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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

DARZALEX is a medicine that contains the active substance daratumumab. It belongs to a group of medicines called “monoclonal antibodies”. Monoclonal antibodies are proteins that have been designed to recognise and attach to specific targets in the body. Daratumumab has been designed to attach to specific abnormal blood cells in your body, so that your immune system can destroy these cells.

What DARZALEX is used for

DARZALEX is used in adults 18 years or older, who have a type of cancer called “multiple myeloma”. This is a cancer of your bone marrow.

 

DARZALEX is also used in adults 18 years or older, who have a type of blood disorder called “AL amyloidosis.” In AL amyloidosis, abnormal blood cells make excessive amounts of abnormal proteins that deposit in various organs, causing these organs to not function properly.


You must not be given DARZALEX

-              if you are allergic to daratumumab or any of the other ingredients of this medicine (listed in section 6).

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

 

Warnings and precautions

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

 

Infusion‑related reactions

DARZALEX is given as a subcutaneous injection using a small needle to inject the medicine under your skin. Before and after each injection, you will be given medicines which help to lower the chance of infusion‑related reactions (see “Medicines given during treatment with DARZALEX” in section 3).

These reactions 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 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). See section 4.

 

Tell your doctor or nurse straight away if you get any of the infusion‑related reactions or related symptoms listed at the top of section 4. 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.

 

Decreased blood cell counts

DARZALEX can decrease white blood cell counts which help fight infections, and blood cells called platelets which help to clot blood. Tell your healthcare provider if you develop any symptoms of infection such as fever or any symptoms of decreased platelet counts such as bruising or bleeding.

 

Blood transfusions

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

 

Hepatitis B

Tell your doctor if you have ever had or might now have a hepatitis B infection. This is because DARZALEX 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. Tell your doctor right away if you get worsening tiredness, or yellowing of your skin or white part of your eyes.

 

Children and adolescents

Do not give DARZALEX to children or adolescents below 18 years of age. This is because it is not known how the medicine will affect them.

 

Other medicines and DARZALEX

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. This includes medicines you can get without a prescription, and herbal medicines.

 

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before you are given this medicine.

If you become pregnant while being treated with this medicine, tell your doctor or nurse straight away. You and your doctor will decide if the benefit of having the medicine is greater than the risk to your baby.

 

Contraception

Women who are being given DARZALEX should use effective contraception during treatment and for 3 months after treatment.

 

Breast‑feeding

You and your doctor will decide if the benefit of breast‑feeding is greater than the risk to your baby. This is because the medicine may pass into the mother’s milk and it is not known how it will affect the baby.

 

Driving and using machines

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

 

DARZALEX solution for subcutaneous injection contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per 15 mL, that is to say essentially ‘sodium‑free’.

 

DARZALEX solution for subcutaneous injection contains sorbitol

Sorbitol is a source of fructose. If your doctor has told you that you have an intolerance to some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down fructose, talk to your doctor before you take this medicine.

 


How much is given

The dose of DARZALEX solution for subcutaneous injection is 1800 mg.

 

DARZALEX may be given alone or together with other medicines used to treat multiple myeloma, or with other medicines used to treat AL amyloidosis. DARZALEX is usually given as follows:

·             once a week for the first 8 weeks

·             then once every 2 weeks for 16 weeks

·             then once every 4 weeks after that as long as your condition does not worsen.

 

When DARZALEX is given together with other medicines your doctor may change the time between doses as well as how many treatments you will receive.

 

How the medicine is given

DARZALEX 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.

 

Medicines given during treatment with DARZALEX

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

 

Before each injection of DARZALEX you will be given medicines which help to lower the chance of infusion‑related reactions. These may include:

·             medicines for an allergic reaction (anti‑histamines)

·             medicines for inflammation (corticosteroids)

·             medicines for fever (such as paracetamol).

 

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

 

People with breathing problems

If you have breathing problems, such as asthma or Chronic Obstructive Pulmonary Disease (COPD), you will be given medicines to inhale which help your breathing problems:

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

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

 

If you are given more DARZALEX than you should

This medicine will be given by your doctor or nurse. In the unlikely event that you are given too much (an overdose) your doctor will check you for side effects.

 

If you forget your appointment to have DARZALEX

It is very important to go to all your appointments to make sure your treatment works. If you miss an appointment, make another one as soon as possible.

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


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

 

Infusion‑related reactions

Tell your doctor or nurse straight away if you get any of the following symptoms within 3‑4 days after the injection. You may need other medicines, or the injection may need to be interrupted or stopped.

 

These reactions include the following symptoms:

 

Very common (may affect more than 1 in 10 people):

·             chills

·             sore throat, cough

·             feeling sick (nausea)

·             vomiting

·             itchy, runny or blocked nose

·             feeling short of breath or other breathing problems.

 

Common (may affect up to 1 in 10 people):

·             chest discomfort

·             dizziness or lightheadedness (hypotension)

·             itching

·             wheezing.

 

Rare (may affect up to 1 in 1000 people):

·             severe allergic reaction which may include a swollen face, lips, mouth, tongue or throat, difficulty swallowing or breathing or an itchy rash (hives). See section 2.

·             eye pain

·             blurred vision.

 

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

 

Injection site reactions

Skin reactions at or near the injection site (local), including injection site reactions, can happen with DARZALEX solution for subcutaneous injection. These reactions are common (may affect up to 1 in 10 people). Symptoms at the site of injection may include redness of the skin, itching, swelling, pain, bruising, rash, bleeding.

 

Other side effects

Very common (may affect more than 1 in 10 people):

·             fever

·             feeling very tired

·             diarrhoea

·             constipation

·             decreased appetite

·             difficulty sleeping

·             headache

·             nerve damage that may cause tingling, numbness, or pain

·             rash

·             muscle spasms

·             joint pain

·             swollen hands, ankles or feet

·             feeling weak

·             back pain

·             lung infection (pneumonia)

·             bronchitis

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

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

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

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

 

Common (may affect up to 1 in 10 people):

·             irregular heart beat (atrial fibrillation)

·             build up of fluid in the lungs making you short of breath

·             urinary tract infection

·             severe infection throughout the body (sepsis)

·             dehydration

·             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)

·             feeling dizzy

·             fainting

·             chest muscle pain

·             flu

·             chills

·             itching

·             unusual feeling in the skin (such as a tingling or crawling feeling)

·             inflamed pancreas

·             high blood pressure

·             COVID-19.

 

Uncommon (may affect up to 1 in 100 people):

·             inflamed liver (hepatitis)

·             type of herpes virus infection (cytomegalovirus infection).

 

Reporting of side effects

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.


DARZALEX solution for subcutaneous injection will be stored at the hospital or clinic.

 

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

 

Do not use this medicine after the expiry date which is stated on the carton and the vial label after EXP. The expiry date refers to the last day of that month.

 

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

 

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

 

Do not throw away any medicines via wastewater or household waste. Your healthcare professional will throw away any medicines that are no longer being used. These measures will help protect the environment.

 


·             The active substance is daratumumab. One mL of solution contains 120 mg daratumumab. One vial of 15 mL solution for injection contains 1800 mg of daratumumab.

The other ingredients are recombinant human hyaluronidase (rHuPH20), L‑histidine, L‑histidine hydrochloride monohydrate, L‑methionine, polysorbate 20, sorbitol (E420), and water for injections (see “DARZALEX contains sodium and sorbitol” in section 2).


DARZALEX solution for subcutaneous injection is a colourless to yellow liquid. DARZALEX solution for subcutaneous injection is supplied as a carton pack containing 1 single dose glass vial.

Marketing Authorisation Holder

Janssen‑Cilag International NV

Turnhoutseweg 30

B‑2340 Beerse

Belgium

 

Manufacturer

Cilag AG, Hochstrasse 201, 8200 Schaffhausen -Switzerland

 

 


To contact us, go to www.janssen.com/contact-us This leaflet was last revised in 9 February 2023. To Report any side effect (s):   • Saudi Arabia ·        The National Pharmacovigilance Centre (NPC):   - SFDA Call Center: 19999 - E-mail: npc.drug@sfda.gov.sa - Website: http://ade.sfda.gov.sa • Other GCC states: − Please contact the relevant competent authority.
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

دارزاليكس هو دواء يحتوي على المادة الفعالة داراتوموماب. ينتمي دارزاليكس إلى مجموعة من الأدوية تسمى "الأجسام المضادة وحيدة النسيلة"؛ وهي بروتينات اُعدّت لغرض التعرف على أهداف محددة في الجسم والإمساك بها. تم تصميم داراتوموماب كي يرتبط بخلايا غير طبيعية معينة في جسمك، حتى يتمكن جهاز المناعة لديك من تدميرها.

 

ما هي دواعي استخدام دارزاليكس
يُستخدم دارزاليكس عند البالغين ممن تبلغ أعمارهم ١٨ عامًا أو أكبر، لعلاج نوع من السرطان يسمى "المايلوما المتعددة"، أي سرطان نخاع العظم.

 

يُستخدم دارزاليكس أيضاً عند البالغين ممن تبلغ أعمارهم ١٨ عامًا أو أكبر، لعلاج نوع من اضطراب في الدم "الداء النشواني". تنتج خلايا الدم غير طبيعية في الداء النشواني كمية مفرطة من البروتينات غير طبيعية التي تترسب في أعضاء متنوعة من الجسم وتؤثر على وظائفها.

يجب ألا تتلقى دارزاليكس:
- إذا كنت تعاني من حساسية تجاه داراتوموماب أو أيّ من المكونات الأخرى لهذا الدواء (انظر القسم ٦).

لا تتلقى دارزاليكس إذا كان ما سبق ينطبق عليك. إذا لم تكن متأكدًا، فتحدث إلى طبيبك أو ممرضك قبل أن تتلقى دارزاليكس.

 

المحاذير والإحتياطات

تحدث إلى طبيبك أو ممرضك قبل أن يتم إعطاؤك دارزاليكس:

 

التفاعلات المرتبطة بالتسريب:

يتم إعطاء دارزاليكس بالحقن تحت الجلد باستخدام إبرة ذات قطر صغير معدة لحقن الدواء تحت جلدك . سيتم إعطاؤك أدوية قبل وبعد كل حقنة، من شأنها أن تساعد على تقليل فرصة حدوث التفاعلات المرتبطة بالتسريب (انظر "الأدوية التي تُعطى أثناء العلاج بدارزاليكس" في القسم ٣). من المرجح أن تحدث التفاعلات هذه مع الحقنة الأولى كما أن معظمها يحدث في يوم الحقن. إذا تعرضت لأحد التفاعلات المتعلقة بالتسريب مرة واحدة فمن غير المرجح أن يحدث مرة أخرى.

