Consumer medicine information

Darzalex SC

Daratumumab

BRAND INFORMATION

Brand name

Darzalex SC

Active ingredient

Daratumumab

Schedule

What is in this leaflet

This leaflet answers some common questions about DARZALEX SC Solution for injection. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given DARZALEX SC against the benefits this medicine is expected to have for you.

If you have any concerns about being given DARZALEX SC ask your doctor.

Keep this leaflet while you are being treated with DARZALEX SC. You may need to read it again.

What DARZALEX SC is used for

DARZALEX SC is an anti-cancer medicine and contains the active substance daratumumab. This belongs to a group of medicines called “monoclonal antibodies”. One of the ways monoclonal antibodies work is by attaching themselves to specific abnormal blood cells in your body, so your immune system can destroy them.

DARZALEX SC is used to treat adults with multiple myeloma (cancer of the bone marrow).

DARZALEX SC is also used to treat adults with AL amyloidosis (also known as light chain amyloidosis, a type of blood disorder). In AL amyloidosis, abnormal blood cells make excessive amounts of abnormal proteins that deposit in various organs, causing these organs to not function properly.

Your doctor may have prescribed DARZALEX SC for another reason.

Ask your doctor if you have any questions about why DARZALEX SC has been prescribed for you.

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

Before you are given DARZALEX SC

When you must not use it:

Do not use DARZALEX SC if:

you know you are allergic (hypersensitive) to daratumumab or other ingredients of DARZALEX SC. See Product Description at the end of this leaflet for a list of ingredients.

Symptoms of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

DARZALEX SC should not be given to children or young people below 18 years of age. This is because it is not known how the medicine will affect them.

Before you start to use it:

Tell your doctor if you have or have had any medical conditions, especially the following:

blood disorder with a low level of white blood cells or platelets.
This disorder may become worse during treatment with DARZALEX SC.
Hepatitis B infection
DARZALEX SC could cause hepatitis B virus to become active again. Your doctor will check you for signs of this infection before, during and for some time after treatment with DARZALEX SC.

Tell your doctor if you are pregnant or intend to become pregnant. Like most medicines used to treat cancer, DARZALEX SC is not recommended for use during pregnancy.

Tell your doctor if you are trying to make your partner pregnant.

Both men and women receiving DARZALEX SC and their partners must use a reliable method of contraception during and for 3 months after ceasing treatment with DARZALEX SC.

Tell your doctor if you are breastfeeding or intend to breastfeed. It is not known whether DARZALEX SC passes into breast milk. Therefore there is a possibility that the breastfed baby may be affected.

If you wish to restart breastfeeding after your DARZALEX SC treatment, you must discuss this with your doctor or nurse, who will tell you when it is safe to do so.

If you have not told your doctor about any of the above, tell them before you start treatment with DARZALEX SC.

Taking other medicines:

Tell your doctor if you are taking any other medicines, including vitamins and herbal supplements and including medicines you can buy with or without a prescription from a pharmacy, supermarket or health food shop. These medicines may be affected by DARZALEX SC or may affect how well DARZALEX SC works. Your doctor or pharmacist can tell you what to do if you are using any other medicines.

How DARZALEX SC is given

How much is given:

Your doctor will work out your dose and schedule of DARZALEX SC. The recommended dose of DARZALEX SC is 1800 mg.

DARZALEX SC may be given alone or together with other medicines used to treat multiple myeloma or AL amyloidosis.

Ask your doctor if you want to know more about the dose of DARZALEX SC you receive.

How it is given:

DARZALEX SC will be given to you by a doctor or nurse as an injection under your skin (subcutaneous injection) over approximately 3 to 5 minutes. It is given in the stomach area (abdomen), not in other sites of the body, and not into areas of the abdomen where the skin is red, bruised, tender, hard or where there are scars. If you experience pain during the injection, the doctor or nurse may interrupt the injection and give you the remaining injection in another area of your abdomen.

When it is given:

Your doctor will tell you when DARZALEX SC will be given. The frequency depends on whether it is given alone or together with other medicines used to treat multiple myeloma or AL amyloidosis.

Medicines given during treatment with DARZALEX SC:

DARZALEX SC may be given alone or together with other medicines used to treat multiple myeloma (with bortezomib, thalidomide and dexamethasone, or with bortezomib, melphalan and prednisone, or with lenalidomide and dexamethasone or with bortezomib and dexamethasone).

DARZALEX SC may also be given together with other medicines used to treat AL amyloidosis (with bortezomib, cyclophosphamide and dexamethasone)

Read the Consumer Medicine Information for all medicines you take in combination with DARZALEX SC.

Before each injection of DARZALEX SC 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 injection of DARZALEX SC you will be given medicines (such as corticosteroids) to lower the chance of infusion-related reactions.

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

People with breathing problems:

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

What do I do if I receive too much? (overdose):

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 SC:

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.

While you are using DARZALEX SC

Things you must do:

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor will want to do some blood, urine and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor. It is important to have your follow-up doses of DARZALEX SC at the appropriate times to get the best effects from your treatment.

Be sure to follow your doctor's instructions about other medicines you should take, and other things you should do.

Tell any other doctors, dentists and pharmacists who are treating you that you are using DARZALEX SC.

If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you are using DARZALEX SC.

If you become pregnant or your partner becomes pregnant while being given DARZALEX SC, tell your doctor immediately.

If you need to have a blood test, tell the person doing the test that you are using DARZALEX SC.

Decreased blood cell counts

DARZALEX SC can decrease white blood cell counts which help fight infections, and blood cells called platelets which help to clot blood. Tell your doctor if you develop fever or if you have signs of bruising or bleeding.

The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it is painful or difficult to urinate.
Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.

Blood transfusions

If you need a blood transfusion, you will have a blood test first to match your blood type. DARZALEX SC can affect the results of this blood test. Tell the person doing the test that you are using DARZALEX SC.

Hepatitis B

If you have ever had a hepatitis B infection, DARZALEX SC could cause hepatitis B virus to become active again. Your doctor will check you for signs of this infection before, during and for some time after treatment with DARZALEX SC.

Tell your doctor right away if you get increasingly tired or get yellowing of your skin or white part of your eyes.

Infusion-related reactions

Before and after each injection of DARZALEX SC, you will be given medicines which help to lower the chance of infusion-related reactions (see “Medicines given during treatment with DARZALEX SC”).

These reactions are most likely to happen with the first injection and most reactions occur on the day of injection. If you have had an infusion-related reaction once it is less likely to happen again. However, delayed reactions can happen up to 3- 4 days after the injection. Your doctor may decide not to use DARZALEX SC if you have a strong reaction after the injection.

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 right away if you get any of the infusion-related reactions or allergic reactions listed in the Side Effects section.

If you get infusion-related reactions, you may need other medicines to treat your symptoms, or the injections may need to be stopped. When these reactions go away or get better, the injection can be started again.

Things to be careful of

Be careful driving or operating machinery until you know how DARZALEX SC affects you. DARZALEX SC may cause tiredness and other effects in some people. Make sure you know how you react to DARZALEX SC before you drive a car, operate machinery, or do anything else that could be dangerous if you have side effects.

Side Effects

Like all medicines, DARZALEX SC can cause side effects, although not everybody gets them. Some of these effects may be serious. However, there may be ways to reduce the discomfort of these effects. You may need medical treatment if you get some of the side effects.

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being treated with DARZALEX SC.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Below is a list of the more common side effects that you could get while being treated with DARZALEX SC:

− Infusion-related reactions

Tell your doctor or nurse right away if you get any of the following signs of an infusion-related reaction up to 3-4 days after the injection. You may need other medicines, or the injection may need to be interrupted or stopped.

chills
sore throat, cough
feeling sick (nausea)
vomiting
itchy, runny or blocked nose
feeling short of breath or other breathing problems
chest discomfort
dizziness or light-headedness (hypotension)
itching
wheezing
eye pain
blurred vision

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

− Injection site reactions

Skin reactions at or near the injection site (local), including injection site reactions, can happen with DARZALEX SC. These reactions may include:

redness of the skin
itching
swelling, pain, bruising, rash, bleeding

− Other side effects

fever
chills
feeling very tired
feeling weak
feeling dizzy
fainting
flu
headache
diarrhoea
constipation
decreased appetite
difficulty sleeping
nerve damage that may cause tingling, numbness or pain
muscle spasms
swollen hands, ankles or feet
other pain (eg back, joints)
lung infection (pneumonia)
bronchitis
infections of the airways – such as nose, sinuses or throat
build-up of fluid in the lungs making you short of breath
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, leukopenia)
low number of a type of blood cell called platelets which help to clot blood (thrombocytopenia)
high level of sugar in the blood
low level of calcium in the blood
low level of antibodies called 'immunoglobulins' in the blood which help fight infections (hypogammaglobulinemia).
irregular heart beat (atrial fibrillation)
heart disorders (heart failure, heart attack)
urinary tract infection
severe infection throughout the body (sepsis)
dehydration
chest pain
high blood pressure
rash, itching
inflamed liver (hepatitis)
inflamed pancreas
small blisters in clusters on the skin (herpes)
a type of herpes virus infection (cytomegalovirus infection)
unusual feeling in the skin (such as tingling or crawling feeling)
COVID-19 infection

If you think you are having an allergic reaction to DARZALEX SC, tell you doctor immediately or go to Accident and Emergency at your nearest hospital.

