Prescribing Information

Adverse event reporting information can be found at the bottom of this page

Prothromplex TOTAL is licensed for the 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.

Welcome to the Prothromplex TOTAL 500 IU resource hub.

Watch our video demonstrating product reconstitution and explore our library, featuring Prothromplex TOTAL 500 IU formulary and guideline support documents.

To find out more including how to book a training session with one of our Key Account Managers and details of further reconstitution resources, please fill in the contact form below.

In response to valuable feedback from healthcare professionals (HCPs) like yourself, we have made significant enhancements to Prothromplex TOTAL.

Single-use, sterile Mix2Vial® Transfer Device and needle-free reconstitution

Prothromplex TOTAL 500 IU Mix2Vial presentation provides a more simplified, needle-free reconstitution and more rapid preparation vs the previous Prothromplex TOTAL presentation1,2

500 IU allows ease of dosing1

Prothromplex TOTAL 500 IU Mix2Vial allows ease of dosing, increasing HCP and health system choice within existing clinical protocols based on multiples of 500 IU prothrombin complex concentrates (PCCs)3,4

Number 1 Tender Ranking5

Prothromplex TOTAL continues to maintain its position as the Most Economically Advantageous Tender (MEAT) position in comparison to alternative PCCs, based on cost, ease of use and security of supply.5

Explore the latest Prothromplex resources

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Prothromplex TOTAL 500 IU Digital Dosing Guide

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Prothromplex TOTAL 500 IU Dosing Calculator

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Prothromplex TOTAL Guideline Support Pack

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Prothromplex TOTAL rapidly restores haemostatic balance*4,6

*100% of patients (n=59) achieved normalisation of INR (≤1.3) with 30 minutes of a single dose of Prothromplex TOTAL.6
†Based on one clinical study (n=61) and post-marketing study (n=142).6,10

References
  1. Prothromplex® TOTAL 500 IU SmPC. Available from: https://products.mhra.gov.uk/;
  2. Takeda Data on File (EXA/GB/PROT/0003);
  3. Eichinger S. Hematology Am Soc Hematol Educ Program. 2016;1:605-611;
  4. Milling T and Pollack CV. Am J Emerg Med. 2020;38(9):1890-1903;
  5. NHS National Framework Agreement for the supply of products for the treatment of Blood Disorders including Haemophilia A and B - July 2024. Reference Number: CM/PHS/22/5661.
  6. Altorjay, A. et al. Thrombosis Research. 2015;135(3):485-491;
  7. Quinlan, D. et al. Circulation. 2013;128(11):1179-81;
  8. Sadeghi N, et al. Clin Appl Thromb Hemost. 2014;20(3):256-259;
  9. Sorensen, B. et al. Crit Care. 2011;15(1):201;
  10. Leal-Noval, S. et al. Blood Coagul Fibrinolysis. 2013;24:862–868.

Prothromplex TOTAL is licensed for the 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.

An international, multicentre, prospective study of Prothromplex TOTAL for vitamin K antagonist (VKA) reversal

Primary Outcome: Proportion of subjects who achieved normalisation of international normaIised ratio (INR) to ≤ 1.3 within 30 minutes ± 5 minutes after INR reading

*n=59 included in the full analysis set, normal INR defined as ≤1.3 (2/61 subjects were excluded from the full analysis set, 1 due to blood draw outside of the 30±5 minutes time window, 1 due to lack of central laboratory assessment for primary endpoint).

Graph adapted from Altorjay A, 20151

Efficacy: 100% of patients achieved normalisation of (≤ 1.3) INR within 30 minutes of a single dose in the study (n=59)1

* n=59 included in the full analysis set, normal INR defined as ≤1.3 (2/61 subjects were excluded from the full analysis set, 1 due to blood draw outside of the 30±5 minutes time window, 1 due to lack of central laboratory assessment for primary endpoint).

