Consumer medicine information

Cablivi

Caplacizumab

BRAND INFORMATION

Brand name

Cablivi

Active ingredient

Caplacizumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cablivi.

SUMMARY CMI

Cablivi™

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Cablivi?

Cablivi contains the active ingredient caplacizumab. Cablivi is used to treat an episode of acquired thrombotic thrombocytopenic purpura (aTTP).

For more information, see Section 1. Why am I using Cablivi? in the full CMI.

2. What should I know before I use Cablivi?

Do not use if you have ever had an allergic reaction to caplacizumab or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Cablivi? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Cablivi and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Cablivi?

  • Treatment with Cablivi is started by a doctor experienced in blood disorders, before plasma exchange treatment begins.
  • Subsequent doses will be given after each daily plasma exchange and then for at least 30 days after plasma exchange treatment has finished.
  • If your doctor decides you or your caregiver can inject Cablivi, they will train you on how to do so safely.

More instructions can be found in Section 4. How do I use Cablivi? in the full CMI.

5. What should I know while using Cablivi?

Things you should do
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine
  • Remind any doctor, dentist or pharmacist you visit that you are using Cablivi.
Things you should not do
  • Do not use Cablivi if you think that it has been frozen or exposed to temperatures above 30°C.
Looking after your medicine
  • Before use, keep Cablivi in a refrigerator where the temperature is between 2-8°C.
  • It may be stored at room temperature up to 25°C for a single period of up to 2 months. Do not return Cablivi to refrigerated storage after storage at room temperature.
  • Keep Cablivi in the original carton to protect from light.
  • Do not allow it to freeze. Discard if frozen.

For more information, see Section 5. What should I know while using Cablivi? in the full CMI.

6. Are there any side effects?

Serious side effects may include unusual or excessive bleeding events and stroke. Common side effects may include bleeding nose or gums, as well as fever, headache, fatigue or hives.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

Cablivi™

Active ingredient: caplacizumab

Consumer Medicine Information (CMI)

This leaflet provides important information about using Cablivi. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Cablivi.

Where to find information in this leaflet:

1. Why am I using Cablivi?
2. What should I know before I use Cablivi?
3. What if I am taking other medicines?
4. How do I use Cablivi?
5. What should I know while using Cablivi?
6. Are there any side effects?
7. Product details

1. Why am I using Cablivi?

Cablivi contains the active ingredient caplacizumab.

It is used to treat an episode of acquired thrombotic thrombocytopenic purpura (aTTP).

aTTP is a rare blood clotting disorder where blood clots form in small blood vessels. These clots can block blood vessels and damage the brain, heart, kidneys or other organs.

Cablivi prevents the formation of these blood clots by stopping platelets in the blood from clumping together.

It can also reduce the risk of experiencing another episode of aTTP soon after the first.

2. What should I know before I use Cablivi?

Warnings

Do not use Cablivi if:

  • you are allergic to caplacizumab, or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
  • you notice any particulate matter or discolouration in the syringe prior to injection.

Check with your doctor if you:

  • bleed excessively or experience unusual symptoms such as headache, shortness of breath, tiredness, drop in blood pressure or fainting during treatment. Your doctor may ask you to stop the treatment.
  • are using anticoagulants such as Vitamin K antagonists, rivaroxaban, apixaban (which treat blood clots).
  • are using anti-platelet agents such as aspirin, or low molecular weight heparin (which prevent blood clots).
  • have a bleeding disorder, such as haemophilia.
  • have severely reduced liver function.
  • are going to have an operation or dental treatment. Your doctor will decide if it can be postponed or if you should stop Cablivi before your surgery or dental treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

If you become pregnant while using this medicine, tell your doctor immediately.

Use in children

  • There is not enough information to recommend the use of this medicine for children under the age of 18 years.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Cablivi and affect how it works:

  • medicines used to treat blood clots such as vitamin K antagonists, rivaroxaban, apixaban
  • anti-platelet agents, medicines used to prevent blood clots, such as aspirin, low molecular weight heparin.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Cablivi.

4. How do I use Cablivi?

How much to use

First dose

  • The recommended treatment is 1 vial injected into a vein by a healthcare professional. The injection will be given before starting plasma exchange.

Subsequent doses

  • The recommended treatment is 1 vial once daily as a subcutaneous injection (under the skin of the belly).