 

ومع ذلك، يمكن أن تحدث تفاعلات متأخرة لمدة تصل إلى ٣-٤ أيام بعد الحقن. قد يقرر طبيبك عدم استخدام دارزاليكس إذا تعرّضت لرد فعل قوي بعد الحقن.

 

قد تتعرض في بعض الأحيان لرد فعل تحسسي شديد قد يشمل تورّم الوجه والشفتين والفم، اللسان أو الحلق، صعوبة في البلع أو التنفس أو طفح جلدي مثير للحكة (خلايا النحل). راجع القسم ٤.


أخبر طبيبك أو الممرض(ة) على الفور إذا تعرّضت لأي من التفاعلات المرتبطة بالتسريب أو الأعراض ذات الصلة المدرجة في أعلى القسم ٤.

 

إذا تعرّضت لتفاعلات مرتبطة بالتسريب، فقد تحتاج إلى أدوية أخرى لعلاج تلك التفاعلات، أو قد تحتاج إلى التوقف عن الحقن. ويمكن العودة للحقن مرة أخرى عندما تختفي هذه الأعراض أو تتحسن.

 

انخفاض عدد خلايا الدم

يمكن أن يقلل دارزاليكس من تعداد خلايا الدم البيضاء التي تساعد في مكافحة الالتهابات، وخلايا الدم التي تسمى الصفائح الدموية والتي تساعد على تجلط الدم. أخبر مقدم الرعاية الصحية إذا ظهرت لديك أعراض تدل على وجود عدوى مثل الحمّى أو أي أعراض تدل على نقص الصفائح الدموية مثل الكدمات أو النزيف.

 

نقل الدم

إذا كنت بحاجة إلى نقل دم، فسيتم إجراء فحص دم أولاً لتحديد الفصيلة التي تتطابق مع فصيلة دمك.

يمكن أن يُؤثر دارزاليكس على نتائج تحديد فصيلة الدم هذا. أخبر الشخص المسؤول عن إجراء الفحص أنك تستخدم دارزاليكس.

 

التهاب الكبد الوبائي ب

أخبر طبيبك إذا كنت مصابًا حاليًا أو سبق وأصبت بعدوى التهاب الكبد الوبائي ب. وذلك لأن دارزاليكس قد يتسبب في تنشيط فيروس التهاب الكبد ب مرة أخرى. سيقوم طبيبك بفحصك بحثًا عن علامات هذه العدوى قبل وأثناء ولبعض الوقت بعد العلاج بدارزالكس. أخبر طبيبك على الفور إذا شعرت بالتعب المتفاقم، أو تعرضت لاصفرار بشرتك أو الجزء الأبيض من عينيك.


الأطفال والمراهقين

لا تُعطِ دارزاليكس للأطفال أو الشباب الذين تقل أعمارهم عن ١٨عامًا. وذلك لأنه لا يُعرف إلى الآن كيف سيؤثر الدواء عليهم.

 

الأدوية الأخرى ودارزاليكس

أخبر طبيبك أو ممرضك إذا كنت تتناول، أو تناولت مؤخرا أو قد تتناول أي أدوية أخرى. وذلك يشمل الأدوية التي يمكنك الحصول عليها دون وصفة طبية، والأدوية العشبية.


الحمل

إذا كنتِ حاملاً، أو تعتقدين أنك قد تكونين حاملاً أو تخططين لإنجاب طفل، فاستشيري طبيبك قبل أن تتلقي العلاج بهذا الدواء

إذا أصبحتِ حاملاً أثناء العلاج بهذا الدواء، أخبري طبيبك أو ممرضك على الفور.

 

ستقررين أنت وطبيبك ما إذا كانت فائدة استخدام هذا الدواء أكبر من الخطر الذي يتعرض له طفلك.


منع الحمل

يجب على النساء اللائي يخضعن للعلاج بدارزاليكس استخدام وسائل منع الحمل الفعالة أثناء العلاج ولمدة  ٣ أشهر بعد العلاج.

 

الرضاعة الطبيعية
ستقررين أنت وطبيبك ما إذا كانت فائدة الرضاعة الطبيعية أكبر من الخطر الذي يتعرض له طفلك، وذلك لأن الدواء قد ينتقل إلى حليب الأم ولا يُعرف كيف سيؤثر ذلك على الطفل.

 

القيادة واستخدام الآلات

قد تشعر بالتعب بعد تلقّي دارزاليكس مما قد يؤثر على قدرتك على القيادة أو استخدام الآلات.
 

يحتوي محلول دارزاليكس للحقن تحت الجلد على الصوديوم

يحتوي هذا الدواء على أقل من ١ ميليمول من الصوديوم (٢٣ مجم) في كل ١٥ مل من المحلول، أي أنه خالٍ من الصوديوم في الأساس.
 

يحتوي محلول دارزاليكس للحقن تحت الجلد على السوربيتول
السوربيتول مصدر للفركتوز. إذا أخبرك طبيبك أنك تعاني من عدم تحمل بعض السكريات أو إذا تم تشخيص إصابتك بمرض عدم القدرة على تحمل الفركتوز الوراثي (HFI)، وهو اضطراب وراثي نادر لا يستطيع الشخص المصاب به تكسير الفركتوز، فتحدث إلى طبيبك قبل تناول هذا الدواء .

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الجرعة الدوائيّة
تبلغ جرعة دارزاليكس للحقن تحت الجلد ١٨٠٠ مجم.

 

قد يتم إعطاء دارزاليكس بمفرده أو مع الأدوية الأخرى المستخدمة لعلاج المايلوما المتعددة.

أو مع أدوية أخرى تُستخدم لعلاج الداء النشواني ؛ فإنه يُعطى عادة على النحو التالي:

• مرة واحدة في الأسبوع لأول ٨ أسابيع

• ثم مرة كل أسبوعين لمدة ١٦ أسبوعًا

• ثم مرة واحدة كل ٤ أسابيع بعد ذلك طالما لم تتدهور حالتك.


أما عند استخدام دارزاليكس مع أدوية أخرى، فقد يغير طبيبك المدة الزمنية بين الجرعات وكذلك عدد العلاجات التي ستتلقاها.

 

طريقة إعطاء الدواء
سيتم إعطاء دارزاليكس لك من قبل طبيب أو ممرض. يتم إعطاؤه بالحقن تحت الجلد على مدى ٣-٥ دقائق. يتم حقنه في منطقة البطن بالتحديد، وليس في أماكن أخرى من الجسم، كما لن يتم إعطاؤه في مناطق البطن حيث يكون الجلد أحمر، أو رقيقاً، أو صلباً، أو في مواضع الندبات أو الكدمات.

 

إذا شعرت بألم أثناء الحقن، فقد يقاطع الطبيب أو الممرض(ة) الحقن ويعطيك ما تبقى من الحقنة في موضع آخر من بطنك.

 

الأدوية التي قد تُستخدم أثناء العلاج بدارزاليكس
قد يتم إعطاؤك أدوية لتقليل فرصة إصابتك بالهربس النطاقي "الحزام الناري".

 

سيتم إعطاؤك أدوية تساعد على تقليل فرصة الإصابة بالتفاعلات المرتبطة بالتسريب قبل كل حقن لدارزاليكس. قد تشمل هذه الأدوية ما يلي:

• أدوية لعلاج الحساسية (مضادات الهيستامين)

• أدوية لعلاج الالتهاب (الكورتيكوستيرويدات)

• أدوية للسيطرة على الحمى (مثل الباراسيتامول).

 

كما سيتم إعطاؤك أدوية (مثل الكورتيكوستيرويدات) بعد كل حقنة دارزاليكس، للتقليل من حدوث التفاعلات المرتبطة بالتسريب.
 

الأشخاص الذين يعانون من مشاكل في التنفس
إذا كنت تعاني من مشاكل في التنفس، مثل الربو أو مرض الانسداد الرئوي المزمن (COPD)، فسيتم إعطاؤك أدوية عن طريق الاستنشاق تساعد على التنفس كما يلي:

• الأدوية التي تساعد على إبقاء الشعب الهوائية في رئتيك مفتوحة (موسّعات الشعب الهوائية).

• الأدوية التي تُقلّل التورم والتهيج في رئتيك (الكورتيكوستيرويدات).
 

إذا تم إعطاؤك من دارزاليكس أكثر مما يجب

سيتم إعطاء هذا الدواء لك من قبل الطبيب أو الممرض(ة). في حالة إعطائك جرعة أكثر من اللازم (جرعة زائدة)، وهذا مُستبعد، سيقوم طبيبك بفحصك للتعرف على أي أعراض جانبية قد تواجهك.

 

إذا نسيت موعدك لتلقي إحدى جرعات دارزاليكس

من المهم للغاية الانتظام في جميع مواعيدك للتأكد من حصولك على التأثير الأقصى للدواء. إذا فاتك موعد، فقم بتحديد موعد آخر في أسرع وقت ممكن.

إذا كان لديك أي أسئلة أخرى حول استخدام هذا الدواء، اسأل طبيبك أو ممرضك.

يمكن أن يسبب هذا الدواء أعراضًا جانبية كما هو الحال مع سائر الأدوية، على الرغم من أنها لا تحدث لدى جميع من يستخدمه.

 

التفاعلات المرتبطة بالتسريب

أخبر طبيبك أو ممرضك على الفور إذا تعرضت لأي من الأعراض التالية خلال ٣-٤ أيام بعد الحقن. قد تحتاج إلى أدوية أخرى، أو قد تحتاج إلى مقاطعة الحقن أو إلى إيقافه.

 

تتضمن هذه الأعراض ما يلي:

 

أعراض شائعة جدًا (قد تؤثر على أكثر من ١ من كل ١٠ أشخاص):

• قشعريرة

• التهاب الحلق والسعال

• الشعور بالغثيان

• القيء

• حكة، سيلان أو انسداد الأنف.
• الشعور بضيق في التنفس أو مشاكل أخرى في التنفس.
 

