Darzalex 100mg5ml concentrate for solution for infusion vials

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Daratumumab
Available from:
Janssen-Cilag Ltd
ATC code:
L01XC24
INN (International Name):
Daratumumab
Dosage:
20mg/1ml
Pharmaceutical form:
Solution for infusion
Administration route:
Intravenous
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 08010500; GTIN: 5012674902899

Read the complete document

Package leaflet: Information for the patient

DARZALEX 20 mg/mL concentrate for solution for infusion

daratumumab

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. See the end of section 4

for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or nurse.

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What DARZALEX is and what it is used for

What you need to know before you are given DARZALEX

How DARZALEX is given

Possible side effects

How to store DARZALEX

Contents of the pack and other information

1.

What DARZALEX is and what it is used for

What DARZALEX is

DARZALEX is a cancer medicine that contains the active substance daratumumab. It belongs to a

group of medicines called “monoclonal antibodies”. Monoclonal antibodies are proteins that have

been designed to recognise and attach to specific targets in the body. Daratumumab has been designed

to attach to specific cancer cells in your body, so that your immune system can destroy the cancer

cells.

What DARZALEX is used for

DARZALEX is used in adults 18 years or older, who have a type of cancer called “multiple

myeloma”. This is a cancer of your bone marrow. DARZALEX is used if your cancer has not

responded to, or has come back after treatment.

2.

What you need to know before you are given DARZALEX

You must not be given DARZALEX:

if you are allergic to daratumumab or any of the other ingredients of this medicine (listed in

section 6).

Do not use DARZALEX if the above applies to you. If you are not sure, talk to your doctor or nurse

before you are given DARZALEX.

Warnings and precautions

Talk to your doctor or nurse before you are given DARZALEX:

Infusion-related reactions

DARZALEX is given as an infusion (drip) into a vein. Before and after each infusion of DARZALEX,

you will be given medicines which help to lower the chance of infusion-related reactions (see

“Medicines given during treatment with DARZALEX” in section 3). These reactions can happen

during the infusion or in the 3 days after the infusion.

In some cases you may have a severe allergic reaction which may include a swollen face, lips, mouth,

tongue or throat, difficulty swallowing or breathing or an itchy rash (hives).

Tell your doctor or nurse straight away if you get any of the infusion-related reactions listed at the top

of section 4.

If you get infusion-related reactions, you may need other medicines, or the infusion may need to be

slowed down or stopped. When these reactions go away, or get better, the infusion can be started

again.

These reactions are most likely to happen with the first infusion. If you have had an infusion-related

reaction once it is less likely to happen again. Your doctor may decide not to use DARZALEX if you

have a strong infusion reaction.

Decreased blood cell counts

DARZALEX can decrease white blood cell counts which help fight infections, and blood cells called

platelets which help to clot blood. Tell your healthcare provider if you develop fever or if you have

signs of bruising or bleeding.

Blood transfusions

If you need a blood transfusion, you will have a blood test first to match your blood type.

DARZALEX can affect the results of this blood test. Tell the person doing the test that you are using

DARZALEX.

Children and adolescents

Do not give DARZALEX to children or young people below 18 years of age. This is because it is not

known how the medicine will affect them.

Other medicines and DARZALEX

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.

This includes medicines you can get without a prescription, and herbal medicines.

Pregnancy

Talk to your doctor or nurse before you are given DARZALEX if you are pregnant, think you might

be pregnant or are planning to have a baby.

If you become pregnant while being treated with this medicine, tell your doctor or nurse straight away.

You and your doctor will decide if the benefit of having the medicine is greater than the risk to your

baby.

Contraception

Women who are being given DARZALEX should use effective contraception during treatment and for

3 months after treatment.

Breast-feeding

You and your doctor will decide if the benefit of breastfeeding is greater than the risk to your baby.

This is because the medicine may pass into the mother’s milk and it is not known how it will affect the

baby.

Driving and using machines

You may feel tired after taking DARZALEX which may affect your ability to drive or use machines.

DARZALEX contains sodium

This medicine contains 9.3 mg sodium (main component of cooking/table salt) in each 5 mL vial. This

is equivalent to 0.46% of the recommended maximum daily dietary intake of sodium for an adult.

This medicine contains 37.3 mg sodium (main component of cooking/table salt) in each 20 mL vial.

This is equivalent to 1.86% of the recommended maximum daily dietary intake of sodium for an adult.

3.

How DARZALEX is given

How much is given

Your doctor will work out your dose and schedule of DARZALEX. The dose of DARZALEX will

depend on your body weight.

The usual starting dose of DARZALEX is 16 mg per kg of body weight. DARZALEX may be given

alone or together with other medicines used to treat multiple myeloma.

When given alone or with some medicines, DARZALEX is given as follows:

once a week for the first 8 weeks

then once every 2 weeks for 16 weeks

then once every 4 weeks after that

When DARZALEX may also be given with some medicines as follows:

once a week for the first 9 weeks

then once every 3 weeks for 15 weeks

then once every 4 weeks after that

How the medicine is given

DARZALEX will be given to you by a doctor or nurse. It is given as a drip into a vein (“intravenous

infusion”) over several hours.

Medicines given during treatment with DARZALEX

You may be given medicines to lower the chance of getting shingles.

Before each infusion of DARZALEX you will be given medicines which help to lower the chance of

infusion-related reactions. These may include:

medicines for an allergic reaction (anti-histamines)

medicines for inflammation (corticosteroids)

medicines for fever (such as paracetamol).