Symptoms of allergic reactions usually include some or all of the following:

rash, itching or hives on the skin
shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body

Other side effects not listed above may also occur in some people.

Tell your doctor, nurse or pharmacist if you notice any other effect that is making you feel unwell.

Product Description

Storage

Unopened vials:

DARZALEX SC should be stored in a refrigerator (2 to 8 degrees Celsius) and equilibrated to ambient temperature (15 to 30 degrees Celsius) before use. The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours.

Do not freeze.

Store in the original package to protect from light. Do not shake.

Prepared syringe:

If the syringe containing DARZALEX SC is not used immediately, it can be stored for up to 24 hours refrigerated followed by up to 12 hours at 15 to 25 degrees Celsius and ambient light. The syringe should be discarded if it is not used within 24 hours of being refrigerated or within 12 hours of being at 15 to 25 degrees Celsius. If stored in the refrigerator, allow the solution to come to ambient temperature before administration.

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

What it looks like:

DARZALEX SC is available as a colourless to yellow, clear to opalescent, preservative-free solution for subcutaneous administration.

DARZALEX SC is supplied as a carton pack containing one single use glass vial.

Ingredients

Active ingredient:

daratumumab 1800 mg (120 mg/mL)

Other ingredients:

vorhyaluronidase alfa
histidine
histidine hydrochloride monohydrate
sorbitol
methionine
polysorbate 20
water for injections.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Rd
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

Registration numbers

DARZALEX SC 1800 mg/15 mL (AUST R 322685)

This leaflet was prepared 28 October 2022.

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Darzalex SC

Active ingredient

Daratumumab

Schedule

1 Name of Medicine

Daratumumab.

2 Qualitative and Quantitative Composition

15 mL vial.

Each single-use vial contains 1800 mg of daratumumab (120 mg/mL).
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody against CD38 antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
Recombinant human hyaluronidase (rHuPH20; vorhyaluronidase alfa) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is produced by mammalian CHO cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). It is a glycosylated single-chain protein with an approximate molecular weight of 61 kD.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Darzalex SC is available as a colourless to yellow, clear to opalescent, preservative-free solution for subcutaneous administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Darzalex SC is indicated for the treatment of patients:
with newly diagnosed multiple myeloma:
who are eligible for autologous stem cell transplant. For use in combination with: bortezomib, thalidomide, and dexamethasone.
who are ineligible for autologous stem cell transplant. For use in combination with: bortezomib, melphalan and prednisone, or lenalidomide and dexamethasone.
with relapsed or refractory multiple myeloma who have received:
at least one prior therapy. For use in combination with: bortezomib and dexamethasone, or lenalidomide and dexamethasone, or carfilzomib and dexamethasone, or pomalidomide and dexamethasone (after at least one prior therapy including lenalidomide and a proteasome inhibitor (PI)).
at least three prior lines of therapy including a PI and an immunomodulatory agent or who are refractory to both a PI and an immunomodulatory agent. For use as: monotherapy.
Darzalex SC in combination with bortezomib, cyclophosphamide and dexamethasone, is indicated for the treatment of patients with light chain AL amyloidosis.

4.2 Dose and Method of Administration

Darzalex SC is for subcutaneous use only. Darzalex SC has different dosage and administration instructions than intravenous daratumumab. Do not administer intravenously.
Serious Infusion-Related Reactions (IRRs) can occur with administration of IV or SC Darzalex. The rate of IRRs in clinical trials is higher in IV than SC administration. Darzalex should be administered by a healthcare professional, and the first SC dose in daratumumab-naïve patients should be administered in an environment where resuscitation facilities are available.
Before Darzalex SC therapy is commenced, clinicians should arrange for extended red cell phenotyping of patients (see Section 4.4 Special Warnings and Precautions for Use, Effect on laboratory tests).
Pre- and post-injection medications should be administered (see Recommended concomitant medications below).
For patients currently receiving daratumumab intravenous formulation, Darzalex SC solution for subcutaneous injection may be used as an alternative to the intravenous daratumumab formulation starting at the next scheduled dose.

Dosage - adults (≥ 18 years).

Recommended dose for multiple myeloma.

Darzalex SC with VTd combination therapy (4-week cycle dosing regimen).

The Darzalex SC dosing schedule in Table 1 is for combination therapy with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT.
The recommended dose is Darzalex SC 1800 mg administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

Bortezomib is administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4.

Darzalex SC with VMP combination therapy (6-week cycle dosing regimen).

The Darzalex SC dosing schedule in Table 2 is for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma ineligible for ASCT.
The recommended dose is Darzalex SC 1800 mg administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

Bortezomib is given twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (8 doses), followed by once weekly at Weeks 1, 2, 4 and 5 for eight additional 6-week cycles (32 additional doses for a total of 40 doses). For information on the VMP dose and dosing schedule when administered with Darzalex SC, see Section 5.1 Pharmacodynamic Properties, Clinical trials.

Darzalex SC with Vd combination therapy (3-week cycle dosing regimen).

The Darzalex SC dosing schedule in Table 3 is for combination therapy with 3 week cycle regimen (bortezomib and dexamethasone) for patients with relapsed/refractory multiple myeloma.
The recommended dose is Darzalex SC 1800 mg administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

For dosing instructions for medicinal products administered with Darzalex SC, see Section 5.1 Pharmacodynamic Properties, Clinical trials and manufacturer's Product Information.

Darzalex SC with Rd, Pd, Kd combination therapy or Darzalex SC monotherapy (4-week cycle dosing regimens).

The Darzalex SC dosing schedule in Table 4 is for combination therapy with 4 week cycle regimens (e.g. lenalidomide, pomalidomide, carfilzomib) and for monotherapy as follows:
combination therapy with lenalidomide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant (ASCT);
combination therapy with lenalidomide or pomalidomide and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma;
combination therapy with carfilzomib and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma;
monotherapy for patients with relapsed/refractory multiple myeloma.
The recommended dose is Darzalex SC 1800 mg administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

Recommended dose for AL amyloidosis. The Darzalex SC dosing schedule in Table 5 is for combination therapy with bortezomib, cyclophosphamide and dexamethasone (4-week cycle regimen) for patients with AL amyloidosis.
The recommended dose is Darzalex SC 1800 mg administered subcutaneously, over approximately 3-5 minutes, according to the following dosing schedule:

For dosing instructions of medicinal products administered with Darzalex SC, see Section 5.1 Pharmacodynamic Properties, Clinical trials and manufacturer's Product Information.
Recommended concomitant medications.

Pre-injection medication.

Pre-injection medications (oral or intravenous) should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every administration of Darzalex SC subcutaneous injection as follows:
Corticosteroid (long-acting or intermediate-acting). Monotherapy: Methylprednisolone 100 mg, or equivalent. Following the second injection, the dose of methylprednisolone may be reduced to 60 mg.
Combination therapy: Administer 20 mg dexamethasone (or equivalent) prior to every Darzalex SC injection.
When dexamethasone is the background regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre medication on Darzalex SC administration days (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Additional background-regimen specific corticosteroids (e.g. prednisone) should not be taken on Darzalex SC administration days when patients have received dexamethasone (or equivalent) as a pre-medication.
Antipyretics (oral paracetamol 500 to 1000 mg).
Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Post-injection medication.

Administer post-injection medication to reduce the risk of delayed IRRs as follows:
Monotherapy: Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate acting or long acting corticosteroid in accordance with local standards) on each of the 2 days following all Darzalex SC injections (beginning the day after the injection).
Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after the Darzalex SC injection.
However, if a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the Darzalex SC injection, additional post-injection medications may not be needed (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
If the patient experiences no major IRRs after the first three injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued.
Additionally, for patients with a history of chronic obstructive pulmonary disease, consider the use of post-injection medications including short and long acting bronchodilators, and inhaled corticosteroids. Following the first four injections, if the patient experiences no major IRRs, these inhaled post-injection 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.

Missed dose(s).

If a planned dose of Darzalex SC is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval.

Dose modifications.

No dose reductions of Darzalex SC are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see Section 4.4 Special Warnings and Precautions for Use). For information concerning medicinal products given in combination with Darzalex SC, see manufacturer's Product Information.

Darzalex SC and management of infusion-related reactions.

In clinical trials, no modification to rate or dose of Darzalex SC was required to manage infusion-related reactions.

