestations of Gaucher disease is necessary for individualisation of therapy. Caution should be exercised when prescribing to pregnant women. There is insufficient information on the excretion of velaglucerase alfa or its metabolites in human milk. Velaglucerase is a synthetic form of beta-glucocerebrosidase, which is a normal component of breast-milk. A risk-benefit assessment is required for women who are considering breast-feeding. Effects on ability to drive and use machines: None.

Undesirable effects: Very common (≥1/10): headache, dizziness, abdominal pain/abdominal pain upper, bone pain, arthralgia, back pain, infusion-related reaction, asthenia/fatigue, pyrexia/body temperature increased. Common (≥1/100 to <1/10): hypersensitivity reactions (includes dermatitis allergic and anaphylactic/anaphylactoid reactions), tachycardia, dyspnoea, hypertension, hypotension, flushing, nausea, rash, urticaria, pruritus, chest discomfort, activated partial thromboplastin time prolonged, neutralising antibody positive. Other serious undesirable effects: Vomiting. Refer to the SmPC for details on full side effect profile and interactions.

UK Basic NHS price: 20 ml vial. £1410.20 per vial.

Legal Classification: POM.

Marketing authorisation (MA): GB: PLGB 54937/0018; NI: EU/1/10/646/002; EU/1/10/646/005; EU/1/10/646/006.

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

PI approval code: pi-02429.

Date of preparation: April 2023.

VPRIV is a registered trademark.

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

RIXUBIS® (nonacog gamma) 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: RIXUBIS vials contain nonacog gamma, recombinant human coagulation factor IX (rDNA) powder and solvent (5 ml sterilised water for injection). After reconstitution, nominally 250, 500, 1000, 2000 and 3000 IU per vial.

Indication: Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency) in all age groups.

Dosage and administration: Treatment should be under the supervision of a physician experienced in the treatment of haemophilia. Dose and duration of the substitution therapy depends on the severity of the factor IX (FIX) deficiency, on the location and extent of the bleeding, and on the patient’s clinical condition, age and pharmacokinetic parameters of FIX, such as incremental recovery and half-life (refer to the SmPC for dosing calculations). Should be administered via the intravenous route at a maximum rate of 10 ml/min. Do not administer RIXUBIS by continuous infusion.

Contraindications: Hypersensitivity to the active substance or to any of the excipients or known allergic reaction to hamster protein.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be recorded. Hypersensitivity: Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with RIXUBIS. The risk is highest during the early phases of initial exposure to FIX concentrates in previously untreated patients (PUPs), in particular, in patients with high-risk gene mutations. Cease treatment and seek medical attention if such reactions occur. Inhibitors: After repeated treatment, all patients should be monitored for the development of inhibitors. Nephrotic syndrome: Has been reported following attempted immune tolerance induction in haemophilia B patients with FIX inhibitors. Thromboembolism: Due to the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated when administering to patients with liver disease, postoperatively, new-born infants, or to patients at risk of thrombotic phenomena or DIC (disseminated intravascular coagulation). Cardiovascular events: In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk. Catheter-related complications: If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered. Excipient-related considerations: After reconstitution this medicinal product contains less than 1 mmol (23 mg) sodium per vial. To be taken into consideration in patients on a controlled sodium diet. Elderly: Clinical studies of RIXUBIS did not include subjects aged 65 and over. It is not known whether they respond differently from younger subjects. As for all patients, dose selection should be individualised. Paediatric population: The listed warnings and precautions apply both to adults and children.

Interactions: None reported.

Fertility, pregnancy and lactation: There are no or limited amount of data from the use of FIX in pregnant women. It is unknown whether FIX/metabolites are excreted in human milk. FIX should be used during pregnancy and breast-feeding only if clearly indicated.

Undesirable effects: Common (≥1/100 to <1/10): Dysgeusia, pain in extremity. Other serious undesirable effects (unknown frequency): Hypersensitivity.The low purity FIX has been associated with instances of myocardial infarction, DIC, venous thrombosis and pulmonary embolism. High purity FIX is rarely associated with such adverse reactions. Refer to the SmPC for details on full side effect profile and interactions.

Legal classification: POM.

Marketing authorisation numbers: 250 IU: PLGB 34078/0028, 500 IU: PLGB 34078/0030, 1000 IU: PLGB 34078/0026, 2000IU: PLGB 34078/0027, 3000 IU: PLGB 34078/0029.

UK basic NHS price: 60.72p per IU.

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

PI approval code: pi-01812.

Date of preparation: December 2021.

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

 

Elaprase (idursulfase) 2mg/ml concentrate for solution for infusion 

PRESCRIBING INFORMATION FOR GREAT BRITAIN.

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

Presentation: 1 ml Elaprase concentrate contains 2 mg of idursulfase.

Indication: For the long-term treatment of patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Heterozygous females were not studied in the clinical trials.

Dosage and administration: Children, adolescents and adults 0.5 mg/kg body weight every week by intravenous infusion over a 3 hour period. The infusion may be gradually reduced to 1 hour if no infusion associated reactions observed. Treatment should be supervised by a physician or other healthcare professional experienced in the management of patients with inherited metabolic disorders. Infusion of Elaprase at home may be considered for patients who have received several months of treatment in the clinic and who are tolerating their infusions well. Home infusions should be performed under the surveillance of a physician or other healthcare professional.

Contraindications: Severe or life threatening hypersensitivity to the active substance or to any of the excipients if hypersensitivity is not controllable.

Warnings and precautions: Infusion-related reactions: In clinical trials infusion-related reactions were treated or ameliorated by slowing infusion rate, interrupting infusion, or by administration of medicinal products such as antihistamines, antipyretics, low-dose corticosteroids or beta-agonist nebulisation. No patient discontinued treatment due to an infusion reaction during clinical studies. Patients with severe underlying airway disease should be closely monitored during infusion in an appropriate clinical setting. This is particularly important for patients on antihistamines or other sedative medicinal product. Use of these medicinal products in patients with severe underlying airway disease should be limited where possible. Institution of positive airway pressure may be necessary in some cases. Consider delaying infusion in patients with acute febrile respiratory illness. Patients using supplementary oxygen should have this readily available during infusion, in the event of an infusion-related reaction. Anaphylactoid/anaphylactic reactions: These have the potential to be life-threatening and have been observed in some patients treated with Elaprase up to several years after initiating treatment. Late emergent symptoms and signs of anaphylactoid/anaphylactic reactions have been observed as long as 24 hours after an initial reaction. If an anaphylactoid/anaphylactic reaction occurs, the infusion should be immediately suspended and appropriate treatment and observation initiated. The current medical standards for emergency treatment should be observed. Patients experiencing severe or refractory anaphylactoid/anaphylactic reactions may require prolonged clinical monitoring and should be treated with caution when re-administering Elaprase, with appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) available during infusions. Patients with the complete deletion/large rearrangement genotype: Paediatric patients with this genotype have a high probability of developing antibodies, including neutralizing antibodies, in response to idursulfase and have a higher probability of developing infusion related adverse events and tend to show a muted response as assessed by decrease in urinary output of glycosaminoglycans, liver size and spleen volume. Sodium: This medicinal product contains 0.482 mmol of sodium (or 11.1 mg) per vial. This should be taken into consideration for patients on a controlled sodium diet.