After each infusion of DARZALEX you will be given medicines (such as corticosteroids) to lower the

chance of infusion-related reactions.

People with breathing problems

If you have breathing problems, such as asthma or Chronic Obstructive Pulmonary Disease (COPD),

you will be given medicines to inhale which help your breathing problems:

medicines to help the airways in your lungs stay open (bronchodilators)

medicines to lower swelling and irritation in your lungs (corticosteroids)

If you are given more DARZALEX than you should

This medicine will be given by your doctor or nurse. In the unlikely event that you are given too much

(an overdose) your doctor will check you for side effects.

If you forget your appointment to have DARZALEX

It is very important to go to all your appointments to make sure your treatment works. If you miss an

appointment, make another one as soon as possible.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Infusion-related reactions

Tell your doctor or nurse straight away if you get any of the following signs of an infusion-related

reaction during or in the 3 days after the infusion. You may need other medicines, or the infusion may

need to be slowed down or stopped.

These reactions are very common (may affect more than 1 in 10 people)

chills

sore throat, cough

feeling sick (nausea)

vomiting

itchy, runny or blocked nose

feeling short of breath or other breathing problems

Other common symptoms (affecting up to 1 in 10 people) are:

chest discomfort

dizziness or lightheadedness (hypotension)

itching

wheezing

Rare (may affect up to 1 in 1,000 people):

Severe allergic reaction which may include a swollen face, lips, mouth, tongue or throat, difficulty

swallowing or breathing or an itchy rash (hives).

If you get any of the infusion-related reactions above, tell your doctor or nurse straight away.

Other side effects

Very common

(may affect more than 1 in 10 people):

fever

feeling very tired

diarrhoea

headache

nerve damage that may cause tingling, numbness, or pain

muscle spasms

swollen hands, ankles or feet

lung infection (pneumonia)

infections of the airways – such as nose, sinuses or throat

low number of red blood cells which carry oxygen in the blood (anaemia)

low number of white blood cells which help fight infections (neutropenia, lymphopenia)

low number of a type of blood cell called platelets which help to clot blood (thrombocytopenia).

Common

(may affect up to 1 in 10 people):

irregular heart beat (atrial fibrillation)

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not

listed in this leaflet.

In the UK,

you can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App

Store.

In Ireland,

you can also report side effects directly via: HPRA Pharmacovigilance, Earlsfort Terrace,

IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail:

medsafety@hpra.ie

In Malta,

report side effects to: ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store DARZALEX

DARZALEX will be stored at the hospital or clinic.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry

date refers to the last day of that month.

Store in a refrigerator (2 °C-8 °C). Do not freeze.

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

Medicines should not be disposed of via wastewater or household waste. Your healthcare professional

will throw away any medicines that are no longer being used. These measures will help protect the

environment.

6.

Contents of the pack and other information

What DARZALEX contains

The active substance is daratumumab. One mL of concentrate contains 20 mg daratumumab.

Each vial of 5 mL concentrate contains 100 mg of daratumumab. Each vial of 20 mL

concentrate contains 400 mg of daratumumab.

The other ingredients are glacial acetic acid, mannitol (E421), polysorbate 20, sodium acetate

trihydrate, sodium chloride and water for injections (see “DARZALEX contains sodium” in

section 2).

What DARZALEX looks like and contents of the pack

DARZALEX is a concentrate for solution for infusion and is a colourless to yellow liquid.

DARZALEX is supplied as a carton pack containing 1 glass vial.

Marketing Authorisation Holder

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

Manufacturer

Janssen Biologics B.V.

Einsteinweg 101

NL-2333 CB Leiden

The Netherlands

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

Ireland

Janssen-Cilag Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire HP12 4EG

United Kingdom

Tel: +44 1 494 567 444

Malta

AM MANGION LTD.

Mangion Building, Triq Ġdida fi Triq Valletta

MT-Ħal-Luqa LQA 6000

Tel: +356 2397 6000

United Kingdom

Janssen-Cilag Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire HP12 4EG - UK

Tel: +44 1 494 567 444

This leaflet was last revised in 04/2017

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

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

---------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

This medicinal product is for single-use only.

Prepare the solution for infusion using aseptic technique as follows:

Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number

of DARZALEX vials needed based on patient weight.

Check that the DARZALEX solution is colourless to yellow. Do not use if opaque particles,

discolouration or other foreign particles are present.

Using aseptic technique, remove a volume of 0.9% Sodium Chloride from the infusion

bag/container that is equal to the required volume of DARZALEX solution.

Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume

by adding to an infusion bag/container containing 0.9% Sodium Chloride. Infusion

bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene

(PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any

unused portion left in the vial.

Gently invert the bag/container to mix the solution. Do not shake.

Visually inspect parenteral medicinal products for particulate matter and discolouration prior to

administration. The diluted solution may develop very small, translucent to white proteinaceous

particles, as daratumumab is a protein. Do not use if visibly opaque particles, discolouration or

foreign particles are observed.

Since DARZALEX does not contain a preservative, diluted solutions should be administered

within 15 hours (including infusion time) at room temperature (15°C - 25°C) and in room light.

If not used immediately, the diluted solution can be stored prior to administration for up to

24 hours at refrigerated conditions (2°C - 8°C) and protected from light. Do not freeze.

Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow

regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone

(PES) filter (pore size 0.22 or 0.2 micrometre). Polyurethane (PU), polybutadiene (PBD), PVC,

PP or PE administration sets must be used.

Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.

