ADZYNMA 1500UI powder + solvent for injection medication leaflet

ADZYNMA 500 IU powder and solvent for solution for injection

ADZYNMA 1 500 IU powder and solvent for solution for injection

ADZYNMA 500 IU powder and solvent for solution for injection

Each vial of powder contains nominally 500 international units (IU) of rADAMTS13* activity, asmeasured in terms of its potency.

After reconstitution with the 5 mL solvent provided, the solution has a potency of approximately100 IU/mL.

ADZYNMA 1 500 IU powder and solvent for solution for injection

Each vial of powder contains nominally 1 500 IU of rADAMTS13* activity, as measured in terms ofits potency.

After reconstitution with the 5 mL solvent provided, the solution has a potency of approximately300 IU/mL.

*ADZYNMA is a purified bivariant human recombinant “A disintegrin and metalloproteinase withthrombospondin motifs 13” (rADAMTS13) expressed in Chinese Hamster Ovary (CHO) cells usingrecombinant DNA technology (a mixture of native rADAMTS13 Q23 and variant rADAMTS13 R23with a controlled range of the two variants ratio), referred to as rADAMTS13.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

White lyophilised powder.

The solvent is a clear and colourless solution.

The reconstituted solution has a pH of 6.7 - 7.3 and an osmolality of no lower than 240 mOsmol/kg.

ADZYNMA is an enzyme replacement therapy (ERT) indicated for the treatment of ADAMTS13deficiency in children and adult patients with congenital thrombotic thrombocytopenic purpura(cTTP).

ADZYNMA can be used for all age groups.

ADZYNMA treatment should be initiated under the supervision of a physician experienced in themanagement of patients with haematological disorders.

Prophylactic enzyme replacement therapy

- 40 IU/kg of body weight once every other week.

- The prophylaxis dosing frequency may be adjusted to 40 IU/kg of body weight once weeklybased on clinical response (see sections 5.1 and 5.2).

On-demand enzyme replacement therapy for acute TTP episodes

In case of acute thrombotic thrombocytopenic purpura (TTP) episode, the recommended dose of

ADZYNMA to treat acute TTP episodes is as follows:

- 40 IU/kg of body weight on day 1.

- 20 IU/kg of body weight on day 2.

- 15 IU/kg of body weight starting day 3 once daily until two days after the acute event isresolved (see section 5.1).

There are limited data on the use of ADZYNMA in patients over 65 years of age. Based on the resultsfrom population pharmacokinetics analysis, no dose adjustment is required for elderly patients (seesection 5.2).

As rADAMTS13 is a recombinant protein with a high molecular weight, it is not excreted renally andno dose adjustment is needed for patients with renal impairment (see section 5.2).

As rADAMTS13 is a recombinant protein with high molecular weight, it is cleared via catabolism(rather than hepatic metabolism), and no dose adjustment is needed for patients with hepaticimpairment (see section 5.2).

The recommended body-weight based dosing regimen in paediatric patients is the same as in adults.

Based on the results from population pharmacokinetics analysis, it might be more likely for infants< 10 kg body weight to require adjustment to dosing frequency from every other week to once weeklydosing (see section 5.2).

For intravenous use after reconstitution only.

ADZYNMA 500 IU and ADZYNMA 1 500 IU powder and solvent for solution for injection isadministered at a rate of 2 to 4 mL per minute.

Home or self-administration

Home or self-administration under the supervision of a healthcare professional may be considered forpatients who are tolerating their injections well. The decision to have a patient move to home orself-administration should be made after evaluation and recommendation by the treating physician.

Appropriate training should be given by the treating physician and/or nurse to the patient and/orcaregiver prior to initiation of home or self‑administration. Dose and administration rate should remainconstant while at home, and not be changed without consulting the treating physician. If the patientexperiences early signs of hypersensitivity during the home administration, the administration processshould be stopped immediately, and appropriate treatment should be initiated (see section 4.4).

