CABLIVI 10mg powder + solvent for injection medication leaflet

Cablivi 10 mg powder and solvent for solution for injection

Each vial of powder contains 10 mg of caplacizumab*.

Each pre-filled syringe of solvent contains 1 mL of water for injections.

* Caplacizumab is a humanised bivalent Nanobody produced in Escherichia coli by recombinant

DNA technology.

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, colourless liquid.

Cablivi is indicated for the treatment of adults and adolescents of 12 years of age and older weighingat least 40 kg experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), inconjunction with plasma exchange and immunosuppression.

Treatment with Cablivi should be initiated and supervised by physicians experienced in themanagement of patients with thrombotic microangiopathies.

First dose

Intravenous injection of 10 mg of caplacizumab prior to plasma exchange.

Daily subcutaneous administration of 10 mg of caplacizumab after completion of each plasmaexchange for the duration of daily plasma exchange treatment, followed by daily subcutaneousinjection of 10 mg of caplacizumab for 30 days after stopping daily plasma exchange treatment.

If at the end of this period there is evidence of unresolved immunological disease, it is recommendedto optimise the immunosuppression regimen and continue daily subcutaneous administration of 10 mgof caplacizumab until the signs of underlying immunological disease are resolved (e.g. sustainednormalisation of ADAMTS13 activity level).

In the clinical development program, caplacizumab has been administered daily for up to 71 daysconsecutively. Data on re-treatment with caplacizumab are available (see section 5.1).

The first dose of caplacizumab should be administered intravenously before the initial plasmaexchange. If the administration of the first intravenous dose of caplacizumab is missed and plasmaexchange is already administered, the first caplacizumab dose should still be administeredintravenously after the plasma exchange is complete and the next dose should be administeredsubcutaneously on the following day according to the usual dosing schedule. If a dose of Cablivi ismissed, it can be administered within 12 hours. If more than 12 hours have passed since the dose wasto have been given, the missed dose should NOT be administered and the next dose should beadministered per the usual dosing schedule.

No dose adjustment is necessary for patients with renal impairment (see section 5.2).

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2). See section 4.4for special considerations in patients with severe hepatic impairment.

While experience with the use of caplacizumab in the elderly is limited, there is no evidence to suggestthat dose adjustment or special precautions are needed for elderly patients (see section 5.2).

The safety and efficacy of caplacizumab in the paediatric population have not been established inclinical studies. The posology of Cablivi in adolescents of 12 years of age and older weighing at least40 kg is the same as in adults (see section 5.2). No recommendations can be made on the posology of

Cablivi for paediatric patients below 40 kg of body weight.

The first dose of Cablivi is to be administered as an intravenous injection. Subsequent doses are to beadministered via subcutaneous injection in the abdomen.

Injections into the area around the navel should be avoided and consecutive injections should not beadministered in the same abdominal quadrant.

Patients or caregivers may inject the medicinal product after proper training in the subcutaneousinjection technique.

For instructions on reconstitution of Cablivi before administration, see section 6.6.

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.

Cablivi increases the risk of bleeding. Cases of major bleeding, including life-threatening and fatalbleeding have been reported in patients receiving caplacizumab, mainly in those using concomitantanti-platelet agents or anticoagulants. Caplacizumab should be used with caution in patients withunderlying conditions that may predispose them to a higher risk of bleeding.

In case of clinically significant bleeding, treatment with Cablivi should be interrupted. If needed, theuse of von Willebrand Factor concentrate could be considered to correct haemostasis. Cablivi shouldonly be restarted upon the advice of a physician experienced in the management of thromboticmicroangiopathies. If Cablivi is restarted, monitor closely for signs of bleeding.

In the setting of concomitant use of oral anticoagulants, anti-platelet agents, thrombolytic agents orheparin

The risk of bleeding is increased with concomitant use of Cablivi with other medicinal productsaffecting haemostasis and coagulation. Initiation or continuation of treatment with oral anticoagulants(e.g., vitamin K antagonists or direct oral anticoagulants [DOAC] such as thrombin inhibitors or factor

Xa inhibitors), anti-platelet agents, thrombolytic agents such as urokinase, tissue plasminogenactivator (t-PA) (e.g. alteplase) or heparin requires careful consideration and close clinical monitoring.

Due to a potential increased risk of bleeding, use of Cablivi in patients with underlying coagulopathies(e.g. haemophilia, other coagulation factor deficiencies) must be accompanied by close clinicalmonitoring.