Do not store any unused portion of the infusion solution for reuse. Any unused product or waste

material should be disposed of in accordance with local requirements.

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch

number of the administered product should be clearly recorded.

Read the complete document

Object 1

DARZALEX 20 mg/mL concentrate for solution

for infusion

Summary of Product Characteristics Updated 29-Jun-2018 | Janssen-Cilag Ltd

This medicinal product is subject to additional monitoring. This will allow quick identification of

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See

section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

DARZALEX 20 mg/mL concentrate for solution for infusion.

2. Qualitative and quantitative composition

Each 5 mL vial contains 100 mg of daratumumab (20 mg daratumumab per mL).

Each 20 mL vial contains 400 mg of daratumumab (20 mg daratumumab per mL).

Daratumumab is a human monoclonal IgG1κ antibody against CD38 antigen, produced in a mammalian

cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.

Excipients with known effect

Each 5 mL and 20 mL vial of DARZALEX contains 0.4 mmol and 1.6 mmol (9.3 mg and 37.3 mg)

sodium, respectively.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion.

The solution is colourless to yellow.

4. Clinical particulars

4.1 Therapeutic indications

DARZALEX is indicated:

as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma,

whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have

demonstrated disease progression on the last therapy.

in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the

treatment of adult patients with multiple myeloma who have received at least one prior therapy

4.2 Posology and method of administration

DARZALEX should be administered by a healthcare professional, in an environment where resuscitation

facilities are available.

Posology

Pre- and post-infusion medications should be administered to reduce the risk of infusion-related reactions

(IRRs) with daratumumab. See below “Recommended concomitant medications”, “Management of

infusion-related reactions” and section 4.4.

Dose

Standard dosing for monotherapy and in combination with lenalidomide (4-week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion

according to the following dosing schedule in Table 1.

Table 1: Standard DARZALEX dosing schedule for monotherapy and in combination with

lenalidomide (4-week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 8

weekly (total of 8 doses)

Weeks 9 to 24

every two weeks (total of 8 doses)

Week 25 onwards until disease progression

every four weeks

First dose of the every-2-week dosing schedule is given at week 9

First dose of the every-4-week dosing schedule is given at week 25

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and the

corresponding Summary of Product Characteristics.

Modified dosing schedule in combination with bortezomib (3-week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion

according to the following dosing schedule in Table 2.

Table 2: Modified DARZALEX dosing schedule in combination with bortezomib (3-week cycle

dosing regimen)

Weeks

Schedule

Weeks 1 to 9

weekly (total of 9 doses)

Weeks 10 to 24

every three weeks (total of 5 doses)

Week 25 onwards until disease progression

every four weeks

First dose of the every-3-week dosing schedule is given at week 10

First dose of the every-4-week dosing schedule is given at week 25

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and the

corresponding Summary of Product Characteristics.

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the initial infusion

rate presented in Table 3 below. Incremental escalation of the infusion rate should be considered only in

the absence of infusion reactions.

Table 3: Infusion rates for DARZALEX administration

Dilution volume

Initial infusion rate

(first hour)

Increments of

infusion rate

a

Maximum infusion

rate

First infusion

1,000 mL

50 mL/hour

50 mL/hour every

hour

200 mL/hour

Second infusion

b

500 mL

50 mL/hour

50 mL/hour every

hour

200 mL/hour

Subsequent

infusions

c

500 mL

100 mL/hour

50 mL/hour every

hour

200 mL/hour

Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.

A dilution volume of 500 mL should be used only if there were no IRRs during the first 3 hours of the

first infusion. Otherwise, continue to use a dilution volume of 1,000 mL and instructions for the first

infusion.

A modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if

there were no IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use

instructions for the second infusion.

Management of infusion-related reactions

Pre-infusion medications should be administered to reduce the risk of infusion-related reactions (IRRs)

prior to treatment with DARZALEX.

For IRRs of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms.

Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of

DARZALEX as outlined below (see section 4.4).

Grade 1-2 (mild to moderate): Once reaction symptoms resolve, the infusion should be resumed at no

more than half the rate at which the IRR occurred. If the patient does not experience any further IRR

symptoms, infusion rate escalation may be resumed at increments and intervals as clinically appropriate

up to the maximum rate of 200 mL/hour (Table 3).

Grade 3 (severe): Once reaction symptoms resolve, restarting of the infusion may be considered at no

more than half the rate at which the reaction occurred. If the patient does not experience additional

symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate (Table 3).

The procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently

discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion reaction.

Grade 4 (life-threatening): Permanently discontinue DARZALEX treatment.

Missed dose (s)

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the

dosing schedule should be adjusted accordingly, maintaining the treatment interval.

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of

blood cell counts in the event of haematological toxicity (see section 4.4). For information concerning

medicinal products given in combination with DARZALEX, see corresponding Summary of Product

Characteristics.

Recommended concomitant medications

Pre-infusion medication

Pre-infusion medications should be administered to reduce the risk of IRRs to all patients 1-3 hours prior

to every infusion of DARZALEX as follows:

Corticosteroid (long-acting or intermediate-acting)

Monotherapy:

Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion,

the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).

Combination therapy:

Dexamethasone 20 mg, administered prior to every DARZALEX infusion (see section 5.1).

Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration

may be considered prior to subsequent infusions.

Antipyretics (oral paracetamol 650 to 1,000 mg)

Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Post-infusion medication

Post-infusion medications should be administered to reduce the risk of delayed infusion-related reactions

as follows:

Monotherapy:

Oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-

acting corticosteroid in accordance with local standards) should be administered on each of the two days

following all infusions (beginning the day after the infusion).

