TAKHZYRO 300mg injection solution in pre-filled syringe medication leaflet

TAKHZYRO 150 mg solution for injection in pre-filled syringe

TAKHZYRO 300 mg solution for injection in pre-filled syringe

TAKHZYRO 300 mg solution for injection in pre-filled pen

TAKHZYRO 300 mg solution for injection

TAKHZYRO 150 mg solution for injection in pre-filled syringe

One unit (pre-filled syringe) contains 150 mg of lanadelumab* in 1 ml solution.

TAKHZYRO 300 mg solution for injection (pre-filled syringe, pre-filled pen, or vial)

One unit (pre-filled syringe, pre-filled pen, or vial) contains 300 mg of lanadelumab* in 2 ml solution.

*Lanadelumab is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection

The solution is colourless to slightly yellow, appearing either clear or slightly opalescent.

The solution has a pH of approximately 6.0 and an osmolality of approximately 300 mOsm/kg.

TAKHZYRO is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE)in patients aged 2 years and older.

This medicinal product should be initiated under the supervision of a physician experienced in themanagement of patients with hereditary angioedema (HAE).

Adults and Adolescents 12 to less than 18 years of age

The recommended starting dose is 300 mg lanadelumab every 2 weeks. In patients who are stablyattack free on treatment, a dose reduction to 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 weeksmay also be considered. In patients who are stably attack free on treatment, a dose reduction to 150 mglanadelumab every 4 weeks may be considered.

Children 2 to less than 12 years of age

The recommended dose of lanadelumab for children 2 to less than 12 years of age is based on bodyweight (see table below) and should only be administered via a pre-filled syringe or vial.

The pre-filled pen has not been studied in children 2 to less than 12 years of age and therefore shouldnot be used.

Patients with a body weight of 20 to less than 40 kg who are stably attack free may continue with thesame dose when reaching 12 years of age.

Table 1. Recommended dose in children 2 to less than 12 years of age

Body Weight (kg) Recommended Starting Dose Dose Adjustment

A dose increase to 150 mglanadelumab every 3 weeks may10 to less than 20 kg 150 mg lanadelumab every 4 weeksbe considered in patients withinsufficient control of attacks

A dose reduction to 150 mglanadelumab every 4 weeks may20 to less than 40 kg 150 mg lanadelumab every 2 weeksbe considered in patients who arestably attack free on treatment

A dose reduction to 300 mglanadelumab every 4 weeks may40 kg or more 300 mg lanadelumab every 2 weeksbe considered in patients who arestably attack free on treatment

Consideration should be given to discontinuing treatment in patients with HAE with normal C1esterase inhibitor (nC1-INH) who have shown insufficient reduction in attacks after 3 months oftreatment (see section 4.4 and 5.1).

TAKHZYRO is not intended for treatment of acute HAE attacks (see section 4.4).

If a dose of TAKHZYRO is missed, the patient or caregiver should be instructed to administer thedose as soon as possible. The subsequent dosing schedule may need adjustment according to theintended 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,

- at least 24 days between doses for patients on every 4 weeks dosing regimen.

Age is not expected to affect exposure to lanadelumab. No dose adjustment is required for patientsabove 65 years of age (see section 5.2).

No studies have been conducted in patients with hepatic impairment. Hepatic impairment is notexpected to affect exposure to lanadelumab. No dose adjustment is required in patients with hepaticimpairment (see section 5.2).

No studies have been conducted in patients with severe renal impairment. Renal impairment is notexpected to affect exposure to lanadelumab or the safety profile. No dose adjustment is required inpatients with renal impairment (see section 5.2).

The safety and efficacy of TAKHZYRO in children aged less than 2 years have not been established.

No data are available.

TAKHZYRO is intended for subcutaneous (SC) administration only.

Each TAKHZYRO unit (pre-filled syringe, pre-filled pen, or vial) is intended for single use only (seesection 6.6).

The injection should be restricted to the recommended injection sites: the abdomen, the thighs, and theupper outer arms (see section 5.2). Rotation of the injection site is recommended.

For adults and adolescents (12 to less than 18 years of age), TAKHZYRO may be self-administered oradministered by a caregiver only after training on subcutaneous injection technique by a healthcareprofessional.

For children (2 to less than 12 years of age), TAKHZYRO should only be administered by a caregiverafter training on subcutaneous injection technique by a healthcare professional.