If a patient is to undergo elective surgery, an invasive dental procedure or other invasive interventions,the patient must be advised to inform the physician or dentist that they are using caplacizumab and it isrecommended to withhold treatment for at least 7 days before the planned intervention. The patientmust also notify the physician who supervises the treatment with caplacizumab about the plannedprocedure. After the risk of surgical bleeding has resolved, and caplacizumab is resumed, the patientshould be monitored closely for signs of bleeding.

If emergency surgery is needed, the use of von Willebrand Factor concentrate is recommended tocorrect haemostasis.

No formal study with caplacizumab has been conducted in patients with severe acute or chronichepatic impairment and no data regarding the use of caplacizumab in these populations are available.

Use of Cablivi in this population requires a benefit/risk assessment and close clinical monitoring.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially“sodium-free”.

No interaction studies evaluating use of caplacizumab with oral anticoagulants (e.g. vitamin Kantagonists, direct oral anticoagulants [DOAC] such as thrombin inhibitors or factor Xa inhibitors),antiplatelet agents, thrombolytic agents such as urokinase, tPA (e.g. alteplase) or heparin have beenperformed (see section 4.4 In the setting of concomitant use of oral anticoagulants, anti-plateletagents, thrombolytic agents or heparin).

There are no data on the use of caplacizumab in pregnant women. Studies in guinea pigs showed noeffect of caplacizumab on the dams or foetuses (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Cablivi during pregnancy.

There are no data on the use of caplacizumab in breastfeeding women. It is unknown whethercaplacizumab is excreted in human milk. A risk to the child cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to abstain/discontinue from therapy,taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

The effects of caplacizumab on fertility in humans are unknown. In animal toxicology studies, noimpact of caplacizumab on male and female fertility parameters was observed (see section 5.3).

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

The most frequent adverse reactions in the TITAN and HERCULES clinical studies were epistaxis,headache and gingival bleeding. The most common serious adverse reaction was epistaxis.

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).

Table 1 . List of adverse reactions in TITAN and HERCULES studies

MedDRA System organ class Very common Common

Nervous system disorders Headache Cerebral infarction

Eye disorders Eye Haemorrhage*

Vascular disorders Haematoma*

Respiratory, thoracic and mediastinal disorders Epistaxis* Dyspnoea, Haemoptysis*

Gastrointestinal disorders Gingival Haematemesis*,bleeding* haematochezia*, melaena*,upper gastrointestinalhaemorrhage*,haemorrhoidalhaemorrhage*, rectalhaemorrhage *, abdominalwall haematoma*

Skin and subcutaneous tissue disorders Urticaria

Musculoskeletal and connective tissue disorders Myalgia

Renal and urinary disorders Haematuria*

Reproductive system and breast disorders Menorrhagia*, vaginalhaemorrhage*

General disorders and administration site Pyrexia, Fatigue Injection site haemorrhage*,conditions injection site pruritus,injection site erythema,injection site reaction

Injury, poisoning and procedural complications Subarachnoid haemorrhage*

*Bleeding events: see below

In clinical studies, bleeding events occurred in different body systems, independent of treatmentduration. In the postmarketing setting, cases of major bleeding, including life-threatening and fatalbleeding have been reported in patients receiving caplacizumab, mainly in those using concomitantanti-platelet agents or anticoagulants. In case of clinically significant bleeding, consider actionsoutlined in sections 4.4 and 4.9.

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 case of overdose, based on the pharmacological action of caplacizumab, there is the potential for anincreased risk of bleeding. Close monitoring for signs and symptoms of bleeding is recommended.(see section 4.4).

Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX07.

Caplacizumab is a humanised bivalent Nanobody that consists of two identical humanised buildingblocks (PMP12A2hum1), genetically linked by a three-alanine linker, targeting the A1-domain of von

Willebrand factor and inhibiting the interaction between von Willebrand factor and platelets. As such,caplacizumab prevents the ultra large von Willebrand factor-mediated platelet adhesion, which ischaracteristic of aTTP. It also affects the disposition of von Willebrand factor, leading to transientreductions of total von Willebrand factor antigen levels and to concomitant reduction of factor VIII:Clevels during treatment.