Combination therapy:

Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after the

DARZALEX infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is

administered the day after the DARZALEX infusion, additional post-infusion medications may not be

needed (see section 5.1).

Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-infusion

medications including short and long acting bronchodilators, and inhaled corticosteroids should be

considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled

post-infusion medications may be discontinued at the discretion of the physician.

Prophylaxis for herpes zoster virus reactivation

Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

Special populations

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Based on

population pharmacokinetic (PK) analyses no dosage adjustment is necessary for patients with renal

impairment (see section 5.2).

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted.

Based on population PK analyses, no dosage adjustments are necessary for patients with hepatic

impairment (see section 5.2).

Elderly

No dose adjustments are considered necessary (see section 5.2).

Paediatric population

The safety and efficacy of DARZALEX in children aged below 18 years of age have not been

established.

No data are available (see section 5.1).

Method of administration

DARZALEX is for intravenous use. It is administered as an intravenous infusion following dilution with

sodium chloride 9 mg/mL (0.9%) solution for injection. For instructions on dilution of the medicinal

product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Infusion-related reactions

DARZALEX can cause serious infusion related reactions (IRRs), including anaphylactic reactions (see

section 4.8).

All patients should be monitored throughout the infusion for IRRs. For patients that experience any Grade

IRRs, continue monitoring post-infusion until symptoms resolve.

In clinical trials IRRs were reported in approximately half of all patients treated with DARZALEX.

The majority of IRRs occurred at the first infusion and were Grade 1-2 (see section 4.8). Four percent of

all patients had an IRR at more than one infusion. Severe reactions have occurred, including

bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema and pulmonary oedema. Symptoms

predominantly included nasal congestion, cough, throat irritation, chills, vomiting and nausea. Less

common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus and hypotension

(see section 4.8).

Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk

of IRRs prior to treatment with DARZALEX. DARZALEX infusion should be interrupted for IRRs of

any severity and medical management/supportive treatment for IRRs should be instituted as needed. For

patients with Grade 1, 2, or 3 IRRs, the infusion rate should be reduced when re-starting the infusion. If

an anaphylactic reaction or life-threatening (Grade 4) infusion reaction occurs, appropriate emergency

resuscitation should be initiated immediately. DARZALEX therapy should be discontinued immediately

and permanently (see sections 4.2 and 4.3).

To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following

DARZALEX infusions. Additionally the use of post-infusion medications (e.g. inhaled corticosteroids,

short and long acting bronchodilators) should be considered for patients with a history of chronic

obstructive pulmonary disease to manage respiratory complications should they occur (see section 4.2).

Neutropenia/Thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (see

section 4.8).

Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing

information for background therapies. Monitor patients with neutropenia for signs of infection.

DARZALEX delay may be required to allow recovery of blood cell counts. No dose reduction of

DARZALEX is recommended. Consider supportive care with transfusions or growth factors.

Interference with Indirect Antiglobulin Test (Indirect Coombs Test)

Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive

indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist for up to 6

months after the last daratumumab infusion. It should be recognised that daratumumab bound to RBCs

may mask detection of antibodies to minor antigens in the patient's serum. The determination of a

patient's ABO and Rh blood type are not impacted.

Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may be

considered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping is not

impacted by daratumumab and may be performed at any time.

In the event of a planned transfusion blood transfusion centres should be notified of this interference with

indirect antiglobulin tests (see section 4.5). If an emergency transfusion is required, non-cross-matched

ABO/RhD-compatible RBCs can be given per local blood bank practices.

Interference with determination of Complete Response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein

electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous

M-protein (see section 4.5). This interference can impact the determination of complete response and of

disease progression in some patients with IgG kappa myeloma protein.

Excipients

Each 5 mL and 20 mL vial of DARZALEX contains 0.4 mmol and 1.6 mmol (9.3 mg and 37.3 mg)

sodium, respectively. This corresponds to 0.46% and 1.86% of the WHO recommended maximum daily

intake of 2 g sodium for an adult, respectively.

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch number

of the administered product should be clearly recorded.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact

daratumumab are unlikely to represent major elimination routes. As such, variations in drug-metabolising

enzymes are not expected to affect the elimination of daratumumab. Due to the high affinity to a unique

epitope on CD38, daratumumab is not anticipated to alter drug-metabolising enzymes.

Clinical pharmacokinetic assessments of pomalidomide, thalidomide, and bortezomib indicated no

clinically-relevant drug-drug interaction between DARZALEX and these combination therapies.

Interference with Indirect Antiglobulin Test (Indirect Coombs Test)

Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody

screening and cross matching (see section 4.4). Daratumumab interference mitigation methods include

treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locally

validated methods. Since the Kell blood group system is also sensitive to DTT treatment, Kell-negative

units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.

Alternatively, phenotyping or genotyping may also be considered (see section 4.4).

Interference with Serum Protein Electrophoresis and Immunofixation Tests

Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays

used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive

SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of

complete responses by International Myeloma Working Group (IMWG) criteria. In patients with

persistent very good partial response, where daratumumab interference is suspected, consider using a

validated daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous

M protein in the patient's serum, to facilitate determination of a complete response.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential/Contraception

Women of child-bearing potential should use effective contraception during, and for 3 months after

cessation of daratumumab treatment.

