Argatra 1 mg/ml Infusionslösung

Beipackzettel - Argatra 1 mg/ml Infusionslösung

Zusammenfassung des Risikomanagement-Plans gemäß § 34

Public Summary of the Risk Management Plan according to Section 34 Sentence 1a sub-section 3 of the

Medicinal Products Act(2)

Administrative Information:

Wirkstoff	Argatroban 1 H2O
ATC-Code	B01AE03
Darreichungsform	Infusionslösung
Art der Anwendung	intravenöse Anwendung
Inhaber der Zulassung	Mitsubishi Tanabe Pharma GmbH Willstätterstraße 30 40549 Düsseldorf Deutschland
Zulassungsnummer	94283.00.00
Datum der Zulassung	03.06.2016
Verkaufsabgrenzung	verschreibungspflichtig
Version und Datum des Risikomanagement-Plans	3.0 / 22.10.2015
Datum der Genehmigung des RMPs	07.12.2015

Der im Folgenden wiedergegebene Ausschnitt des Risikomanagement-Plans (RMP) des o. g. Arzneimittels ist eine Zusammenfassung der wesentlichen Inhalte des RMP. Der RMP beschreibt die zu ergreifenden Maßnahmen zur Arzneimittelsicherheit, die Aktivitäten im Risikomanagement und in der Risikoanalyse um sicherzustellen, dass dieses Arzneimittel so sicher wie möglich angewendet wird.

Weitere Informationen zu RMP-Zusammenfassungen finden Sie hier (nur auf Englisch verfügbar).

Diese RMP-Zusammenfassung sollte in Verbindung mit der Zusammenfassung des öffentlichen Bewertungsberichts und der Produktinformation zu o. g. Arzneimittel gelesen werden, welche Sie auf der Produktseite auf PharmNet.Bund hier finden können.

Diese Zusammenfassung des RMPs wurde durch das Bundesinstitut für Arzneimittel und Medizinprodukte am 21. Januar 2020 veröffentlicht.

Part VI: Summary of the risk management plan by product

V I.1 Elements for summary tables in the EPAR
V I.1.1 Summary table of Safety concerns
Summary of safety concerns
Important identified risks
Haemorrhage
Abnormal hepatic function
Cerebral haemorrhage

Important Potential Risk

Related to argatroban ^ready to useʼ formulation

Medication error (underdosing)

Missing information

Pregnant patients
Breast feeding patients
Paediatric patients

V I.1.2 Table of ongoing and planned studies in the Post-authorisation Pharmacovigilance Development Plan

In Europe, as required by the French Regulatory Authority (ANSM), a Drug Utilisation study is being performed in France to better quantify the real use of the product in current practice, including the possibility of off-label prescription. The safety data from this study have been captured in the company safety database. The study protocol is included in the appendix.

In Japan, three post marketing surveillance studies are ongoing (see Table 18).

V I.1.3 Summary of Post authorisation efficacy development plan

No post-authorization efficacy studies have been planned.

V I.1.4 Summary table of Risk Minimisation Measures

Safety concern	Routine risk minimisation measures	Additional risk minimisation measures
Haemorrhage	Listed in SmPC sections 4.3 contraindication, section 4.4 special warnings and precautions regarding bleeding section 4.5 concurrent use with anticoagulants, thrombolytics and anti-platelet agents	None proposed

Safety concern	Routine risk minimisation measures	Additional risk minimisation measures
	increase the risk of bleeding and section 4.2 treatment with argatroban to be initiated under guidance of a physician with experience in coagulation disorder
Abnormal hepatic function	Listed in SmPC section 4.3 contraindication Section 4.4 special warnings and precautions regarding use in hepatic impairment Section 5.2 slow clearance of argatroban in presence of hepatic impairment and listed in section 4.2 dose reduction for hepatic impaired patients	None proposed
Cerebral haemorrhage	Listed in SmPC section 4.4 special warnings and precautions regarding bleeding including post-operative and section 4.5 concurrent use with anticoagulants, thrombolytics and anti-platelet agents increase the risk of bleeding	None proposed
Pregnant and breast feeding	Listed in SmPC section 4.6 regarding use during pregnancy and ^breastfeeding not recommended during treatmentʼ	None proposed

Safety concern related to argatroban ‘ready to useʼ formulation

Safety concern

Routine risk minimisation measures

Additional risk minimisation measures

Medication error (under

dosing)

Update in SmPC

1. Two different formulations will be differentiated by;

Brand name
Pack colour (carton, label and Flip-Off® seal)
Vial size (2.5 ml vs 50 ml)
Specific labelling to

differentiate the strength and concentration (1mg^ml vs 100mg^ml)

Package Insert describing

^ready to useʼ formulation 1mg^ml which does not need dilution prior to administration

External carton size
2. Healthcare professional education programme

V I.2 Elements for a Public Summary
V I.2.1 Overview of disease epidemiology

HIT Type II is an immune-mediated condition which can develop following administration of heparin, an anticoagulant (blood thinner) and is usually manifested by development of thrombocytopenia (a low platelet count) and can lead to thrombosis (abnormal formation of blood clots inside a blood vessel). HIT Type II is caused by the formation of abnormal antibodies that activate platelets. If someone receiving heparin develops a new blood clot or if the platelet count falls, HIT Type II should be suspected and it can be confirmed by specific blood tests.

HIT Type II is reported to occur in 2–5% of adult patients treated with heparin. In children, the incidence of HIT Type II is reported to be 2.3% to 3.7%. Ma^ority of HIT Type II patients who present with low platelets develop Deep vein thrombosis and^or Pulmonary embolism (clot in the lungs) if untreated. Approximately 5–10% of patients with HIT Type II die, usually as a result of thrombotic complications. The risk of developing HIT Type II is higher in surgical patients and if heparin is used for prolonged duration. In addition, females are twice more likely to develop this condition compared to males.