Special populations.

Paediatrics (17 years of age and younger).

The safety and efficacy of Darzalex SC have not been established in paediatric patients.

Elderly (65 years of age and older).

No dose adjustments are considered necessary in elderly patients (see Section 5.2 Pharmacokinetic Properties; Section 4.8 Adverse Effects (Undesirable Effects)).

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 Pharmacokinetic Properties).

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. Based on population PK analyses, no dosage adjustments are necessary for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Administration.

Darzalex SC should be administered by a healthcare professional.
To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Darzalex SC for subcutaneous injection and not intravenous daratumumab. Darzalex SC subcutaneous (SC) formulation is not intended for intravenous administration and should be administered via a subcutaneous injection only.
Darzalex SC is for single use only and is ready to use.
Darzalex SC is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles.
Darzalex SC should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use if opaque particles, discolouration or other foreign particles are present.
Remove the Darzalex SC vial from refrigerated storage (2°C - 8°C) and equilibrate to ambient temperature (15°C-30°C). The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake.
Prepare the dosing syringe in controlled and validated aseptic conditions.
To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.

Storage of prepared syringe.

If the syringe containing Darzalex SC is not used immediately, store the Darzalex SC solution for up to 24 hours refrigerated followed by up to 12 hours at 15°C-25°C and ambient light. Discard if stored more than 24 hours of being refrigerated or more than 12 hours of being at 15°C-25°C, if not used. If stored in the refrigerator, allow the solution to come to ambient temperature before administration.

Instructions for use.

Inject 15 mL Darzalex SC into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel (umbilicus) over approximately 3-5 minutes. Do not inject Darzalex SC at other sites of the body as no data are available.
Injection sites should be rotated for successive injections.
Darzalex SC should never be injected into areas where the skin is red, bruised, tender, hard or areas where there are scars.
Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by slowing down the injection, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.
During treatment with Darzalex SC, do not administer other medications for subcutaneous use at the same site as Darzalex SC.

4.3 Contraindications

Patients with a history of severe hypersensitivity (e.g. anaphylactic reaction) to daratumumab, or to any of the excipients.
Before starting therapy, refer to the Product Information for medicinal products used in combination with Darzalex SC.

4.4 Special Warnings and Precautions for Use

Before starting combination therapy, also refer to the Product Information for relevant other medicines (bortezomib, lenalidomide, thalidomide, dexamethasone, prednisone, melphalan, cyclophosphamide as appropriate).
Patients receiving Darzalex SC in combination with lenalidomide and dexamethasone or thalidomide and dexamethasone should adhere to the pregnancy prevention programmes of lenalidomide or thalidomide (also see Section 4.6 Fertility, Pregnancy and Lactation).

Infusion-related reactions.

In clinical trials, systemic reactions that were assessed as being related to daratumumab were termed 'infusion-related reactions (IRRs)', regardless of the route of administration.
Darzalex SC can cause severe and/or serious IRRs, including anaphylactic reactions.
In clinical trials, approximately 9% (77/898) of patients experienced an infusion-related reaction. Most IRRs occurred following the first injection and were Grade 1-2 (see Section 4.8 Adverse Effects (Undesirable Effects)). IRRs occurring with subsequent injections were seen in 1% of patients.
The median time to onset of IRRs following Darzalex SC was 3.2 hours (range 0.07-83 hours). The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurred in 1% of patients.
Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse events (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be monitored and counselled regarding IRRs, especially during and following the first and second injections. If an anaphylactic reaction or life threatening (Grade 4) reactions occur, institute appropriate emergency care and permanently discontinue Darzalex SC.
To reduce the risk of IRRs, pre-medicate patients with antihistamines, antipyretics and corticosteroids. To reduce the risk of delayed IRRs, administer oral corticosteroids to all patients following Darzalex SC injections. Patients with a history of chronic obstructive pulmonary disease may require additional post-injection medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. If ocular symptoms occur, interrupt Darzalex SC injection and seek immediate ophthalmologic evaluation prior to restarting Darzalex SC (see Section 4.2 Dose and Method of Administration).

Neutropenia/thrombocytopenia.

Darzalex SC increases the incidence of neutropenia and thrombocytopenia (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor complete blood cell counts periodically during treatment. This should be done as per clinical judgment but not less frequently than prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Darzalex SC dose delay may be required to allow recovery of blood cell counts. In lower body weight patients (≤ 65 kg) receiving Darzalex SC subcutaneous formulation, higher rates of neutropenia were observed, this includes an increase in Grade 3 - 4 neutropenia; No dose reduction of Darzalex SC is recommended. Consider supportive care with transfusions or growth factors.

Hepatitis B virus (HBV) reactivation.

Hepatitis B virus (HBV) reactivation, in some cases fatal, has been reported in patients treated with daratumumab. HBV screening should be performed in all patients before initiation of treatment with Darzalex SC.
For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of Darzalex SC treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated.
In patients who develop reactivation of HBV while on Darzalex SC, suspend treatment with Darzalex SC and any concomitant steroids, chemotherapy, and institute appropriate treatment. Resumption of Darzalex SC treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

Use in the elderly.

No overall differences in safety or effectiveness were observed between older (≥ 65 years) and younger patients.
No dose adjustments are considered necessary (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Darzalex SC have not been established in paediatric patients.

Effect on laboratory tests.

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 administration. 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.
Type and screen patients prior to starting Darzalex SC.
In the event of a planned transfusion, notify blood transfusion centres of this interference with indirect antiglobulin tests (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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 Interactions with Other Medicines and Other Forms of Interactions). This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug-drug interactions.

No formal drug-drug interaction studies have been performed.
As an IgG1κ monoclonal antibody, renal excretion and hepatic enzyme mediated metabolism of intact daratumumab are unlikely to represent major elimination routes. As such, variations in drug metabolizing 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 metabolizing enzymes.
Clinical pharmacokinetic assessments of daratumumab IV or SC formulations in combination with lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib, cyclophosphamide and dexamethasone indicated no clinically-relevant drug-drug interaction between daratumumab and these small molecule medicinal products.

Effects of Darzalex on laboratory tests.

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. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. 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 (see Section 4.4 Special Warnings and Precautions for Use, Effect on laboratory tests).

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, consider other methods to evaluate the depth of response.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data are available to determine potential effects of daratumumab on fertility in males or females.
(Category C)
There are no human or animal data to assess the risk of Darzalex SC use during pregnancy. IgG1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore, Darzalex SC 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 drug, the patient should be informed of the potential risk to the fetus.
To avoid exposure to the fetus, women of reproductive potential should use effective contraception during and for 3 months after cessation of Darzalex SC treatment. However, when Darzalex SC is used in combination with lenalidomide and dexamethasone, or thalidomide and dexamethasone, patients must also follow advice about use in pregnancy of those products - see below.

Use of Darzalex SC with lenalidomide or thalidomide.

Lenalidomide and thalidomide (both Pregnancy Category X) are associated with risk of fetal harm, including severe life-threatening human birth defects. Refer to the lenalidomide and thalidomide PI for additional information. Patients receiving Darzalex SC in combination with lenalidomide and dexamethasone, or thalidomide and dexamethasone, should adhere to the pregnancy prevention programme of these medicines.
It is not known whether daratumumab is excreted into human or animal milk or affects milk production. There are no studies to assess the effect of daratumumab on the breast-fed infant.
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. Because the risks of Darzalex SC to the infant from oral ingestion are unknown, a decision should be made whether to discontinue breast-feeding, or discontinue Darzalex SC therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Darzalex SC 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 Adverse Effects (Undesirable Effects)

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of daratumumab based on the comprehensive assessment of the available adverse event information. A causal relationship with daratumumab cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety data of Darzalex SC (subcutaneous formulation 1800 mg) was established in 705 patients with multiple myeloma (MM) including 260 patients from a Phase 3 active-controlled trial (Study MMY3012) who received Darzalex SC (subcutaneous formulation) as monotherapy, 149 patients from a Phase 3 active-controlled trial (Study MMY3013) who received Darzalex SC formulation in combination with pomalidomide and dexamethasone (DPd), and three open-label, clinical trials in which patients received Darzalex SC (subcutaneous formulation) either as monotherapy (N = 31; MMY1004 and MMY1008) and MMY2040 in which patients received Darzalex SC (subcutaneous formulation) in combination with either bortezomib, melphalan and prednisone (DVMP, n = 67), lenalidomide and dexamethasone (DRd, n = 65) or bortezomib, lenalidomide and dexamethasone (DVRd, n = 67) or carfilzomib and dexamethasone (DKd, n=66).
The safety data of Darzalex SC subcutaneous formulation (1800 mg) was established in patients with newly diagnosed AL amyloidosis from a Phase 3 active-controlled trial (Study AMY3001) in which patients received Darzalex SC in combination with bortezomib, cyclophosphamide and dexamethasone (DVCd, n = 193).