Pregnancy

There are no human or animal data to assess the risk of daratumumab use during pregnancy. IgG1

monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore

daratumumab should not be used during pregnancy unless the benefit of treatment to the woman is

considered to outweigh the potential risks to the fetus. If the patient becomes pregnant while taking this

medicine, the patient should be informed of the potential risk to the fetus.

Breast-feeding

It is not known whether daratumumab is excreted into human or animal milk.

Maternal IgG is excreted in human milk, but does not enter the neonatal and infant circulations in

substantial amounts as they are degraded in the gastrointestinal tract and not absorbed.

The effect of daratumumab on newborns/infants is unknown. A decision should be made whether to

discontinue breast-feeding or to discontinue DARZALEX therapy taking into account the benefit of

breast feeding for the child and the benefit of therapy for the woman.

Fertility

No data are available to determine potential effects of daratumumab on fertility in males or females (see

section 5.3).

4.7 Effects on ability to drive and use machines

DARZALEX has no or negligible influence on the ability to drive and use machines. However, fatigue

has been reported in patients taking daratumumab and this should be taken into account when driving or

using machines.

4.8 Undesirable effects

Summary of the safety profile

The most frequent adverse reactions (> 20%) in individual randomised controlled studies were infusion

reactions, fatigue, nausea, diarrhoea, muscle spasms, pyrexia, cough, dyspnoea, neutropenia,

thrombocytopenia and upper respiratory tract infection. In addition, in combination with bortezomib,

peripheral oedema and peripheral sensory neuropathy were frequently reported. Serious adverse reactions

were pneumonia, upper respiratory tract infection, influenza, pyrexia, diarrhoea, atrial fibrillation.

Tabulated list of adverse reactions

Table 4 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data

reflects exposure to DARZALEX (16 mg/kg) in 820 patients with multiple myeloma including 526

patients from two Phase III active-controlled trials who received DARZALEX in combination with either

lenalidomide (DRd; n = 283; Study MMY3003) or bortezomib (DVd; n = 243; Study MMY3004) and

five open-label, clinical trials in which patients received DARZALEX either in combination with

pomalidomide (DPd; n = 103), in combination with lenalidomide (n = 35) or as monotherapy (n = 156).

Post-marketing adverse reactions are also included.

Frequencies are defined as 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) and very rare (< 1/10,000). Within each frequency grouping,

where relevant, adverse reactions are presented in order of decreasing seriousness.

Table 4: Adverse reactions in multiple myeloma patients treated with DARZALEX 16 mg/kg

System Organ Class

Adverse reaction

Frequency

Incidence (%)

Any Grade

Grade 3-4

Infections and infestations

Pneumonia

Very Common

Upper respiratory tract

infection

Influenza

Common

Blood and lymphatic system

disorders

Neutropenia

Very Common

Thrombocytopenia

Anaemia

Lymphopenia

Immune system disorders

Anaphylactic reaction

Rare

Nervous system disorders

Peripheral sensory

neuropathy

Very Common

Headache

Very Common

< 1*

Cardiac disorders

Atrial fibrillation

Common

Respiratory, thoracic and

mediastinal disorders

Cough

Very Common

< 1*

Dyspnoea

Gastrointestinal disorders

Diarrhoea

Very Common

Nausea

Vomiting

Musculoskeletal and

connective tissue disorders

Muscle spasms

Very Common

< 1*

General disorders and

administration site conditions

Fatigue

Very Common

Pyrexia

Oedema peripheral

Injury, poisoning and

procedural complications

Infusion-related

reaction

Very common

* No Grade 4

Indicates grouping of terms

Postmarketing adverse reaction

Infusion-related reaction includes terms determined by investigators to be related to infusion, see below

Infusion-related reactions

In clinical trials (monotherapy and combination treatments; N = 820) the incidence of any grade infusion-

related reactions was 46% with the first infusion of DARZALEX, 2% with the second infusion, and 3%

with subsequent infusions. Less than 1% of patients had a Grade 3 infusion-related reaction with second

or subsequent infusions.

The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of

infusion interruptions due to reactions was 42%. Median durations of infusion for the 1

subsequent infusions were 7, 4.3 and 3.5 hours respectively.

Severe (Grade 3) infusion-related reactions included bronchospasm, dyspnoea, laryngeal oedema,

pulmonary oedema, hypoxia, and hypertension. Other adverse infusion-related reactions (any Grade, ≥

5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea (see section 4.4).

Infections

In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with

DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd:

28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies.

Discontinuations from treatment were reported in 2% to 5% of patients. Fatal infections were reported in

0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis.

Haemolysis

There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed

in clinical studies and post-marketing safety data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple

App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: [email

protected]

4.9 Overdose

Symptoms and signs

There has been no experience of overdosage in clinical studies. Doses up to 24 mg/kg have been

administered intravenously in a clinical study.

Treatment

There is no known specific antidote for daratumumab overdose. In the event of an overdose, the patient

should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment

should be instituted immediately.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC24

Mechanism of action

Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed

at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at

various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and

enzymatic activity.

Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.

Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune

mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through

complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-

dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived

suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T

regs

) and B cells (CD38+B

regs

) are

decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to

express CD38 depending on the stage of development and the level of activation. Significant increases in

CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with

daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA

sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune

modulatory effects that may contribute to clinical response.

Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab

modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase

activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour

growth, are not well-understood.

Pharmacodynamic effects

Natural killer (NK) cell and T-cell count

NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell

lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated

(CD16+CD56

) NK cells in peripheral whole blood and bone marrow were observed with

daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical

response.

Immunogenicity

Patients treated with daratumumab monotherapy (n = 199) and combination therapy (n = 299) were

evaluated for anti-therapeutic antibody responses to daratumumab at multiple time points during

treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab

treatment, none of the monotherapy patients and 2 (0.7%) of the combination therapy patients tested

positive for anti-daratumumab antibodies; 1 of the combination therapy patients developed transient

neutralising antibodies against daratumumab.

However, the employed assay has limitations in detecting anti-daratumumab antibodies in the presence of

high concentrations of daratumumab. Therefore, the incidence of antibody development might not have

been reliably determined.

Clinical efficacy and safety

Monotherapy

The clinical efficacy and safety of DARZALEX monotherapy for the treatment of adult patients with

relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an

immunomodulatory agent and who had demonstrated disease progression on the last therapy, was

demonstrated in two open-label studies.

In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg

DARZALEX until disease progression. The median patient age was 63.5 years (range, 31 to 84 years),

11% of patients were ≥ 75 years of age, 49% were male and 79% were Caucasian. Patients had received a

median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell

transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide

(63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment,

95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77%

were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were

refractory to carfilzomib.

Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC)

assessment are presented in Table 5 below.

Table 5: IRC assessed efficacy results for study MMY2002

Efficacy endpoint

DARZALEX 16 mg/kg

N = 106

Overall response rate

(ORR: sCR+CR+VGPR+PR) [n (%)]

31 (29.2)

95% CI (%)

(20.8, 38.9)

Stringent complete response (sCR) [n (%)]

3 (2.8)

Complete response (CR) [n]

Very good partial response (VGPR) [n (%)]

10 (9.4)

Partial response (PR) [n (%)]

18 (17.0)

Clinical Benefit Rate (ORR+MR) [n (%)]

36 (34.0)

Median Duration of Response [months (95% CI)]

7.4 (5.5, NE)

Median Time to Response [months (range)]

1 (0.9; 5.6)

Primary efficacy endpoint (International Myeloma Working Group criteria)

CI = confidence interval; NE = not estimable; MR = minimal response

Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy.

At a survival update with a median duration of follow-up of 14.7 months, median Overall Survival (OS)

was 17.5 months (95% CI:13.7, not estimable).

In Study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg

DARZALEX until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64%

were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of

therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib

(100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients

were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were

refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to

carfilzomib.

Pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORR

with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median

duration of response was not reached (95% CI: 5.6 months, not estimable).

At a survival update with a median duration of follow-up of 15.2 months, median OS was not reached

(95% CI: 19.9 months, not estimable), with 74% of subjects still alive.

Combination treatment with lenalidomide

Study MMY3003, an open-label, randomised, active-controlled Phase III trial, compared treatment with

DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to

treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory

multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on

Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone at 40 mg/week

(or a reduced dose of 20 mg/week for patients > 75 years or body mass index [BMI] < 18.5). On

DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication

and the remainder given the day after the infusion. Treatment was continued in both arms until disease

progression or unacceptable toxicity.

A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baseline

demographic and disease characteristics were similar between the DARZALEX and the control arm. The

median patient age was 65 years (range 34 to 89 years) and 11% were ≥ 75 years. The majority of patients

(86%) received a prior PI, 55% of patients had received a prior IMiD, including 18% of patients who had

received prior lenalidomide; and 44% of patients had received both a prior PI and IMiD. At baseline, 27%

of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory

to a PI only, and 21% were refractory to bortezomib. Patients refractory to lenalidomide were excluded

from the study.

Study MMY3003 demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as

compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in

the Rd arm (hazard ratio [HR]=0.37; 95% CI: 0.27, 0.52; p < 0.0001), representing 63% reduction in the

risk of disease progression or death in patients treated with DRd (see Figure 1).

Figure 1: Kaplan-Meier Curve of PFS in Study MMY3003

Additional efficacy results from Study MMY3003 are presented in Table 6 below.

Table 6: Additional efficacy results from Study MMY3003

Response evaluable patient number

DRd (n = 281)

Rd (n = 276)

Overall response (sCR+CR+VGPR+PR) n(%)

261 (92.9)

211 (76.4)

p-value

< 0.0001

Stringent complete response (sCR)

51 (18.1)

20 (7.2)

Complete response (CR)

70 (24.9)

33 (12.0)

Very good partial response (VGPR)

92 (32.7)

69 (25.0)

Partial response (PR)

48 (17.1)

89 (32.2)

Median Time to Response [months (95% CI)]

1.0 (1.0, 1.1)

1.3 (1.1, 1.9)

Median Duration of Response [months (95% CI)] NE (NE, NE)

17.4 (17.4, NE)

MRD negative rate (95% CI)

29.0 (23.8, 34.7)

7.8 (4.9, 11.5)

Odds ratio with 95% CI

4.85 (2.93, 8.03)

P-value

< 0.000001

DRd = daratumumab-lenalidomide-dexamethasone; Rd = lenalidomide-dexamethasone; MRD = minimal

residual disease; CI = confidence interval; NE = not estimable.

p-value from Cochran Mantel-Haenszel Chi-Squared test.

Based on Intent-to-treat population and threshold of 10

A Chi-Squared estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for

DRd.

p-value is from a likelihood-ratio Chi-Squared test.

Median OS was not reached for either treatment group. With an overall median follow-up of 13.5 months,

the hazard ratio for OS was 0.64 (95% CI: 0.40, 1.01; p = 0.0534).