أعراض شائعة (قد تؤثر على ما يصل إلى شخص واحد من كل ١٠ أشخاص):

• الشعور بعدم الراحة في الصدر

• الدوخة أو الدوار (انخفاض ضغط الدم)

• حكة.

• الصفير.

 

نادرة (قد تؤثر على ما يصل إلى شخص واحد من كل ١٠٠٠ شخص):

• الحساسية الشديدة التي قد تشمل تورم الوجه أو الشفتين أو الفم أو اللسان أو الحلق، وصعوبة البلع أو التنفس أو طفح جلدي مثير للحكة (خلايا النحل).. راجع القسم ٢.

• ألم في العين

•عدم وضوح الرؤية
 

إذا واجهت أي من التفاعلات المُرتبطة بالتسريب المذكورة أعلاه، أخبر طبيبك أو الممرض(ة) على الفور.
 

ردود الفعل الموضعية في موضع الحقن

يمكن أن ينجم عن حقن محلول دارزاليكس  تحت الجلد ردود فعل جلدية في موضع الحقن أو بالقرب منه (موضعية)، بما في ذلك تفاعلات موضع الحقن، ردود الفعل هذه شائعة (قد تؤثر على ما يصل إلى ١ من كل ١٠ أشخاص) وقد تشمل الأعراض احمرار الجلد، الحكة، التورم، الألم، الكدمات، طفح جلدي، نزيف.


أعراض جانبية أخرى

 

شائعة جدًا (قد تُؤثر على أكثر من شخص من كل ١٠ أشخاص):

• حمّى

• الشعور بالتعب الشديد

• إسهال
• إمساك
• نقص الشهية
• صعوبة في النوم

• صداع الرأس

• تلف الأعصاب الذي قد يسبب وخز أو تنميل أو ألم

• طفح جلدي

• تشنجات العضلات
• ألم المفاصل
 

• تورم اليدين أو الكاحلين أو القدمين
• الشعور بالضعف
• ألم الظهر

• التهاب الرئة (الالتهاب الرئوي)
• التهاب الشعب الهوائية

• التهابات مجرى التنفس - مثل الأنف والجيوب الأنفية أو الحلق

• انخفاض عدد خلايا الدم الحمراء التي تحمل الأكسجين في الدم (فقر الدم)

• انخفاض عدد خلايا الدم البيضاء التي تساعد في مكافحة الالتهابات (قلة العدلات، قلة اللمفاويات، نقص في عدد كريات الدم البيضاء).

• قلة عدد خلايا الدم التي تسمى الصفائح الدموية والتي تساعد على تجلط الدم (نقص الصفيحات).
 

شائعة (قد تُؤثر على ما يصل إلى شخص واحد من كل ١٠ أشخاص):

• عدم انتظام ضربات القلب (الرجفان الأذيني)

• تراكم السوائل في الرئتين مما يجعلك تعاني من ضيق في التنفس.
• التهاب المسالك البولية

• عدوى شديدة في جميع أنحاء الجسم (تعفن الدم)

• الجفاف

• ارتفاع نسبة السكر في الدم

• انخفاض مستوى الكالسيوم في الدم

• انخفاض مستوى الأجسام المضادة في الدم تسمى"immunoglobulins"، التي تساعد على محاربة العدوى “hypogammaglobulinemia”

• الشعور بالدوار

• الإغماء

• آلام في عضلات الصدر

• أنفلونزا

• قشعريرة

• الحكة

• شعور غير عادي في الجلد (مثل الشعور بالوخز أو الشكشكة)

• التهاب البنكرياس

• ضغط دم مرتفع

• كوفيد-19

 

 

غير شائعة (قد تُؤثّر على ما يصل إلى شخص من ١٠٠ شخص):
• التهاب الكبد

• نوع من أنواع فيروس الهيربس (عدوى الفيروس المضخم للخلايا)

 

الإبلاغ عن الأعراض الجانبية

إن كان لديك أعراض جانبية أو لاحظت أعراض جانبية غير مذكورة في هذه النشرة، فضلًا ابلغ الطبيب أو الممرض.

يُحفظ دارزاليكس، محلول للحقن تحت الجلد في المستشفى أو العيادة.

 

احفظ هذا الدواء بعيدا عن مرأى ومتناول الأطفال.

 

لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحية المُدرج على علبة الكرتون والقارورة بعد كلمة EXP. يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من ذلك الشهر.

 

يُحفظ في الثلاجة (٢ درجة مئوية -٨ درجة مئوية). لا تجمده.

 

يُحفظ في علبته الأصلية من أجل حمايته من الضوء.

 

لا ينبغي التخلص من الأدوية عن طريق مياه الصرف أو النفايات المنزلية. سيقوم المشرف على رعايتك الصحية بالتخلص من أي أدوية لم تعد تستخدم. سوف تساعد هذه التدابير في حماية البيئة.

 

المادة الفعالة هي داراتوموماب. يحتوي كل ١ مل من المحلول على ١٢٠ مجم داراتوموماب. تحتوي كل قارورة سعة ١٥ مل على ١٨٠٠ مجم من داراتوموماب.
• المكونات الأخرى هي الهيالورونيداز البشري المؤتلف "بالهندسة الوراثية"(rHuPH20) ، إل- هيستيدين، إل- هيستيدين هيدروكلوريد أحادي الهيدرات، إل- ميثيونين، بوليسوربات 20، سوربيتول (E420)، وماء مُخصّص للحقن (انظر "دارزاليكس يحتوي على الصوديوم والسوربيتول" في القسم ٢).

كيف يبدو دارزاليكس وما هي محتويات العبوة

دارزاليكس هو محلول للحقن تحت الجلد وهو سائل عديم اللون مائل إلى اللون الأصفر.

يتوفر دارزاليكس في قوارير زجاجية محفوظة في علب كرتونية، تحتوي كل علبة على قارورة زجاجية واحدة.

حامل رخصة التسويق
جانسن - سيلاج الدولية إن في
تورنهاوتسويج 30
بيرسه بي-2340  

بلجيكا

 

المُصنّع
سيلاج إيه جي
هوتشستراسا 201
8200 شافهاوزن، سويسرا

للاتصال بنا، اذهب إلى www.janssen.com/contact-us تم آخر مراجعة لهذه النشرة بتاريخ ٩ فبراير ٢٠٢٣ للإبلاغ حول الأعراض الجانبية التي قد تحدث يرجى التواصل عبر العناوين التالية: • المملكة العربية السعودية: المركز الوطني للتيقظ الدوائي: مركز اتصال هيئة الغذاء والدواء السعودية: ١٩٩٩٩ البريد الإلكتروني: npc.drug@sfda.gov.sa الموقع الإلكتروني: http://ade.sfda.gov.sa • دول الخليج العربي الأخرى: الرجاء الاتصال بالجهات الوطنية في كل دولة
 Read this leaflet carefully before you start using this product as it contains important information for you

DARZALEX 1800 mg solution for injection

Each 15 mL vial of solution for injection contains 1800 mg of daratumumab (120 mg daratumumab per mL). Daratumumab is a human monoclonal IgG1κ antibody against CD38 antigen, produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology. Excipient with known effect Each 15 mL vial of solution for injection contains 735.1 mg of sorbitol (E420). For the full list of excipients, see section 6.1.

Solution for injection. The solution is clear to opalescent, colourless to yellow.

Multiple myeloma

 

DARZALEX is indicated:

·             in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

·             in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

·             in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

·             in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one prior therapy containing a proteasome inhibitor and lenalidomide and were lenalidomide‑refractory, or who have received at least two prior therapies that included lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or after the last therapy (see section 5.1).

·             as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

 

Light chain (AL) amyloidosis

 

DARZALEX is indicated in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic AL amyloidosis.


DARZALEX subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified.

 

DARZALEX should be administered by a healthcare professional, and the first dose should be administered in an environment where resuscitation facilities are available.

 

It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being given to the patient as prescribed.

 

For patients currently receiving daratumamab intravenous formulation, DARZALEX solution for subcutaneous injection may be used as an alternative to the intravenous daratumumab formulation starting at the next scheduled dose.

 

Pre‑ and post‑injection medicinal products should be administered to reduce the risk of infusion‑related reactions (IRRs) with daratumumab. See below “Recommended concomitant medicinal products” and section 4.4.

 

Posology

 

Multiple myeloma

Dosing schedule in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone (4‑week cycle regimen) and for monotherapy

 

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in table 1.

 

Table 1:      DARZALEX dosing schedule in combination with lenalidomide and dexamethasone (Rd), pomalidomide and dexamethasone (Pd) (4‑week cycle dosing regimen) and monotherapy

Weeks

Schedule

Weeks 1 to 8

weekly (total of 8 doses)

Weeks 9 to 24a

every two weeks (total of 8 doses)

Week 25 onwards until disease progressionb

every four weeks

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

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

 

Dexamethasone should be administered at 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years).

 

For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Dosing schedule in combination with bortezomib, melphalan and prednisone (6‑week cycle regimens)

 

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in table 2.

 

Table 2:      DARZALEX dosing schedule in combination with bortezomib, melphalan and prednisone ([VMP]; 6‑week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 6

weekly (total of 6 doses)

Weeks 7 to 54a

every three weeks (total of 16 doses)

Week 55 onwards until disease progressionb

every four weeks

a     First dose of the every-3-week dosing schedule is given at week 7.

b      First dose of the every-4-week dosing schedule is given at week 55.

 

Bortezomib is given twice weekly at weeks 1, 2, 4 and 5 for the first 6‑week cycle, followed by once weekly at weeks 1, 2, 4 and 5 for eight more 6‑week cycles. For information on the VMP dose and dosing schedule when administered with DARZALEX solution for subcutaneous injection, see section 5.1.

 

Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4‑week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT)

 

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in table 3.

 

Table 3:      DARZALEX dosing schedule in combination with bortezomib, thalidomide and dexamethasone ([VTd]; 4‑week cycle dosing regimen)

Treatment phase

Weeks

Schedule

Induction

Weeks 1 to 8

weekly (total of 8 doses)

Weeks 9 to 16a

every two weeks (total of 4 doses)

Stop for high dose chemotherapy and ASCT

Consolidation

Weeks 1 to 8b

every two weeks (total of 4 doses)

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

b     First dose of the every-2-week dosing schedule is given at week 1 upon re-initiation of treatment following ASCT.

 

Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 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 should be administered on days 1, 2, 8, 9, 15, 16 in cycles 5 and 6.