Monotherapy - relapsed/refractory multiple myeloma.

MMY3012, a Phase 3 randomised, study compared treatment with Darzalex SC (subcutaneous formulation 1800 mg) vs. intravenous (16 mg/kg) daratumumab in patients with relapsed or refractory multiple myeloma. The median Darzalex SC (subcutaneous formulation) treatment duration was 5.5 months (range: 0.03 to 19.35 months) and 6.0 months (range: 0.03 to; 16.69 months) for intravenous daratumumab. The most common adverse reactions of any grade (≥ 20% patients) with Darzalex SC (subcutaneous formulation) were upper respiratory tract infections. Pneumonia was the only serious adverse reaction occurring in ≥ 5% of patients (6% IV vs. 6% SC).
Table 6 lists the adverse reactions that occurred in patients who received Darzalex SC (subcutaneous formulation) or intravenous daratumumab in Study MMY3012.

Laboratory abnormalities worsening during treatment from baseline are listed in Table 7.

Combination therapies in multiple myeloma.

Combination treatments: DVMP, DRd, DVRd, DKd.

MMY2040 was an open-label trial of Darzalex SC (subcutaneous formulation) in combination with bortezomib, melphalan, prednisone (DVMP) in patients with newly diagnosed MM who are ineligible for transplant, in combination with lenalidomide and dexamethasone (DRd) in patients with relapsed or refractory MM, and in combination with bortezomib, lenalidomide, dexamethasone (DVRd) in patients with newly diagnosed MM who are transplant eligible and in combination with carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory MM. The median treatment duration was as follows: 10.6 months (0.36 to 13.17 months) for DVMP; 11.1 months (0.49 to 13.57 months) for DRd; 2.6 months (0.46 to 3.91 months) for DVRd; 8.3 months (0 to 17 months) for DKd.
The most common adverse reactions of any grade (≥ 20% patients) with Darzalex SC (subcutaneous formulation) were constipation, diarrhoea, nausea, vomiting, pyrexia, fatigue, asthenia, upper respiratory tract infection, pneumonia, back pain, muscle spasms, peripheral sensory neuropathy, insomnia, cough, hypertension, headache, oedema peripheral and dyspnoea. Serious adverse reactions reported in ≥ 5% of patients included pneumonia (DVMP 9%; DRd 12%; DVRd 1%; DKd 3%); pyrexia (DVMP 6%; DRd 5%; DVRd 6%; DKd 3%), and influenza (DVMP 1%; DRd 6%; DVRd 0%; DKd 2%), and diarrhoea (DVMP 1%; DRd 6%; DVRd 0%; DKd 0%).
Table 8 lists the adverse reactions that occurred in patients who received Darzalex SC (subcutaneous formulation) in Study MMY2040.

Laboratory abnormalities worsening during treatment from baseline are listed in Table 9.

Combination treatment: DPd.

MMY3013 was a Phase 3 randomised, open-label, active controlled study that compared treatment with Darzalex SC formulation in combination with pomalidomide and low-dose dexamethasone (DPd) with pomalidomide and low-dose dexamethasone (Pd) in patients with relapsed or refractory multiple myeloma who received at least 1 prior treatment with lenalidomide and a protease inhibitor (PI). The median treatment duration was 11.5 months (0.13 to 36.17 months) for DPd and 6.6 months (0.03 to 27.33 months) for Pd.
The most common adverse reactions of any grade (≥ 20% patients) were fatigue, upper respiratory infection, asthenia, diarrhoea, and pneumonia. Serious adverse reactions with a 2% greater incidence in the DPd arm compared to the Pd arm were pneumonia (DPd 26% vs Pd 17%), neutropenia (DPd 5% vs. Pd 3%), thrombocytopenia (DPd: 3% vs Pd: 1%), and syncope (DPd: 2% vs Pd: 0%).
Table 10 summarises the adverse reactions in Study MMY3013.

Laboratory abnormalities worsening during treatment from baseline are listed in Table 11.

Combination treatment for AL amyloidosis.

The safety of Darzalex SC formulation (1800 mg) with bortezomib, cyclophosphamide and dexamethasone (DVCd) compared to bortezomib, cyclophosphamide and dexamethasone (VCd) in patients with newly diagnosed AL amyloidosis was evaluated in an open-label, randomised, Phase 3 study, AMY3001. The median treatment duration was 9.6 months (range: 0.03 to 21.16 months) for DVCd and 5.3 months (range: 0.03 to 7.33 months) for VCd.
Serious adverse reactions occurred in 43% of patients who received Darzalex SC in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DVCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).
Permanent discontinuation of Darzalex SC due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of Darzalex SC in more than one patient were pneumonia, sepsis, and cardiac failure.
Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received Darzalex SC. Adverse reactions which required a dosage interruption in ≥ 3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnoea (3%), and neutropenia (3%).
The most common adverse reactions (≥ 20%) were upper respiratory tract infection, diarrhoea, peripheral oedema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnoea, and cough.
Table 12 summarises the adverse reactions in AMY3001.

Clinically relevant adverse reactions not included in Table 16 and occurred in patients who received Darzalex SC with bortezomib, cyclophosphamide and dexamethasone included:

Skin and subcutaneous tissue disorders.

Rash, pruritus.

Nervous system disorders.

Paresthesia.

General disorders and administration site conditions.

Infusion reaction, chills.

Cardiac disorders.

Cardiac failure^a, cardiac arrest.

Metabolism and nutrition disorders.

Hyperglycemia, hypocalcemia, dehydration.

Infections.

Bronchitis, herpes zoster, sepsis, urinary tract infection, influenza.

Vascular disorders.

Hypertension.

Musculoskeletal and connective tissue disorders.

Musculoskeletal chest pain.

Gastrointestinal disorders.

Pancreatitis.

Respiratory, thoracic and mediastinal disorders.

Pulmonary oedema.
^a Cardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary oedema, and left ventricular dysfunction occurred in 11% of patients.
Laboratory abnormalities worsening during treatment from baseline are listed in Table 13.

Experience with intravenous daratumumab combination therapies.

The safety of intravenous (IV) daratumumab (16 mg/kg) has been established in 1910 patients with multiple myeloma including 1772 patients from five Phase 3 active-controlled trials who received IV daratumumab in combination with either lenalidomide and dexamethasone (DRd, n = 283; MMY3003), bortezomib and dexamethasone (DVd, n = 243; MMY3004), bortezomib, melphalan and prednisone (DVMP, n = 346; MMY3007), or lenalidomide and dexamethasone (DRd, n = 364; MMY3008), or bortezomib and thalidomide and dexamethasone (DVTd, n = 536; MMY3006) and two open-label, clinical trials in which patients received IV daratumumab either in combination with pomalidomide and dexamethasone (DPd, n = 103; MMY1001) or in combination with lenalidomide and dexamethasone (n = 35).
Adverse reactions in Table 14 reflect exposure to IV daratumumab for a median treatment duration as follows:

MMY3008.

25.3 months (range: 0.1 to 40.44 months) for the daratumumab-lenalidomide-dexamethasone (DRd) group; 21.3 months (range: 0.03 to 40.64 months) for the lenalidomide-dexamethasone (Rd) group.

MMY3007.

14.7 months (range: 0 to 25.8 months) for the daratumumab-bortezomib, melphalan-prednisone (DVMP) group; 12 months (range: 0.1 to 14.9 months) for the VMP group.

MMY3003.

13.1 months (range: 0 to 20.7 months) for the daratumumab-lenalidomide-dexamethasone (DRd) group; 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide-dexamethasone (Rd) group.

MMY3004.

6.5 months (range: 0 to 14.8 months) for the daratumumab-bortezomib-dexamethasone (DVd) group; 5.2 months (range: 0.2 to 8.0 months) for the bortezomib-dexamethasone (Vd) group.
Additionally, adverse reactions described in Table 14 reflect exposure to IV daratumumab up to day 100 post-transplant in a Phase 3 active-controlled study MMY3006 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for the DVTd group and 8.7 months (range: 6.4 to 11.5 months) for the VTd group.
The most frequent adverse reactions (≥ 20%) were infusion-related reactions, fatigue, asthenia, nausea, diarrhoea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, chills, pyrexia, dizziness, insomnia, cough, dyspnoea, peripheral oedema, peripheral sensory neuropathy, bronchitis, pneumonia, and upper respiratory tract infection. Serious adverse reactions with a 2% higher incidence in the IV daratumumab arms were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea, and atrial fibrillation.

Laboratory abnormalities worsening during IV daratumumab combination treatment trials are listed in Table 15.

Infusion-related reactions.