Hypersensitivity to the active substance or to any of the excipients listed in section 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.

Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction,administration of TAKHZYRO must be stopped immediately and appropriate treatment must beinitiated.

TAKHZYRO is not intended for treatment of acute HAE attacks. In case of a breakthrough HAEattack, individualized treatment should be initiated with an approved rescue medication.

There is limited clinical data on the use of lanadelumab in HAE patients with normal C1-INH (seesection 5.1).

Patients with HAE nC1-INH having mutations that are not associated with the kallikrein-kinin system(KKS) pathway are not expected to respond to TAKHZYRO. It is recommended to perform genetictesting, if available, according to the current HAE guidelines and to discontinue the treatment ifclinical response is not observed (see section 4.2 and 5.1).

Interference with coagulation test

Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction oflanadelumab with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsiccoagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasmakallikrein by lanadelumab can increase aPTT in this assay. None of the increases in aPTT in patientstreated with TAKHZYRO were associated with abnormal bleeding adverse events. There were nodifferences in international normalised ratio (INR) between treatment groups.

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, pre-filledpen, or vial, that is to say essentially ‘sodium-free’.

No dedicated drug-drug interaction studies have been conducted. Based on the characteristics oflanadelumab, no pharmacokinetic interactions with co-administered medicinal products is expected.

As expected, concomitant use of the rescue medication C1 esterase inhibitor results in an additiveeffect on lanadelumab-cHMWK response based on the mechanism of action of lanadelumab and C1esterase inhibitor (see section 5.1).

There are no or limited data from the use of lanadelumab in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive or developmental toxicity (seesection 5.3). As a precautionary measure, it is preferable to avoid the use of lanadelumab duringpregnancy.

It is unknown whether lanadelumab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which is decreasing to low concentrations soonafterwards; consequently, a risk to the breast-fed child cannot be excluded during this short period.

Afterwards, lanadelumab could be used during breast-feeding if clinically needed.

Lanadelumab’s effect on fertility has not been evaluated in humans. Lanadelumab had no effect onmale or female fertility in cynomolgus monkeys (see section 5.3).

TAKHZYRO has no or negligible influence on the ability to drive and use machines.

The most commonly (52.4%) observed adverse reaction associated with TAKHZYRO was injectionsite reactions (ISR) including injection site pain, injection site erythema and injection site bruising. Ofthese ISRs, 97% were of mild intensity, 90% resolved within 1 day after onset with a median durationof 6 minutes.

Hypersensitivity reaction (mild and moderate pruritus, discomfort and tingling of tongue) wasobserved (1.2%), see section 4.4.

Table 2 summarises adverse reactions observed in the HELP study that included 84 subjects with

HAE, who received at least one dose of TAKHZYRO.

The frequency of adverse reactions listed in Table 2 is defined using the following convention:

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).

Table 2. Adverse reactions reported with lanadelumab

System organ class Adverse drug reaction Frequency

Immune system disorders Hypersensitivity* Common

Nervous system disorders Dizziness Common

Skin and subcutaneous tissue

Rash maculo-papular Commondisorders

Musculoskeletal and connective tissue

Myalgia Commondisorders

General disorders and administration

Injection site reactions** Very commonsite conditions

Alanine aminotransferase increased Common

Investigations Aspartate aminotransferase

Commonincreased

*Hypersensitivity includes: pruritus, discomfort and tingling of tongue.

**Injection site reactions include: pain, erythema, bruising, discomfort, haematoma, haemorrhage,pruritus, swelling, induration, paraesthesia, reaction, warmth, oedema and rash.

Safety data available from the HELP study extension are consistent with the safety data from the

HELP study (described in Table 2).

The safety of TAKHZYRO 300 mg/2 ml was evaluated in a subgroup of 23 subjects 12 to less than18 years of age in the HELP and HELP study extension. In the SPRING study, safety of TAKHZYROwas also evaluated at 150 mg/1 ml in 21 subjects 2 to less than 12 years of age (see section 5.1). Nosubject below the age of 3.5 years was receiving lanadelumab in the study. No new adverse reactionswere identified. Safety and tolerability results for paediatric subjects were consistent with overallstudy results for all subjects.

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.