Interactions: No formal medicinal product interaction studies have been conducted. Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for cytochrome P450 mediated interactions.

Fertility, pregnancy and lactation: As a precautionary measure, it is preferable to avoid the use of Elaprase during pregnancy. Use of Elaprase during breastfeeding should only be undertaken when the potential benefit is judged by the physician to justify the risk.

Effects on ability to drive and use machines: No or negligible influence.

Undesirable effects: Very common (≥1/10): headache, flushing, wheezing, dyspnoea, abdominal pain, nausea, diarrhoea, vomiting, urticaria, rash, pruritus, erythema, pyrexia, chest pain, infusion-related reaction. Common (≥1/100 to <1/10): dizziness, tremor, cyanosis, arrhythmia, tachycardia, hypertension, hypotension, hypoxia, bronchospasm, cough, swollen tongue, dyspepsia, arthralgia, infusion-site swelling, face oedema, peripheral oedema. Other Serious undesirable effects: anaphylactoid/anaphylactic reaction. Refer to the SmPC for details on full side effect profile and interactions.

UK Basic NHS price: Vials of 5 ml (containing 3 ml concentrate) in a pack size of 1 vial. £1985 for one 5 ml vial.

Legal Classification: POM.

Marketing authorisation (MA) number: PLGB 54937/0021.

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

PI approval code: pi-02301.

Date of preparation: January 2023.

This medicinal product is subject to additional monitoring.

Adverse events should be reported to the Medicines and Healthcare products Regulatory Agency. 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.

Elaprase▼ (idursulfase) 2mg/ml concentrate for solution for infusion

PRESCRIBING INFORMATION FOR NORTHERN IRELAND.

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

Presentation: 1 ml Elaprase concentrate contains 2 mg of idursulfase.

Indication: For the long-term treatment of patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Heterozygous females were not studied in the clinical trials.

Dosage and administration: Children, adolescents and adults 0.5 mg/kg body weight every week by intravenous infusion over a 3 hour period. The infusion may be gradually reduced to 1 hour if no infusion associated reactions observed. Treatment should be supervised by a physician or other healthcare professional experienced in the management of patients with inherited metabolic disorders. Infusion of Elaprase at home may be considered for patients who have received several months of treatment in the clinic and who are tolerating their infusions well. Home infusions should be performed under the surveillance of a physician or other healthcare professional.

Contraindications: Severe or life threatening hypersensitivity to the active substance or to any of the excipients if hypersensitivity is not controllable.

Warnings and precautions: Infusion-related reactions: In clinical trials infusion-related reactions were treated or ameliorated by slowing infusion rate, interrupting infusion, or by administration of medicinal products such as antihistamines, antipyretics, low-dose corticosteroids or beta-agonist nebulisation. No patient discontinued treatment due to an infusion reaction during clinical studies. Patients with severe underlying airway disease should be closely monitored during infusion in an appropriate clinical setting. This is particularly important for patients on antihistamines or other sedative medicinal product. Use of these medicinal products in patients with severe underlying airway disease should be limited where possible. Institution of positive airway pressure may be necessary in some cases. Consider delaying infusion in patients with acute febrile respiratory illness. Patients using supplementary oxygen should have this readily available during infusion, in the event of an infusion-related reaction. Anaphylactoid/anaphylactic reactions: These have the potential to be life-threatening and have been observed in some patients treated with Elaprase up to several years after initiating treatment. Late emergent symptoms and signs of anaphylactoid/anaphylactic reactions have been observed as long as 24 hours after an initial reaction. If an anaphylactoid/anaphylactic reaction occurs, the infusion should be immediately suspended and appropriate treatment and observation initiated. The current medical standards for emergency treatment should be observed. Patients experiencing severe or refractory anaphylactoid/anaphylactic reactions may require prolonged clinical monitoring and should be treated with caution when re-administering Elaprase, with appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) available during infusions. Patients with the complete deletion/large rearrangement genotype: Paediatric patients with this genotype have a high probability of developing antibodies, including neutralizing antibodies, in response to idursulfase and have a higher probability of developing infusion related adverse events and tend to show a muted response as assessed by decrease in urinary output of glycosaminoglycans, liver size and spleen volume. Sodium: This medicinal product contains 0.482 mmol of sodium (or 11.1 mg) per vial. This should be taken into consideration for patients on a controlled sodium diet.

Interactions: No formal medicinal product interaction studies have been conducted. Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for cytochrome P450 mediated interactions.

Fertility, pregnancy and lactation: As a precautionary measure, it is preferable to avoid the use of Elaprase during pregnancy. Use of Elaprase during breastfeeding should only be undertaken when the potential benefit is judged by the physician to justify the risk.

Effects on ability to drive and use machines: No or negligible influence.

Undesirable effects: Very common (≥1/10): headache, flushing, wheezing, dyspnoea, abdominal pain, nausea, diarrhoea, vomiting, urticaria, rash, pruritus, erythema, pyrexia, chest pain, infusion-related reaction. Common (≥1/100 to <1/10): dizziness, tremor, cyanosis, arrhythmia, tachycardia, hypertension, hypotension, hypoxia, bronchospasm, cough, swollen tongue, dyspepsia, arthralgia, infusion-site swelling, face oedema, peripheral oedema. Other Serious undesirable effects: anaphylactoid/anaphylactic reaction. Refer to the SmPC for details on full side effect profile and interactions.

UK Basic NHS price: Vials of 5 ml (containing 3 ml concentrate) in a pack size of 1 vial. £1985 for one 5 ml vial.

Legal Classification: POM.

Marketing authorisation (MA) number(s): EU/1/06/365/001-003.

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

PI approval code: pi-02168.

Date of preparation: October 2022

This medicinal product is subject to additional monitoring.

Adverse events should be reported to the Medicines and Healthcare products Regulatory Agency. 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.