In clinical trials (monotherapy and combination treatments; N = 898) with Darzalex SC subcutaneous formulation, the incidence of any grade IRRs was 8.2% with the first injection of Darzalex SC subcutaneous formulation (1800 mg, Week 1), 0.4% with the Week 2 injection, and 1.1% with subsequent injections. Grade 3 IRRs were seen in 1% of patients. No patients had Grade 4 IRRs.
Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing, as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension and tachycardia (see Section 4.4 Special Warnings and Precautions for Use).

Injection site reactions (ISRs).

In clinical trials (N = 898) with Darzalex SC formulation, the incidence of any grade injection site reaction was 7.7%. There were no Grade 3 or 4 ISRs. The most common (> 1%) ISR was erythema.

Infections.

In patients with multiple myeloma receiving daratumumab monotherapy, the overall incidence of infections was 52.9% for Darzalex SC subcutaneous formulation and 50.0% for IV daratumumab. Additionally, Grade 3 or 4 infections also occurred at the following frequencies: Darzalex SC subcutaneous formulation (11.7%) and IV daratumumab (14.3%). Most infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported Grade 3 or 4 infection across studies. In active-controlled studies, discontinuations from treatment due to infections occurred in 1-4% of patients. Fatal infections were primarily due to pneumonia and sepsis.
In patients with multiple myeloma receiving intravenous daratumumab combination therapy, the following infections were reported:

Grade 3 or 4 infections.

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%; DKd^a: 36%, Kd^a: 27%; DKd^b: 21%.
^a Where carfilzomib 20/56 mg/m² was administered twice-weekly.
^b Where carfilzomib 20/70 mg/m² was administered once-weekly.
Newly diagnosed patient studies: DVMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%, VTd: 20%.

Grade 5 (fatal) infections.

Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd^a: 5%, Kd^a: 3%; DKd^b: 0%.
^a Where carfilzomib 20/56 mg/m² was administered twice-weekly.
^b Where carfilzomib 20/70 mg/m² was administered once-weekly.
Newly diagnosed patient studies: DVMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.
In patients with multiple myeloma receiving Darzalex SC formulation combination therapy, the following were reported:
Grade 3 or 4 infections: DPd: 28%, Pd: 23%;
Grade 5 (fatal) infections: DPd: 5%, Pd: 3%.
In patients with AL amyloidosis receiving Darzalex SC formulation combination therapy, the following were reported:
Grade 3 or 4 infections: DVCd: 17%, VCd:10%;
Grade 5 (fatal) infections: DVCd: 1%, VCd: 1%.

Cardiac disorders and AL amyloidosis-related cardiomyopathy.

The majority of patients in AMY3001 had AL amyloidosis-related cardiomyopathy at baseline (DVCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of DVCd patients compared to 10% of VCd patients, while serious cardiac disorders occurred in 16% vs. 13% of DVCd and VCd patients, respectively. Serious cardiac disorders occurring in ≥ 2% of patients included cardiac failure (DVCd 6.2% vs. VCd 4.3%), cardiac arrest (DVCd 3.6% vs. VCd 1.6%) and atrial fibrillation (DVCd 2.1% vs. VCd 1.1%). All DVCd patients who experienced serious or fatal cardiac disorders had AL amyloidosis-related cardiomyopathy at baseline. The longer median duration of treatment in the DVCd arm compared to the VCd arm (9.6 months vs. 5.3 months, respectively) should be taken into consideration when comparing the frequency of cardiac disorders between the two treatment groups. Exposure-adjusted incidence rates (number of patients with the event/100 patient-months at risk) of overall Grade 3 or 4 cardiac disorders (1.2 vs. 2.3), cardiac failure (0.5 vs. 0.6), cardiac arrest (0.1 vs. 0.0) and atrial fibrillation (0.2 vs. 0.1) were comparable in the DVCd arm vs. the VCd arm, respectively.
With a median follow-up of 11.4 months (range 0.03 - 21.3), overall deaths (DVCd 14% vs. VCd 15%) in Study AMY3001 were primarily due to AL amyloidosis-related cardiomyopathy in both treatment arms.

Other adverse reactions.

Other adverse reactions reported in patients treated with daratumumab in clinical trials are listed in Table 16.

Other special population.

Elderly.

Of the 3615 patients who received daratumumab (n = 898 SC; n = 2717 IV) at the recommended dose, 38% were 65 to 75 years of age, and 16% were 75 years of age or older. No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older than in younger patients (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). Among patients with relapsed and refractory multiple myeloma (n = 2042), the most common serious adverse reactions that occurred more frequently in elderly (≥ 65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n = 777), the most common serious adverse reaction that occurred more frequently in elderly (≥ 75 years of age) was pneumonia. Among patients with newly diagnosed AL amyloidosis (n = 193), the most common serious adverse reaction that occurred more frequently in elderly (≥ 65 years of age) was pneumonia.

Post-marketing data.

Adverse reactions identified during post-marketing experience with daratumumab are included in Table 17. The frequencies are provided according to the following convention:
Very common ≥ 1/10; Common ≥ 1/100 to < 1/10; Uncommon ≥ 1/1000 to < 1/100; Rare ≥ 1/10,000 to < 1/1000; Very rare < 1/10,000, including isolated reports; Not known frequency cannot be estimated from the available data.
In Table 17, adverse reactions are presented by frequency category based on spontaneous reporting rates.

Reporting suspected adverse reactions.

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 https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

There has been no experience of overdosage in clinical studies.

Treatment.

There is no known specific antidote for Darzalex SC overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment be instituted immediately.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: monoclonal antibodies, ATC code: L01FC01.
Darzalex SC subcutaneous formulation contains recombinant human hyaluronidase (vorhyaluronidase alfa, rHuPH20). Vorhyaluronidase alfa works locally and transiently to degrade hyaluronan ((HA), a naturally occurring glycoaminoglycan found throughout the body) in the extracellular matrix of the subcutaneous space by cleaving the linkage between the two sugars (N-acetylglucosamine and glucuronic acid) which comprise HA. Vorhyaluronidase alfa has a half-life in skin of less than 30 minutes. Hyaluronan levels in subcutaneous tissue return to normal within 24 to 48 hours because of the rapid biosynthesis of hyaluronan.

Mechanism of action.

Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed on the surface of cells in a variety of haematological malignancies, including clonal plasma cells in multiple myeloma and AL amyloidosis, as well as other cell types and tissues. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Daratumumab has been shown to inhibit the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilize multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) 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. 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 Darzalex SC treatment in peripheral whole blood and bone marrow. T-cell receptor DNA sequencing verified that T-cell clonality was increased with Darzalex SC 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^dim) NK cells in peripheral whole blood and bone marrow were observed with Darzalex SC treatment. However, baseline levels of NK cells did not show an association with clinical response.

Immunogenicity.

In multiple myeloma and AL amyloidosis patients treated with Darzalex SC subcutaneous formulation in monotherapy and combination clinical trials, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.
In multiple myeloma and AL amyloidosis patients, the incidence of treatment-emergent non-neutralizing anti-rHuPH20 antibodies was 7.1% (58/812); in monotherapy and combination Darzalex SC clinical trials. The anti-rHuPH20 antibodies did not appear to impact daratumumab exposures. The clinical relevance of the development of anti-daratumumab or anti-rHuPH20 antibodies after treatment with Darzalex SC subcutaneous formulation is not known.
Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to daratumumab with the incidence of antibodies to other products may be misleading.

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_max. The mean time-averaged QTcF interval increase was 10.1 ms (n = 3) and 4.3 ms (n = 42) in the 16 mg/kg cohorts from these analyses.

Clinical trials.

Clinical experience with Darzalex SC subcutaneous formulation.

Monotherapy - relapsed/refractory multiple myeloma. MMY3012, an open-label, randomised, Phase 3 non-inferiority study, compared efficacy and safety of treatment with Darzalex SC subcutaneous formulation (1800 mg) vs. intravenous (16 mg/kg) daratumumab in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. Treatment continued until unacceptable toxicity or disease progression.
A total of 522 patients were randomised: 263 to the Darzalex SC subcutaneous formulation arm and 259 to the IV daratumumab arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median patient age was 67 years (range: 33-92 years), 55% were male and 78% were Caucasian. The median patient weight was 73 kg (range: 29 - 138 kg). Patients had received a median of 4 prior lines of therapy. A total of 51% of patients had prior autologous stem cell transplant (ASCT), 100% of patients were previously treated with both PI(s) and IMiD(s) and most patients were refractory to a prior systemic therapy, including both PI and IMiD (49%).
The study was designed to demonstrate non-inferiority of treatment with Darzalex SC subcutaneous formulation versus IV daratumumab based on co-primary endpoints of overall response rate (ORR) by the IMWG response criteria and maximum C_trough at pre-dose Cycle 3 Day 1 (see Section 5.2 Pharmacokinetic Properties). The ORR, defined as the proportion of patients who achieve partial response (PR) or better, was 41.1% (95% CI: 35.1%, 47.3%) in the Darzalex SC subcutaneous formulation arm and 37.1% (95% CI: 31.2%, 43.3%) in the IV daratumumab arm.
This study met its primary objectives to show that Darzalex SC subcutaneous formulation is non-inferior to IV daratumumab in terms of ORR and maximum trough concentration. The results are provided in Table 18.