Combination treatment with bortezomib

Study MMY3004, an open-label, randomised, active-controlled Phase III trial, compared treatment with

DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with

bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had

received at least one prior therapy. Bortezomib was administered by SC injection or IV infusion at a dose

of 1.3 mg/m

body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-

week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg

on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three

weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients > 75 years, BMI < 18.5,

poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of DARZALEX

infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. DARZALEX

treatment was continued until disease progression or unacceptable toxicity.

A total of 498 patients were randomised; 251 to the DVd arm and 247 to the Vd arm. The baseline

demographic and disease characteristics were similar between the DARZALEX and the control arm. The

median patient age was 64 years (range 30 to 88 years) and 12% were ≥ 75 years. Sixty-nine percent

(69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an

IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of

treatment. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were

refractory to lenalidomide. Patients refractory to bortezomib were excluded from the study.

Study MMY3004 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the

median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39

[0.28, 0.53]; p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death

for patients treated with DVd versus Vd. (see Figure 2).

Figure 2: Kaplan-Meier Curve of PFS in Study MMY3004

Additional efficacy results from Study MMY3004 are presented in Table 7 below.

Table 7: Additional efficacy results from Study MMY3004

Response evaluable patient number

DVd (n = 240)

Vd (n = 234)

Overall response (sCR+CR+VGPR+PR) n(%)

199 (82.9)

148 (63.2)

P-value

< 0.0001

Stringent complete response (sCR)

11 (4.6)

5 (2.1)

Complete response (CR)

35 (14.6)

16 (6.8)

Very good partial response (VGPR)

96 (40.0)

47 (20.1)

Partial response (PR)

57 (23.8)

80 (34.2)

Median Time to Response [months (range)]

0.9 (0.8, 1.4)

1.6 (1.5, 2.1)

Median Duration of Response [months (95% CI)]

NE (11.5, NE)

7.9 (6.7, 11.3)

MRD negative rate (95% CI)

13.5% (9.6%, 18.4%)

2.8% (1.1%, 5.8%)

Odds ratio with 95% CI

5.37 (2.33, 12.37)

P-value

0.000006

DVd = daratumumab- bortezomib-dexamethasone; Vd = bortezomib-dexamethasone; MRD = minimal

residual disease; CI = confidence interval; NE = not estimable.

p-value from Cochran Mantel-Haenszel Chi-Squared test.

Based on Intent-to-treat population and threshold of 10

A Chi-Squared estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for

DVd.

p-value is from a likelihood-ratio chi-squared test.

Median OS was not reached for either treatment group.With an overall median follow-up of 7.4 months

(95% CI: 0.0, 14.9), the hazard ratio for OS was 0.77 (95% CI: 0.47, 1.26; p = 0.2975).

Cardiac electrophysiology

Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect of

daratumumab on the QTc interval was evaluated in an open-label study for 83 patients (Study GEN501)

with relapsed and refractory multiple myeloma following daratumumab infusions (4 to 24 mg/kg). Linear

mixed PK-PD analyses indicated no large increase in mean QTcF interval (i.e., greater than 20 ms) at

daratumumab C

Paediatric population

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

DARZALEX in all subsets of the paediatric population in multiple myeloma (see section 4.2 for

information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumab

monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels

from 0.1 mg/kg to 24 mg/kg. A population PK model of daratumumab was developed to describe the PK

characteristics of daratumumab and to evaluate the influence of covariates on the disposition of

daratumumab in patients with multiple myeloma. The population PK analysis included 223 patients

receiving DARZALEX monotherapy in two clinical trials (150 subjects received 16 mg/kg).

In the 1- to 24 mg/kg cohorts, peak serum concentrations (C

) after the first dose increased in

approximate proportion to dose and volume of distribution was consistent with initial distribution into the

plasma compartment. Following the last weekly infusion, C

increased in a greater than dose-

proportional manner, consistent with target mediated drug disposition. Increases in AUC were more than

dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38

may become saturated at higher doses, after which the impact of target binding clearance is minimised

and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also

decreased with multiple doses, which may be related to tumour burden decreases.

Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation

[SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days.

The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are

insufficient data for a reliable estimation. Based on population PK analysis, the mean (SD) half-life

associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-

life that can be expected upon complete saturation of target mediated clearance and repeat dosing of

daratumumab.

At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean

(SD) serum C

value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following

the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was

573 (331.5) micrograms/mL.

Based on the population PK analysis of daratumumab monotherapy, daratumumab steady state is

achieved approximately 5 months into the every 4-week dosing period (by the 21

infusion), and the

mean (SD) ratio of C

at steady-state to C

after the first dose was 1.6 (0.5). The mean (SD) central

volume of distribution is 56.98 (18.07) mL/kg.

An additional population PK analysis was conducted in patients with multiple myeloma that received

daratumumab in various combination therapies from four clinical trials (694 patients of which 684

received daratumumab at 16 mg/kg). Daratumumab concentration-time profiles were similar following

the monotherapy and combination therapies. The mean (SD) estimated terminal half-life associated with

linear clearance in combination therapy was approximately 23 (12) days.

Based on population PK analysis body weight was identified as a statistically significant covariate for

daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the

multiple myeloma patients.