No case of overdose has been reported. There is no available information to identify potential signsand symptoms of overdose. If symptoms should occur, symptomatic treatment is recommended. Thereis no antidote available.

Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema, ATCcode: B06AC05

Lanadelumab is a fully human, monoclonal antibody (IgG1/ κ-light chain). Lanadelumab inhibitsactive plasma kallikrein proteolytic activity. Increased plasma kallikrein activity leads to proteolysis ofhigh-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin,which is associated with inflammation and swelling in HAE attacks.

In adult and adolescent (12 to less than 18 years of age) patients, concentration-dependent inhibition ofplasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneousadministration of TAKHZYRO 150 mg every 4 weeks, 300 mg every 4 weeks or 300 mg every2 weeks in subjects with HAE.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship between TAKHZYRO and cHMWK isdescribed by an indirect exposure-response pharmacological model. The cHMWK formation rate wasmaximally reduced by 53.7% and the TAKHZYRO concentration associated with the 50% inhibition(IC50) was 5 705 ng/ml.

For children aged 2 to less than 6 years (150 mg every 4 weeks) and 6 to less than 12 years (150 mgevery 2 weeks), the observed mean percent change from baseline in cHMWK levels was similar tothat observed in adult and adolescent (12 to less than 18 years of age) patients.

HELP study

The HELP study was a multicenter, randomised, double-blind, placebo-controlled parallel-group studyin 125 (115 adults and 10 adolescents) subjects with symptomatic type I or II HAE. Subjects wererandomised into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio(placebo, lanadelumab 150 mg every 4 weeks, lanadelumab 300 mg every 4 weeks, or lanadelumab300 mg every 2 weeks by subcutaneous injection) for the 26-week treatment period.

The median (range) age of the study population was 42 (12 to 73) years with 88 female subjects(70%). A history of laryngeal angioedema attacks was reported in 65% (81/125) of subjects and56% (70/125) were on prior long-term prophylaxis (LTP). During the study run-in period, the meanattack rate was 3.7 attacks/month with 52% (65/125) of subjects experiencing ≥ 3 attacks/month.

All TAKHZYRO treatment arms produced statistically significant reductions in the mean HAE attackrate compared to placebo across all primary and secondary endpoints in the Intent-to-Treat population(ITT) (Table 3).

Table 3. Results of primary and secondary efficacy measures-ITT population

Lanadelumaba Placebo 150 mg 300 mg 300 mg

Endpoint statistics(N = 41) every every every4 weeks 4 weeks 2 weeks(N = 28) (N = 29) (N = 27)

Primary endpoint - Number of HAE attacks from Day 0 to 182

LS Mean (95% CI) monthly attack 1.97 (1.64, 0.48 (0.31, 0.53 (0.36, 0.26 (0.14,rateb 2.36) 0.73) 0.77) 0.46)% Reduction relative to placebo 76 (61, 85) 73 (59, 82) 87 (76, 93)(95% CI)c

Adjusted p-valuesd < 0.001 < 0.001 < 0.001

Secondary endpoint - Number of HAE attacks requiring acute treatment from Day 0 to 182

LS Mean (95% CI) monthly attack 1.64 (1.34, 0.31 (0.18, 0.42 (0.28, 0.21 (0.11,rateb 2.00) 0.53) 0.65) 0.40)% Reduction relative to placebo 81 (66, 89) 74 (59, 84) 87 (75, 93)(95% CI)c

Adjusted p-valuesd < 0.001 < 0.001 < 0.001

Secondary endpoint - Number of moderate or severe HAE attacks from Day 0 to 182

LS Mean (95% CI) monthly attack 1.22 (0.97, 0.36 (0.22, 0.32 (0.20, 0.20 (0.11,rateb 1.52) 0.58) 0.53) 0.39)% Reduction relative to placebo 70 (50, 83) 73 (54, 84) 83 (67, 92)(95% CI)c

Adjusted p-valuesd < 0.001 < 0.001 < 0.001

Note: CI = confidence interval; LS = least squares.a Results are from a Poisson regression model accounting for over dispersion with fixed effects fortreatment group (categorical) and normalized baseline attack rate (continuous), and the logarithm oftime in days each subject was observed during the treatment period as an offset variable in the model.b Model-based treatment period HAE attack rate (attacks/4 weeks).c % reduction relative to placebo corresponds to 100% * (1-rate ratio). The rate ratio is ratio of themodel-based treatment period HAE attack rates.d Adjusted p-values for multiple testing.