After a median follow-up of 29.3 months, 127 deaths (48.3%) were observed in the Darzalex SC subcutaneous formulation and 130 deaths (50.2%) in the IV daratumumab arm. The median overall survival (OS) was 28.2 months (95% CI: 22.8, NE) in the Darzalex SC formulation arm and was 25.6 months (95% CI: 22.1, NE) in the IV daratumumab arm.
Safety and tolerability results, including in lower weight patients, were consistent with the known safety profile for Darzalex SC subcutaneous formulation and IV daratumumab.
Combination treatments in multiple myeloma. MMY2040 was an open-label trial evaluating the efficacy and safety of Darzalex SC subcutaneous formulation 1800 mg:

DVMP arm.

In combination with bortezomib, melphalan, and prednisone (DVMP) in patients with newly diagnosed multiple myeloma (MM) who are ineligible for transplant. Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m² body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2-9; 4 doses per cycle). Melphalan at 9 mg/m², and prednisone at 60 mg/m² were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). Darzalex SC subcutaneous formulation was continued until disease progression or unacceptable toxicity. The median duration of follow-up for patients was 6.9 months.
The median age was 75 years and approximately 51% were ≥ 75 years of age. The sex of the patients was evenly distributed. Most patients were white (69%). 33% had ISS Stage I, 45% had ISS Stage II, and 22% had ISS Stage III disease at screening.

DRd arm.

In combination with lenalidomide and dexamethasone (DRd) in patients with relapsed or refractory MM. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or BMI < 18.5). Darzalex SC subcutaneous formulation was continued until disease progression or unacceptable toxicity. The median duration of follow-up for patients was 7.1 months.
The median age was 69 years. The majority of patients were male (69%). Most patients were white (69%). 42% had ISS Stage I, 30% had ISS Stage II, and 28% had ISS Stage III disease at screening. Patients had received a median of 1 prior line of therapy, 52% of patients received prior autologous stem cell transplantation (ASCT). The majority of patients (95%) received prior PI, 59% received a prior Immunomodulatory Agent including 22% who received prior lenalidomide. 54% of patients received both a prior PI and Immunomodulatory Agents.

DVRd arm.

In combination with bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed MM who are transplant eligible. Bortezomib was administered by SC injection at a dose of 1.3 mg/m² body surface area twice weekly at Weeks 1 and 2. Lenalidomide was administered orally at 25 mg once daily on Days 1-14; low dose dexamethasone was administered 40 mg/week in 3-week cycles. Total treatment duration was 4 cycles.
The median age was 59 years of age. The majority of patients (81%) fell in the range of 18 to < 65 years of age and were male (72%). Most patients were white (57%); 45% had ISS Stage I, 34% had ISS Stage II, and 21% had ISS Stage III disease at screening.

DKd arm.

In combination with carfilzomib and dexamethasone (DKd) for patients in first relapse or refractory MM after initial treatment with a lenalidomide-containing regimen. Carfilzomib was administered by IV infusion at a dose of 20 mg/m² on Cycle 1 Day 1. If a dose of 20 mg/m² was tolerated, carfilzomib was administered at a dose of 70 mg/m² as a 30-minute IV infusion, on Cycle 1 Day 8 and Day 15, and then Day 1, 8 and 15 of each cycle. This was given with low dose dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients ≥ 75 years or BMI < 18.5). Darzalex SC formulation was continued until disease progression or unacceptable toxicity. The median duration of follow-up for patients was 9.2 months.
The median age was 61 years and 52% were male. Most patients were white (73%). 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease at screening. A total of 79% of patients had received prior ASCT; 91% of patients received prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.
A total of 265 patients (DVMP: 67; DRd: 65; DVRd: 67; DKd: 66) were enrolled. Efficacy results were determined by computer algorithm using IMWG response criteria during the study. Primary endpoints ORR for DVMP, DRd and DKd and VGPR or better for DVRd were met (see Table 19).

The minimal residual disease (MRD) negativity rate for patients in the DKd arm was 24%, based on all treated population and a threshold of 10^-5.

Combination treatment with pomalidomide and dexamethasone in patients with multiple myeloma.

Study MMY3013 was an open-label, randomised, active-controlled Phase 3 trial that compared treatment with Darzalex SC formulation (1800 mg) in combination with pomalidomide and low-dose dexamethasone (DPd) to treatment with pomalidomide and low-dose dexamethasone (Pd) in patients with multiple myeloma who had received at least one prior therapy with lenalidomide and a protease inhibitor (PI). Pomalidomide (4 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years). On Darzalex SC formulation administration days, 20 mg of the dexamethasone dose was given as a pre-administration medication and the remainder given the day after the administration. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a Darzalex SC formulation pre-administration medication. Dose adjustments for pomalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 304 patients were randomised: 151 to the DPd arm and 153 to the Pd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median patient age was 67 years (range 35 to 90 years), 18% were ≥ 75 years, 53% were male, 89% Caucasian, 45% had ISS Stage II and 22% had ISS Stage III disease. Patients had received a median of 2 prior lines of therapy, with 11% of patients having received one prior line of therapy. All patients received a prior treatment with a proteasome inhibitor (PI) and lenalidomide, and 56% of patients received prior stem cell transplantation (ASCT). The majority of patients were refractory to lenalidomide (80%), a PI (48%), or both an immunomodulator and a PI (42%). Efficacy was evaluated by PFS based on IMWG criteria.
The primary analysis of PFS in Study MMY3013 demonstrated a statistically significant improvement in the DPd arm as compared to the Pd arm; the median PFS was 12.4 months in the DPd arm and 6.9 months in the Pd arm (HR [95% CI]: 0.63 [0.47, 0.85]; p-value = 0.0018), representing a 37% reduction in the risk of disease progression or death for patients treated with DPd versus Pd. See Figure 1.

Additional efficacy results from Study MMY3013 are presented in Table 20.

In responders, the median time to response was 1 month (range: 0.9 to 9.1 months) in the DPd group and 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had not been reached in the DPd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.
With a median follow-up of 16.9 months, 99 deaths were observed; 48 in the DPd arm and 51 in the Pd arm. Median OS was not reached for either treatment group.

Combination treatment with bortezomib, cyclophosphamide and dexamethasone in patients with AL amyloidosis.

Study AMY3001, an open-label, randomised, active-controlled Phase 3 study, compared treatment with Darzalex SC subcutaneous formulation (1800 mg) in combination with bortezomib, cyclophosphamide and dexamethasone (DVCd) to treatment with bortezomib, cyclophosphamide and dexamethasone (VCd) alone in patients with newly diagnosed AL amyloidosis. Randomisation was stratified by AL amyloidosis Cardiac Staging System, countries that typically offer autologous stem cell transplant (ASCT) for patients with AL amyloidosis, and renal function. All patients enrolled in Study AMY3001 had newly diagnosed AL amyloidosis with at least one affected organ, measurable hematologic disease, Cardiac Stage I-IIIA (based on European Modification of Mayo 2004 Cardiac Stage), and NYHA Class I-IIIA. Patients with NYHA Class IIIB and IV were excluded.
Bortezomib (SC; 1.3 mg/m² body surface area), cyclophosphamide (oral or IV; 300 mg/m² body surface area; max dose 500 mg), and dexamethasone (oral or IV; 40 mg or a reduced dose of 20 mg for patients > 70 years or body mass index [BMI] < 18.5 kg/m² or those who have hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) were administered weekly on Days 1, 8, 15, and 22 of repeated 28-day [4-week] cycles. On the days of Darzalex SC dosing, 20 mg of the dexamethasone dose was given as a pre-injection medication and the remainder given the day after Darzalex SC administration. Bortezomib, cyclophosphamide and dexamethasone were given for six 28-day [4-week] cycles in both treatment arms, while Darzalex SC treatment was continued until disease progression, start of subsequent therapy, or a maximum of 24 cycles (~2 years) from the first dose of study treatment. Dose adjustments for bortezomib, cyclophosphamide and dexamethasone were applied according to manufacturer's Product Information.
A total of 388 patients were randomised: 195 to the DVCd arm and 193 to the VCd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The majority (79%) of patients had lambda free light chain disease. The median patient age was 64 years (range: 34 to 87); 47% were ≥ 65 years; 58% were male; 76% Caucasian, 17% Asian, and 3% African American; 23% had AL amyloidosis Clinical Cardiac Stage I, 40% had Stage II, 35% had Stage IIIA, and 2% had Stage IIIB. The median number of organs involved was 2 (range: 1-6) and 66% of patients had 2 or more organs involved. Vital organ involvement was: 71% cardiac, 59% renal and 8% hepatic. The major efficacy outcome measure was haematologic complete response (Hem CR) rate as determined by the Independent Review Committee assessment based on International Consensus Criteria.
Study AMY3001 demonstrated an improvement in Hem CR in the DVCd arm as compared to the VCd arm. Efficacy results are summarised in Table 21.