Subsequent injections need to occur in a clinical setting. Treatment should be closely followed by thetreating physician.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Life-threatening hypersensitivity to the active substance or to any of the excipients listed insection 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Allergic-type hypersensitivity including anaphylactic reactions may occur. Patients should beinformed of the early signs of hypersensitivity reactions including but not limited to tachycardia,tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalised urticaria,pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paraesthesia, restlessness, andmay progress to anaphylactic shock. If signs and symptoms of severe allergic reactions occur, theadministration of this medicinal product should be discontinued immediately and appropriatesupportive care should be provided.

As with all therapeutic proteins, there is a potential for immunogenicity. Patients may developantibodies to rADAMTS13 following treatment with ADZYNMA which could potentially result in adecreased response to rADAMTS13 (see section 5.1). If such antibodies are suspected and there is alack of efficacy, consider other therapeutic strategies.

This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially‘sodium free’.

No interaction studies have been performed.

There are no or limited amount of data from the use of ADZYNMA in pregnant women. Animalstudies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (seesection 5.3). The use of ADZYNMA during pregnancy may only be considered after a thoroughindividual risk benefit analysis by the treating physician before and during treatment.

There is insufficient information on the excretion of rADAMTS13 in human or animal milk but it isunlikely that it is excreted in human milk due to its high molecular weight. The decision either todiscontinue breast-feeding or discontinue ADZYNMA should take into account the importance of thismedicinal product to the mother.

No human data are available on the effects of rADAMTS13 on male and female fertility. Animal datado not indicate direct or indirect harmful effects with respect to male or female fertility (seesection 5.3).

Recombinant ADAMTS13 may have a minor influence on the ability to drive and use machines.

Dizziness and somnolence may occur following the administration of ADZYNMA (see section 4.8).

The most common adverse reactions reported in clinical studies were headache (31.5%),diarrhoea (17.8%), dizziness (16.4%), upper respiratory tract infection (15.1%), nausea (13.7%), andmigraine (11%).

The adverse drug reactions (ADRs) are listed in Table 1.

Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies aredefined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to< 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated fromthe available data). Within each System Organ Class (SOC), ADRs are presented in order ofdecreasing frequency. Within each frequency grouping, ADRs are presented in order of decreasingseriousness.

Table 1: Adverse reactions reported in patients treated with ADZYNMA

MedDRA system organ class Adverse reaction by Frequency category by(SOC) preferred term (PT) subject

Infections and infestations Upper respiratory tract Very commoninfection

Blood and lymphatic system disorders Thrombocytosis Common

Nervous system disorders Headache Very common

Dizziness Very common

Migraine Very common

Somnolence Common

Gastrointestinal disorders Diarrhoea Very common

Nausea Very common

Constipation Common

Abdominal distension Common

General disorders and administration Asthenia Commonsite conditions Feeling hot Common

Investigations ADAMTS13 activity Commonabnormal

There is limited information from controlled studies of ADZYNMA in paediatric patients. The safetyassessment in paediatric patients is based on the safety data from one phase 3 clinical study comparing

ADZYNMA to plasma-based therapies (fresh frozen plasma [FFP], pooled solvent/detergent [S/D]treated plasma, or factor VIII:von Willebrand factor [FVIII-VWF] concentrates, as assigned by theinvestigator) and one phase 3b study. The studies included 20 and 1 paediatric patients aged 2 to17 years of age in the prophylactic and on-demand cohorts, respectively. Overall, the safety profile inthese paediatric patients was similar to that observed in the adult population.

One neonate aged 36 hours old was treated with ADZYNMA in a compassionate use program and hadno reported safety or immunogenicity concerns after 2 years of prophylactic treatment.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, single doses up to 160 IU/kg were used and their safety profile was generallyconsistent with results from clinical study results in cTTP patients.

In case of overdose, based on the pharmacological action of rADAMTS13, there is the potential forincreased risk of bleeding (see section 5.1).