The pharmacologic effect of caplacizumab on target inhibition was assessed using two biomarkers forvon Willebrand factor activity; ristocetin-induced platelet aggregation (RIPA) and ristocetin cofactor(RICO). Full inhibition of von Willebrand factor-mediated platelet aggregation by caplacizumab isindicated by RIPA and RICO levels dropping below 10% and 20%, respectively. All clinical studieswith caplacizumab demonstrated rapid decreases in RIPA and/or RICO levels after the start of thetreatment, with recovery to baseline levels within 7 days of discontinuation. The 10 mg subcutaneousdose in patients with aTTP elicited full inhibition of von Willebrand factor-mediated plateletaggregation, as evidenced by RICO levels of < 20% throughout the treatment period.

The pharmacologic effect of caplacizumab on target disposition was measured using von Willebrandfactor antigen and factor VIII clotting activity (factor VIII:C) as biomarkers. Upon repeatedadministration of caplacizumab, a decrease of 30-50% in von Willebrand factor antigen levels wasobserved in clinical studies, reaching a maximum within 1-2 days of treatment. Because von

Willebrand factor acts as a carrier for factor VIII, reduced von Willebrand factor antigen levelsresulted in a similar reduction in factor VIII:C levels. The reduced von Willebrand factor antigen and

FVIII:C levels were transient and returned to baseline upon cessation of treatment.

The efficacy and safety of caplacizumab in adults experiencing an episode of aTTP were establishedin 3 randomised, controlled studies: Phase III study ALX0681-C301 “HERCULES”, Phase III study

ALX0681-C302 “Post-HERCULES” and Phase II study ALX-0681-2.1/10 “TITAN”.

Study ALX0681-C301 (HERCULES)

In this double-blind, placebo-controlled study, patients with an episode of aTTP were randomised 1:1to receive either caplacizumab or placebo in addition to daily plasma exchange andimmunosuppression. Patients received a single intravenous bolus injection of 10 mg caplacizumab orplacebo prior to the first plasma exchange on study. This was followed by daily subcutaneousinjections of 10 mg caplacizumab or placebo after completion of each plasma exchange for theduration of the daily plasma exchange period and for 30 days thereafter. If at the end of this treatmentperiod there was evidence of persistent underlying disease activity (indicative of an imminent risk forrecurrence), treatment could be extended weekly for a maximum of 4 weeks, together withoptimisation of immunosuppression. If a recurrence occurred while on study drug treatment, patientswere switched to open-label caplacizumab. They were again treated for the duration of daily plasmaexchange and for 30 days thereafter. If at the end of this treatment period there was evidence ofongoing underlying disease, open-label treatment with caplacizumab could be extended weekly for amaximum of 4 weeks, together with optimisation of immunosuppression. Patients were followed for1 month after discontinuation of treatment. In case of recurrence during the follow up period (i.e. afterall study drug treatment had been stopped), there was no re-initiation of study drug and the recurrencewas to be treated according to the standard of care.

In this study, 145 patients experiencing an episode of aTTP were randomised (72 to caplacizumab and73 to placebo). Patient age ranged from 18 to 79 years, with a mean of 46 years. Half of the patientswere experiencing their first episode of aTTP. Baseline disease characteristics were typical of aTTP.

The median treatment duration with caplacizumab in the double blind period was 35 days.

Treatment with caplacizumab resulted in a statistically significant reduction in time to platelet countresponse (p<0.01). Patients treated with caplacizumab were 1.55 times more likely to achieve plateletcount response at any given time point, compared to patients treated with placebo.

Treatment with caplacizumab resulted in a 74% reduction in the composite endpoint of the percentageof patients with aTTP-related death (0/72; placebo 3/73), exacerbation of aTTP (3/72; placebo 28/73),or at least one major thromboembolic event during study drug treatment (6/72; placebo 6/73)(p<0.0001). There were no deaths in the caplacizumab group and 3 deaths in the placebo group duringthe study drug treatment period.

The proportion of patients with a recurrence of aTTP (exacerbation or relapse) in the overall studyperiod (including the 28 day follow-up after discontinuation of study drug treatment) was 67% lowerin the caplacizumab group (9/72; relapse : 6/72) compared to the placebo group (28/73; relapse 0/73)(p<0.001).

No patients treated with caplacizumab (0/72) were refractory to treatment (defined as absence ofplatelet count doubling after 4 days of standard treatment and elevated LDH) compared to threepatients treated with placebo (3/73).