In responders, the median time to Hem CR was 60 days (range: 8 to 299 days) in the DVCd group and 85 days (range: 14 to 340 days) in the VCd group. The median time to VGPR or better was 17 days (range: 5 to 336 days) in the DVCd group and 25 days (range: 8 to 171 days) in the VCd group. The median duration of Hem CR had not been reached in either arm.
The median follow-up for the study is 11.4 months. The median major organ deterioration progression-free survival (MOD-PFS) was not reached for patients in either arm. The median major organ deterioration event-free survival (MOD-EFS) was not reached for patients receiving DVCd and was 8.8 months for patient receiving VCd. The hazard ratio for MOD-EFS was 0.39 (95 CI: 0.27, 0.56).
Overall survival (OS) data were not mature. A total of 56 deaths were observed [N = 27 (13.8%) DVCd vs. N = 29 (15%) VCd group].

Clinical experience with daratumumab intravenous formulation.

Newly diagnosed multiple myeloma eligible for ASCT.

Combination treatment with bortezomib, thalidomide and dexamethasone in patients eligible for autologous stem cell transplant (ASCT).

Study MMY3006, an open-label, randomised, active-controlled Phase 3 study compared induction and consolidation treatment with IV daratumumab 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete.
Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of Cycles 1 and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of IV daratumumab infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer's Product Information. See Table 22.

A total of 1085 patients were randomised: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 (range: 22 to 65 years). The majority were male (59%), 48% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.
Efficacy was evaluated by the stringent Complete Response (sCR) rate at Day 100 post-transplant. See Table 23.

With a median follow up of 18.8 months, the primary analysis of PFS in study MMY3006 demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR = 0.47; 95% CI: 0.33, 0.67; p < 0.0001). Results of an updated PFS analysis after a median follow-up of 44.5 months showed that median PFS was not reached in the DVTd arm and was 51.5 months in the VTd arm (HR=0.58; 95% CI: 0.47, 0.71; p < 0.0001).
Newly diagnosed multiple myeloma ineligible for ASCT.

Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients ineligible for autologous stem cell transplant.

Study MMY3007, an open-label, randomised, active-controlled Phase 3 study, compared treatment with IV daratumumab 16 mg/kg in combination with bortezomib, melphalan and prednisone (DVMP), to treatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m² body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight additional 6-week cycles (Cycles 2-9; 4 doses per cycle). Melphalan at 9 mg/m², and prednisone at 60 mg/m² were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). IV daratumumab treatment was continued until disease progression or unacceptable toxicity. See Table 24.

A total of 706 patients were randomised: 350 to the DVMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients ≥ 75 years of age. The majority were white (85%), female (54%), and 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Light chain myeloma in 64%/22%/10% of instances, 19% had ISS Stage I, 42% had ISS Stage II and 38% had ISS Stage III disease. Efficacy was evaluated by PFS based on IMWG criteria.
With a median follow-up of 16.5 months, the primary analysis of PFS in study MMY3007 demonstrated an improvement in PFS in the DVMP arm as compared to the VMP arm; the median PFS had not been reached in the DVMP arm and was 18.1 months in the VMP arm (HR = 0.5; 95% CI: 0.38, 0.65; p < 0.0001), representing 50% reduction in the risk of disease progression or death in patients treated with DVMP. Results of an updated PFS analysis after a median follow-up of 40 months continued to show an improvement in PFS for patients in the DVMP arm compared with the VMP arm. Median PFS was 36.4 months (95% CI: 32.1, 45.9) in the DVMP arm and 19.3 months (95% CI: 18.0, 20.4) in the VMP arm.
After a median follow-up of 40 months, an improvement in overall survival (OS) was demonstrated for the DVMP arm (83 death, 23.7%) as compared to the VMP arm (126 deaths, 35.6%) (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the DVMP arm. Median OS was not reached for either arm.
In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the DVMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median duration of response had not been reached in the DVMP group and was 21.3 months (range: 18.4, not estimable) in the VMP group.
Additional efficacy results from Study MMY3007 are presented Table 28.

Combination treatment with lenalidomide and dexamethasone (Rd) in patients ineligible for autologous stem cell transplant.

Study MMY3008 an open-label, randomised, active-controlled Phase 3 study, compared treatment with IV daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or body mass index [BMI] < 18.5). On IV daratumumab infusion days, the dexamethasone dose was given as a pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's Product Information. Treatment was continued in both arms until disease progression or unacceptable toxicity. See Table 25.

A total of 737 patients were randomised: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of the patients ≥ 75 years of age. The majority were white (92%), male (52%), 34% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥ 2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.
With a median follow up of 28 months, the primary analysis of PFS in study MMY3008 demonstrated an improvement in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR] = 0.56; 95% CI: 0.43, 0.73; p < 0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd. Results of an updated PFS analysis after a median follow-up of 64 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 61.9 months in the DRd arm and 34.4 months (95% CI: 29.6, 39.2) in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67; p < 0.0001), representing a 45% reduction in the risk of disease progression or death in patients treated with DRd.
After a median follow-up of 56 months, an improvement in OS was demonstrated for the DRd arm (117 deaths, 31.8%) as compared to the Rd arm (156 deaths, 42.3%) (HR=0.68; 95% CI: 0.53, 0.86; p=0.0013), representing a 32% reduction in the risk of death in patients treated in the DRd arm. Median OS was not reached for either arm. The 60 month survival rate was 66% (95% CI: 61, 71) in the DRd arm and was 53% (95% CI: 47, 59) in the Rd arm.
In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.
Additional efficacy results from Study MMY3008 are presented in Table 28.
Relapsed/refractory multiple myeloma.

Combination treatment with bortezomib and dexamethasone.

Study MMY3004, an open-label, randomised, active-controlled Phase 3 trial, compared treatment with IV daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had received at least one prior therapy. Bortezomib was administered by SC injection or IV injection at a dose of 1.3 mg/m² 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 the 8 bortezomib cycles (80 mg/week for two out of three weeks of each of the bortezomib cycle) or a reduced dose of 20 mg/week for patients > 75 years, BMI < 18.5 kg/m, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of IV daratumumab infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. IV daratumumab was continued until disease progression or unacceptable toxicity. Patients refractory to bortezomib were excluded from the study. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's Product Information. See Table 26.

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 IV daratumumab and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥ 75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). 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 and the proportions of patients refractory to any specific prior therapy were well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Efficacy was evaluated by PFS based on IMWG criteria.
With a median follow-up of 7.4 months, the primary analysis of PFS in study MMY3004 demonstrated an improvement 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. Results of an updated PFS analysis after a median follow-up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months (95% CI: 13.1, 19.4) in the DVd arm and 7.1 months (95% CI: 6.2, 7.7) in the Vd arm (HR [95% CI]: 0.31 [0.24, 0.39]; p-value < 0.0001), representing a 69% reduction in the risk of disease progression or death in patients treated with DVd versus Vd.
After a median follow-up of 73 months, an improvement in OS was demonstrated for the DVd arm (148 deaths, 59.0%) as compared to the Vd arm (171 deaths, 69.2%) (HR=0.74: 95% CI: 0.59, 0.92; p=0.0075), representing a 26% reduction in the risk of death in patients treated in the DVd arm. The median OS was 49.6 months (95% CI: 42.2, 62.3) in the DVd arm and 38.5 months (95% CI: 31.2, 46.2) in the Vd arm. The 72-month survival rate was 39% (95% CI: 33, 45) in the DVd arm and was 25% (95% CI: 20, 31) in the Vd arm. Additional efficacy results from Study MMY3004 are presented in Table 28.

Combination treatment with lenalidomide and dexamethasone.

Study MMY3003, an open-label, randomised, active-controlled Phase 3 trial, compared treatment with IV daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with 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 oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or BMI < 18.5). On IV daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's Product Information. Treatment was continued in both arms until disease progression or unacceptable toxicity. Patients refractory to lenalidomide were excluded from the study. See Table 27.