The mean reduction in HAE attack rate was consistently higher across the TAKHZYRO treatmentarms compared to placebo regardless of the baseline history of LTP, laryngeal attacks, or attack rateduring the run-in period. The percentage of subjects who were attack free is provided in Table 4.

Table 4. Percentage of subjects who were attack free through treatment

Lanadelumab

Criteria Placebo 150 mg 300 mg 300 mgevery every every4 weeks 4 weeks 2 weeks

Treatment period (Day 0 to Day 182, 26 weeks)

N 41 28 29 27

Attack free 2% 39% 31% 44%

The percentage of patients who were attack free for the last 16-weeks (Day 70 to Day 182) of thestudy was 77% in the 300 mg every 2 weeks group, compared to 3% of patients in the placebo group.

100% of the subjects on 300 mg every 2 weeks or every 4 weeks and 89% on 150 mg every 4 weeksachieved at least a 50% reduction in HAE attack rate compared to the run-in period.

Health related quality of life

All TAKHZYRO treatment groups observed an improvement in Angioedema Quality of Life

Questionnaire (AE-QoL) total and domain (functioning, fatigue/mood, fear/shame, and nutrition)scores compared to the placebo group; the largest improvement was observed in the functioning scoreas shown in Table 5. A reduction of 6 points is considered a clinically meaningful improvement. Thepercentage of patients who achieved a clinically meaningful improvement in AE-QoL total score was65% (Odds ratio vs placebo, [95% CI] = 3.2 [1.1, 9.2]), 63% (2.9 [1.1, 8.1]), and 81% (7.2 [2.2, 23.4]),in TAKHZYRO 150 mg every 4 weeks, 300 mg every 4 weeks, and 300 mg every 2 weeks groups,respectively, compared to 37% of patients in the placebo group.

Table 5. Change in AE-QoL scorea placebo vs TAKHZYRO at week 26 in HELP study

TAKHZYRO

LS mean change (SD) from baseline at week 26 Placebototal

AE-QoL Total score -4.7 (18.8) -19.5 (18.6)

Functioning score -5.4 (22.7) -29.3 (22.9)

Fatigue/Mood score -1.8 (23.3) -13.0 (23.1)

Fear/Shame score -9.0 (24.0) -18.8 (23.7)

Nutrition score 0.5 (22.5) -17.0 (22.3)

Note: AE-QoL = Angioedema Quality of Life; LS = least squares; SD = standard deviation.a Lower scores indicate lower impairment (or better health-related quality of life).

HELP study extension

Long-term safety and efficacy, PK, and impact on health-related quality of life (HRQoL) of

TAKHZYRO for prophylaxis to prevent HAE attacks were evaluated in an open-label uncontrolled

HELP study extension.

A total of 212 adult and adolescent (≥ 12 years) subjects with symptomatic type I or II HAE receivedat least one dose of lanadelumab 300 mg every 2 weeks in this study, including 109 subjects whoentered as rollover subjects from the HELP study. Rollover subjects, regardless of randomisationgroup in the HELP Study, received a single dose of lanadelumab 300 mg at study entry and did notreceive additional treatment until the occurrence of an HAE attack. After the first HAE attack, allsubjects received open-label treatment with lanadelumab 300 mg every 2 weeks. The study alsoincluded 103 new or non-rollover subjects (including 19 subjects from Phase1b study) who had ahistorical baseline attack rate of ≥ 1 attack per 12 weeks. The non-rollover subjects receivedlanadelumab 300 mg every 2 weeks at study entry. Subjects were allowed to initiateself-administration after receiving the first 2 doses from a health care professional in clinic andcompleting appropriate training.

The majority of subjects (173/212; 81.6%) who were treated in this study completed at least30 months of treatment (either as a rollover or non-rollover subjects). The mean (SD) time in the

HELP study extension was 29.6 (8.20) months. The majority of subjects self-administeredlanadelumab (60.6% of 8,018 injections).