 

REPLAGAL® (agalsidase alfa) 1 mg/ml concentrate for solution for infusion 

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

Refer to Summary of Product Characteristics (SmPC) before prescribing 

Presentation: 1 ml contains 1 mg of agalsidase alfa. Each vial of 3.5 ml of concentrate contains 3.5mg of agalsidase alfa

Indication: Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry Disease (α-galactosidase A deficiency).

Dosage and administration: Treatment should be supervised by a physician experienced in the management of patients with Fabry Disease or other inherited metabolic diseases. Replagal home infusion, and administration by the patient or patient’s caregiver (self-administration), may be considered for patients who are tolerating their infusions well. The decision to have a patient move to home infusion and/or self- administration should be made after evaluation and recommendation by the treating physician. Any patients experiencing adverse events during the home infusion/ self- administration need to immediately stop the infusion process and seek the attention of a healthcare professional. Posology: Replagal is administered at a dose of 0.2 mg/kg body weight by IV infusion over 40 min every other week. No dosage regimen in children aged 0-6 years or elderly patients over 65 years can presently be recommended as safety and efficacy have not yet been sufficiently established. In children aged 7-18 years, Replagal 0.2mg/kg every other week led to no unexpected safety issues. Renal and hepatic impairment: No dosage adjustment is recommended for patients with renal impairment or those on dialysis or post-kidney transplantation; however extensive renal damage (eGFR <60mL/min) may limit the renal response to enzyme replacement therapy. No data is available in hepatic impairment.

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

Warnings and precautions: 13.7% of adult patients treated with Replagal in clinical trials had idiosyncratic infusion-related reactions (generally within 2–4 months of starting treatment although later onset [after 1 year] has been reported as well). Four of 17 paediatric patients ≥7 years of age and 3 of 8 paediatric patients <7 years experienced at least one infusion reaction over a period of approximately 4 years of treatment. These effects have decreased with time. If mild or moderate acute infusion reactions occur, seek medical attention immediately. The infusion can be temporarily interrupted (for 5–10 minutes) until symptoms subside. If severe hypersensitivity or anaphylactic-type reactions occur, discontinue Replagal immediately and initiate appropriate treatment. A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease. Patients may develop IgG antibodies to the protein. A low titre antibody response was seen in approximately 24% of male patients treated with Replagal, the remaining 76% remained antibody negative throughout. In paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies. No increase in the incidence of adverse events was detected for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients. Sodium: This medicinal product contains 14.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 

Interactions: Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin since these substances have the potential to inhibit intra-cellular α-galactosidase activity.

Fertility, pregnancy and lactation: There is very limited data on pregnancies exposed to Replagal, therefore, caution should be exercised. Use with caution during breast-feeding.

Undesirable effects: Very common (≥1/10): peripheral oedema, headache, dizziness, neuropathic pain, tremor, hypoesthesia, paraesthesia, tinnitus, palpitations, dyspnoea, cough, nasopharyngitis, pharyngitis, vomiting, nausea, abdominal pain, diarrhoea, rash, arthralgia, pain in limb, myalgia, back pain, chest pain, rigors, pyrexia, pain, asthenia, fatigue; Common (≥1/100, <1/10): dysgeusia, hypersomnia, increased lacrimation, tinnitus aggravated, tachycardia, atrial fibrillation, hypertension, hypotension, flushing, hoarseness, throat tightness, rhinorrhoea, abdominal discomfort, urticaria, erythema, pruritus, acne, hyperhidrosis, musculoskeletal discomfort, peripheral swelling, joint swelling, hypersensitivity, chest tightness, aggravated fatigue, feeling hot, feeling cold, influenza-like illness, discomfort, malaise; Other Serious undesirable effects: anaphylactic reaction, myocardial ischaemia, heart failure.  Refer to the SmPC for details on full side effect profile and interactions.

UK Basic NHS price: Vials of 5 ml (containing 3.5 ml concentrate) in a pack size of 1 vial. £1049.94 for one 5 ml vial.

Legal Classification: POM.

Marketing authorisation (MA): PLGB 54937/0022.

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

PI approval code: pi-02315.

Date of preparation: January 2023.

Replagal is a registered trade name

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

REPLAGAL® (agalsidase alfa) 1 mg/ml concentrate for solution for infusion

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

Refer to Summary of Product Characteristics (SmPC) before prescribing 

Presentation: 1 ml contains 1 mg of agalsidase alfa. Each vial of 3.5 ml of concentrate contains 3.5mg of agalsidase alfa

Indication: Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry Disease (α-galactosidase A deficiency).

Dosage and administration: Treatment should be supervised by a physician experienced in the management of patients with Fabry Disease or other inherited metabolic diseases. Replagal home infusion, and administration by the patient or patient’s caregiver (self-administration), may be considered for patients who are tolerating their infusions well. The decision to have a patient move to home infusion and/or self- administration should be made after evaluation and recommendation by the treating physician. Any patients experiencing adverse events during the home infusion/ self- administration need to immediately stop the infusion process and seek the attention of a healthcare professional. Posology: Replagal is administered at a dose of 0.2 mg/kg body weight by IV infusion over 40 min every other week. No dosage regimen in children aged 0-6 years or elderly patients over 65 years can presently be recommended as safety and efficacy have not yet been sufficiently established. In children aged 7-18 years, Replagal 0.2mg/kg every other week led to no unexpected safety issues. Renal and hepatic impairment: No dosage adjustment is recommended for patients with renal impairment or those on dialysis or post-kidney transplantation; however extensive renal damage (eGFR <60mL/min) may limit the renal response to enzyme replacement therapy. No data is available in hepatic impairment.

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

Warnings and precautions: 13.7% of adult patients treated with Replagal in clinical trials had idiosyncratic infusion-related reactions (generally within 2–4 months of starting treatment although later onset [after 1 year] has been reported as well). Four of 17 paediatric patients ≥7 years of age and 3 of 8 paediatric patients <7 years experienced at least one infusion reaction over a period of approximately 4 years of treatment. These effects have decreased with time. If mild or moderate acute infusion reactions occur, seek medical attention immediately. The infusion can be temporarily interrupted (for 5–10 minutes) until symptoms subside. If severe hypersensitivity or anaphylactic-type reactions occur, discontinue Replagal immediately and initiate appropriate treatment. A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease. Patients may develop IgG antibodies to the protein. A low titre antibody response was seen in approximately 24% of male patients treated with Replagal, the remaining 76% remained antibody negative throughout. In paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies. No increase in the incidence of adverse events was detected for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients. Sodium: This medicinal product contains 14.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Interactions: Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin since these substances have the potential to inhibit intra-cellular α-galactosidase activity.

Fertility, pregnancy and lactation: There is very limited data on pregnancies exposed to Replagal, therefore, caution should be exercised. Use with caution during breast-feeding.