V I.2.2 Summary of treatment benefits

Study ARG-911

The efficacy and safety of argatroban as an anticoagulant in patients with HIT Type II were evaluated in this study. The study was designed as a multicentre, open label, flexible dose (i.e. dose titration), prospective, non-randomized study where the efficacy and safety outcomes were compared with historical controls. 304 patients were included in the treatment group, [HIT (without thrombosis) =160 and HITTS (with thrombosis) =144] and the reference group contained 193 patients (HIT=147, HITTS = 46). Patients were followed for up to 37 days after the therapy. The primary end-point was a composite of three individual endpoints of increasing severity: development of new thrombosis, amputation (all causes) and death (all causes).

Efficacy outcome:

Significant improvement in the composite outcome (death, amputation and thrombosis) at 37 days was observed in the argatroban group compared to historical control group in HIT (25.6% vs 38.8%, p=0.014) and HITTS (43.8 % vs 56.5%, p=0.131)

Study ARG-915

This study was similar to ARG 911 in terms of design and ob^ective. It used the same composite outcome as ARG 911. The historical control group in the ARG 911 was used in this study as well as a reference group. 264 patients were included in the treatment group, [HIT (without thrombosis) =125 and HITTS (with thrombosis) =139] and the reference group contained 193 patients (HIT=146, HITTS = 46). Patients were followed for up to 37 days after the therapy.

Efficacy outcome:

The above two studies demonstrated that treatment with argatroban showed statistically significant in the incidence of death, amputation and development of new thrombosis.

V I.2.3 Unknowns relating to treatment benefits

The current evidence suggests that efficacy and safety profile of argatroban is similar across a diverse group of patient populations regardless of age, sex and race.

V I.2.4 Summary of safety concerns

Important identified risks

Risk	What is known	Preventability
Bleeding (Haemorrhage)	Argatroban can increase the risk of bleeding. Certain other medications (oral anticoagulants, thrombolytics, antiplatelet drugs) can enhance the blood thinning effect and if used along with argatroban can increase the risk of bleeding.	Blood thinning (anticoagulant) effect of argatroban can be easily monitored by blood test (aPTT) and treating physician can use this information to ad^ust the dose. Argatroban should be used with caution in disease states where there is an increased danger of bleeding. Argatroban must not be used (contraindicated) in patients with uncontrolled bleeding. Drugs which work by making blood thin should not be use along with argatroban. In addition, argatroban must only be used by trained physicians.
Abnormal liver function	Argatroban is metabolised mainly in liver and excretion of argatroban is slower in patients with liver impairment.	Caution should be exercised in patients with liver impairment and reduced dose is recommended. Argatroban must not be used (contraindicated) in

Risk	What is known	Preventability
		patients with severely impaired liver function.
Cerebral haemorrhage (bleeding into the brain)	Argatroban can increase the risk of bleeding. Reports suggest that the treatment with argatroban can increase the risk of bleeding into the brain (cerebral haemorrhage). Patients with high blood pressure, those taking blood thinning medications and those with conditions where risk of bleeding is high are thought to increase the risk of cerebral bleeding.	Risk factors for bleeding into the brain should be identified and preventative measures should be applied. Caution should be exercised when other anticoagulant medications are used concomitantly in patients with high risk of bleeding into the brain.

Important potential risks

Risk

What is known (Including reason why it is considered a potential risk)

Medication error (underdosing)

MTPE has developed argatroban as ^ready to useʼ formulation which does not require dilution. As argatroban is already available as a concentrate for infusion which needs dilution before infusion, the new ^ready to useʼ formulation may be mistaken for this formulation. If ^ready to useʼ formulation is diluted erroneously and then infused to the patient then this may result in ^under doseʼ and may lead to failure in achieving optimal anticoagulant effect.

Missing information

Risk	What is known
Pregnancy and lactation, effect of exposure of argatroban to foetus in motherʼs womb	No information is currently available on this subset of patients. Caution should be exercised in pregnant patients. Breast feeding is not recommended while during treatment with argatroban.
Paediatric patients	In Europe, argatroban has not been approved for use in paediatric population but it has been approved in the USA for use in certain paediatric patients. There is limited data regarding the use of argatroban in paediatric patients.

V I.2.5 Summary of risk minimisation measures by safety concern

Argatroban should be used by trained healthcare professional in a suitable healthcare setting. This product has additional risk minimization measures. These additional risk minimisation measures are for the risk which is related to argatroban ^ready to useʼ formulation:

Safety concern in lay terms (medical term): Medication error (underdosing)

Risk minimisation measure(s): Healthcare professional (HCP) education

Ob^ective and rationale

Prescribing physicians and pharmacists to understand the difference between two available formulations of argatroban

Summary description of main additional risk minimisation measures

1. Two different formulations will be differentiated by;

Brand name
Pack colour (carton, label and Flip-Off® seal)
Vial size (2.5 ml vs 50 ml)
Specific labelling to differentiate the strength and concentration (1mg^ml vs 100mg^ml)
Package Insert describing ^ready to useʼ formulation 1mg^ml which does not need dilution prior to administration
External carton size
2. Healthcare Professional education programme

Proposed action:

HCP educational materials to be provided to prescribing physicians and pharmacists

VI.2.6 Planned post-authorisation development plan

No post-authorization studies have been planned for this product.

VI.2.7 Summary of changes to the Risk Management Plan over time

Summary of safety concerns
Important identified risks	Haemorrhage

Argatra 1 mg/ml Infusionslösung - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel - Argatra 1 mg/ml Infusionslösung