There was a sustained reduction in attack rates compared to baseline during the HELP study extension,with a similar response to TAKHZYRO observed in both rollover (92.4%) and non-rollover groups(82.0%) and an overall reduction rate of 87.4%. Though the magnitude of the attack rate reduction inthe HELP study limited the potential for further reductions in the HELP extension study, mean attackrates for the rollover subjects decreased further at the time of the final analysis and ranged from0.08 to 0.26 attacks per month. In addition, the mean (SD) percentage of attack-free days was97.7 (6.0)% and the mean (SD) duration of the attack-free period was 415.0 (346.1) days. Theproportion of patients with a maximum attack-free period of 6 months or more or 12 months or morewas 81.8% and 68.9%, respectively.

CASPIAN study

The CASPIAN study was a multicenter, randomised, double-blind, placebo-controlled study in77 adult subjects to evaluate the efficacy of lanadelumab in preventing acute attacks ofnon-histaminergic angioedema in subjects with normal C1-INH. Of the subjects enrolled, 5 (6.5%)were HAE nC1-INH subjects with known mutations (FXII, PLG), 13 (16.9%) were HAE nC1-INHsubjects with a family history of angioedema but who did not have a known mutation, and 59 (76.6%)were subjects with idiopathic non-histaminergic angioedema who did not meet the clinical definitionof HAE. No statistically significant treatment effect compared to placebo was observed in anysubgroup.

SPRING study

The safety and efficacy of TAKHZYRO for prophylaxis to prevent HAE attacks in children wereevaluated in an open-label, multicenter, Phase 3 SPRING study. Dosing regimens were based on thefollowing pre-defined age groups: children from 2 to less than 6 years of age were to receivelanadelumab 150 mg every 4 weeks and children from 6 to less than 12 years of age were to receivelanadelumab 150 mg every 2 weeks. The overall treatment period was 52 weeks, equally divided into

Treatment Period A and B. The study enrolled 21 paediatric subjects who had a baseline attack rate of≥ 1 attack per 3 months (12 weeks) and a confirmed diagnosis of type I or II HAE.

In Treatment Period A, subjects aged 2 to < 6 years (n = 4) and 6 to < 12 years (n = 17) receivedlanadelumab 150 mg every 4 weeks and 150 mg every 2 weeks, respectively. The youngest patientincluded in the study was 3.5 years old.

In Treatment Period B, subjects receiving lanadelumab 150 mg every 2 weeks (i.e., subjects 6 to lessthan 12 years of age) could reduce dosing to 150 mg every 4 weeks if they were well-controlled (e.g.,attack free) for 26 weeks with lanadelumab treatment. Seven subjects in the 6 to less than 12 years agegroup switched to 150 mg every 4 weeks during Treatment Period B, and one subject (enrolled in the2 to less than 6 years age group) turned 6 years of age during Treatment Period A and switched to150 mg every 2 weeks during Treatment Period B after experiencing recurrent attacks.

The total exposure was 5.5 patient-years in the “every 4 weeks”-dosing regimen group (age range3.5-10.4 years) and 14.47 patient-years in the “every 2 weeks”-dosing regimen group (age range6-10.9 years).

The TAKHZYRO dose regimen in both age groups produced reduction in mean HAE attack ratecompared to baseline and an increased percentage of attack-free subjects in Treatment Period A(Table 6). Similar results were observed for the overall, 52-week treatment period.

Table 6. Results of efficacy measures

TAKHZYRO

Criteria 150 mg 150 mgevery 4 weeksa Totalevery 2 weeksa

Treatment Period A (26 weeks)

N 4 17 21

Baseline attack rate1.9 (1.0) 1.8 (1.6) 1.8 (1.5)(attacks/monthb), mean (SD)

On-treatment attack rateb 0.2 (0.3) 0.1 (0.2) 0.1 (0.2)(attacks/month ), mean (SD)

Attack-free subjects, N (%) 3 (75.0) 14 (82.4) 17 (81.0)a The actual treatment received during the given study period.b Month is defined as 28 days. Attack rates at baseline and on-treatment were calculatedover the 4-12-week observation period and the 26-week treatment Period A, respectively.

Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact onpharmacokinetics, efficacy or safety was observed.