Undesirable effects: Very common (≥1/10): peripheral oedema, headache, dizziness, neuropathic pain, tremor, hypoesthesia, paraesthesia, tinnitus, palpitations, dyspnoea, cough, nasopharyngitis, pharyngitis, vomiting, nausea, abdominal pain, diarrhoea, rash, arthralgia, pain in limb, myalgia, back pain, chest pain, rigors, pyrexia, pain, asthenia, fatigue; Common (≥1/100, <1/10): dysgeusia, hypersomnia, increased lacrimation, tinnitus aggravated, tachycardia, atrial fibrillation, hypertension, hypotension, flushing, hoarseness, throat tightness, rhinorrhoea, abdominal discomfort, urticaria, erythema, pruritus, acne, hyperhidrosis, musculoskeletal discomfort, peripheral swelling, joint swelling, hypersensitivity, chest tightness, aggravated fatigue, feeling hot, feeling cold, influenza-like illness, discomfort, malaise; Other Serious undesirable effects: anaphylactic reaction, myocardial ischaemia, heart failure Refer to the SmPC for details on full side effect profile and interactions.

UK Basic NHS price: Vials of 5 ml (containing 3.5 ml concentrate) in a pack size of 1 vial. £1049.94 for one 5 ml vial.

Legal Classification: POM.

Marketing authorisation (MA): EU/1/01/189/001-003.

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

PI approval code: pi 02117.

Date of preparation: December 2022.

Replagal is a registered trade name

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

 

Cuvitru (human normal immunoglobulin) 200 mg/ml solution for subcutaneous injection

PRESCRIBING INFORMATION FOR UNITED KINGDOM (ENGLAND, SCOTLAND, WALES & NORTHERN IRELAND)

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

Presentation: One ml contains: 200mg human normal immunoglobulin. Each vial of 5ml, 10ml, 20ml, 40ml & 50ml contains: 1g, 2g, 4g, 8g & 10g of human normal immunoglobulin respectively.

Indication: Replacement therapy in adults, and children and adolescents (0-18 years) in:

- Primary immunodeficiency (PID) syndromes with impaired antibody production.

- Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4g/l. *PSAF = failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines.

Dosage and administration: Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency. Posology: The dose and dose regimen is dependent on the indication. The product should be administered via the subcutaneous route. In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. Dose based on bodyweight may require adjustment in underweight or overweight patients. The following dose regimens are given as a guideline. Replacement therapy in primary immunodeficiency syndromes: The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/l and aim to be within the reference interval of serum IgG for age. A loading dose of at least 0.2 to 0.5 g/kg (1 to 2.5 ml/kg) body weight may be required. This may need to be divided over several days, with a maximal daily dose of 0.1 to 0.15 g/kg. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.3 to 1.0 g/kg (refer to SmPC). Each single dose may need to be injected at different anatomic sites. Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dose and aim for higher trough levels. Replacement therapy in secondary immunodeficiencies: The recommended dose administered at repeated intervals is to reach a cumulative monthly dose to the order of 0.2-0.4 g/kg. Each single dose may need to be injected at different anatomic sites. IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections, an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection-free. Paediatric population: The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned indications. No clinical trials have been conducted with Cuvitru in children at age 0-< 2 years, but experience with immunoglobulins suggests that no harmful effects on treatment of children at age 0-< 2 years with Cuvitru are to be expected. Method of administration: For subcutaneous use only. Cuvitru should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter and/or discoloration is observed. The infusion must be started immediately upon transfer of Cuvitru into the syringe. The administration is foreseen to take up to two hours. Should an administration shorter than two hours not be possible due to required dose or administration rate of Cuvitru, the required dose is to be portioned and administered at different infusion sites. If Cuvitru remains in siliconized syringes for more than two hours, visible particles may form. Cuvitru must not be diluted. Subcutaneous infusion for home treatment should be initiated and monitored by a physician experienced in the guidance of patients for home treatment. Infusion pumps or manual administration using a syringe appropriate for subcutaneous administration of immunoglobulins may be used. The patient or caregiver must be instructed in the use of a syringe driver (device-assisted) or a syringe (manual administration), the infusion techniques, the keeping of treatment diary, recognition of and measures to be taken in case of severe adverse reactions. Cuvitru may be injected into sites such as abdomen, thigh, upper arm, and lateral hip. Adjustment of the infusion rate and infusion volume per site is based on subject tolerability. Infusion rate: Cuvitru can be infused using an infusion device, or by manual administration using a syringe. The recommended initial infusion rate depends on the individual patient’s needs. An increase in the infusion rate of successive infusions may be considered at the discretion of the patient and based on the healthcare professionals’ judgement. Device-assisted infusion: It is recommended to use an initial administration speed of 10 ml/h/infusion site. If well tolerated, the rate of administration may be increased at intervals of at least 10 minutes to a maximum of 20 ml/h/infusion site for the initial two infusions. For further infusions, the infusion rate may be increased as tolerated. More than one pump can be used simultaneously. The amount of product infused into a particular site varies. In infants and children, infusion site may be changed every 5-15 ml. In adults doses over 30 ml may be divided according to patient preference. There is no limit to the number of infusion sites. Manual administration infusion: Cuvitru may be administered using a syringe at a single infusion site. If administration at additional sites is required, a new sterile injection needle should be used. The proposed maximum infusion rate is approximately 1-2 ml per minute. The rate of administration should be adjusted for each patient’s local tolerance which may depend on the site of each subcutaneous infusion and the amount of the individual patient’s subcutaneous tissue at that site. The amount of product infused into a particular site varies. In infants and children, infusion site may be changed every 5-15 ml. In adults doses over 30 ml may be divided according to patient preference.

Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in the SmPC. Severe IgA deficiency and a history of hypersensitivity to human immunoglobulin treatment. Cuvitru must not be given intravascularly or intramuscularly.