When to use Cablivi

  • The injection will be given after each daily plasma exchange for as long as you are having plasma exchange treatment.
  • After the daily plasma exchange treatment finishes, your treatment with Cablivi will continue for at least 30 days with injection of 1 vial once daily.
  • Your doctor may ask you to continue daily treatment until the underlying signs of your disease are resolved.

How to inject Cablivi

  • Treatment with Cablivi is started by a doctor experienced in blood disorders.
  • Your doctor may decide that you or your caregiver can inject Cablivi. In this case, your doctor or healthcare provider will train you or your caregiver on how to use Cablivi.
  • Read carefully the "Instructions for Use" leaflet provided in the carton. If you do not understand the instructions, ask your doctor or pharmacist for help.

If you forget to use Cablivi

Cablivi should be used regularly at the same time each day.

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, inject it as soon as you remember, and then go back to using Cablivi as you would normally.

Do not take a double dose to make up for the dose you missed.

If you use too much Cablivi

If you think that you have used too much Cablivi, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Cablivi?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Cablivi.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine.

Call your doctor straight away if you:

  • become pregnant while using this medicine

Remind any doctor, dentist or pharmacist you visit that you are using Cablivi.

Things you should not do

  • Do not use Cablivi if you think that it has been frozen or exposed to temperatures above 30°C.
  • Do not use Cablivi to treat other complaints.
  • Do not give the medicine to anyone else, even if they have the same condition as you
  • Do not stop using Cablivi without checking with your doctor.

Looking after your medicine

  • Before use, keep Cablivi in a refrigerator where the temperature is between 2-8°C.
  • Cablivi may be stored at room temperature up to 25°C for a single period of up to 2 months. Do not return Cablivi to refrigerated storage after storage at room temperature.
  • Keep Cablivi in the original carton to protect from light.
  • Do not allow it to freeze. Discard if frozen.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

When to discard your medicine

After injecting Cablivi, immediately throw away the used pre-filled syringe and vial in a sharps container as instructed by your doctor or pharmacist.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Injection site-related:
  • redness
  • rash
  • itching
  • bleeding
Bleeding-related:
  • bleeding gums
  • nose bleeds
Other:
  • fever
  • tiredness
  • headache
  • muscle pain
  • hives
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Bleeding-related:
  • bleeding that may be serious or life-threatening
  • long or excessive bleeding
  • severe, sudden-onset headache with vomiting, decreased level of consciousness, fever and sometimes seizures and neck stiffness/pain. This could indicate bleeding on the brain.
  • bleeding from your eye
  • vomiting blood
  • blood in the stools
  • black, tar-like stools
  • bleeding from the stomach
  • bleeding haemorrhoids
  • rectal (back passage) bleeding
  • blood in the urine
  • excessive menstrual bleeding
  • vaginal bleeding
  • coughing blood
  • bruising
  • shortness of breath
Other:
  • Stroke
Allergic reaction-related:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Cablivi contains

Active ingredient
(main ingredient)		Caplacizumab 10 mg
Other ingredients
(inactive ingredients)		sucrose
citric acid
sodium citrate dihydrate
polysorbate 80

Do not take this medicine if you are allergic to any of these ingredients.

What Cablivi looks like

Cablivi is a freeze-dried white powder for reconstitution with diluent for injection. Following reconstitution, the solution is clear, colourless or slightly yellowish.

Cablivi comes in a carton containing:

  • 1 vial with caplacizumab powder
  • 1 pre-filled syringe with diluent
  • 1 vial adaptor
  • 1 needle
  • 2 alcohol swabs.

(AUST R 318058)

Who distributes Cablivi

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall No: 1800 818 806

This leaflet was prepared in December 2021.
cablivi-ccdsv4-cmiv3-03dec21

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Cablivi

Active ingredient

Caplacizumab

Schedule

S4

 

1 Name of Medicine

Caplacizumab.

2 Qualitative and Quantitative Composition

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 List of Excipients.

3 Pharmaceutical Form

Powder and solvent for solution for injection.
White lyophilised powder.
The solvent is a clear, colourless liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Cablivi is indicated for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression.

4.2 Dose and Method of Administration

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

Posology.

First dose.

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

Subsequent doses.

Daily subcutaneous administration of 10 mg of caplacizumab after completion of each plasma exchange for the duration of daily plasma exchange treatment, followed by daily subcutaneous injection 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 recommended to optimise the immunosuppression regimen and continue daily subcutaneous administration of 10 mg of caplacizumab until the signs of underlying immunological disease are resolved (e.g. sustained normalisation of ADAMTS13 activity level).
In the clinical development program, caplacizumab has been administered daily for up to 65 days. No data on re-treatment with caplacizumab are available.