 

For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Dosing schedule in combination with bortezomib and dexamethasone (3‑week cycle regimen)

 

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in table 4.

 

Table 4:      DARZALEX dosing schedule in combination with bortezomib and dexamethasone (Vd) (3‑week cycle dosing regimen)

Weeks

Schedule

Weeks 1 to 9

weekly (total of 9 doses)

Weeks 10 to 24a

every three weeks (total of 5 doses)

Week 25 onwards until disease progressionb

every four weeks

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

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

 

Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib treatment cycles or a reduced dose of 20 mg/week for patients > 75 years, underweight (BMI < 18.5), poorly controlled diabetes mellitus or prior intolerance to steroid therapy.

 

For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

 

AL amyloidosis

Dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4‑week cycle regimens)

 

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in table 5.

 

Table 5:      DARZALEX dosing schedule for AL amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone ([VCd];4‑week cycle dosing regimen)a

Weeks

Schedule

Weeks 1 to 8

weekly (total of 8 doses)

Weeks 9 to 24b

every two weeks (total of 8 doses)

Week 25 onwards until disease progressionc

every four weeks

a    In the clinical study, DARZALEX was given until disease progression or a maximum of 24 cycles (~ 2 years) from the first dose of study treatment.

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

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

 

For dose and schedule of medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

 

Missed dose

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.

 

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4). For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.

 

In clinical studies, no modification to rate or dose of DARZALEX solution for subcutaneous injection was required to manage IRRs.

 

Recommended concomitant medicinal products

 

Pre‑injection medicinal product

Pre‑injection medicinal products (oral or intravenous) should be administered to reduce the risk of IRRs to all patients 1‑3 hours prior to every administration of DARZALEX solution for subcutaneous injection as follows:

 

·             Corticosteroid (long‑acting or intermediate‑acting)

-              Monotherapy:

Methylprednisolone 100 mg, or equivalent. Following the second injection, the dose of corticosteroid may be reduced to methylprednisolone 60 mg.

-              Combination therapy:

Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEX solution for subcutaneous injection. When dexamethasone is the background‑regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre‑injection medicinal product on DARZALEX administration days (see section 5.1). Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX administration days when patients have received dexamethasone (or equivalent) as a pre‑injection medicinal product.

·             Antipyretics (paracetamol 650 to 1000 mg).

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

 

Post‑injection medicinal product

Post‑injection medicinal products should be administered to reduce the risk of delayed IRRs as follows:

 

-              Monotherapy:

Oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate‑acting or long‑acting corticosteroid in accordance with local standards) should be administered on each of the two days following all injections (beginning the day after the injection).

-              Combination therapy:

Consider administering low‑dose oral methylprednisolone (≤ 20 mg) or equivalent the day after the DARZALEX injection. However, if a background regimen specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX injection, additional post‑injection medicinal products may not be needed (see section 5.1).

 

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, the use of post‑injection medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four injections, if the patient experiences no major IRRs, these inhaled post‑injection medicinal products may be discontinued at the discretion of the physician.

 

Prophylaxis for herpes zoster virus reactivation

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

 

Special populations

 

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses no dose adjustment is necessary for patients with renal impairment (see section 5.2).

 

Hepatic impairment

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

No dose adjustments are necessary for patients with hepatic impairment (see section 5.2).

 

Elderly

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

 

Paediatric population

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

No data are available.

 

Body weight (> 120 kg)

Limited number of patients with body weight > 120 kg have been studied using flat‑dose (1800 mg) DARZALEX solution for subcutaneous injection and efficacy in these patients has not been established. No dose adjustment based on body weight can currently be recommended (see sections 4.4 and 5.2).

 

Method of administration

 

DARZALEX subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See section 6.6 for special precautions prior to administration.

 

To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.

 

Inject 15 mL DARZALEX solution for subcutaneous injection into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel over approximately 3‑5 minutes. Do not inject DARZALEX solution for subcutaneous injection at other sites of the body as no data are available.

Injection sites should be rotated for successive injections.

 

DARZALEX solution for subcutaneous injection 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 solution for subcutaneous injection, do not administer other medicinal products for subcutaneous use at the same site as DARZALEX.

 


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

Traceability

 

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

 

Infusion‑related reactions

 

DARZALEX solution for subcutaneous injection can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical studies, approximately 9% (74/832) of patients experienced an IRR. Most IRRs occurred following the first injection and were grade 1‑2. IRRs occurring with subsequent injections were seen in 1% of patients (see section 4.8).

 

The median time to onset of IRRs following DARZALEX injection was 3.2 hours (range 0.15‑83 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, pruritis, chills, vomiting, nausea, hypotension and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see section 4.8).

 

Patients should be pre‑medicated with antihistamines, antipyretics, and corticosteroids as well as 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, appropriate emergency care should be initiated immediately. DARZALEX therapy should be discontinued immediately and permanently (see sections 4.2 and 4.3).

 

To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX injection (see section 4.2). Patients with a history of chronic obstructive pulmonary disease may require additional post‑injection medicinal products to manage respiratory complications. The use of post‑injection medicinal products (e.g. short‑ and long‑acting bronchodilators and inhaled corticosteroids) should be considered for patients with chronic obstructive pulmonary disease. If ocular symptoms occur, interrupt DARZALEX and seek immediate ophthalmologic evaluation prior to restarting DARZALEX (see section 4.2).

 

Neutropenia/thrombocytopenia

 

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (see section 4.8).

Complete blood cell counts should be monitored periodically during treatment according to manufacturer’s prescribing information for background therapies. Patients with neutropenia should be monitored for signs of infection. DARZALEX delay may be required to allow recovery of blood cell counts. In lower body weight patients receiving DARZALEX subcutaneous formulation, higher rates of neutropenia were observed; however, this was not associated with higher rates of serious infections. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.

 

Interference with indirect antiglobulin test (indirect Coombs test)

 

Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test. Daratumumab‑mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab 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.

 

Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may be considered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping is not impacted by daratumumab and may be performed at any time.

 

In the event of a planned transfusion blood transfusion centres should be notified of this interference with indirect antiglobulin tests (see section 4.5). If an emergency transfusion is required, non‑cross‑matched ABO/RhD‑compatible RBCs can be given per local blood bank practices.

 

Interference with determination of complete response

 

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M‑protein (see section 4.5). This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

 

Hepatitis B virus (HBV) reactivation

 

Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening should be performed in all patients before initiation of treatment with DARZALEX.

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 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, suspend treatment with DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

 

Body weight (> 120 kg)

 

There is a potential for reduced efficacy with DARZALEX solution for subcutaneous injection in patients with body weight > 120 kg (see sections 4.2 and 5.2).

 

Excipients

 

This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) should not be given this medicinal product.

 

This medicinal product also contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially ‘sodium‑free’.


No interaction studies have been performed.

 

As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme‑mediated metabolism of intact daratumumab are unlikely to represent major elimination routes. As such, variations in drug‑metabolising enzymes are not expected to affect the elimination of daratumumab. Due to the high affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug‑metabolising enzymes.

 

Clinical pharmacokinetic assessments with daratumumab intravenous or subcutaneous formulations and 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.

 

Interference with indirect antiglobulin test (indirect Coombs test)

 

Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching (see section 4.4). Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locally validated methods. Since the Kell blood group system is also sensitive to DTT treatment, Kell‑negative units should be supplied after ruling out or identifying alloantibodies using DTT‑treated RBCs. Alternatively, phenotyping or genotyping may also be considered (see section 4.4).

 

Interference with serum protein electrophoresis and immunofixation tests

 

Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a validated daratumumab‑specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.


 

Women of child‑bearing potential/contraception

 

Women of child‑bearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment.

 

Pregnancy

 

There are no or limited amount of data from the use of daratumumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). DARZALEX is not recommended during pregnancy and in women of childbearing potential not using contraception.

 

Breast‑feeding

 

It is unknown whether daratumumab is excreted in human milk.

A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast‑feeding or to discontinue/abstain from DARZALEX therapy taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman.

 

Fertility

 

No data are available to determine potential effects of daratumumab on fertility in males or females (see section 5.3).


DARZALEX has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking daratumumab and this should be taken into account when driving or using machines.


Summary of the safety profile

 

The most frequent adverse reactions of any grade (≥ 20% patients) with daratumumab (either intravenous or subcutaneous formulations) when administered either as monotherapy or combination treatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope.

 

The safety profile of the DARZALEX subcutaneous formulation was similar to that of intravenous formulation with the exception of a lower rate of IRRs. In the phase III study MMY3012, neutropenia was the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX subcutaneous formulation compared to intravenous daratumumab (grade 3 or 4: 13% vs 8%, respectively).

 

Tabulated list of adverse reactions

 

Table 6 summarises the adverse reactions that occurred in patients receiving DARZALEX subcutaneous formulation or intravenous formulation of daratumumab.

 

The data reflects exposure to DARZALEX subcutaneous formulation (1800 mg) in 639 patients with multiple myeloma (MM). The data includes 260 patients from a phase III active‑controlled study (MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy and 149 patients from a phase III active-controlled study (MMY3013) who received DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd). The data also reflects three open‑label, clinical studies in which patients received DARZALEX solution for subcutaneous injection either as monotherapy (N=31, MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX solution for subcutaneous injection in combination with either bortezomib, melphalan and prednisone (D‑VMP, n=67), lenalidomide and dexamethasone (D‑Rd, n=65) or bortezomib, lenalidomide and dexamethasone (D‑VRd, n=67). Additionally, data reflect exposure to 193 patients with newly diagnosed AL amyloidosis from a phase III active-controlled study (AMY3001) in which patients received DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd).

 

The safety data also reflects exposure to intravenous daratumumab (16 mg/kg) in 2324 patients with multiple myeloma including 1910 patients who received intravenous daratumumab in combination with background regimens and 414 patients who received intravenous daratumumab as monotherapy. Post‑marketing adverse reactions are also included.