Pharmacotherapeutic group: Antithrombotic agents, enzymes, ATC code: B01AD13

Mechanism of actionrADAMTS13 is a recombinant form of the endogenous ADAMTS13. ADAMTS13 is a plasma zincmetalloprotease that regulates the activity of von Willebrand factor (VWF) by cleaving large and ultra-large VWF multimers to smaller units and thereby reducing the platelet binding properties of VWFand its propensity to form microthrombi. rADAMTS13 is expected to reduce or eliminate thespontaneous formation of VWF-platelet microthrombi that leads to platelet consumption andthrombocytopenia in patients with cTTP.

Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact onpharmacokinetics, efficacy or safety was observed, however, data are still limited (see section 4.4).

The clinical efficacy and safety were assessed in two ongoing studies (Study 281102 and Study 3002).

Study 281102

ADZYNMA was studied in a global phase 3, prospective, randomized, controlled, open-label,multicentre, two-period crossover study followed by a single arm continuation period (Study 281102)evaluating the efficacy and safety of the prophylactic and on-demand ERT with ADZYNMAcompared to plasma-based therapies in patients with severe cTTP (ADAMTS13 activity < 10%).

Prophylactic enzyme replacement therapy in patients with cTTP

The efficacy of ADZYNMA in the prophylactic treatment of patients with cTTP was evaluated in46 patients in the prophylaxis cohort who were randomized to receive 6 months of prophylactictreatment with either 40 IU/kg (± 4 IU/kg) of ADZYNMA or plasma-based therapies (period 1) onceweekly (for patients who were previously treated with plasma-based therapies once weekly prior tojoining the study) or every other week then crossed over to the other treatment for 6 months (period 2).

After periods 1 and 2, all patients entered a 6 month single arm treatment period with ADZYNMA(period 3). The initial ADZYNMA prophylactic treatment frequency was every other week for35 (76.1%) patients and once weekly for 9 (19.6%) patients.

The mean (SD) age was 30.5 (16.0) years (range: 3 to 58 years). Of the 46 patients,4 (8.7%) were < 6 years of age, 4 (8.7%) were ≥ 6 to < 12 years of age, 4 (8.7%) were ≥ 12 to< 18 years of age, and 34 (73.9%) were ≥ 18 years of age. The mean (SD) weight was 65.9 kg (21.8)(range: 18.5 to 102.4 kg), and the majority of patients were white (65.2%), and were female (58.7%)of whom 74.1% were of child-bearing potential.

Prior to joining the study, the majority (69.6%) of patients received FFP treatment, 21.7% receivedsolvent/detergent (S/D) plasma and 6.5% received FVIII-VWF concentrate.

The efficacy of prophylactic treatment with ADZYNMA in patients with cTTP was evaluated basedon the incidence of acute TTP events (as defined by a drop in platelet count [≥ 50% of baseline or aplatelet count < 100 x 109/L] and an elevation of lactate dehydrogenase [LDH] [> 2 × baseline or> 2 × upper limit normal (ULN)]), subacute TTP events (as defined by a thrombocytopenia event or amicroangiopathic haemolytic anaemia event; and organ specific signs and symptoms including but notlimited to renal dysfunction events, neurological symptoms events, fever, fatigue/lethargy, and/orabdominal pain), and TTP manifestations (such as thrombocytopenia, microangiopathic haemolyticanaemia, neurological symptoms, renal dysfunction, and abdominal pain); as well as the incidence ofsupplemental doses prompted by subacute TTP events (see Table 2).

Table 2: Prophylactic cohort efficacy results in cTTP patients (periods 1 and 2)

ADZYNMA Plasma-Based

N = 45 Therapies

N = 46

Acute TTP events

Number of subjects with event 0 1(number of events) (0) (1)

Subacute TTP events

Number of subjects with event 1 6(number of events) (1) (7)

Number of subjects receiving a supplemental dose 0 4prompted by a subacute event

Number of supplemental doses prompted by a subacute 0 9event

TTP manifestations

Thrombocytopenia eventsa

Number of subjects with event 13 23(number of events) (49) (91)

Model based annualized event rate,b LSM (SE) 0.92 (0.262) 1.72 (0.457)

Microangiopathic haemolytic anaemia eventsc

Number of subjects with event 8 12(number of events) (23) (32)

Model based annualized event rate,b LSM (SE) 0.37 (0.136) 0.59 (0.194)