Missed dose.

If a dose of Cablivi is missed, it can be administered within 12 hours. If more than 12 hours have passed since the dose was to have been given, the missed dose should not be administered and the next dose should be administered per the usual dosing schedule.

Special populations.

Renal impairment.

No dose adjustment is necessary for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

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

Elderly.

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

Paediatric population.

The safety and efficacy of caplacizumab in the paediatric population have not yet been established. No data are available.

Method of administration.

The first dose of Cablivi is to be administered as an intravenous injection. Subsequent doses are to be administered via subcutaneous injection in the abdomen.
Injections into the area around the navel should be avoided and consecutive injections should not be administered in the same abdominal quadrant.
Patients or caregivers may inject the medicinal product after proper training in the subcutaneous injection technique.
For both intravenous and subcutaneous administration, reconstitute the powder contained in the vial using the vial adapter and all solvent in the pre-filled syringe. The solvent should be added slowly and mixed gently to avoid foaming of the solution. Allow the vial with connected syringe to stand on a surface for 5 minutes at room temperature.
The reconstituted solution is clear, colourless, or slightly yellowish. It must be visually inspected for particulate matter. Do not use solution exhibiting particulates.
Transfer the entire volume of the reconstituted solution back to the glass syringe and immediately administer the entire volume of the syringe (see Section 6.3 Shelf Life).
Cablivi is for single use in one patient only. Discard any residue.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Bleeding.

Cablivi increases the risk of bleeding. Cases of major bleeding, including life-threatening and fatal bleeding have been reported in patients receiving caplacizumab, mainly in those using concomitant anti-platelet agents or anticoagulants. Caplacizumab should be used with caution in patients with underlying conditions that may predispose them to a higher risk of bleeding.
In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal haemorrhage, and metrorrhagia were each reported in 1% of subjects. Overall, bleeding events occurred in approximately 58% of patients on Cablivi versus 43% of patients on placebo.
Active clinically significant bleeding. In case of active, clinically significant bleeding, treatment with Cablivi should be interrupted. If needed, the use of von Willebrand Factor-containing concentrate could be considered to correct haemostasis. Cablivi should only be restarted upon the advice of a physician experienced in the management of thrombotic microangiopathies.
Increased risk of bleeding.

In the setting of concomitant use of oral anticoagulants, anti-platelet agents, thrombolytic drugs or heparin (both unfractionated heparin (UFH) and low molecular weight heparin (LMWH).

The risk of bleeding is increased with concomitant use of Cablivi with drugs affecting 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 drugs such as urokinase, tissue plasminogen activator (t-PA) (e.g. alteplase) or heparin (both UFH and LMWH) requires a benefit/risk assessment and close clinical monitoring.

In patients with coagulopathies.

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

In patients undergoing surgery.

If a patient is to undergo elective surgery or a dental procedure, the patient should be advised to inform the physician or dentist that they are using Cablivi, and treatment should be stopped at least 7 days before the planned intervention. The patient should also notify the physician who supervises the treatment with Cablivi about the planned procedure.
If emergency surgery is needed, the use of von Willebrand Factor concentrate could be considered to correct haemostasis.

Severe hepatic impairment.

No formal study with caplacizumab has been conducted in patients with severe acute or chronic hepatic 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.

Use in the elderly.

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

Paediatric use.