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 IV daratumumab and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥ 75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior proteasome inhibitor (PI), 55% of patients had received a prior immunomodulatory agent (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. Efficacy was evaluated by PFS based on IMWG criteria.
With a median follow-up of 13.5 months, the primary analysis of PFS in study MMY3003 demonstrated an improvement 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 (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. Results of an updated PFS analysis after a median follow-up of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 45.0 months (95% CI: 34.1, 53.9) in the DRd arm and 17.5 months (95% CI: 13.9, 20.8) in the Rd arm (HR=0.44; 95% CI: 0.35, 0.54; p < 0.0001), representing a 56% reduction in the risk of disease progression or death in patients treated with DRd.
After a median follow-up of 80 months, an improvement in OS was demonstrated for DRd arm (153 deaths, 53.5%) as compared to the Rd arm (175 deaths, 61.8%) (HR=0.73; 95% CI: 0.58, 0.91; p=0.0044), representing a 27% reduction in the risk of death in patients treated in the DRd arm. The median OS was 67.6 months (95% CI: 53.1, 80.5) in the DRd arm and 51.8 months (95% CI: 44.0, 60.0) in the Rd arm. The 78-month survival rate was 47% (95% CI: 41, 52) in the DRd arm and was 35% (95% CI: 30, 41) in the Rd arm.
Additional efficacy results from Study MMY3003 are presented in Table 28.

5.2 Pharmacokinetic Properties

In patients with multiple myeloma, daratumumab exposure in a monotherapy study (MMY3012) following the recommended 1800 mg administration of Darzalex SC subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter) as compared to 16 mg/kg IV daratumumab for the same dosing schedule, showed non-inferiority for the co-primary endpoint of maximum C_trough (Cycle 3 Day 1 pre-dose), with mean ± SD of 593 ± 306 microgram/mL compared to 522 ± 226 microgram/mL for IV daratumumab, with a geometric mean ratio of 107.93% (90% CI: 95.74-121.67).
In a combination study, AMY3001, in patients with AL amyloidosis, the maximum C_trough (Cycle 3 Day 1 pre-dose) was similar to that in multiple myeloma with mean ± SD of 597 ± 232 microgram/mL following the recommended 1800 mg administration of Darzalex SC formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).
Daratumumab exhibits both concentration and time-dependent pharmacokinetics with first order absorption and parallel linear and nonlinear (saturable) elimination that is characteristic of target-mediated clearance. Following the recommended dose of 1800 mg Darzalex SC subcutaneous formulation, peak concentrations (C_max) increased 4.8-fold and total exposure (AUC_{0-7 days}) increased 5.4-fold from first dose to last weekly dose (8th dose). Highest trough concentrations for Darzalex SC subcutaneous formulation are typically observed at the end of the weekly dosing regimens for both monotherapy and combination therapy.
In patients with multiple myeloma, the simulated trough concentrations following 6 weekly doses of 1800 mg Darzalex SC for combination therapy were similar to 1800 mg Darzalex SC monotherapy.
In patients with multiple myeloma, daratumumab exposure in a combination study with pomalidomide and dexamethasone (MMY3013) was similar to that in monotherapy, with the maximum C_trough (Cycle 3 Day 1 pre-dose) mean ± SD of 537 ± 277 microgram/mL following the recommended 1800 mg administration of Darzalex SC formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).

Absorption.

At the recommended dose of 1800 mg in multiple myeloma patients, the absolute bioavailability of Darzalex SC formulation is 69%, with an absorption rate of 0.012 hour^-1, with peak concentrations occurring at 70 to 72 h (T_max). At the recommended dose of 1800 mg in AL amyloidosis patients, the absolute bioavailability was not estimated, the absorption rate constant was 0.77 day^-1 (8.31% CV) and peak concentrations occurred at 3 days.

Distribution.

In multiple myeloma patients, the modeled mean estimate of the volume of distribution for the central compartment (V1) is 5.25 L (36.9% CV) and peripheral compartment (V2) was 3.78 L, in daratumumab monotherapy, and the modeled mean estimate of the volume of distribution for V1 is 4.36 L (28.0% CV) and V2 was 2.80 L when daratumumab was administered in combination with pomalidomide and dexamethasone. In AL amyloidosis patients, the model estimated apparent volume of distribution after SC administration is 10.8 L (3.1% CV). These results suggest that daratumumab is primarily localised to the vascular system with limited extravascular tissue distribution.

Metabolism and excretion.

Daratumumab is cleared by parallel linear and nonlinear saturable target mediated clearances. In multiple myeloma patients, the population PK model estimated mean clearance value of daratumumab is 4.96 mL/h (58.7% CV) in daratumumab monotherapy and 4.32 mL/h (43.5% CV) when daratumumab was administered in combination with pomalidomide and dexamethasone. In AL amyloidosis patients, the apparent clearance after SC administration is 210 mL/day (4.1% CV).
In multiple myeloma patients, the model-based geometric mean post hoc estimate for half-life associated with linear elimination is 20.4 days (22.4% CV) in daratumumab monotherapy and 19.7 days (15.3% CV) when daratumumab was administered in combination with pomalidomide and dexamethasone. In AL amyloidosis patients, the model-based geometric mean post hoc estimate for half-life associated with linear elimination is 27.5 days (74.0% CV). For the monotherapy and combination regimens, the steady state is achieved at approximately 5 months into every 4 weeks dosage at the recommended dose and schedule (1800 mg; once weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks thereafter).
A population PK analysis, using data from Darzalex SC subcutaneous formulation monotherapy and combination therapy in multiple myeloma patients, was conducted with data from 487 patients who received Darzalex SC subcutaneous formulation and 255 patients who received IV daratumumab. The predicted PK exposures are summarised in Table 29.

A population PK analysis, using data from Darzalex SC formulation combination therapy in AL amyloidosis patients, was conducted with data from 211 patients. At the recommended dose of 1800 mg, predicted daratumumab concentrations were slightly higher, but generally within the same range, in comparison with multiple myeloma patients. See Table 30.

Additional information on special populations.

Age and gender.

Based on population PK analyses in patients (33-92 years) receiving monotherapy or various combination therapies, age had no statistically significant effect on the PK of Darzalex SC. No individualisation is necessary for patients on the basis of age.
Gender had a statistically significant effect on PK parameter in patients with multiple myeloma but not in patients with AL amyloidosis, slightly higher exposure in females were observed than males, but the difference in exposure is not considered clinically meaningful. No individualisation is necessary for patients on the basis of gender.

Renal impairment.

No formal studies of Darzalex SC formulation in patients with renal impairment have been conducted. Population PK analyses were performed based on pre-existing renal function data in patients with multiple myeloma receiving Darzalex SC monotherapy or various combination therapies, in patients with multiple myeloma or AL amyloidosis including 295 patients with normal renal function (creatinine clearance [CrCl] ≥ 90 mL/min), 340 with mild renal impairment (CrCl < 90 and ≥ 60 mL/min), 274 with moderate renal impairment (CrCl < 60 and ≥ 30 mL/min), and 43 with severe renal impairment or end stage renal disease (CrCl < 30 mL/min) and no clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.

Hepatic impairment.

No formal studies of Darzalex SC formulation in patients with hepatic impairment have been conducted. Population PK analyses were performed in patients with multiple myeloma receiving Darzalex SC formulation monotherapy or various combination therapies, in patients with multiple myeloma or in AL amyloidosis including 821 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 124 with mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)] and 8 patients with moderate (1.5 x ULN < total bilirubin ≤ 3 x ULN) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with normal hepatic function and mild hepatic impairment. There were very few patients with moderate and severe hepatic impairment to make meaningful conclusions for these populations.

Race.

Based on the population PK analyses in patients receiving either Darzalex SC formulation monotherapy or various combination therapies, the daratumumab exposure was similar across races.

Body weight.

The flat dose administration of Darzalex SC formulation 1800 mg as monotherapy achieved adequate exposure for all body-weight subgroups. In patients with multiple myeloma, the mean Cycle 3 Day 1 C_trough in the lower body-weight subgroup (≤ 65 kg) was 60% higher and in the higher body weight (> 85 kg) subgroup, 12% lower than the IV daratumumab subgroup. However, no body weight-based dose adjustments are needed, as the exposure changes are not considered clinically relevant.
In patients with AL amyloidosis, no meaningful differences were observed in C_trough across body weight.

5.3 Preclinical Safety Data

Genotoxicity.

Routine genotoxicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Vorhyaluronidase alfa (recombinant human hyaluronidase; rHuPH20); histidine; histidine hydrochloride monohydrate; sorbitol; methionine; polysorbate 20; water for injections.

6.2 Incompatibilities

This medicinal product should only be used with the materials mentioned, see Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

Unopened vials.

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.

Shelf life of prepared syringe.

6.4 Special Precautions for Storage

Store Darzalex SC in a refrigerator (2°C - 8°C) and equilibrate to ambient temperature (15°C-30°C) before use. The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake. Do not freeze.
For storage conditions of the prepared syringe, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Darzalex SC is available in a carton containing 1 vial:
15 mL solution in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a dark grey flip off cap containing 1800 mg of daratumumab.
Product is for single use subcutaneous injection in one patient only.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

CAS Registry Number: 945721-28-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Service Unavailable

Consumer medicine information

Darzalex SC

Daratumumab

Keep track of your medicines

BRAND INFORMATION