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. If Cuvitru is accidentally administered into a blood vessel, patients could develop shock. The recommended infusion rate and administration instructions given in the SmPC must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. If the product remains in a siliconized syringe for more than two hours, visible particles may form. Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion. Potential complications can often be avoided by: initially injecting the product slowly (refer to SmPC), ensuring that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative immunoglobulin product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration. In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. Suspicion of severe hypersensitivity or anaphylactic-type reactions requires immediate discontinuation of the injection. The treatment required depends on the nature and severity of the adverse reaction. In case of shock, standard medical treatment for shock should be implemented. An increase in the number and the severity of adverse events may occur when patients begin manual administration. As a consequence, patients considered for manual administration should be medically stable and adequately trained on the recognition and measures to be taken in case of severe adverse reactions. Hypersensitivity: True allergic reactions are rare. They can particularly occur in patients with anti-IgA antibodies who should be treated with particular caution. Patients with anti-IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be treated with Cuvitru only under close medical supervision. Cuvitru contains trace amounts of IgA (not more than 280 micrograms/ml). Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin. Thromboembolism: Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Caution should be exercised in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilization, severely hypovolemic patients, patients with diseases which increase blood viscosity). Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Renal complications: Severe renal adverse reactions have been reported in patients receiving immune globulin treatment, particularly those products containing sucrose (Cuvitru does not contain sucrose). These include acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis. Factors that increase the risk of renal complications include, but are not limited to pre-existing renal insufficiency, diabetes mellitus, hypovolemia, concomitant nephrotoxic medicinal products, age over 65, sepsis, hyperviscosity and paraproteinemia. Aseptic meningitis syndrome (AMS): Aseptic meningitis syndrome (AMS) has been reported to occur in association with immune globulin treatments, including Cuvitru (refer to SmPC). AMS may occur more frequently in female patients. Discontinuation of Ig treatment may result in remission of AMS within several days without sequelae. The symptoms usually begin within several hours to 2 days following IG treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. Patients should be informed about first symptoms which encompass severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting. Haemolysis: Cuvitru contains blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells (RBC) with immunoglobulin. This may cause a positive direct antiglobulin reaction (DAT, direct Coombs test) and, rarely, haemolysis. Delayed haemolytic anaemia can develop subsequent to IG therapy due to enhanced RBC sequestration. Acute haemolytic anaemia, consistent with intravascular haemolysis, has been reported. Interference with serological testing: After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing, for example, Hepatitis A, Hepatitis B, measles, and varicella. Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some serological tests for red cell antibodies, for example the direct antiglobulin test (DAT, direct Coombs test). Administration of Cuvitru can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product. Transmissible agents: Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non enveloped viruses hepatitis A and parvovirus B19. There is reassuring clinical experience regarding the lack of hepatitis A or Parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety. It is strongly recommended that every time that Cuvitru 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. Paediatric population: The listed warnings and precautions apply both to adults and children.

InteractionsLive attenuated virus vaccines: Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of Cuvitru an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked. Paediatric population: The listed interactions apply both to adults and children.

Fertility, pregnancy and lactation: Physicians must balance the potential risk and only prescribe Cuvitru if clearly needed Pregnancy: The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore it should only be given with caution to pregnant women and breast-feeding mothers. IG products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Breast feeding: Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry. Fertility: Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

Effects on ability to drive and use machines: The ability to drive and operate machines may be impaired by some adverse reactions associated with Cuvitru. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Undesirable effectsVery common (≥1/10): Headache, diarrhoea, nausea, local reaction, infusion site erythema (including injection site erythema), injection site pain (including infusion site discomfort & infusion site pain), fatigue. Common (≥1/100 to <1/10): dizziness, migraine, somnolence, hypotension, abdominal pain, pruritus, urticaria, myalgia, infusion site swelling, injection site pruritus (including infusion site pruritus), infusion site urticaria, infusion site bruising, pain. Other serious undesirable effects: Uncommon (≥1/1,000 to <1/100) or unknown frequency: Burning sensation, abdominal pain lower, infusion site oedema, Anti-GAD antibody positive, coombs direct test positive, anaphylactic shock & meningitis aseptic.  Refer to the SmPC for details on full side effect profile and interactions.

UK basic NHS price: £69.00 per gram.

Legal classification: POM.

Marketing authorisation (MA) numberPL 34078/0011.

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

PI approval code: pi-02946

Date of preparationFebruary 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 UK Ltd at: AE.GBR-IRL@takeda.com

Cinryze®(Human C1-esterase inhibitor) 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: Each single-use powder vial contains 500 International Units (IU) of Human C1-esterase inhibitor produced from the plasma of human donors. After reconstitution, one vial contains 500 IU of Human C1-esterase inhibitor per 5 ml corresponding to a concentration of 100 IU/ml.

Indications: Treatment and pre-procedure prevention of angioedema attacks in adults, adolescents and children (2 years old and above) with hereditary angioedema (HAE). Routine prevention of angioedema attacks in adults, adolescents and children (6 years old and above) with severe and recurrent attacks of HAE, who are intolerant to or insufficiently protected by oral prevention treatments, or patients who are inadequately managed with repeated acute treatment.

Dosage and administration: Therapy should be initiated under the supervision of a physician experienced in the care of patients with HAE. The reconstituted product should be given by intravenous injection at a rate of 1 ml per minute. Posology: Adults, adolescents (12 to 17 years old) and children (2-11 years old, >25 kg); 1000 IU of Cinryze at the first sign of the onset of an angioedema attack. A second dose of 1000 IU may be administered if the patient has not responded adequately after 60 minutes. For adults and adolescents experiencing laryngeal attacks or if initiation of treatment is delayed, the second dose can be given sooner than 60 minutes. Children (2-11 years old, 10-25 kg): 500 IU of Cinryze at the first sign of the onset of an acute attack. A second dose of 500 IU may be administered if the patient has not responded adequately after 60 minutes. Routine preventionAdults and adolescents (12 to 17 years old): The recommended starting dose is 1000 IU of Cinryze every 3 or 4 days. Children (6-11 years old): The recommended starting dose is 500 IU of Cinryze every 3 or 4 days. For all patients, the dosing interval and dose may need to be adjusted according to individual response, and the continued need for regular prophylaxis should be regularly reviewed. Pre-procedure prevention: Adults, adolescents (12 to 17 years old) and children (2-11 years old, >25 kg): 1000 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure. Children (2 -11 years old, 10-25 kg): 500 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure. Children less than 2 years old: Not recommended due to limited data on safety and efficacy.

Contraindications: Hypersensitivity to the active substance or to any of the excipients of the product.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Thrombotic events: Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1-esterase inhibitor product (up to 500 Units/kg). Patients with known risk factors for thrombotic events (including indwelling catheters) should be monitored closely. Transmissible agents: The standard measures used to prevent infections resulting from the use of medicinal products prepared from human blood or plasma are taken for Cinryze and are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19. Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived C1-esterase inhibitor product. Hypersensitivity: Hypersensitivity reactions may occur and have symptoms similar to angioedema attacks. Patients should be informed of the early signs including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If symptoms occur after administration, they should alert their physician. In case of anaphylactic reactions or shock, emergency medical treatment should be administered. Home-treatment and self-administration: Limited data exist on the use of this medicinal product in home- or self-administration. Potential risks associated with home-treatment are related to the administration itself as well as the handling of adverse drug reactions, particularly hypersensitivity. For suitable patients, the treating physician should ensure that appropriate training is provided and the use reviewed at intervals. Sodium: Each vial of Cinryze contains approximately 11.5 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

Fertility, pregnancy and lactation: The potential risk during pregnancy is unknown. Therefore, Cinryze should be used during pregnancy only if clearly indicated. It is unknown whether C1-esterase inhibitor is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to either discontinue breastfeeding or to discontinue/abstain from Cinryze therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Effects on ability to drive and use machines: Cinryze has minor influence on the ability to drive and use machines.