The safety and efficacy of caplacizumab in the paediatric population have not yet been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies evaluating use of caplacizumab with oral anticoagulants (e.g. vitamin K antagonists, direct oral anticoagulants [DOAC] such as thrombin inhibitors or factor Xa inhibitors), antiplatelet agents, thrombolytic drugs such as urokinase, tPA (e.g. alteplase) or heparin have been performed (see Section 4.4 Special Warnings and Precautions for Use, In the setting of concomitant use of oral anticoagulants, anti-platelet agents, thrombolytic drugs or heparin (both unfractionated heparin (UFH) and low molecular weight heparin (LMWH)).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of caplacizumab on fertility in humans are unknown. No effects on sperm or male or female reproductive tissues to suggest impairment of fertility were observed in cynomolgus monkeys receiving caplacizumab at subcutaneous doses up to 40 mg/kg/day, yielding almost 40 times the plasma AUC in patients at the maximum recommended clinical dose of 10 mg/day. Functional fertility studies have not been performed with caplacizumab in animals.
(Category B1)
There are no adequate and well-controlled studies with Cablivi in pregnant women. No adverse effects on embryofetal development were observed with caplacizumab in guinea pigs at intramuscular doses up to 20 mg/kg/day, yielding 50 times the plasma AUC in patients at the maximum recommended clinical dose. Limited placental transfer of caplacizumab was shown in guinea pigs.
Cablivi should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the foetus. All patients receiving Cablivi, including pregnant women, are at risk of bleeding. Monitor pregnant women and neonates for any evidence of excessive bleeding.
 There are no data on the use of caplacizumab in breastfeeding women. It is unknown whether caplacizumab 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety of Cablivi was evaluated in two placebo-controlled clinical studies (HERCULES, in which 71 patients received Cablivi; and TITAN, in which 35 patients received Cablivi). The data described below reflect exposure to Cablivi during the blinded periods of both studies, which include 106 patients with aTTP who received at least one dose, age 18 to 79 years, of whom 69% were female and 73% were Caucasian. The median treatment duration with Cablivi was 35 days (range 1-77 days).
The most frequent adverse reactions in clinical trials were epistaxis, headache and gingival bleeding. The most common serious adverse reaction was epistaxis.

Tabulated list of adverse reactions.

Adverse reactions that occurred in ≥ 2% of patients treated with Cablivi and more frequently than in those treated with placebo across the pooled data from the two trials are summarized in Table 1. Adverse reactions are also listed by MedDRA system organ class and by frequency. Frequencies are defined 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 from the available data).
One case of subarachnoid haemorrhage was observed in each study, which could have been related to TTP or treatment.

Description of selected adverse reactions.

Bleeding.

In clinical studies, bleeding events occurred in different body systems, independent of treatment duration. Although in some cases these events were serious and required medical attention, most were self-limited and all resolved. In case of active clinically significant bleeding, consider actions outlined in Section 4.4 Special Warnings and Precautions for Use and Section 4.9 Overdose.

Post-marketing experience.

The following adverse reactions have been identified during post approval use of Cablivi. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to caplacizumab exposure.

General disorders and administration site conditions.

Frequency not known: injection site erythema.

Blood and lymphatic system disorders.

Frequency not known: major bleeding including life-threatening and fatal events.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia).

4.9 Overdose

In the case of overdose, based on the pharmacological action of caplacizumab, there is the potential for an increased risk of bleeding. Close monitoring of signs and symptoms of bleeding is recommended (see Section 4.4 Special Warnings and Precautions for Use).
For general advice on overdose management, contact the Poisons Information Centre, telephone number 13 11 26 (Australia) or the National Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Caplacizumab is a humanised bivalent nanobody that consists of two identical humanised building blocks (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 ultralarge von Willebrand Factor-mediated platelet adhesion, which is characteristic of aTTP. It also affects the disposition of von Willebrand Factor, leading to transient reductions of total von Willebrand Factor antigen levels and to concomitant reduction of factor VIII:C levels during treatment.

Pharmacodynamic effects.

Target inhibition.

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

Target disposition.

The pharmacologic effect of caplacizumab on target disposition was measured using von Willebrand Factor antigen and factor VIII clotting activity (factor VIII:C) as biomarkers. Upon repeated administration of caplacizumab, a decrease of 30-50% in von Willebrand Factor antigen levels was observed 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 levels resulted 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.

Clinical trials.

The efficacy and safety of caplacizumab in adults experiencing an episode of aTTP was established in a pivotal multicentre, randomised, double-blind, placebo-controlled trial ALX0681-C301 (HERCULES).
Efficacy.

Study ALX0681-C301.