Graph adapted from Altorjay A, 20151

Secondary Outcomes: Number of doses required to achieve normalisation of INR, the shortening of prothrombin time and the in vivo recovery of coagulation factors II, VII, IX and X at 30 minutes ± 5 minutes after administration of prothrombin complex concentrate (PCC)1

Coagulation factors

Prothrombin time

*n=59 included in the full analysis set, normal INR defined as ≤1.3 (2/61 subjects were excluded from the full analysis set, 1 due to blood draw outside of the 30±5 minutes time window, 1 due to lack of central laboratory assessment for primary endpoint).

Graphs adapted from Altorjay A, 20151

Exploratory Outcome: Clinician’s efficacy rating

Overall haemostatic efficacy of Prothromplex TOTAL was rated “excellent” for 60 of 61 subjects1*

* The overall haemostatic efficacy of Prothromplex TOTAL was assessed in all 61 subjects.

Graphs adapted from Altorjay A, 20151

Safety profile

The safety profile of Prothromplex TOTAL was confirmed in a phase IV study1*

Safety outcome measures included the incidence of treatment-emergent adverse events (TEAEs) and levels of coagulation markers1

  • 66 adverse events (AEs) (33 mild, 28 moderate and 5 severe) were reported in 39.3% (24/61) patients infused with Prothromplex TOTAL during the 15-day safety follow-up period
    • 8/66 adverse events, were classed as serious adverse events (SAEs) and occurred in 3 subjects (4.9%)
    • 2 deaths occurred during the study, which were not considered treatment-related†

Incidence of TEAEs

  • Of the 66 AEs reported, three were considered possibly treatment-related, two of which were serious and one was non-serious:
    • SAE: Acute myocardial infarction occurred 1 day after infusion (25 IU/kg dose) in an 83-year- old patient with a history of diverse cardiovascular pathologies including myocardial infarction, ischemic heart disease, hypertension and atrial fibrillation. This patient died 14 days after infusion following ventricular fibrillation
    • SAE: Deep vein thrombosis (DVT) in the left upper limb occurred 5 days after infusion (25 IU/kg dose) in an 82-year-old male with a history of previous of deep vein thrombosis (DVT) in the lower limbs
    • Pyrexia occurring 2 hours after infusion

Levels of coagulation factors markers

  • Protein C activity - median activity from 37% at baseline to 88% at 15 minutes after infusion
  • Antithrombin activity – median within 88% and 94% of normal for the duration of the 72-hour follow-up period (reference range 70% to 120%)
  • Fibrinogen level – median 350 mg/dL at baseline, stayed within reference range (180 to 390 mg/dL) up to 48 hours after infusion and then rose slightly above the reference range beyond 48 hours (460 to 510 mg/dL)
  • D-dimer – median 0.36 μg/dL at baseline, stayed within reference range (0 to 0.49 μg/dL) up to 6 hours after infusion and then rose above reference range beyond 6 hours (0.70 to 1.14ug/dL)

*Safety outcome measures were assessed in all 61 subjects.

† One 89-year-old subject died of septic shock (following perforation of the sigmoid colon and subsequent peritonitis) 13 days after the infusion; and one 83-year-old subject died of ventricular fibrillation 14 days after the infusion.

Click on the button below to find out about the details of the phase IV study design

Study Design

Prothromplex TOTAL demonstrated real-world efficacy in critical care patients2*

Primary Outcome: INR

Secondary Outcome: Blood loss

Secondary Outcome: Transfused blood

Exploratory Outcome:
Activated partial thromboplastin time

*Based on a retrospective, single-centre (Spain) study performed between January 2009 and December 2012, including analysis of 142 patients treated with Prothromplex TOTAL (69% for reversing the anticoagulant effects of VKA). The median dose was 1,200 (900–1,500) IU per patient (≈15 IU/kg).

Graphs adapted from Leal-Noval S, 20132

The safety profile of Prothromplex TOTAL was confirmed in real-world critical care patients2*

Adverse Events

  • No severe thromboembolic adverse events related to Prothromplex TOTAL infusion were observed
  • No new episodes of acute myocardial infarction, cerebral stroke or pulmonary embolisms were found
  • One patient with a previous history of deep vein thrombosis (DVT) developed a new DVT episode 5 days after the infusion of 1,200 IU of Prothromplex TOTAL, which was not considered treatment-related

* Based on a retrospective, single-centre (Spain) study performed between January 2009 and December 2012, including analysis of 142 patients treated with Prothromplex TOTAL (69% for reversing the anticoagulant effects of VKA). The median dose was 1,200 (900–1,500) IU per patient (≈15 IU/kg).