Undesirable effects: Very common (≥1/10): Headache, nausea. Common (≥1/100 to <1/10): Hypersensitivity, rash, erythema, pruritus, dizziness, vomiting, injection site rash/erythema, infusion site pain, pyrexia. Uncommon (≥1/1,000 to <1/100): Hyperglycaemia, venous thrombosis, phlebitis, venous burning, hot flush, cough, diarrhoea, abdominal pain, contact dermatitis, joint swelling, arthralgia, myalgia, chest discomfort.

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

UK basic NHS price: £1,336 per 1000 IU dose (2 vials).

Legal classification: POM.

Marketing authorisation number: PLGB 06009/0036.

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

PI approval code: pi-02372.

Date of preparation: April 2023.

This medicinal product is subject to additional monitoring.

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

CINRYZE®(Human C1-esterase inhibitor) 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: Each single-use powder vial contains 500 International Units (IU) of Human C1-esterase inhibitor produced from the plasma of human donors. After reconstitution, one vial contains 500 IU of Human C1-esterase inhibitor per 5 ml corresponding to a concentration of 100 IU/ml.

Indications: Treatment and pre-procedure prevention of angioedema attacks in adults, adolescents and children (2 years old and above) with hereditary angioedema (HAE). Routine prevention of angioedema attacks in adults, adolescents and children (6 years old and above) with severe and recurrent attacks of HAE, who are intolerant to or insufficiently protected by oral prevention treatments, or patients who are inadequately managed with repeated acute treatment.

Dosage and administration: Therapy should be initiated under the supervision of a physician experienced in the care of patients with HAE. The reconstituted product should be given by intravenous injection at a rate of 1 ml per minute. Posology: Adults, adolescents (12 to 17 years old) and children (2-11 years old, >25 kg); 1000 IU of Cinryze at the first sign of the onset of an angioedema attack. A second dose of 1000 IU may be administered if the patient has not responded adequately after 60 minutes. For adults and adolescents experiencing laryngeal attacks or if initiation of treatment is delayed, the second dose can be given sooner than 60 minutes. Children (2-11 years old, 10-25 kg): 500 IU of Cinryze at the first sign of the onset of an acute attack. A second dose of 500 IU may be administered if the patient has not responded adequately after 60 minutes. Routine prevention: Adults and adolescents (12 to 17 years old): The recommended starting dose is 1000 IU of Cinryze every 3 or 4 days. Children (6-11 years old): The recommended starting dose is 500 IU of Cinryze every 3 or 4 days. For all patients, the dosing interval and dose may need to be adjusted according to individual response, and the continued need for regular prophylaxis should be regularly reviewed. Pre-procedure prevention: Adults, adolescents (12 to 17 years old) and children (2-11 years old, >25 kg): 1000 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure. Children (2 -11 years old, 10-25 kg): 500 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure. Children less than 2 years old: Not recommended due to limited data on safety and efficacy.

Contraindications: Hypersensitivity to the active substance or to any of the excipients of the product.

Warnings and precautions: Traceability: Name and the batch number of the administered product should be clearly recorded. Thrombotic events: Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1-esterase inhibitor product (up to 500 Units/kg). Patients with known risk factors for thrombotic events (including indwelling catheters) should be monitored closely. Transmissible agents: The standard measures used to prevent infections resulting from the use of medicinal products prepared from human blood or plasma are taken for Cinryze and are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19. Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived C1-esterase inhibitor product. Hypersensitivity: Hypersensitivity reactions may occur and have symptoms similar to angioedema attacks. Patients should be informed of the early signs including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If symptoms occur after administration, they should alert their physician. In case of anaphylactic reactions or shock, emergency medical treatment should be administered. Home-treatment and self-administration: Limited data exist on the use of this medicinal product in home- or self-administration. Potential risks associated with home-treatment are related to the administration itself as well as the handling of adverse drug reactions, particularly hypersensitivity. For suitable patients, the treating physician should ensure that appropriate training is provided and the use reviewed at intervals. Sodium: Each vial of Cinryze contains approximately 11.5 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

Fertility, pregnancy and lactation: The potential risk during pregnancy is unknown. Therefore, Cinryze should be used during pregnancy only if clearly indicated. It is unknown whether C1-esterase inhibitor is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to either discontinue breastfeeding or to discontinue/abstain from Cinryze therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Effects on ability to drive and use machines: Cinryze has minor influence on the ability to drive and use machines.

Undesirable effects: Very common (≥1/10): Headache, nausea. Common (≥1/100 to <1/10): Hypersensitivity, rash, erythema, pruritus, dizziness, vomiting, injection site rash/erythema, infusion site pain, pyrexia. Uncommon (≥1/1,000 to <1/100): Hyperglycaemia, venous thrombosis, phlebitis, venous burning, hot flush, cough, diarrhoea, abdominal pain, contact dermatitis, joint swelling, arthralgia, myalgia, chest discomfort.

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

UK basic NHS price: £1,336 per 1000 IU dose (2 vials)

Legal classification: POM.

Marketing authorisation number: EU/1/11/688/001.

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

PI approval codepi-02195

Date of preparation: October 2022

This medicinal product is subject to additional monitoring.

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 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 are 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 antibodies, von Willebrand factor therapy may not be effective and other therapeutic options should be considered. 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-02463.
 
Date of preparation: June 2023.
 

This medicinal product is subject to additional monitoring.

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

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 are 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 antibodies, von Willebrand factor therapy may not be effective and other therapeutic options should be considered. 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-02204.

Date of preparation: January 2023.

This medicinal product is subject to additional monitoring.

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

TAKHZYRO®▼(lanadelumab) 300 mg solution for injection

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

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

Presentation: Pre-filled syringe (PFS): 300 mg lanadelumab in 2 ml solution.

Indication: Routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients 12 years and older.

Dosage and administration: TAKHZYRO should be initiated under the supervision of a physician experienced in the management of patients with HAE. Posology: The recommended starting dose is 300 mg lanadelumab every 2 weeks. In stably attack-free patients on treatment, a dose reduction of 300 mg lanadelumab every 4 weeks may be considered, especially in patients with low weight. Missed doses: If a dose of TAKHZYRO is missed, the patient should be instructed to administer the dose as soon as possible ensuring at least 10 days between doses. Refer to the SmPC for more information on posology. Method of administration: Subcutaneous administration only.