 

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

 

Table 6:      Adverse reactions in multiple myeloma and AL amyloidosis patients treated with intravenous daratumumab or subcutaneous daratumumab

System organ class

Adverse reaction

Frequency

Incidence (%)

Any grade

Grade 3-4

Infections and infestations

Upper respiratory tract infectiona

Very common

37

2

Pneumoniaa

17

10

Bronchitisa

14

1

Urinary tract infection

Common

6

1

Influenza

4

1#

Sepsisa

4

3

COVID-19g

7

4

Cytomegalovirus infectiona

Uncommon

< 1

< 1#

Hepatitis B Virus reactivationa

< 1

< 1

Blood and lymphatic system disorders

Neutropeniaa

Very common

39

33

Thrombocytopeniaa

29

17

Anaemiaa

27

12

Lymphopeniaa

14

11

Leukopeniaa

11

6

Immune system disorders

Hypogammaglobulinemiaa

Common

2

< 1#

Anaphylactic reactionb

Rare

-

-

Metabolism and nutrition disorders

Decreased appetite

Very common

10

1

Hyperglycaemia

Common

6

3

Hypocalcaemia

5

1

Dehydration

2

1#

Psychiatric disorders

Insomnia

Very common

15

1#

Nervous system disorders

Peripheral sensory neuropathy

Very common

26

3

Headache

10

< 1#

Dizziness

Common

9

< 1#

Paraesthesia

9

< 1

Syncope

3

2#

Cardiac disorders

Atrial fibrillation

Common

3

1

Vascular disorders

Hypertensiona

Common

9

4

Respiratory, thoracic and mediastinal disorders

Cougha

Very common

21

< 1#

Dyspnoeaa

18

2

Pulmonary oedemaa

Common

1

< 1

Gastrointestinal disorders

Diarrhoea

Very common

29

4

Constipation

28

1

Nausea

22

1#

Vomiting

14

1#

Pancreatitisa

Common

1

< 1

Skin and subcutaneous tissue disorders

Rash

Very common

10

1#

Pruritus

Common

6

< 1#

Musculoskeletal and connective tissue disorders

Back pain

Very common

16

2

Muscle spasms

11

< 1#

Arthralgia

10

< 1#

Musculoskeletal chest pain

Common

6

< 1#

General disorders and administration site conditions

Fatigue

Very common

23

4

Oedema peripherala

22

1

Pyrexia

21

1

Asthenia

18

2

Chills

Common

8

< 1#

Injection site reactionsd,e

8

0

Injury, poisoning and procedural complications

Infusion‑related reactionsc

 

 

 

Daratumumab intravenousf

Very common

39

5

Daratumumab subcutaneouse

Common

9

1#

#     No grade 4.

a     Indicates a grouping of terms.

b     Based on post-marketing adverse reactions.

c     Infusion-related reactions includes terms determined by investigators as related to infusion/injection of daratumumab.

d     Injection site reactions includes terms determined by investigators as related to injection of daratumumab.

e     Frequency based on daratumumab subcutaneous studies only (N=832).

f     Frequency based on daratumumab intravenous studies only (N=2324).

Note: Based on 3156 multiple myeloma and AL amyloidosis patients treated with daratumumab intravenous or daratumumab subcutaneous.

g    Incidence is based on a subset of patients who received at least one dose of study treatment on or after 01 February 2020 (the start of the COVID-19 pandemic) from studies MMY3003, MMY3006, MMY3008 and MMY3013.

 

Description of selected adverse reactions

 

Infusion‑related reactions (IRRs)

In clinical studies (monotherapy and combination treatments; N=832) with DARZALEX subcutaneous formulation, the incidence of any grade IRRs was 8.2% with the first injection of DARZALEX (1800 mg, week 1), 0.4% with the week 2 injection, and 1.1% with subsequent injections. Grade 3 IRRs were seen in 0.8% of patients. No patients had grade 4 IRRs.

 

Signs and symptoms of IRR may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, blurred vision and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see section 4.4).

 

Injection site reactions (ISRs)

In clinical studies (N=832) with DARZALEX subcutaneous 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 at the site of injection was erythema.

 

Infections

In patients with multiple myeloma receiving daratumumab as monotherapy, the overall incidence of infections was similar between DARZALEX subcutaneous formulation (52.9%) versus intravenous daratumumab groups (50.0%). Grade 3 or 4 infections also occurred at similar frequencies between DARZALEX subcutaneous formulation (11.7%) and intravenous 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 were reported:

Grade 3 or 4 infections:

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%

Newly diagnosed patient studies: D‑VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D‑VTd: 22%, VTd: 20%.

Grade 5 (fatal) infections:

Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%

Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.

 

In patients with multiple myeloma receiving DARZALEX subcutaneous formulation combination therapy, the following were reported:

Grade 3 or 4 infections: DPd: 28%, Pd: 23%

Grade 5 (fatal) infections: DPd: 5%, Pd: 3%

Key: D=daratumumab; Vd=bortezomib-dexamethasone; Rd=lenalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; VMP=bortezomib-melphalan-prednisone; VTd=bortezomib-thalidomide-dexamethasone.

 

In patients with AL amyloidosis receiving DARZALEX subcutaneous formulation combination therapy, the following were reported:

Grade 3 or 4 infections: D-VCd: 17%, VCd:10%

Grade 5 infections: D-VCd: 1%, VCd: 1%

Key: D=daratumumab; VCd=bortezomib-cyclophosphamide-dexamethasone

 

Haemolysis

There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed in clinical studies and post‑marketing safety data.

 

Cardiac disorders and AL amyloidosis-related cardiomyopathy

The majority of patients in AMY3001 had AL amyloidosis-related cardiomyopathy at baseline (D‑VCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of D-VCd patients compared to 10% of VCd patients, while serious cardiac disorders occurred in 16% vs. 13% of D-VCd and VCd patients, respectively. Serious cardiac disorders occurring in ≥ 2% of patients included cardiac failure (D-VCd 6.2% vs. VCd 4.3%), cardiac arrest (D-VCd 3.6% vs. VCd 1.6%) and atrial fibrillation (D-VCd 2.1% vs. VCd 1.1%). All D-VCd patients who experienced serious or fatal cardiac disorders had AL amyloidosis-related cardiomyopathy at baseline. The longer median duration of treatment in the D-VCd 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 per 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 D‑VCd arm vs. the VCd arm, respectively.

 

With a median follow-up of 11.4 months, overall deaths (D-VCd 14% vs. VCd 15%) in study AMY3001 were primarily due to AL amyloidosis-related cardiomyopathy in both treatment arms.

 

Other special populations

 

In the phase III study MMY3007, which compared treatment with D‑VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D‑VMP: n=89, VMP: n=84), was consistent with the overall population (see section 5.1).

 

Elderly patients

Of the 3549 patients who received daratumumab (n=832 subcutaneous; n=2717 intravenous) at the recommended dose, 38% were 65 to less than 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. Among patients with relapsed and refractory multiple myeloma (n=1976), 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.

 

Reporting of suspected adverse reactions

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

To reports any side effect(s):

Saudi Arabia:

 

·       The National Pharmacovigilance Centre (NPC):

- SFDA Call Center: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa/

 

Other GCC States:

-        Please contact the relevant competent authority.


Symptoms and signs

 

There has been no experience of overdose in clinical studies.

 

Treatment

 

There is no known specific antidote for daratumumab overdose. In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment should be instituted immediately.


Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, CD38 (Clusters of Differentiation 38) inhibitors, ATC code: L01FC01.

 

DARZALEX solution for subcutaneous injection contains recombinant human hyaluronidase (rHuPH20). rHuPH20 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. rHuPH20 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 potently inhibit the in vivo growth of CD38‑expressing tumour cells. Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement‑dependent cytotoxicity, antibody‑dependent cell‑mediated cytotoxicity, and antibody‑dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T‑cell receptor DNA sequencing verified that T‑cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.

 

Daratumumab induced apoptosis in vitro after Fc mediated cross‑linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well‑understood.

 

Pharmacodynamic effects

 

Natural killer (NK) cell and T‑cell count

NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical response.

 

Immunogenicity

 

In multiple myeloma and AL amyloidosis patients treated with subcutaneous daratumumab in monotherapy and combination clinical studies, 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 7.3% (55/750) in patients who received either monotherapy DARZALEX subcutaneous formulation or combination DARZALEX subcutaneous formulation. 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 subcutaneous formulation is not known.

 

Clinical experience of DARZALEX solution for subcutaneous injection (subcutaneous formulation)

 

Monotherapy – relapsed/refractory multiple myeloma

MMY3012, an open‑label, randomised, phase III non‑inferiority study, compared efficacy and safety of treatment with DARZALEX solution for subcutaneous injection (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 PI and an IMiD. Treatment continued until unacceptable toxicity or disease progression.

 

A total of 522 patients were randomised: 263 to the DARZALEX subcutaneous formulation arm and 259 to the intravenous 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 met its co‑primary endpoints of overall response rate (ORR) by the IMWG response criteria (table 7) and maximum Ctrough at pre‑dose cycle 3 day 1, (see section 5.2).

 

Table 7:      Key results from study MMY3012

 

Subcutaneous daratumumab

(N=263)

Intravenous daratumumab

(N=259)

Primary endpoint

 

 

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

108 (41.1%)

96 (37.1%)

95% CI (%)

(35.1%, 47.3%)

(31.2%, 43.3%)

Ratio of response rates (95% CI)b

 

1.11 (0.89, 1.37)

CR or better, n (%)

5 (1.9%)

7 (2.7%)

Very good partial response (VGPR)

45 (17.1%)

37 (14.3%)

Partial response (PR)

58 (22.1%)

52 (20.1%)

Secondary endpoint

 

 

Rate of infusion‑related reaction, n (%)c

33 (12.7%)

89 (34.5%)

Progression‑free survival, months

 

 

Median (95% CI)

5.59 (4.67, 7.56)

6.08 (4.67, 8.31)

Hazard ratio (95% CI)

 

0.99 (0.78, 1.26)

a     Based on intent-to-treat population.

b     p-value < 0.0001 from Farrington-Manning test for non-inferiority hypothesis.

c     Based on safety population. P-value< 0.0001 from Cochran-Mantel-Haenszel Chi-Squared test.

 

After a median follow-up of 29.3 months, the median OS was 28.2 months (95% CI: 22.8, NE) in the DARZALEX subcutaneous formulation arm and was 25.6 months (95% CI: 22.1, NE) in the intravenous daratumumab arm.

 

Safety and tolerability results, including in lower weight patients, were consistent with the known safety profile for DARZALEX subcutaneous formulation and intravenous daratumumab.

 

Results from the modified‑CTSQ, a patient reported outcome questionnaire that assesses patient satisfaction with their therapy, demonstrated that patients receiving DARZALEX subcutaneous formulation had greater satisfaction with their therapy compared with patients receiving intravenous daratumumab. However, open‑label studies are subject to bias.