The safety profile of Prothromplex TOTAL was confirmed in a Phase IV study and in real-world critical care patients1-3

Prothromplex TOTAL: Common adverse events3

Prothromplex TOTAL: Other safety considerations3

Thromboembolism, disseminated intravascular coagulation, fibrinolysis

There is a risk of thromboembolic episodes, following the administration of human prothrombin complex. In each situation, the potential benefit of treatment should be weighed against the risk of complications.

Particularly close monitoring should be exercised when administering PCCs 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

Virus Safety

When medicinal products prepared from human blood or plasma are administered, infectious diseases due to transmission of infective agents cannot be totally excluded.

Inhibitory antibodies

Replacement therapy with human PCCs, including therapy with Prothromplex TOTAL, may result in the formation of circulating antibodies inhibiting one or more of the human prothrombin complex factors. If such inhibitors occur, the condition will manifest itself as a poor clinical response.

Class reactions

  • Skin and subcutaneous tissue disorders: Angioedema, Paraesthesia
  • General disorders and administrative site conditions: Infusion site reaction
  • Nervous system disorders: Lethargy
  • Psychiatric disorders: Restlessness

Sodium

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 2 g sodium for an adult.

Heparin

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.

For full details please see the Summary of Product Characteristics

References
  1. Altorjay, Á. et al. Thrombosis Research. 2015;135(3):485-491;
  2. Leal-Noval, S. et al. Blood Coagul Fibrinolysis. 2013;24:862–868;
  3. Prothromplex TOTAL 500 IU SmPC. Available from: https://www.medicines.org.uk/emc/product/15237 (accessed June 2024);
  4. Beriplex P/N SmPC. Available at: https://www.medicines.org.uk/emc/product/6236 (accessed June 2024);
  5. Octaplex SmPC. Available at: https://www.medicines.org.uk/emc/product/6566 (accessed June 2024);
  6. Sadeghi, N. et al. Clin Appl Thromb Hemost. 2014;20(3):256-259;
  7. Patriarcheas, V. et al. Cureus. 2020;12(3):e7385;
  8. Hogan, M. and Berger, JS. Vasc Med. 2020;25(2):160–173;
  9. Heparin 5000 IU/mL Solution for injection (with preservative) SmPC.

Explore and download the latest Prothromplex TOTAL Resources

Prothromplex TOTAL 500 IU Digital Dosing Guide

Prothromplex TOTAL 500 IU Dosing Calculator

Prothromplex TOTAL Guideline Support Pack

Prothromplex TOTAL Formulary Support Document

Watch our Prothromplex TOTAL Demonstration Video

Prothromplex TOTAL 500 IU Mix2Vial® presentation is a simplified needle-free reconstitution vs the previous Prothromplex TOTAL presentation, which may reduce the likelihood of needle stick injuries1,2

Preparation

Monitoring of international normalised ratio (INR) during treatment is mandatory
Refer to the Summary of Product Characteristics before use

For reconstitution only the enclosed reconstitution set should be used

  • Remove the protective caps from the powder vial and the solvent vial
  • Disinfect each stopper with a separate sterile alcohol swab (or other suitable sterile solution) by wiping the stopper for several seconds
  • Allow the rubber stopper to dry. Place the vials on a flat surface
  • Open the Mix2Vial® device package but do not remove from packaging

Mixing

  • Turn the package with the Mix2Vial® device upside down and place it over the top of the solvent vial
  • Firmly insert the blue plastic spike of the device into the centre of the solvent vial stopper
  • Turn the solvent vial over, place it on top of the vial containing Prothromplex TOTAL powder, then gently and continuously swirl the connected vials until dissolved or allow the reconstituted product to stand for 5 minutes then gently swirl to ensure that the powder is completely dissolved
  • Do not shake. Shaking will adversely affect the product. Do not refrigerate after reconstitution
  • Do not use if the vacuum has been lost and the solvent does not flow into the Prothromplex TOTAL vial