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

Warnings and precautions: Traceability: Name and batch number of the administered product should be clearly recorded. Hypersensitivity: Hypersensitivity reactions have been observed. In the case of a severe hypersensitivity reaction, administration must be stopped immediately, and appropriate treatment initiated. General: TAKHZYRO is not intended for treatment of acute HAE attacks, individualised treatment should be initiated with an approved rescue medication in the event of a breakthrough HAE attack. Interference with coagulation test: Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay, this increase is not associated with bleeding adverse events in treated patients. Sodium: This medicinal product contains less than 1mmol sodium (23 mg) per vial, essentially ‘sodium-free’.

Interactions: No dedicated drug-drug interactions have been conducted, based on the characteristics of lanadelumab, no pharmacokinetic interactions with co-administered medicinal products are expected.

Fertility, pregnancy and lactation: As a precaution it is preferable to avoid the use of lanadelumab during pregnancy and in the few days following childbirth. If clinically needed, lanadelumab can be administered during breast-feeding.

Undesirable effectsVery common (≥1/10): Injection site reactions (includes erythema, bruising, discomfort, haematoma, haemorrhage, pruritus, swelling, induration, paraesthesia, reaction, warmth, oedema and rash). Common (≥1/100to <1/10): Hypersensitivity (includespruritus, discomfort and tingling of tongue), dizziness, rash maculo-papular, myalgia, alanine and aspartate aminotransferase increased. Refer to the SmPC for details on full side effect profile and interactions.

UK Basic NHS price: PFS: £12,420.

Legal classification: POM.

Marketing authorisation number: PLGB 54937/0020.

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

PI approval code: pi-02058.

Date of preparation: June 2022.

This medicinal product is subject to additional monitoring.

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

 

TAKHZYRO®▼(lanadelumab) 300 mg solution for injection

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

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

Presentation: Pre-filled syringe (PFS): 300 mg lanadelumab in 2 ml solution.

Indication: Routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients 12 years and older.

Dosage and administration: TAKHZYRO should be initiated under the supervision of a physician experienced in the management of patients with HAE. Posology: The recommended starting dose is 300 mg lanadelumab every 2 weeks. In stably attack-free patients on treatment, a dose reduction of 300 mg lanadelumab every 4 weeks may be considered, especially in patients with low weight. Missed doses: If a dose of TAKHZYRO is missed, the patient should be instructed to administer the dose as soon as possible ensuring at least 10 days between doses. Refer to the SmPC for more information on posology. Method of administration: Subcutaneous administration only.

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

Warnings and precautions: Traceability: Name and batch number of the administered product should be clearly recorded. Hypersensitivity: Hypersensitivity reactions have been observed. In the case of a severe hypersensitivity reaction, administration must be stopped immediately, and appropriate treatment initiated. General: TAKHZYRO is not intended for treatment of acute HAE attacks, individualised treatment should be initiated with an approved rescue medication in the event of a breakthrough HAE attack. Interference with coagulation test: Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay, this increase is not associated with bleeding adverse events in treated patients. Sodium: This medicinal product contains less than 1mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

Interactions: No dedicated drug-drug interactions have been conducted, based on the characteristics of lanadelumab, no pharmacokinetic interactions with co-administered medicinal products are expected.

Fertility, pregnancy and lactation: As a precaution it is preferable to avoid the use of lanadelumab during pregnancy and in the few days following childbirth. If clinically needed, lanadelumab can be administered during breast-feeding.

Undesirable effects: Very common (≥1/10): Injection site reactions (includes pain, erythema, bruising, discomfort, haematoma, haemorrhage, pruritus, swelling, induration, paraesthesia, reaction, warmth, oedema and rash). Common (≥1/100to <1/10): Hypersensitivity (includespruritus, discomfort and tingling of tongue), dizziness, maculopapular rash, myalgia, alanine and aspartate aminotransferase increased. Refer to the SmPC for details on full side effect profile and interactions.

UK basic NHS price: PFS: £12,420.

Legal classification: POM.

Marketing authorisation number: EU/1/18/1340/004.

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

PI approval code: pi-02069.

Date of preparation: June 2022.

This medicinal product is subject to additional monitoring.

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

LIVTENCITY▼(maribavir) 200 mg film coated tablets 

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

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

Presentation: Each tablet contains 200 mg maribavir 

Indication: Treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT). LIVTENCITY is indicated in adults.  

Dosage and administration: Treatment with LIVTENCITY should be initiated by a physician experienced in the management of patients who have undergone solid organ transplant or haematopoietic stem cell transplant. Posology: Recommended dose is 400 mg (two 200 mg tablets) twice daily resulting in a daily dose of 800 mg for 8 weeks. Treatment duration may need to be individualised based on the clinical characteristics of each patient. Elderly patients:No dose adjustment is required for patients over 65 years. Paediatric population: The safety and efficacy in patients below 18 years of age have not been established. No data are available. Method of administration: Intended for oral use only and can be taken with or without food. The film coated tablet can be taken as a whole tablet, a crushed tablet, or a crushed tablet through a nasogastric or orogastric tube. 

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Co administration with ganciclovir or valganciclovir.  

Warnings and precautions: Virologic failure during treatment and relapse post-treatment: Can occur during and after treatment with LIVTENCITY. Virologic relapse during the post-treatment period usually occurred within 4-8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. CMV DNA levels should be monitored and resistance mutations should be investigated in patients who do not respond to treatment.  Treatment should be discontinued if maribavir resistance mutations are detected. CMV disease with CNS involvement: LIVTENCITY was not studied in patients with CMV CNS infection. Based on nonclinical data, CNS penetration of maribavir is expected to be low compared to plasma levels. Therefore, LIVTENCITY is not expected to be effective in treating CMV CNS infections (e.g. meningo encephalitis). Use with immunosuppressants:  LIVTENCITY has the potential to increase the concentrations of immunosuppressants that are cytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus, cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must be frequently monitored throughout treatment, especially following initiation and after discontinuation of LIVTENCITY, and doses should be adjusted, as needed.  Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions:  The concomitant use of LIVTENCITY and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to possible clinically significant adverse reactions from greater exposure of concomitant medicinal products. May also lead to reduced therapeutic effect of LIVTENCITY. Sodium content: LIVTENCITY contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’. 