 

Combination therapies in multiple myeloma

MMY2040 was an open‑label study evaluating the efficacy and safety of DARZALEX subcutaneous formulation 1800 mg:

-              in combination with bortezomib, melphalan, and prednisone (D‑VMP) in patients with newly diagnosed multiple myeloma (MM) who are ineligible for transplant. Bortezomib was administered by subcutaneous 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 subcutaneous formulation was continued until disease progression or unacceptable toxicity.

-              in combination with lenalidomide and dexamethasone (D‑Rd) 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 subcutaneous formulation was continued until disease progression or unacceptable toxicity.

-              in combination with bortezomib, lenalidomide, and dexamethasone (D‑VRd) in patients with newly diagnosed MM who are transplant eligible. Bortezomib was administered by subcutaneous 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.

 

A total of 199 patients (D‑VMP: 67; D‑Rd: 65; D‑VRd: 67) were enrolled. Efficacy results were determined by computer algorithm using IMWG criteria. The study met its primary endpoint ORR for D‑VMP and D‑Rd and the primary endpoint VGPR or better for D‑VRd (see table 8).

 

Table 8:      Efficacy results from study MMY2040

 

D-VMP (n=67)

D-Rd (n=65)

D-VRd (n=67)

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

60 (89.6%)

61 (93.8%)

65 (97.0%)

90% CI(%)

(81.3%, 95.0%)

(86.5%, 97.9%)

(90.9%, 99.5%)

Stringent complete response (sCR)

13 (19.4%)

12 (18.5%)

6 (9.0%)

Complete response (CR)

19 (28.4%)

13 (20.0%)

5 (7.5%)

Very good partial response (VGPR)

20 (29.9%)

26 (40.0%)

37 (55.2%)

Partial response (PR)

8 (11.9%)

10 (15.4%)

17 (25.4%)

 

 

 

 

VGPR or better (sCR + CR + VGPR)

52 (77.6%)

51 (78.5%)

48 (71.6%)

90% CI(%)

(67.6%, 85.7%)

(68.4%, 86.5%)

(61.2%, 80.6%)

D-VMP=Daratumumab-bortezomib-melphalan-prednisone; D-Rd=Daratumumab-lenalidomide-dexamethasone; D-VRd=Daratumumab-bortezomib-lenalidomide-dexamethasone; Daratumumab=DARAZALEX subcutaneous formulation; CI=confidence interval.

a      Based on treated subjects.

 

Combination treatment with pomalidomide and dexamethasone (Pd)

Study MMY3013 was an open-label, randomised, active-controlled phase III study that compared treatment with DARZALEX subcutaneous formulation (1800 mg) in combination with pomalidomide and low-dose dexamethasone (D-Pd) to treatment with pomalidomide and low-dose dexamethasone (Pd) in patients with multiple myeloma who had received at least one prior line of therapy with lenalidomide and a proteasome 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 subcutaneous formulation administration days, 20 mg of the dexamethasone dose was given as a pre-administration medicinal product 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 subcutaneous formulation pre-administration medicinal product. 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 D-Pd arm and 153 to the Pd arm. Patients with documented evidence of disease progression on or after the last regimen were included in the study. Patients who had ≥ grade 3 rash during prior therapy were excluded as per the pomalidomide Summary of Product Characteristics. 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, and 89% Caucasian. Patients had received a median of 2 prior lines 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). Ninety‑six percent (96%) of patients received prior treatment with bortezomib. The majority of patients were refractory to lenalidomide (80%), a PI (48%), or both an immunomodulator and a PI (42%). Eleven percent of patients received 1 prior line of therapy; all were refractory to lenalidomide and 32.4% were refractory to both lenalidomide and a PI. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

 

With a median follow-up of 16.9 months, the primary analysis of PFS in study MMY3013 showed a statistically significant improvement in the D-Pd arm as compared to the Pd arm; the median PFS was 12.4 months in the D-Pd 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 D-Pd versus Pd.

 

Figure 1:     Kaplan-Meier curve of PFS in study MMY3013

 

 

An additional planned follow-up analysis of OS after a median follow-up of 39.6 months was performed. At OS maturity of 57%, the median OS was 34.4 months in the D-Pd arm and 23.7 months in the Pd arm (HR [95% CI]: 0.82 [0.61, 1.11]).

 

Additional efficacy results from study MMY3013 are presented in table 9 below.

 

Table 9:      Efficacy results from study MMY3013a

 

D-Pd (n=151)

Pd (n=153)

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

104 (68.9%)

71 (46.4%)

P-valueb

< 0.0001

Stringent complete response (sCR)

14 (9.3%)

2 (1.3%)

Complete response (CR)

23 (15.2%)

4 (2.6%)

Very good partial response (VGPR)

40 (26.5%)

24 (15.7%)

Partial response (PR)

27 (17.9%)

41 (26.8%)

MRD negativity ratec n(%)

13 (8.7%)

3 (2.0%)

95% CI (%)

(4.7%, 14.3%)

(0.4%, 5.6%)

P-valued

0.0102

D-Pd=daratumumab-pomalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval.

a     Based on intent-to-treat population.

b     p-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors.

c     MRD Negative rate is based on the intent-to-treat population and a threshold of 10-5.

d     p-value from Fisher’s exact test.

 

In responders, the median time to response was 1 month (range: 0.9 to 9.1 months) in the D-Pd 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 D-Pd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.

 

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

Study AMY3001, an open-label, randomised, active-controlled phase III study, compared treatment with DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd) to treatment with bortezomib, cyclophosphamide and dexamethasone (VCd) alone in patients with newly diagnosed systemic 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 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 dosing, 20 mg of the dexamethasone dose was given as a pre-injection medicinal product and the remainder given the day after DARZALEX administration. Bortezomib, cyclophosphamide and dexamethasone were given for six 28-day [4‑week] cycles in both treatment arms, while DARZALEX 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 prescribing information.

 

A total of 388 patients were randomised: 195 to the D-VCd 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. All patients had one or more affected organs and 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. Patients with grade 2 sensory or grade 1 painful peripheral neuropathy were excluded. The primary efficacy endpoint was hematologic complete response (HemCR) rate as determined by the Independent Review Committee assessment based on International Concensus Criteria. Study AMY3001 demonstrated an improvement in HemCR in the D‑VCd arm as compared to the VCd arm. Efficacy results are summarised in table 10.

 

Table 10:    Efficacy results from study AMY3001a

 

 

D-VCd

(n=195)

VCd

(n=193)

P value

Hematologic complete response (HemCR), n (%)

104 (53.3%)

35 (18.1%)

< 0.0001b

Very good partial response (VGPR), n (%)

49 (25.1%)

60 (31.1%)

 

Partial response (PR), n (%)

26 (13.3%)

53 (27.5%)

 

Hematologic VGPR or better (HemCR + VGPR), n (%)

153 (78.5%)

95 (49.2%)

< 0.0001b

Major organ deterioration progression-free survival (MOD-PFS), Hazard ratio with 95% CIc

0.58 (0.36, 0.93)

0.0211d

 

D-VCd=daratumumab-bortezomib-cyclophosphamide-dexamethasone; VCd=bortezomib-cyclophosphamide-dexamethasone.

a     Based on intent-to-treat population.

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

c      MOD-PFS defined as hematologic progression, major organ (cardiac or renal) deterioration or death.

d      Nominal p-value from inverse probability censoring weighted log-rank test.

 

In responders, the median time to HemCR was 60 days (range: 8 to 299 days) in the D-VCd 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 D-VCd group and 25 days (range: 8 to 171 days) in the VCd group. The median duration of HemCR 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.

 

Overall survival (OS) data were not mature. A total of 56 deaths were observed [n=27 (13.8%) D-VCd vs. n=29 (15%) VCd group].

 

Clinical experience with daratumumab concentrate for solution for infusion (intravenous formulation)

 

Newly diagnosed multiple myeloma

Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologous stem cell transplant

Study MMY3008, an open‑label, randomised, active‑controlled phase III study, compared treatment with intravenous 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 intravenous daratumumab infusion days, the dexamethasone dose was given as a pre‑infusion medicinal product. Dose adjustments for lenalidomide 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 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 Eastern Cooperative Oncology Group (ECOG) performance score of 0, 49.5% 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 and overall survival (OS).

 

With a median follow-up of 28 months, the primary analysis of PFS in study MMY3008 showed 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 in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67).

 

Figure 2:     Kaplan-Meier curve of PFS in study MMY3008

 

 

With a median follow-up of 56 months, DRd has shown an OS advantage over the Rd arm (HR=0.68; 95% CI: 0.53, 0.86; p=0.0013). Results of an updated OS analysis after a median of 64 months continued to show an improvement in OS for patients in the DRd arm compared to the Rd arm. Median OS was not reached in the DRd arm and was 65.5 months in the Rd arm (HR= 0.66; 95% CI: 0.53, 0.83).

 

Figure 3:     Kaplan-Meier curve of OS in study MMY3008

 

 

Additional efficacy results from study MMY3008 are presented in table 11 below.

 

Table 11:    Additional efficacy results from study MMY3008a

 

DRd (n=368)

Rd (n=369)

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

342 (92.9%)

300 (81.3%)

p-valueb

< 0.0001

 

Stringent complete response (sCR)

112 (30.4%)

46 (12.5%)

Complete response (CR)

63 (17.1%)

46 (12.5%)

Very good partial response (VGPR)

117 (31.8%)

104 (28.2%)

Partial response (PR)

50 (13.6%)

104 (28.2%)

CR or better (sCR + CR)

175 (47.6%)

92 (24.9%)

p-valueb

< 0.0001

 

VGPR or better (sCR + CR + VGPR)

292 (79.3%)

196 (53.1%)

p-valueb

< 0.0001

 

MRD negativity ratea,c n(%)

89 (24.2%)

27 (7.3%)

95% CI (%)

(19.9%, 28.9%)

(4.9%, 10.5%)

Odds ratio with 95% CId

4.04 (2.55, 6.39)

p-valuee

< 0.0001

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval.

a     Based on intent-to-treat population.

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

c      Based on threshold of 10-5.

d      Mantel-Haenszel estimate of the odds ratio for un-stratified tables is used. An odds ratio > 1 indicates an advantage for DRd.

e     p-value from Fisherʼs exact test.