Treatment with caplacizumab reduced the mean number of days of plasma exchange, the volume ofplasma used, the mean length of Intensive Care Unit stay and the mean length of hospitalizationduring the study drug treatment period.

Table 2. Summary of number of days of plasma exchange (PE), total volume of PE used, numberof days in hospital and ICU in the ITT population

Placebo Caplacizumab

Number of days of Plasma Exchange (days) N 73 71

Mean (SE) 9.4 (0.81) 5.8 (0.51)

Total volume of plasma used (litre) N 73 71

Mean (SE) 35.93 (4.17) 21.33 (1.62)

Length of hospitalization (days) N 73 71

Mean (SE) 14.4 (1.22) 9.9 (0.70)

Number of days in ICU N 27 28

Mean (SE) 9.7 (2.12) 3.4 (0.40)

N: number of patients evaluated; SE: Standard Error; ICU: Intensive Care Unit

Study ALX0681-C302 (Post-HERCULES)

The Post-HERCULES study was a Phase III, 36-month follow-up study from HERCULES (parentstudy) to evaluate the long-term outcomes as well as the safety and efficacy of repeat use ofcaplacizumab in patients who experienced a recurrence of aTTP. Overall, 104 out of 108 patients whocompleted the parent study (75 who received caplacizumab in HERCULES, of whom 49 did not haveaTTP recurrences prior to the enrollment in Post-HERCULES, and 29 who had received only standardof care (SoC) in HERCULES) entered the Post-HERCULES study in which patients attended twiceyearly visits. Patients could receive open-label (OL) caplacizumab for the treatment of an aTTPrecurrence along with SoC.

Overall, 19 patients had at least 1 recurrence of aTTP and six patients had a 2nd recurrence. Forpatients treated with caplacizumab for a recurrence, all events of aTTP from the first recurrenceepisode were resolved or were resolving at the end of the study.

The overall safety profile of caplacizumab re-treatment was consistent with that observed in otherclinical studies of aTTP.

In clinical studies, up to 11% of patients developed treatment-emergent anti-drug antibodies (ADA).

No impact on clinical efficacy was observed and no serious adverse events were found to beassociated with these ADA responses.

See section 4.2 for information on paediatric use and section 5.2 for results of modelling andsimulation studies for paediatric patients. There are no clinical data for paediatric patients.

The pharmacokinetics of caplacizumab have been investigated in healthy subjects after singleintravenous infusions and after single and repeated subcutaneous injections. Pharmacokinetics inpatients with aTTP were investigated upon single intravenous and repeated subcutaneous injections.

Pharmacokinetics of caplacizumab appear as non-dose proportional, as characterized bytarget-mediated disposition. In healthy volunteers receiving 10 mg caplacizumab subcutaneously oncedaily, the maximum concentration was observed at 6-7 hours post-dose and steady-state was reachedfollowing the first administration, with minimal accumulation.

After subcutaneous administration, caplacizumab is rapidly and almost completely absorbed(estimated F> 0.901) in the systemic circulation.

After absorption, caplacizumab binds to the target and distributes to well perfused organs. In patientswith aTTP the central volume of distribution was estimated at 6.33 L.

Biotransformation/Elimination

The pharmacokinetics of caplacizumab depend on the expression of the target von Willebrand factor.

Higher levels of von Willebrand factor antigen, such as in patients with aTTP, increase the fraction ofdrug-target complex retained in the circulation. The t1/2 of caplacizumab is, therefore, concentration-and target level-dependent. Target-bound caplacizumab is assumed to be catabolised within the liver,whereas unbound caplacizumab is assumed to be renally cleared.

The pharmacokinetics of caplacizumab were determined using a population pharmacokinetic analysis.

Body weight affected the pharmacokinetics of caplacizumab (see below, Paediatric population).

Differences in the different subpopulations were investigated. In studied populations; gender, age,blood group and race did not affect the pharmacokinetics of caplacizumab to a clinically significantextent.

No formal study of the effect of hepatic or renal impairment on the pharmacokinetics of caplacizumabhas been conducted. In the population PK/PD model, renal function (CRCL) had a statisticallysignificant effect resulting in limited increase in predicted exposure (AUCss) in severe renalimpairment. In the clinical studies of patients with TTP, those with renal impairment did not showadditional risk of adverse events.