Interactions: Effect of other medicinal products on maribavir: Maribavir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of maribavir. Co-administration of maribavir and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of maribavir. However, no dose adjustment is needed when maribavir is co administered with CYP3A inhibitors. Concomitant administration of strong or moderate CYP3A inducers, is expected to significantly decrease maribavir plasma concentrations, which may result in decrease in efficacy. Therefore, alternative medicinal products with no CYP3A induction potential should be considered. Co-administration of maribavir with strong cytochrome P450 3A (CYP3A) inducers is not recommended. If co-administration of maribavir with other strong or moderate CYP3A inducers cannot be avoided, the maribavir dose should be increased to 1200 mg twice daily. Effect of maribavir on other medicinal products: Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated. LIVTENCITY may antagonise the antiviral effect of ganciclovir and valganciclovir by inhibiting human CMV UL97 serine/threonine kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir. General information: If dose adjustments of concomitant medicinal products are made due to treatment with maribavir, doses should be readjusted after treatment with maribavir is completed. Please refer to SmPC for further information and guidance.

Fertility, pregnancy and lactation:  Pregnancy: There are no data of maribavir use in pregnant women. Studies in animals have shown reproductive toxicity. LIVTENCITY is not recommended during pregnancy and in women of childbearing potential not using contraception. Maribavir is not expected to affect the plasma concentrations of systemically acting oral contraceptive steroids. Breast feeding: It is unknown whether maribavir or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast feeding should be discontinued during treatment with LIVTENCITY. Fertility: Studies were not conducted in humans with LIVTENCITY. 

Undesirable effects: Very common (≥1/10): Taste disturbance, Diarrhoea, Nausea, Vomiting and Fatigue. Common (≥1/100 to <1/10): Headache, Abdominal pain upper, Decreased appetite, Immunosuppressant drug level increased and Weight decreased.  Refer to the SmPC for details on full side effect profile and interactions. UK basic NHS price: £206.25 per tablet. Legal Classification: POM. Marketing authorisation (MA) number: PLGB  16189/0127. Business responsible for sale and supply: Takeda UK Limited, 1 Kingdom Street, London, W2 6BD, United Kingdom.  

PI approval code: pi-02176 

Date of preparation: November 2022 

This medicinal product is subject to additional monitoring.

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. 

LIVTENCITY▼(maribavir) 200 mg film coated tablets 

PRESCRIBING INFORMATION FOR NORTHERN IRELAND 

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

Presentation: Each tablet contains 200 mg maribavir 

Indication: Treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT). LIVTENCITY is indicated in adults.  

Dosage and administration: Treatment with LIVTENCITY should be initiated by a physician experienced in the management of patients who have undergone solid organ transplant or haematopoietic stem cell transplant. Posology: Recommended dose is 400 mg (two 200 mg tablets) twice daily resulting in a daily dose of 800 mg for 8 weeks. Treatment duration may need to be individualised based on the clinical characteristics of each patient. Elderly patients:No dose adjustment is required for patients over 65 years. Paediatric population: The safety and efficacy in patients below 18 years of age have not been established. No data are available. Method of administration: Intended for oral use only and can be taken with or without food. The film coated tablet can be taken as a whole tablet, a crushed tablet, or a crushed tablet through a nasogastric or orogastric tube. 

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Co administration with ganciclovir or valganciclovir.

Warnings and precautions: Virologic failure during treatment and relapse post-treatment: Can occur during and after treatment with LIVTENCITY. Virologic relapse during the post-treatment period usually occurred within 4-8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. CMV DNA levels should be monitored and resistance mutations should be investigated in patients who do not respond to treatment.  Treatment should be discontinued if maribavir resistance mutations are detected. CMV disease with CNS involvement: LIVTENCITY was not studied in patients with CMV CNS infection. Based on nonclinical data, CNS penetration of maribavir is expected to be low compared to plasma levels. Therefore, LIVTENCITY is not expected to be effective in treating CMV CNS infections (e.g. meningo encephalitis). Use with immunosuppressants:  LIVTENCITY has the potential to increase the concentrations of immunosuppressants that are cytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus, cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must be frequently monitored throughout treatment, especially following initiation and after discontinuation of LIVTENCITY, and doses should be adjusted, as needed.  Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions:  The concomitant use of LIVTENCITY and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to possible clinically significant adverse reactions from greater exposure of concomitant medicinal products. May also lead to reduced therapeutic effect of LIVTENCITY. Sodium content: LIVTENCITY contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’. 

Interactions: Effect of other medicinal products on maribavir: Maribavir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of maribavir. Co-administration of maribavir and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of maribavir. However, no dose adjustment is needed when maribavir is co administered with CYP3A inhibitors. Concomitant administration of strong or moderate CYP3A inducers, is expected to significantly decrease maribavir plasma concentrations, which may result in decrease in efficacy. Therefore, alternative medicinal products with no CYP3A induction potential should be considered. Co-administration of maribavir with strong cytochrome P450 3A (CYP3A) inducers is not recommended. If co-administration of maribavir with other strong or moderate CYP3A inducers cannot be avoided, the maribavir dose should be increased to 1200 mg twice daily. Effect of maribavir on other medicinal products: Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated. LIVTENCITY may antagonise the antiviral effect of ganciclovir and valganciclovir by inhibiting human CMV UL97 serine/threonine kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir. General information: If dose adjustments of concomitant medicinal products are made due to treatment with maribavir, doses should be readjusted after treatment with maribavir is completed. Please refer to SmPC for further information and guidance.

Fertility, pregnancy and lactation:  Pregnancy: There are no data of maribavir use in pregnant women. Studies in animals have shown reproductive toxicity. LIVTENCITY is not recommended during pregnancy and in women of childbearing potential not using contraception. Maribavir is not expected to affect the plasma concentrations of systemically acting oral contraceptive steroids. Breast feeding: It is unknown whether maribavir or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast feeding should be discontinued during treatment with LIVTENCITY. Fertility: Studies were not conducted in humans with LIVTENCITY. 

Undesirable effects: Very common (≥1/10): Taste disturbance, Diarrhoea, Nausea, Vomiting and Fatigue. Common (≥1/100 to <1/10): Headache, Abdominal pain upper, Decreased appetite, Immunosuppressant drug level increased and Weight decreased.  Refer to the SmPC for details on full side effect profile and interactions. UK basic NHS price: £206.25 per tablet. Legal Classification: POM. Marketing authorisation (MA) number(s): EU/1/22/1672/001, EU/1/22/1672/002.    

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

PI approval code: pi-02238 

Date of preparation: November 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. 

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. 

 

 

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

Rare Disease Hub is for UK healthcare professionals only. This website has been initiated and developed by Takeda.

Copyright © 2023 Takeda UK Ltd.

 

C-APROM/GB/CUVI/0057

February 2024