 

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.

 

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 III study, compared treatment with intravenous daratumumab 16 mg/kg in combination with bortezomib, melphalan and prednisone (D‑VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomib was administered by subcutaneous 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). Intravenous daratumumab treatment was continued until disease progression or unacceptable toxicity.

 

A total of 706 patients were randomised: 350 to the D‑VMP 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%), 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, 38% had ISS stage III disease and 84% had standard risk cytogenetics. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).

 

With a median follow‑up of 16.5 months, the primary analysis of PFS in study MMY3007 showed an improvement in the D‑VMP arm as compared to the VMP arm; the median PFS had not been reached in the D‑VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p < 0.0001). 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 D‑VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D‑VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51; p < 0.0001), representing a 58% reduction in the risk of disease progression or death in patients treated with D‑VMP.

 

Figure 4:     Kaplan-Meier curve of PFS in study MMY3007

 

 

After a median follow‑up of 40 months, D‑VMP has shown an OS advantage over the VMP arm (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 D‑VMP arm. Median OS was not reached for either arm.

 

Figure 5:     Kaplan-Meier curve of OS in study MMY3007

 

 

Additional efficacy results from study MMY3007 are presented in table 12 below.

 

Table 12:    Additional efficacy results from study MMY3007a

 

D-VMP (n=350)

VMP (n=356)

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

318 (90.9)

263 (73.9)

p-valueb

< 0.0001

 

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

63 (18.0)

25 (7.0)

Complete response (CR) [n(%)]

86 (24.6)

62 (17.4)

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

100 (28.6)

90 (25.3)

Partial response (PR) [n(%)]

69 (19.7)

86 (24.2)

MRD negativity rate (95% CI) c (%)

22.3 (18.0, 27.0)

6.2 (3.9, 9.2)

Odds ratio with 95% CId

4.36 (2.64, 7.21)

 

p-valuee

< 0.0001

 

D-VMP=daratumumab-bortezomib-melphalan-prednisone; VMP=bortezomib-melphalan-prednisone; MRD=minimal residual disease; CI=confidence interval.

a     Based on intent-to-treat population.

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

c     Based on threshold of 10-5.

d     A Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. An odds ratio > 1 indicates an advantage for D-VMP.

e     p-value from Fisherʼs exact test.

 

In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D‑VMP 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 D‑VMP group and was 21.3 months (range: 18.4, not estimable) in the VMP group.

 

A subgroup analysis was performed on patients at least 70 years old, or those 65‑69 years old with ECOG performance score of 2, or aged less than 65 years of age with significant comorbidity or ECOG performance score of 2 (D‑VMP: n=273, VMP: n=270). The efficacy results in this subgroup were consistent with the overall population. In this subgroup, median PFS was not reached in the D‑VMP group and was 17.9 months in the VMP group (HR=0.56; 95% CI: 0.42, 0.75; p < 0.0001). The overall response rate was 90% in the D‑VMP group and 74% in theVMP group (VGPR rate:29% in D‑VMP group and 26% in VMP group; CR: 22% in D‑VMP group and 18% in VMP group; sCR rate: 20% in D‑VMP group and 7% in VMP group). The safety results of this subgroup were consistent with the overall population. Furthermore, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D‑VMP: n=89, VMP: n=84), was also consistent with the overall population.

 

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

Study MMY3006 is a 2 part, open‑label, randomised, active‑controlled phase III study. Part 1 compared induction and consolidation treatment with intravenous daratumumab 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D‑VTd) 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. In part 2, subjects with at least a partial response (PR) by day 100 post‑transplant were re‑randomised in a 1:1 ratio to daratumumab maintenance or observation only. Only results from part 1 are described henceforth.

 

Bortezomib was administered by subcutaneous injection or intravenous 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 and 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 intravenous daratumumab infusion, the dexamethasone dose was administered intravenously as a pre‑infusion medicinal product. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

 

A total of 1085 patients were randomised: 543 to the D‑VTd 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. All patients were ≤ 65 years: 43% were in the age group ≥ 60‑65 years, 41% were in the age group ≥ 50‑60 years and 16% below age of 50 years. The majority were male (59%), 48% had an 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 International Staging System (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 and PFS.

 

Table 13:    Efficacy results from study MMY3006a

 

D-VTd (n=543)

VTd (n=542)

P valueb

Response assessment day 100 post‑transplant

 

 

 

Stringent complete response (sCR)

157 (28.9%)

110 (20.3%)

0.0010

CR or better (sCR+CR)

211 (38.9%)

141 (26.0%)

< 0.0001

Very good partial response or better (sCR+CR+VGPR)

453 (83.4%)

423 (78.0%)

 

MRD negativityc, d n(%)

346 (63.7%)

236 (43.5%)

< 0.0001

95% CI (%)

(59.5%, 67.8%)

(39.3%, 47.8%)

 

Odds ratio with 95% CIe

2.27 (1.78, 2.90)

 

MRD negativity in combination with CR or betterc n(%)

183 (33.7%)

108 (19.9%)

< 0.0001

95% CI (%)

(29.7%, 37.9%)

(16.6%, 23.5%)

 

Odds ratio with 95% CIe

2.06 (1.56, 2.72)

 

D-VTd=daratumumab-bortezomib-thalidomide-dexamethasone; VTd=bortezomib-thalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval.

a     Based on intent-to-treat population.

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

c     Based on threshold of 10-5.

d     Regardless of response per IMWG.

e      Mantel-Haenszel estimate of the common odds ratio for stratified tables is used.

 

With a median follow-up of 18.8 months, the primary analysis of PFS by censoring patients who were randomised to daratumumab maintenance in the second randomisation at the date of the second randomisation showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005. Results of an updated PFS analysis with a median follow-up of 44.5 months, censoring patients who were randomised to daratumumab maintenance in the second randomisation, showed HR=0.43; 95% CI: 0.33, 0.55; p < 0.0001. Median PFS was not reached in the D‑VTd arm and was 37.8 months in the VTd arm.

 

Figure 6:     Kaplan-Meier curve of PFS in study MMY3006

 

 

Relapsed/refractory multiple myeloma

Monotherapy:

The clinical efficacy and safety of intravenous daratumumab monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who had demonstrated disease progression on the last therapy, was demonstrated in two open‑label studies.

 

In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg intravenous daratumumab until disease progression. The median patient age was 63.5 years (range, 31 to 84 years), 11% of patients were ≥ 75 years of age, 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.

 

Efficacy results of the pre‑planned interim analysis based on Independent Review Committee (IRC) assessment are presented in table 14 below.

 

Table 14:    IRC assessed efficacy results for study MMY2002

Efficacy endpoint

Intravenous daratumumab 16 mg/kg

N=106

Overall response rate1 (ORR: sCR+CR+VGPR+PR) [n (%)]

31 (29.2)

95% CI (%)

(20.8, 38.9)

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

3 (2.8)

Complete response (CR) [n]

0

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

10 (9.4)

Partial response (PR) [n (%)]

18 (17.0)

Clinical benefit rate (ORR+MR) [n (%)]

36 (34.0)

Median duration of response [months (95% CI)]

7.4 (5.5, NE)

Median time to response [months (range)]

1 (0.9; 5.6)

1    Primary efficacy endpoint (International Myeloma Working Group criteria).

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

 

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

At a survival update with a median duration of follow‑up of 14.7 months, median OS was 17.5 months (95% CI: 13.7, not estimable).

 

In study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg intravenous daratumumab until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy‑four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to carfilzomib.

 

Pre‑planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORR with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median duration of response was not reached (95% CI: 5.6 months, not estimable).

 

At a survival update with a median duration of follow‑up of 15.2 months, median OS was not reached (95% CI: 19.9 months, not estimable), with 74% of subjects still alive.

 

Combination treatment with lenalidomide

Study MMY3003, an open‑label, randomised, active‑controlled phase III study, compared treatment with intravenous 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 relapsed or refractory multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on days 1‑21 of repeated 28‑day [4‑week] cycles) was given with low dose dexamethasone at 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or BMI < 18.5). On intravenous daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre‑infusion medicinal product and the remainder given the day after the infusion. Treatment was continued in both arms until disease progression or unacceptable toxicity.

 

A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the intravenous daratumumab and the control arm. The median patient age was 65 years (range 34 to 89 years) and 11% were ≥ 75 years. The majority of patients (86%) received a prior PI, 55% of patients had received a prior IMiD, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Patients refractory to lenalidomide were excluded from the study.

 

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). 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 in the DRd arm and 17.5 months 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 (see figure 7).

 

Figure 7:     Kaplan-Meier curve of PFS in study MMY3003

 

 

After a median follow-up of 80 months, DRd has shown an OS advantage over the Rd arm (HR=0.73; 95% CI: 0.58, 0.91; p=0.0044). The median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm.

 

Figure 8:     Kaplan-Meier curve of OS in study MMY3003

 

 

Additional efficacy results from study MMY3003 are presented in table 15 below.

 

Table 15:    Additional efficacy results from study MMY3003

Response evaluable patient number

DRd (n=281)

Rd (n=276)

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

261 (92.9)

211 (76.4)

p-valuea

< 0.0001

 

Stringent complete response (sCR)

51 (18.1)

20 (7.2)

Complete response (CR)

70 (24.9)

33 (12.0)

Very good partial response (VGPR)

92 (32.7)

69 (25.0)

Partial response (PR)

48 (17.1)

89 (32.2)

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

1.0 (1.0, 1.1)

1.3 (1.1, 1.9)

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

NE (NE, NE)

17.4 (17.4, NE)

MRD negative rate (95% CI) b (%)

21.0 (16.4, 26.2)

2.8 (1.2, 5.5)

Odds ratio with 95% CIc

9.31 (4.31, 20.09)

 

P-valued

< 0.0001

 

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NE=not estimable.

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

b      Based on Intent-to-treat population and threshold of 10-5.

c    Mantel‑Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DRd.

d     p-value is from a Fisher’s exact test.

 

Combination treatment with bortezomib

Study MMY3004, an open‑label, randomised, active‑controlled phase III study, compared treatment with intravenous daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Bortezomib was administered by subcutaneous injection or intravenous 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 each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients > 75 years, BMI < 18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of intravenous daratumumab infusion, 20 mg of the dexamethasone dose was administered as a pre‑infusion medicinal product. intravenous daratumumab treatment was continued until disease progression or unacceptable toxicity.