Based on data pooled from clinical studies in adults, a pharmacokinetic-pharmacodynamic (PK/PD)population model was developed, describing the interaction between caplacizumab and von

Willebrand factor antigen (vWF:Ag), in different adult populations following intravenous andsubcutaneous administration of caplacizumab at various dose levels. For children aged 2 to below18 years of age, simulations were performed based on this PK/PD model predicting that exposure andsuppression of vWF:Ag are expected to be similar to those in adults when 10 mg/day is used inchildren with a bodyweight of ≥40 kg, and when 5 mg/day is used in children with a bodyweight of<40 kg.

Consistent with its mode of action, toxicology studies of caplacizumab have shown an increasedbleeding tendency in guinea pigs (haemorrhagic subcutaneous tissue at the injection sites) andcynomolgus monkeys (haemorrhagic subcutaneous tissue at the injection sites, nose bleed,exaggerated menstrual bleeding, haematoma at sites of animal handling or experimental procedures,prolonged bleeding at injection sites). Furthermore, pharmacology-related decreases of von

Willebrand factor antigen, and consequently factor VIII:C, were noted in cynomolgus monkeys and, toa lesser extent for factor VIII:C, in guinea pigs.

An embryo-foetal development study was conducted in guinea pigs, with no reported signs of toxicity.

A follow-up toxicokinetic study in pregnant guinea pigs assessed exposure of caplacizumab in thedams and foetuses. The results indicated exposure to caplacizumab in dams and, to a much lesserextent, foetuses, with no reported effects on foetal development. Foetal exposure to caplacizumab inprimates and humans remains uncertain, as proteins lacking an Fc portion are not thought to freelypass the placental barrier.

No studies have been performed to evaluate the mutagenic potential of caplacizumab, as such tests arenot relevant for biologicals. Based on a carcinogenicity risk assessment, dedicated studies were notdeemed necessary.

Dedicated animal studies assessing the effects of caplacizumab on male and female fertility have notbeen performed. In repeat-dose toxicity tests in cynomolgus monkeys, no impact of caplacizumab onfertility parameters in male (testicular size, sperm function, histopathological analysis of testis andepididymis) and female (histopathological analysis of reproductive organs, periodic vaginal cytology)animals was observed.

Sucrose

Citric acid anhydrous (E 330)

Trisodium citrate dihydrate (E 331)

Polysorbate 80

Water for injections

In the absence of compatibility studies, Cablivi must not be mixed with other medicinal products.

Unopened vial5 years.

Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C.

From a microbiological point of view, unless the method of reconstitution precludes the risk ofmicrobial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of user.

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

Do not freeze.

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

Cablivi may be stored at a temperature not above 25 °C for a single period of up to 2 months, but notbeyond the expiry date. Do not return Cablivi to refrigerated storage after storage at room temperature.

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

Vial (type I glass) with a stopper (butyl rubber), a seal (aluminium) and a cap (polypropylene),containing 10 mg of caplacizumab.

Pre-filled syringe (type I glass cartridge closed with a bromobutyl rubber stopper) with 1 mL of waterfor injections.

* Single pack containing 1 vial with powder, 1 pre-filled syringe with solvent, 1 vial adapter, 1hypodermic needle (30 gauge) and 2 alcohol swabs.

* Multipack containing 7 single packs.

* Multidose pack containing 7 vials with powder, 7 pre-filled syringes with solvent, 7 vial adapters,7 hypodermic needles (30 gauge) and 14 alcohol swabs.

Not all pack sizes may be marketed.

For both intravenous and subcutaneous administration, reconstitute the powder contained in the vialusing the vial adapter and all solvent in the pre-filled syringe. The solvent should be added slowly andmixed gently to avoid foaming of the solution. Allow the vial with connected syringe to stand on asurface for 5 minutes at room temperature.

The reconstituted solution is clear, colourless, or slightly yellowish. It must be visually inspected forparticulate matter. Do not use solution exhibiting particulates.

Transfer the entire volume of the reconstituted solution back to the glass syringe and immediatelyadminister the entire volume of the syringe (see section 6.3).

Cablivi is for single use only. Any unused medicinal product or waste material should be disposed ofin accordance with local requirements.

Ablynx NV

Technologiepark 219052 Zwijnaarde

Belgium

EU/1/18/1305/001

EU/1/18/1305/002

EU/1/18/1305/003

Date of first authorisation: 31 August 2018

Date of latest renewal: 17 April 2023

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

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