The single and multiple dose pharmacokinetics of lanadelumab have been studied in patients with

HAE. Pharmacokinetics of lanadelumab showed linear dose-exposure response with doses up to400 mg and reproducible exposure following subcutaneous administration up to 12 months. Theabsolute bioavailability of lanadelumab after subcutaneous administration has not been determined. Inthe HELP study, patients treated with 300 mg every 2 weeks presented mean (SD) area under thecurve over the dosing interval at steady-state (AUCtau,ss), maximum concentration at steady-state(Cmax,ss) and minimum concentration at steady-state (Cmin,ss) of 408 µg*day/ml (138),34.4 µg/ml (11.2), and 25.4 µg/ml (9.18), respectively. The anticipated time to reach steady stateconcentration was approximately 70 days.

Following subcutaneous administration, the time to maximum concentration is approximately 5 days.

The site of subcutaneous injection (thigh, arm, or abdomen) and self-administration did not affect theabsorption of lanadelumab.

The mean (SD) volume of distribution of lanadelumab in patients with HAE is 14.5 litres (4.53).

Lanadelumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.

Lanadelumab has a mean (SD) total body clearance of 0.0297 L/h (0.0124) and a terminal eliminationhalf-life of approximately 14 days.

No dedicated studies have been conducted to evaluate the pharmacokinetics of lanadelumab in specialpatient populations including gender, or pregnant women.

Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influencethe pharmacokinetics of lanadelumab. Body weight was identified as an important covariatedescribing the variability of clearance and volume of distribution of lanadelumab.

Following subcutaneous administration of 150 mg every 4 weeks (2 to less than 6 years of age) and150 mg every 2 weeks (6 to less than 12 years of age), the overall exposure (i.e., Cavg,ss) tolanadelumab was similar compared with adult and adolescent (12 to less than 18 years of age) patientswho received TAKHZYRO 300 mg every 2 weeks (ratio to adults ranged from 0.8 to 1.11).

As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment orhepatic impairment is not expected to influence clearance of lanadelumab.

Accordingly, in a population pharmacokinetic analysis, renal impairment (estimated GFR:60 to 89 ml/min/1.73 m2 [mild, N = 98] and 30 to 59 ml/min/1.73 m2 [moderate, N = 9]) had no effecton the clearance or volume of distribution of lanadelumab.

In repeat-dose studies evaluating once weekly subcutaneous injection in both rats (up to 28 days) andcynomolgus monkeys (up to 6 months) lanadelumab was well-tolerated at doses of up to and including50 mg/kg (highest dose tested) with no organs of toxicity identified. Exposures in cynomolgusmonkeys following 6 months of administration were approximately 23-fold greater than that noted at300 mg every 2 weeks based on AUC.

Lanadelumab is not expected to interact directly with DNA or other chromosomal material, as it ismade up entirely of naturally occurring amino acids and contains no inorganic or synthetic linkers orother nonprotein portions; therefore no genotoxicity evaluation has been conducted.

Carcinogenicity has not been evaluated in animals as based on the weight of evidence approach,lanadelumab is considered to have a low risk for carcinogenicity.

The effects of lanadelumab on fertility were evaluated in sexually mature cynomolgus monkeys. In a13-week study, once weekly subcutaneous administration of lanadelumab had no effects on male orfemale fertility at doses of 10 or 50 mg/kg (highest dose tested). Exposures in sexually maturecynomolgus monkeys in the fertility study were approximately 20-and 22-fold greater than that notedat 300 mg every 2 weeks based on Cmax and AUC, respectively.

In the ePPND study in pregnant cynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg(highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition,embryo-foetal development, survival, growth, and/or postnatal development of offspring. Exposures inthe ePPND study were approximately 32-fold greater than that noted at 300 mg every 2 weeks basedon AUC.

Disodium phosphate dihydrate

Citric acid monohydrate

Histidine

Sodium chloride

Polysorbate 80

Water for injections

Not applicable.

TAKHZYRO 150 mg and 300 mg solution for injection in pre-filled syringe2 years

TAKHZYRO 300 mg solution for injection in pre-filled pen2 years

TAKHZYRO 300 mg solution for injection in vial2 years

The injection should be administered within 2 hours of preparing the dosing syringe. If notadministered immediately after preparation, the syringe may be stored in the refrigerator(2 °C to 8 °C), protected from light and administered within 8 hours.

Chemical and physical in-use stability has been demonstrated for 2 hours at 25 °C and for 8 hours at2 °C to 8 °C. From a microbiological point of view, unless the method of preparation precludes therisks of microbial contamination, the product should be used immediately. If not used immediately,in-use storage times and conditions are the responsibility of the user.