Neurological symptoms eventsd

Number of subjects with event 4 7(number of events) (18) (29)

Model based annualized event rate,b LSM (SE) 0.13 (0.068) 0.23 (0.109)

Renal dysfunction eventse

Number of subjects with event 5 2(number of events) (11) (5)

Model based annualized event rate,b LSM (SE) 0.17 (0.090) 0.08 (0.052)

Abdominal pain events

Number of subjects with event 2 6(number of events) (4) (8)

Model based annualized event rate,b LSM (SE) 0.09 (0.055) 0.17 (0.086)

LSM = least squares mean; SE = standard error; TTP = thrombotic thrombocytopenic purpura.a Drop in platelet count ≥ 25% of baseline or a platelet count < 150 x 109/L.b From a negative binominal mixed-effects model.c Elevation of LDH > 1.5 × baseline or > 1.5 x ULN.d Nervous system disorders (e.g., headache, confusion, memory issues, irritability, paraesthesia, dysarthria,dysphonia, visual disturbances, focal or general motor symptoms including seizures).e An increase in serum creatinine > 1.5 × baseline.

Overall ADZYNMA efficacy results were consistent throughout the study, including period 3, andacross age groups.

On-demand enzyme replacement therapy for acute TTP episodes

The efficacy of the on-demand enzyme replacement therapy for acute TTP episodes was evaluatedbased on the proportion of acute TTP events responding to ADZYNMA in both the prophylactic andthe on-demand cohorts throughout the duration of the study.

An acute TTP event responding to ADZYNMA was defined as a resolved TTP event when plateletcount was ≥ 150 x 109/L or platelet count was within 25% of baseline, whichever occurs first, and

LDH ≤ 1.5 x baseline or ≤ 1.5 x ULN, without requiring the use of another ADAMTS13-containingagent.

The on-demand cohort included 5 adult patients (≥ 18 years of age) and 1 paediatric patient (< 6 yearsof age). Patients enrolled in this cohort had a total of 7 acute TTP events. Of these 6 patients,2 patients were randomized to receive on-demand treatment with ADZYNMA and 4 patients wererandomized to receive plasma-based therapies. All 7 acute TTP events resolved after treatment witheither ADZYNMA or plasma-based therapies within 5 days.

Most patients (66.7%) were male, white (50%) with a median (min, max) age of 20 (5, 36) years, amean (SD) weight of 56.4 (18.6) kg and a median (min, max) weight of 64.3 (23.0, 74.0) kg.

Study 3002 (Continuation study)

Patients who completed the phase 3 study (Study 281102) were eligible to enrol in a long-termcontinuation study (Study 3002). The prophylaxis cohort included 65 patients among which 40 rolledover from Study 281102 and 25 were naïve patients. Of the 40 roll-over patients, 7 (17.5%) were ≥ 12to < 18 years of age, and 33 (82.5%) were ≥ 18 years of age. Of the 25 naïve patients, 3 (12%)were < 6 years of age, 3 (12%) were ≥ 6 to < 12 years of age, 3 (12%) were ≥ 12 to < 18 years of age,and 16 (64%) were ≥ 18 years of age. The on-demand cohort included 1 patient aged ≥ 6 to < 12 years.

All patients were treated with ADZYNMA. The mean and maximum prophylactic treatment durationswere 0.98 years and 2.17 years, respectively. Incidence rates of acute and subacute TPP events and

TPP manifestations were consistent with the results from Study 281102.

Overall, the efficacy in paediatric patients was similar to that observed in the adult population.

The European Medicines Agency has deferred the obligation to submit the results of studies with

ADZYNMA in one or more subsets of the paediatric population in the treatment of congenitalthrombotic thrombocytopenic purpura (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

The pharmacokinetic (PK) profile of ADZYNMA was determined based on clinical study

ADAMTS13 activity data analyses.

Following single-dose intravenous administration of ADZYNMA at 5 IU/kg, 20 IU/kg, and 40 IU/kgto adults and adolescents, dose-related increases in individual ADAMTS13 activity were observed andreached a maximum at approximately 1 hour post-administration or earlier. At clinical dose of40 IU/kg the mean (SD) half-life and mean residence time (MRT) in adults and adolescents were47.8 (13.7) hours and 63.8 (16.0) hours, respectively.

