Prescribing Information and Adverse Events Reporting

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 at: AE.GBR-IRL@takeda.com

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

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 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 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: 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 code: pi-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

TAKHZYRO® (lanadelumab) 150 mg and 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): 150 mg lanadelumab in 1 ml solution, 300 mg lanadelumab in 2 ml solution.

Indication: Routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 2 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: In adults and adolescents 12 to less than 18 years of age, 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. In patients with a body weight less than 40 kg, a starting dose of 150 mg lanadelumab every 2 weeks may also be considered. In patients who are stably attack free on treatment, a dose reduction to 150 mg lanadelumab every 4 weeks may be considered. The recommended dose of lanadelumab for children 2 to less than 12 years of age is based on body weight. Children weighing between 10 to less than 20 kg; recommended starting dose is 150 mg lanadelumab every 4 weeks. A dose increase to 150 mg lanadelumab every 3 weeks may be considered in patients with insufficient control of attacks. Children weighing 20 to less than 40 kg; recommended starting dose is 150 mg lanadelumab every 2 weeks. A dose reduction to 150 mg lanadelumab every 4 weeks may be considered in patients who are stably attack free on treatment. Children weighing 40 kg or more; recommended starting dose is 300 mg lanadelumab every 2 weeks. A dose reduction to 300 mg lanadelumab every 4 weeks may be considered in patients who are stably attack free on treatment. Patients with a body weight of 20 to less than 40 kg who are stably attack free may continue with the same dose when reaching 12 years of age. Missed doses: If a dose of TAKHZYRO is missed, the patient or caregiver should be instructed to administer the dose as soon as possible. The subsequent dosing schedule may need adjustment according to the intended dosing frequency to ensure: at least 10 days between doses for patients on every 2 weeks dosing regimen, at least 17 days between doses for patients on every 3 weeks dosing regimen and at least 24 days between doses for patients on every 4 weeks dosing regimen. 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 after the first few days after birth.

Undesirable effects: Very common (≥1/10): Injection site reactions (includes erythema, bruising, discomfort, haematoma, haemorrhage, pruritus, swelling, induration, paraesthesia, reaction, warmth, oedema and rash). Common (≥1/100 to <1/10): Hypersensitivity (includes pruritus, 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: 150 mg and 300 mg PFS: £12,420.

Legal classification: POM.

Marketing authorisation number: PLGB 54937/0027, PLGB 54937/0020.

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

PI approval code: pi-03025.

Date of preparation: April 2024

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

TAKHZYRO® (lanadelumab) 150 mg and 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): 150 mg lanadelumab in 1 ml solution, 300 mg lanadelumab in 2 ml solution.

Indication: Routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 2 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: In adults and adolescents 12 to less than 18 years of age, 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. In patients with a body weight less than 40 kg, a starting dose of 150 mg lanadelumab every 2 weeks may also be considered. In patients who are stably attack free on treatment, a dose reduction to 150 mg lanadelumab every 4 weeks may be considered. The recommended dose of lanadelumab for children 2 to less than 12 years of age is based on body weight. Children weighing between 10 to less than 20 kg; recommended starting dose is 150 mg lanadelumab every 4 weeks. A dose increase to 150 mg lanadelumab every 3 weeks may be considered in patients with insufficient control of attacks. Children weighing 20 to less than 40 kg; recommended starting dose is 150 mg lanadelumab every 2 weeks. A dose reduction to 150 mg lanadelumab every 4 weeks may be considered in patients who are stably attack free on treatment. Children weighing 40 kg or more; recommended starting dose is 300 mg lanadelumab every 2 weeks. A dose reduction to 300 mg lanadelumab every 4 weeks may be considered in patients who are stably attack free on treatment. Patients with a body weight of 20 to less than 40 kg who are stably attack free may continue with the same dose when reaching 12 years of age. Missed doses: If a dose of TAKHZYRO is missed, the patient or caregiver should be instructed to administer the dose as soon as possible. The subsequent dosing schedule may need adjustment according to the intended dosing frequency to ensure: at least 10 days between doses for patients on every 2 weeks dosing regimen, at least 17 days between doses for patients on every 3 weeks dosing regimen and at least 24 days between doses for patients on every 4 weeks dosing regimen. 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 after the first few days after birth.

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 (≥1/100 to <1/10): Hypersensitivity (includes pruritus, 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: 150 mg and 300 mg PFS: £12,420.

Legal classification: POM.

Marketing authorisation number: EU/1/18/1340/007, 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-03069.

Date of preparation: April 2024.

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

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.

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 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 effects: Very 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) number: PL 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 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 UK Ltd 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