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

Do not freeze.

Keep the solution (pre-filled syringe, pre-filled pen, or vial) in the outer carton in order to protect fromlight.

The solution (pre-filled syringe, pre-filled pen, or vial) may be stored below 25 °C for a single periodof 14 days, but not beyond the expiry date. Do not return TAKHZYRO to refrigerated storage afterstorage at room temperature.

When one pre-filled syringe or pre-filled pen from a multi-pack is removed from refrigeration, returnthe remaining pre-filled syringes or pre-filled pens to the refrigerator until future use when needed.

For storage conditions after first opening of the product in vial, see section 6.3.

TAKHZYRO 150 mg solution for injection in pre-filled syringe.

1 ml of solution in pre-filed syringe with a bromobutyl stopper, 27G x 13 mm staked needle and rigidneedle cap. TAKHZYRO is available as unit packs containing 1 or 2 pre-filled syringes and inmultipacks containing 6 (3 packs of 2) pre-filled syringes.

TAKHZYRO 300 mg solution for injection in pre-filled syringe2 ml of solution in pre-filled syringe with a bromobutyl stopper, 27G x 13 mm staked needle and rigidneedle cap. TAKHZYRO is available as unit packs containing 1 or 2 pre-filled syringes and inmultipacks containing 6 (3 packs of 2) pre-filled syringes.

TAKHZYRO 300 mg solution for injection in pre-filled pen2 ml of solution in pre-filled syringe with a bromobutyl stopper, 27G x 13 mm staked needle and rigidneedle cap contained within a pre-filled pen. TAKHZYRO is available as unit packs containing 1 or2 pre-filled pens and in multipacks containing 6 (3 packs of 2) pre-filled pens.

TAKHZYRO 300 mg solution for injection in vial2 ml of solution in a vial (type I glass) with a coated butyl rubber stopper and an aluminium seal withviolet flip-off cap. TAKHZYRO is available as a single pack containing one 2 ml vial and inmultipacks comprising 2 or 6 cartons, each carton containing 1 vial.

Each pack also contains the following items:

- Empty 3 ml syringe

- 18G vial access needle

- 27G x 13 mm injection needle

Not all pack sizes may be marketed.

Lanadelumab is provided in single use pre-filled syringes, pre-filled pens, and vials.

Before use, TAKHZYRO solution should be visually inspected for appearance. The solution should beclear or slightly yellow. Solutions that are discoloured or contain particles should not be used.

Avoid vigorous agitation.

Administration steps

TAKHZYRO 150 mg solution for injection in pre-filled syringe

After removing the single use pre-filled syringe from the refrigerator, wait 15 minutes before injectingto allow the solution to reach room temperature. Caregiver should inject TAKHZYRO subcutaneouslyinto the abdomen, thigh, or upper arm (see section 4.2).

TAKHZYRO 300 mg solution for injection in pre-filled syringe

After removing the single use pre-filled syringe from the refrigerator, wait 15 minutes before injectingto allow the solution to reach room temperature. Inject TAKHZYRO subcutaneously into theabdomen, thigh, or upper arm (see section 4.2).

Each pre-filled syringe is for single use only. Discard the pre-filled syringe after injection iscompleted.

TAKHZYRO 300 mg solution for injection in pre-filled pen

After removing the single use pre-filled pen from the refrigerator, wait 30 minutes before injecting toallow the solution to reach room temperature. Inject TAKHZYRO subcutaneously into the abdomen,thigh, or upper arm (see section 4.2).

Each pre-filled pen is for single use only. Discard the pre-filled pen after injection is completed.

TAKHZYRO 300 mg solution for injection in vial

Using aseptic technique, withdraw the prescribed dose of TAKHZYRO from the vial into the syringeusing an 18 gauge needle.

Change the needle on the syringe to a 27 gauge needle or other needle suitable for subcutaneousinjection. Inject TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm (see section 4.2).

Discard the vial with any unused contents.

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

All needles, syringes and pens should be disposed of in a sharps container.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

IrelandmedinfoEMEA@takeda.com

EU/1/18/1340/001

EU/1/18/1340/002

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EU/1/18/1340/004

EU/1/18/1340/005

EU/1/18/1340/006

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Date of first authorisation: 22 November 2018

Date of latest renewal: 11 August 2023

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

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