The population PK parameters of ADAMTS13 activity following intravenous administration of

ADZYNMA at 40 IU/kg in adults, adolescents, and younger children are described in Table 3.

Table 3: Pharmacokinetic parameters of ADAMTS13 activity following intravenousadministration of ADZYNMA in cTTP patients

Parameter Mean (SD)(unit) Min; Max(N = 83)

Cmax 1.13 (0.29)(IU/mL) 0.72; 2.29

AUC 72.8 (37.4)(IU*h/mL) 38.7; 274

Duration ADAMTS13 activity above 8.85 (2.45)10% 4.51; 14.0(days)

AUC = area under ADAMTS13 activity-time curve; Cmax = maximum ADAMTS13 activity.

Note: 1 IU/mL ADAMTS13 activity corresponds to 100% average normal activity.

ADZYNMA intravenous administration at 40 IU/kg resulted in approximately greater than 5-foldhigher ADAMTS13 activity exposures (Cmax, AUC, and duration above 10% ADAMTS13 activity)and lower variability when compared to plasma-based therapies.

Age, gender, race, and other intrinsic factors

Besides body-weight dosing regimen, no intrinsic factors such as age, gender, race, baseline estimatedglomerular filtration rate (eGFR), and baseline bilirubin were identified as covariates impacting

ADAMTS13 PK.

ADAMTS13 activity PK characteristics (MRT, steady-state volume of distribution [Vss], andclearance [CL]) were similar across age groups in patients with cTTP. Body weight-based

ADZYNMA dosing provides similar ADAMTS13 activity PK parameters (Cmax and average

ADAMTS13 activity [Cave]) across the different age groups including paediatric patients < 12 years ofage.

In infants < 10 kg body weight, median duration above 10% ADAMTS13 activity was estimated to beshorter (approximately 5-6 days) compared to adults (approximately 10 days).

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, singledose toxicity, toxicity to reproduction and development, local tolerance and immunogenicity. Studiesto evaluate the mutagenic and carcinogenic potential of rADAMTS13 have not been performed.

Sodium chloride

Calcium chloride dihydrate

L-Histidine

Mannitol

Sucrose

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial3 years

Chemical and physical in-use stability has been demonstrated for 6 hours at 25 °C.

From a microbiological point of view, unless the method of opening/reconstituting/dilution precludesthe risks of microbial contamination, the product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

ADZYNMA may be stored at room temperature up to 30 °C for a period of up to 6 months inlyophilized form, but not exceeding the expiry date.

Do not return ADZYNMA to refrigerated storage after storage at room temperature.

Record on the carton the date ADZYNMA is removed from refrigeration.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

ADZYNMA 500 IU powder and solvent for solution for injection

Each pack contains: powder in a vial (type I glass), with a butyl rubber stopper 5 mL of solvent in a vial (type I glass), with a butyl rubber stopper one reconstitution device (BAXJECT II Hi-Flow) one disposable 10 mL syringe one 25-gauge infusion set two alcohol swabs

ADZYNMA 1 500 IU powder and solvent for solution for injection

Each pack contains: powder in a vial (type I glass), with a butyl rubber stopper 5 mL of solvent in a vial (type I glass), with a butyl rubber stopper one reconstitution device (BAXJECT II Hi-Flow) one disposable 20 mL syringe one 25-gauge infusion set two alcohol swabs

ADZYNMA is to be administered intravenously after reconstitution of the powder with the providedwater for injections.

General instructions Calculate administration dose and volume based on the patient’s body weight. Use aseptic technique throughout the procedure. Check expiry date of the product prior to use. Do not use ADZYNMA if the expiry date has passed. If the patient needs more than one vial of ADZYNMA per injection, reconstitute each vialaccording to the instructions stated under ‘Reconstitution’. Please note that the BAXJECT II Hi-

Flow device is intended for use with a single vial of ADZYNMA and water for injections only,therefore reconstituting and withdrawing a second vial into the syringe requires a second

BAXJECT II Hi-Flow device.