 

A total of 498 patients were randomised; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the intravenous daratumumab and the control arm. The median patient age was 64 years (range 30 to 88 years) and 12% were ≥ 75 years. Sixty‑nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment. Thirty‑three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Patients refractory to bortezomib were excluded from the study.

 

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). 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 in the DVd arm and 7.1 months 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 (see figure 9).

 

Figure 9:     Kaplan-Meier curve of PFS in study MMY3004

 

 

After a median follow-up of 73 months, DVd has shown an OS advantage over the Vd arm (HR=0.74; 95% CI: 0.59, 0.92; p=0.0075). The median OS was 49.6 months in the DVd arm and 38.5 months in the Vd arm.

 

Figure 10:   Kaplan-Meier curve of OS in study MMY3004

 

 

Additional efficacy results from study MMY3004 are presented in table 16 below.

 

Table 16:    Additional efficacy results from study MMY3004

Response evaluable patient number

DVd (n=240)

Vd (n=234)

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

199 (82.9)

148 (63.2)

P-valuea

< 0.0001

 

Stringent complete response (sCR)

11 (4.6)

5 (2.1)

Complete response (CR)

35 (14.6)

16 (6.8)

Very good partial response (VGPR)

96 (40.0)

47 (20.1)

Partial response (PR)

57 (23.8)

80 (34.2)

Median time to response [months (range)]

0.9 (0.8, 1.4)

1.6 (1.5, 2.1)

Median duration of response [months (95% CI)]

NE (11.5, NE)

7.9 (6.7, 11.3)

MRD negative rate (95% CI)b

8.8% (5.6%, 13.0%)

1.2% (0.3%, 3.5%)

Odds ratio with 95% CIc

9.04 (2.53, 32.21)

 

P-valued

0.0001

 

DVd=daratumumab- bortezomib-dexamethasone; Vd=bortezomib-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NE=not estimable.

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

b     Based on Intent-to-treat population and threshold of 10-5.

c     Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DVd.

d     p-value is from Fisher’s exact test.

 

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 Cmax.

 

Paediatric population

 

The European Medicines Agency has waived the obligation to submit the results of studies with DARZALEX in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).


In patients with multiple myeloma, daratumumab exposure in a monotherapy study following the recommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter) as compared to 16 mg/kg intravenous daratumumab for the same dosing schedule, showed non‑inferiority for the co‑primary endpoint of maximum Ctrough (cycle 3 day 1 pre‑dose), with mean ± SD of 593 ± 306 µg/mL compared to 522 ± 226 µg/mL for intravenous 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 Ctrough (cycle 3 day 1 pre-dose) was similar to that in multiple myeloma with mean ± SD of 597 ± 232 µg/mL following the recommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).

 

Following the recommended dose of 1800 mg DARZALEX solution for subcutaneous injection, peak concentrations (Cmax) increased 4.8‑fold and total exposure (AUC0‑7 days) increased 5.4‑fold from first dose to last weekly dose (8th dose). Highest trough concentrations for DARZALEX solution for subcutaneous injection 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 solution for subcutaneous injection for combination therapy were similar to 1800 mg DARZALEX solution for subcutaneous injection monotherapy.

 

In patients with multiple myeloma, daratumumab exposure in a combination study with pomalidomide and dexamethasone (study MMY3013) was similar to that in monotherapy, with the maximum Ctrough (cycle 3 day 1 pre-dose) mean ± SD of 537 ± 277 µg/mL following the recommended 1800 mg administration of DARZALEX solution for subcutaneous injection (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).

 

Absorption and distribution

 

At the recommended dose of 1800 mg in multiple myeloma patients, the absolute bioavailability of DARZALEX solution for subcutaneous injection is 69%, with an absorption rate of 0.012 hour-1, with peak concentrations occurring at 70 to 72 h (Tmax). 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.

 

The model predicted mean estimate of the volume of distribution for the central compartment was 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 was 4.36 L (28.0% CV) and V2 was 2.80 L when daratumumab was administered in combination with pomalidomide and dexamethasone in multiple myeloma patients. In AL amyloidosis patients, the model estimated apparent volume of distribution after subcutaneous 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 elimination

 

Daratumumab exhibits both concentration and time‑dependent pharmacokinetics with parallel linear and nonlinear (saturable) elimination that is characteristic of target‑mediated clearance. 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 is administered in combination with pomalidomide and dexamethasone in multiple myeloma patients. In AL amyloidosis patients, the apparent clearance after subcutaneous administration is 210 mL/day (4.1% CV). The model‑based geometric mean 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 multiple myeloma patients and 27.5 days (74.0% CV) in AL amyloidosis patients. 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 was conducted using data from DARZALEX solution for subcutaneous injection monotherapy and combination therapy multiple myeloma studies, and the predicted PK exposures are summarised in table 17.

 

Table 17:    Daratumumab exposure following administration of DARZALEX subcutaneous formulation (1800 mg) or intravenous daratumumab (16 mg/kg) monotherapy in patients with multiple myeloma

PK parameters

Cycles

subcutaneous daratumumab

Median (5th; 95th percentile)

intravenous daratumumab

Median (5th; 95th percentile)

Ctrough (µg/mL)

Cycle 1, 1st weekly dose

123 (36; 220)

112 (43; 168)

Cycle 2, last weekly dose (cycle 3 day 1 Ctrough)

563 (177; 1063)

472 (144; 809)

Cmax (µg/mL)

Cycle 1, 1st weekly dose

132 (54; 228)

256 (173; 327)

Cycle 2, last weekly dose

592 (234; 1114)

688 (369; 1061)

AUC0-7 days (µg/mL•day)

Cycle 1, 1st weekly dose

720 (293; 1274)

1187 (773; 1619)

Cycle 2, last weekly dose

4017 (1515; 7564)

4019 (1740; 6370)

 

A population PK analysis, using data from DARZALEX solution for subcutaneous injection 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.

 

Table 18:    Daratumumab exposure following administration of DARZALEX subcutaneous formulation (1800 mg) in patients with AL amyloidosis

PK parameters

Cycles

subcutaneous daratumumab

Median (5th; 95th percentile)

Ctrough (µg/mL)

Cycle 1, 1st weekly dose

138 (86; 195)

Cycle 2, last weekly dose

(cycle 3 day 1 Ctrough)

662 (315; 1037)

Cmax (µg/mL)

Cycle 1, 1st weekly dose

151 (88; 226)

Cycle 2, last weekly dose

729 (390; 1105)

AUC0-7 days (µg/mL•day)

Cycle 1, 1st weekly dose

908 (482; 1365)

Cycle 2, last weekly dose

4855 (2562; 7522)

 

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 daratumumab. No individualisation is necessary for patients on the basis of age.

 

Gender had a statistically significant effect on PK parameters 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 subcutaneous 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 subcutaneous formulation monotherapy or various combination therapies in patients with multiple myeloma or AL amyloidosis. 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 subcutaneous formulation in patients with hepatic impairment have been conducted.

Population PK analyses were performed in patients with multiple myeloma receiving DARZALEX subcutaneous formulation monotherapy or various combination therapies in patients with multiple myeloma and in AL amyloidosis. 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 subcutaneous formulation monotherapy or various combination therapies, the daratumumab exposure was similar across races.

 

Body weight

The flat‑dose administration of DARZALEX subcutaneous formulation 1800 mg as monotherapy achieved adequate exposure for all body‑weight subgroups. In patients with multiple myeloma, the mean cycle 3 day 1 Ctrough in the lower body‑weight subgroup (≤ 65 kg) was 60% higher and in the higher body weight (> 85 kg) subgroup, 12% lower than the intravenous daratumumab subgroup. In some patients with body weight > 120 kg, lower exposure was observed which may result in reduced efficacy. However, this observation is based on limited number of patients.

 

In patients with AL amyloidosis, no meaningful differences were observed in Ctrough across body weight.


Toxicology data have been derived from studies with daratumumab in chimpanzees and with a surrogate anti‑CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has been conducted.

 

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

 

No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development or to determine potential effects on fertility in males or females.

 

No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant human hyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure of hyaluronidase in monkeys given 22000 U/kg/week subcutaneously (12 times higher than the human dose) for 39 weeks. As hyaluronidase is a recombinant form of the endogenous human hyaluronidase, no carcinogenity, mutagenesis, or effects on fertility are expected.


Recombinant human hyaluronidase (rHuPH20)

L‑histidine

L‑histidine hydrochloride monohydrate

L‑methionine

Polysorbate 20

Sorbitol (E420)

Water for injections


This medicinal product must not be used with other materials except those mentioned in section 6.6.


Unopened vial 2 years. During the shelf life, the product in unpunctured vials may be stored at ambient temperature (≤ 30 °C) for a single period of up to 24 hours. Once the product has been taken out of the refrigerator, it must not be returned to the refrigerator (see section 6.6). Prepared syringe Chemical and physical in use stability in syringe has been demonstrated for 24 hours at refrigerated conditions (2 °C-8 °C), followed by no more than 7 hours at 15 °C-30 °C and ambient light. From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2 °C‑8 °C).

Do not freeze.

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

 

For storage conditions of the opened medicinal product (see section 6.3).


15 mL solution in a type 1 glass vial with an elastomeric closure and an aluminium seal with a flip‑off button containing 1800 mg of daratumumab. Pack size of 1 vial.


DARZALEX solution for subcutaneous injection is for single use only and is ready to use.

 

DARZALEX solution for subcutaneous injection should be a clear to opalescent and colourless to yellow solution. Do not use if opaque particles, discolouration or other foreign particles are present.

 

DARZALEX solution for subcutaneous injection is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles.

 

Unopened vial

 

Remove the DARZALEX solution for subcutaneous injection vial from refrigerated storage (2 °C‑8 °C) and equilibrate to ambient temperature (≤30 °C). The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours in the original carton to protect from light. Keep out of direct sunlight. Do not shake.

 

Prepared syringe

 

Prepare the dosing syringe in controlled and validated aseptic conditions. Once transferred from the vial into the syringe, store DARZALEX solution for subcutaneous injection for up to 24 hours refrigerated followed by up to 7 hours at 15 °C-30°C and ambient light (see section 6.3). If stored in the refrigerator, allow the solution to reach ambient temperature before administration.

 

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


Janssen Cilag International NV Turnhoutseweg 30 B 2340 Beerse Belgium

9 February 2023
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