Withdrawal

  • Disconnect the two sides of the Mix2Vial® device from each other and place the Prothromplex TOTAL vial with the clear plastic side on a flat work surface
  • Draw air into an empty, sterile disposable plastic syringe, connect to the clear plastic connector and push all the air from the syringe into the vial. The amount of air should equal the amount of reconstituted Prothromplex TOTAL that you will withdraw from the vial
  • Flip connected syringe and Prothromplex TOTAL vial, so the vial is on top. Be sure to keep the syringe plunger pressed in
  • Draw the Prothromplex TOTAL into the syringe by pulling plunger back slowly, when ready disconnect the syringe

For full details please see the Summary of Product Characteristics

Prothromplex TOTAL 500 IU allows ease of dosing, increasing Healthcare Professional (HCP) and health system choice within existing clinical protocols based on multiples of 500 IU prothrombin complex concentrates (PCCs)3,4

Bleeding and perioperative prophylaxis of bleeding during vitamin K antagonist treatment

If Prothromplex TOTAL administration is based on the INR measurement, the dose will depend on the INR before treatment and the targeted INR.1

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 must be calculated on an individual patient basis. 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.1

Monitoring of INR during treatment is mandatory.1

Bleeding and perioperative prophylaxis in congenital deficiency of any of the vitamin K-dependent coagulation factors when specific coagulation factor product is not available:1

Required units = body weight (kg) x desired factor X rise (IU/ml) x 60

Hereditary combined vitamin K-dependent clotting factors deficiency is a rare inherited coagulation defect that forms part of a wider group of rare disorders named Familial Multiple Coagulation Factor Deficiencies.5

Replacement therapy with Prothromplex TOTAL, may result in the formation of circulating antibodies inhibiting one or more of the human prothrombin complex factors. If such inhibitors occur, the condition will manifest itself as a poor clinical response.1

Allergic or anaphylactic-type reactions have been commonly observed.1

Increase in body temperature has been commonly observed.1

There is a risk of thromboembolic episodes, following the administration of human prothrombin complex.1

For full details please see the Summary of Product Characteristics

References
  1. Prothromplex TOTAL 500 IU SmPC. Available from: https://www.medicines.org.uk/emc/product/15237 (accessed June 2024)
  2. Takeda Data on File (EXA/GB/PROT/0003);
  3. Eichinger S. Hematology Am Soc Hematol Educ Program. 2016;1:605-611;
  4. Milling T and Pollack CV. Am J Emerg Med. 2020;38(9):1890-1903;
  5. Napolitano, M. et al. Orphanet J Rare Dis. 2010;5:21

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Jonathan Cowman,
Key Account Manager,
Northern England,
1st Litre Portfolio
Ritu Vadhera,
Key Account Manager,
Southern England,
1st Litre portfolio

An international, multicentre, prospective study of Prothromplex®
TOTAL for Vitamin K antagonist (VKA) reversal1

Phase IV Study Design

  • International, prospective, open-label, single-armed Phase 4 study
  • Adults on VKA with INR ≥ 2 requiring reversal due to urgent surgery, planned/urgent invasive procedure or acute bleeding episode (n=61)
  • 48 required urgent surgery or invasive procedures
  • 13 treated for acute bleeds

Primary Outcome

  • Proportion of patients who achieved normalisation of INR to ≤1.3 within 30 ± 5 minutes after Prothromplex® TOTAL infusion

Secondary Outcomes

  • Number of doses required to achieve normalisation of INR
  • The shortening of prothrombin time
  • In vivo recovery of coagulation factors II, VII, IX and X at 30 ± 5 minutes after Prothromplex® TOTAL administration

Safety Outcomes

  • Incidence of treatment—related adverse events
  • Incidence of levels of coagulation markers including fibrinogen, D-dimer, protein C activity and antithrombin activity

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard

Adverse events should also be reported to Takeda UK Ltd. at: AE.GBR-IRL@takeda.com

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

Copyright © 2024 Takeda UK Ltd.