Special populations

Age and gender

Based on population PK analysis in patients receiving daratumumab monotherapy, age (range: 31-84

years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab

was similar between younger (aged < 65 years, n = 127) and older (aged ≥ 65 years, n = 96; aged ≥ 75

years, n = 18; aged ≥ 85 years, n = 0) patients. Similar to monotherapy, no clinically important influence

of age on the exposure to daratumumab was observed in the population PK analyses in patients receiving

combination therapies. The difference in exposure was within 6% between younger (age < 65 years, n =

352; or age < 75 years, n = 630) and older subjects (age ≥ 65 years, n = 342; or age ≥ 75 years, n = 64).

Gender did not affect exposure of daratumumab to a clinically relevant degree in both population PK

analyses.

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. A population

PK analysis was performed based on pre-existing renal function data in patients receiving daratumumab

monotherapy, including 71 with normal renal function (creatinine clearance [CRCL] ≥ 90 mL/min), 78

with mild renal impairment (CRCL < 90 and ≥ 60 mL/min), 68 with moderate renal impairment (CRCL <

60 and ≥ 30 mL/min), and 6 with severe renal impairment or end stage renal disease (CRCL< 30

mL/min). No clinically important differences in exposure to daratumumab were observed between

patients with renal impairment and those with normal renal function. Additional population PK analyses

in patients receiving combination treatments also demonstrated no clinically important differences in

exposure to daratumumab between patients with renal impairment (mild, n = 264; moderate, n = 166;

severe, n = 12) and those with normal renal function (n = 251).

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in

hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules

such as daratumumab are not metabolised through hepatic pathways.

The population PK analysis of patients treated with daratumumab monotherapy included 189 patients

with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of

normal [ULN]) and 34 with mild hepatic impairment (TB 1.0 x to 1.5 xULN or AST > ULN). No

clinically important differences in exposure to daratumumab were observed between patients with mild

hepatic impairment and those with normal hepatic function. An additional population PK analysis of

patients with multiple myeloma that received daratumumab in various combination therapies included

598 patients with normal hepatic function, 83 patients with mild hepatic impairment and 5 patients with

moderate (TB > 1.5 x to 3.0 x ULN), or severe (TB > 3.0 x ULN) hepatic impairment. No clinically

important differences in the exposure to daratumumab were observed between patients with hepatic

impairment and those with normal hepatic function.

Race

Based on the population PK analysis of daratumumab monotherapy, the exposure to daratumumab was

similar between white (n=197) and non-white (n=26) subjects. In an additional population PK analysis in

multiple myeloma patients that received daratumumab with various combination therapies, the exposure

to daratumumab was also similar between white (n = 558) and non-white (n = 136) subjects.

5.3 Preclinical safety data

Toxicology data have been derived from studies with daratumumab in chimpanzees and with a surrogate

anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has been conducted.

Carcinogenicity and mutagenicity

No animal studies have been performed to establish the carcinogenic potential of daratumumab.

Reproductive toxicology

No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction

or development.

Fertility

No animal studies have been performed to determine potential effects on fertility in males or females.

6. Pharmaceutical particulars

6.1 List of excipients

Glacial acetic acid

Mannitol (E421)

Polysorbate 20

Sodium acetate trihydrate

Sodium chloride

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3 Shelf life

Unopened vials

24 months

After dilution

From a microbiological point of view, unless the method of opening/ dilution precludes the risk 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 and should be no more than 24 hours at refrigerated

conditions (2 °C-8 °C) protected from light, followed by 15 hours (including infusion time) at room

temperature (15°C - 25°C) and room light.

6.4 Special precautions for storage

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

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

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

6.5 Nature and contents of container

5 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off

button containing 100 mg of daratumumab. Pack size of 1 vial.

20 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-

off button containing 400 mg of daratumumab. Pack size of 1 vial.

6.6 Special precautions for disposal and other handling

This medicinal product is for single-use only.

Prepare the solution for infusion using aseptic technique as follows:

Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of

DARZALEX vials needed based on patient weight.

Check that the DARZALEX solution is colourless to yellow. Do not use if opaque particles,

discolouration or other foreign particles are present.

Using aseptic technique, remove a volume of 0.9% Sodium Chloride from the infusion bag/container

that is equal to the required volume of DARZALEX solution.

Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by

adding to an infusion bag/container containing 0.9% Sodium Chloride (see section 4.2). Infusion

bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or

polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in

the vial.

Gently invert the bag/container to mix the solution. Do not shake.

Visually inspect parenteral medicinal products for particulate matter and discolouration prior to

administration. The diluted solution may develop very small, translucent to white proteinaceous particles,

as daratumumab is a protein. Do not use if visibly opaque particles, discolouration or foreign particles are

observed.

Since DARZALEX does not contain a preservative, diluted solutions should be administered within 15

hours (including infusion time) at room temperature (15°C - 25°C) and in room light.

If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at

refrigerated conditions (2°C - 8°C) and protected from light. Do not freeze.

Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator

and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size

0.22 or 0.2 micrometre). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE administration sets

must be used.

Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.

Do not store any unused portion of the infusion solution for reuse. Any unused product or waste

material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8. Marketing authorisation number(s)

EU/1/16/1101/001

EU/1/16/1101/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 20 May 2016

Date of latest renewal: 24 April 2017

10. Date of revision of the text

03 May 2018

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

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

Company Contact Details

Janssen-Cilag Ltd

Address

50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG

Telephone

+44 (0)1494 567 567

Medical Information Direct Line

+44 (0)800 731 8450

Customer Care direct line

+44 (0)800 731 5550

http://www.janssen-cilag.co.uk

+44 (0)1494 567 568

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0) 1494 567 445

Similar products

Search alerts related to this product

View documents history

Share this information