Prescribing Information and Adverse Events Reporting

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.

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

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

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

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

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

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

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

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

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

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

Interactions: None known.

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

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

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

Legal classification: POM.

UK basic NHS price: 92p per IU.

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

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

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

PRESCRIBING INFORMATION FOR NORTHERN IRELAND

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

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

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

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

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

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

Interactions: None known.

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

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

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

Legal classification: POM.

UK basic NHS price: 92p per IU.

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

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

PI approval code: pi-02850.

Date of preparation: April 2024.

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

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

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. 

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

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

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

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

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

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

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

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

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

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

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

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

UK basic NHS price: £255.00 per vial.

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

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

PI approval code: pi-02715

Date of preparation: September 2023

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

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

PRESCRIBING INFORMATION FOR NORTHERN IRELAND 

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

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

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

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

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

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

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

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

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

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

UK basic NHS price: £255.00 per vial.

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

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

PI approval code: pi-02716

Date of preparation: September 2023

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