 Parenteral medicinal products should be inspected visually for particulate matter anddiscoloration prior to administration, whenever solution and container permit. The reconstituted

ADZYNMA solution should be clear and colourless in appearance.

 Do not administer if particulate matter or discoloration is observed. Administer ADZYNMA within 3 hours after reconstitution when stored at room temperature. Do not administer ADZYNMA in the same tubing or container at the same time with othermedicinal products for infusion.

Reconstitution1. Prepare a clean flat surface and gather all the materials you will need for the reconstitution andadministration (Figure A).

Figure A2. Allow the vials of ADZYNMA and diluent to reach room temperature before use.3. Wash and dry your hands thoroughly.4. Remove plastic caps from the ADZYNMA and diluent vials and place the vials on a flat surface(Figure B).

Figure B5. Wipe the rubber stoppers with an alcohol swab and allow them to dry prior to use (Figure C).

Figure C6. Open the BAXJECT II Hi-Flow device package by peeling away the lid, without touching theinside (Figure D).

- Do not remove the BAXJECT II Hi-Flow device from the package.

- Do not touch the clear plastic spike.

Figure D7. Turn the package with the BAXJECT II Hi-Flow device upside down and place it over the topof the diluent vial. Press straight down until the clear plastic spike pierces through thediluent vial stopper (Figure E).

Figure E8. Grip the BAXJECT II Hi-Flow device package at its edge and pull the package off the device(Figure F).

- Do not remove the blue cap from the BAXJECT II Hi-Flow device.

- Do not touch the exposed purple plastic spike.

Figure F9. Turn the system over so that the diluent vial is now on top. Press the BAXJECT II Hi-Flowdevice straight down until the purple plastic spike pierces through the

ADZYNMA powder vial stopper (Figure G). The vacuum will draw the diluent into the

ADZYNMA powder vial.

- You may notice some bubbles or foam - this is normal and should soon disappear.

Figure G10. Swirl the connected vials gently and continuously until the powder is completely dissolved(Figure H).

- Do not shake the vial.

Figure H11. Visually inspect the reconstituted solution for particulate matter before administration.

- Do not use the product if particulate matter or discoloration is observed.

12. If the dose requires more than one vial of ADZYNMA, reconstitute each vial using the abovesteps.

- Use a different BAXJECT II Hi-Flow device to reconstitute each vial of ADZYNMAand diluent.

Administration instructions13. Take off the blue cap from the BAXJECT II Hi-Flow device (Figure I). Attach a Luer-locksyringe (Figure J).

- Do not inject air into the system.

Figure I Figure J14. Turn the system upside down (ADZYNMA vial is now on top). Draw thereconstituted solution into the syringe by pulling the plunger back slowly (Figure K).

Figure K15. If a patient is to receive more than one vial of ADZYNMA, the contents of multiple vials can bedrawn into the same syringe. Repeat this process for all reconstituted vials of ADZYNMA untilthe total volume to be administered is reached.

16. Disconnect the syringe and attach a suitable injection needle or an infusion set.17. Point the needle up and remove any air bubbles by gently tapping the syringe with your fingerand slowly and carefully pushing air out of the syringe and needle.18. Apply a tourniquet and clean the chosen injection site with an alcohol swab (Figure L).

Figure L19. Insert the needle into the vein and remove the tourniquet.20. Infuse the reconstituted ADZYNMA slowly, at a rate of 2 to 4 mL per minute (Figure M).

- A syringe pump may be used to control the rate of administration.

Figure M21. Take the needle out of the vein and put pressure on the injection site for several minutes.

- Do not recap the needle.

22. Place the needle, syringe, and empty vials in a puncture-resistant sharps container.

- Do not dispose of syringes and needles in the household waste.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda Manufacturing Austria AG

Industriestrasse 671221 Vienna

AustriamedinfoEMEA@takeda.com

EU/1/24/1837/001

EU/1/24/1837/002

Date of first authorisation:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.