In this double-blind, placebo-controlled study, patients with an episode of aTTP were randomised 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression. Patients received a single intravenous bolus injection of 10 mg caplacizumab or placebo prior to the first plasma exchange on study. This was followed by daily subcutaneous injections of 10 mg caplacizumab or placebo after completion of each plasma exchange for the duration of the daily plasma exchange period and for 30 days thereafter. If at the end of this treatment period there was evidence of persistent underlying disease activity (indicative of an imminent risk for recurrence), treatment could be extended weekly for a maximum of 4 weeks, together with optimisation of immunosuppression. If a recurrence occurred while on study drug treatment, patients were switched to open-label caplacizumab. They were again treated for the duration of daily plasma exchange and for 30 days thereafter. If at the end of this treatment period there was evidence of ongoing underlying disease, open-label treatment with caplacizumab could be extended weekly for a maximum of 4 weeks, together with optimisation of immunosuppression. Patients were followed for 1 month after discontinuation of treatment. In case of recurrence during the follow up period (i.e. after all study drug treatment had been stopped), there was no re-initiation of study drug and the recurrence was to be treated according to the standard of care.
In this study, 145 patients experiencing an episode of aTTP were randomised (72 to caplacizumab and 73 to placebo). Patient age ranged from 18 to 79 years, with a mean of 46 years. Half of the patients were 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 count response (p < 0.01). Patients treated with caplacizumab were 1.55 times more likely to achieve platelet count 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 percentage of 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 during the study drug treatment period.
The proportion of patients with a recurrence of aTTP (exacerbation or relapse) in the overall study period (including the 28 day follow-up after discontinuation of study drug treatment) was 67% lower in 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 of platelet count doubling after 4 days of standard treatment and elevated LDH) compared to three patients treated with placebo (3/73).
Treatment with caplacizumab reduced the mean number of days of plasma exchange, the volume of plasma used, the mean length of Intensive Care Unit stay and the mean length of hospitalisation during the study drug treatment period. See Table 2.
Immunogenicity. In clinical studies, up to 9% of patients developed treatment-emergent anti-drug antibodies (ADA). No impact on clinical efficacy was observed and no serious adverse events were found to be associated with these ADA responses.

5.2 Pharmacokinetic Properties

The pharmacokinetics of caplacizumab have been investigated in healthy subjects after single intravenous infusions and after single and repeated subcutaneous injections. Pharmacokinetics in patients with aTTP were investigated upon single intravenous and repeated subcutaneous injections.
Pharmacokinetics of caplacizumab appear as non-dose proportional, as characterised by target-mediated disposition. In healthy volunteers receiving 10 mg caplacizumab subcutaneously once daily, the maximum concentration was observed at 6-7 hours post-dose and steady-state was reached following the first administration, with minimal accumulation.

Absorption.

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

Distribution.

After absorption, caplacizumab binds to the target and distributes to well perfused organs. In patients with 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 of drug-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.

Characteristics in specific groups.

The pharmacokinetics of caplacizumab were determined using a population pharmacokinetic analysis on pooled pharmacokinetic data. Body weight was allometrically included in the model. Differences in the different subpopulations were investigated. In studied populations; gender, age, blood group and race did not affect the pharmacokinetics of caplacizumab.

Renal or hepatic impairment.

No formal study of the effect of hepatic or renal impairment on the pharmacokinetics of caplacizumab has been conducted. In the population PK/PD model, renal function (CrCl) had a statistically significant effect resulting in limited increase in predicted exposure (AUCSS) in severe renal impairment. In the clinical studies of patients with aTTP, those with renal impairment did not show additional risk of adverse events.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been performed to evaluate the genotoxic potential of caplacizumab. As a large protein molecule, caplacizumab is not expected to interact with DNA or other chromosomal material.

Carcinogenicity.

No carcinogenicity studies have been conducted with caplacizumab. Based on findings from general toxicity studies with the drug in animals and considering its mechanism of action, no particular concern for carcinogenicity in patients treated with Cablivi is held.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder.

Sucrose, citric acid, sodium citrate dihydrate, polysorbate 80.

Solvent.

Water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Reconstituted solution.

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 of microbial contamination, the product should be used immediately.

6.4 Special Precautions for Storage

Keep Cablivi in the refrigerator at 2°C to 8°C.
If necessary, Cablivi may be stored at room temperature up to 25°C for a single period of up to 2 months. Once the product has been taken out of the refrigerator the product should be discarded or used, but must not be returned to the refrigerator.
For storage conditions of the reconstituted medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Powder.

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

Solvent.

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

Pack size.

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

6.6 Special Precautions for Disposal

Any unused medicine should be disposed of by taking to your local pharmacy. The syringe and needle cap should be disposed of in a sharps container.

6.7 Physicochemical Properties

Chemical structure.

ALX-0081 is a sequence optimized bivalent Nanobody produced in E. coli that consists of two identical humanized building blocks (denominated PMP12A2h1) that are genetically linked by a tri-alanine linker.
ALX-0081 consists of 259 amino acids and has a molecular weight of 27,876 Dalton. A schematic representation is shown:
CDR-loops are patterned as follow: CDR1 in circles, CDR2 in stripes and CDR3 in squares. Star and triangle residues refer to hallmark residues which are different for a VHH compared to a human VH. CDR: Complementarity Determining Region.

CAS number.

915810-67-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes