2014年7月30日，欧盟委员会（EC）已批准Gazyvaro（obinutuzumab）联合苯丁酸氮芥化疗用于因一些合并症（comorbidities）导致不适合强化治疗（intensive therapy）的初治慢性淋巴细胞白血病（CLL）成人患者的治疗。在欧盟及瑞士以外国家和地区，Gazyvaro以商品名Gazyva上市。罗氏计划于2014年在欧洲一些国家推出该药。此外，罗氏也正在对抗CD-20抗体治疗有效的其他一些类型癌症中评价Gazyvaro的疗效。
Gazyvaro的获批，基于III期CLL11研究的数据。数据表明，与美罗华（MabThera，通用名：rituximab，利妥昔单抗）+苯丁酸氮芥组合疗法相比，Gazyvaro+苯丁酸氮芥组合疗法使疾病恶化或死亡风险显著降低61%，显著延长了患者的疾病无进展生存期（PFS：26.7个月 vs 15.2个月，p＜0.001），同时也增加了缓解深度（以微小残留病（MRD）评价： 37.7% vs 3.3%），并取得了较高的完全缓解率（ 21% vs 7%）。此外，与与苯丁酸氮芥单药疗法相比，Gazyvaro+苯丁酸氮芥组合疗法也增加了初治CLL患者的总生存期（OS）。
关于Gazyvaro（obinutuzumab）：
obinutuzumab在美国的商品名为Gazyva，已获FDA批准，联合苯丁酸氮芥（chlorambucil）化疗，用于既往未经治疗的慢性淋巴细胞白血病（CLL）患者。Gazyva的获批，将减少生物仿制药对罗氏重磅药物美罗华（Rituxan，通用名：rituximab，利妥昔单抗）的冲击。
obinutuzumab又名GA101，是首个糖基化的II型抗CD20单克隆抗体，靶向B细胞表面的CD20分子，能够直接诱导B细胞死亡。obinutuzumab旨在增强抗体依赖性细胞毒性作用（Antibody-Dependent Cellular Cytotoxicity，ADCC）及直接的细胞死亡诱导作用（Direct Cell Death induction）。
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002799/WC500167332.pdf
Gazyvaro 1,000 mg concentrate for solution for infusion
Package leaflet: Information for the patient
Gazyvaro 1,000 mg concentrate for solution for infusion
Obinutuzumab
▼This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
•Keep this leaflet. You may need to read it again.
•If you have any further questions, ask your doctor or nurse.
•If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Gazyvaro is and what it is used for
2. What you need to know before you are given Gazyvaro
3. How Gazyvaro is given
4. Possible side effects
5. How to store Gazyvaro
6. Content of the pack and other information
1. What Gazyvaro is and what it is used for
What Gazyvaro is
Gazyvaro contains the active substance obinutuzumab, which belongs to a group of medicines called “monoclonal antibodies”. Antibodies work by attaching themselves to specific targets in your body.
What Gazyvaro is used for
•Gazyvaro is used together with another cancer medicine called chlorambucil to treat chronic lymphocytic leukaemia (CLL). CLL is a cancer of the blood which affects a type of white blood cell called “B lymphocytes”. The affected B lymphocytes multiply too quickly and live too long. This means that there are too many of them circulating in your blood. CLL can also make your lymph nodes get larger. They are part of a network of vessels running round your body that is filled with clear watery fluid called “lymph”.
Gazyvaro is used in adults:
•who have not had any treatment before, and
•who have other medical conditions which make it unlikely that they would be able to tolerate a full dose of another cancer medicine called fludarabine.
How Gazyvaro works
Gazyvaro binds to targets on the surface of the “B lymphocyte” cells and causes them to die. It is given with chlorambucil to people with CLL to help delay the time it takes for their disease to worsen.
2. What you need to know before you are given Gazyvaro
You must not be given Gazyvaro if:
•you are allergic to obinutuzumab or any of the other ingredients of this medicine (listed in section 6).
If you are not sure about this you should ask your doctor or nurse.
Warnings and precautions
Talk to your doctor or nurse before you are given Gazyvaro if:
•you have an infection, or have had a long-lasting or repeating infection
•you have ever taken medicines which affect your immune system (such as chemotherapy or immunosuppressants)
•you are taking medicines for high blood pressure or medicines used to thin your blood – your doctor might need to change how you take these
•you have ever had heart problems
•you have ever had neurological problems (losing your memory, difficulties moving or feeling, sight problems)
•you have ever had breathing problems or lung problems
•you have ever had a liver disease called hepatitis B
•you are due to have a vaccine or may need one in the near future.
If any of the above apply to you (or you are not sure), talk to your doctor or nurse before you are given Gazyvaro.
Infusion reactions
Tell your doctor or nurse straight away if you get any of the infusion reactions listed at the top of section 4. Infusion reactions can happen during the infusion or any time in the 24 hours after the infusion.
If you get infusion reactions, you may require additional treatment, or the infusion may need to be slowed down or stopped. When these symptoms go away, or improve, the infusion can be continued. These reactions are less likely to happen during the second and later infusions. Your doctor may decide not to continue with Gazyvaro treatment if you have a strong infusion reaction.
Before each infusion of Gazyvaro, you will be given medicines which help to reduce possible infusion reactions or a potentially life-threatening complication known as tumour lysis syndrome, which is caused by chemical disturbances in the blood caused by the breakdown of dying cancer cells (see section 3).
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) is a very rare and life-threatening brain infection that has been reported with Gazyvaro.
Tell your doctor or nurse straight away if you have memory loss, trouble communicating, difficulty with walking or loss of vision. If you had these symptoms prior to treatment with Gazyvaro, tell your doctor immediately about any changes in these symptoms. You may need medical treatment.
Children and adolescents
This medicine should not be given to children or young people below 18 years of age. This is because there is no information about its use in these age groups.
Other medicines and Gazyvaro
Tell your doctor or nurse if you are taking, have recently taken or might start taking any other medicines. This includes herbal medicines and other medicines you can obtain without a prescription.
Contraception
If you could become pregnant you have to use a reliable method of contraception while being treated with Gazyvaro and for 18 months after your last treatment with Gazyvaro.
Pregnancy
You must tell your doctor or nurse if you are pregnant, think you are pregnant or if you intend to become pregnant. Your doctor will weigh up the benefit to you against the risk to your baby of taking Gazyvaro while you are pregnant. If you become pregnant during treatment with Gazyvaro, tell your doctor or nurse as soon as possible, as treatment with Gazyvaro may have implications for your health or that of your baby.
Breast-feeding
Do not breast-feed during treatment with Gazyvaro or for 18 months after your last treatment with Gazyvaro. This is because small amounts of the medicine may pass into your breast milk.
Driving and using machines
Gazyvaro is unlikely to affect your ability to drive, cycle or use any tools or machines. However, infusion reactions are very common during the first infusion. If you get an infusion reaction (see section 4), do not drive or use machines until the reaction stops.
3. How Gazyvaro is given
Gazyvaro is given under the supervision of a doctor experienced in such treatment. It is given into a vein (intravenously) as a drip (infusion) over several hours.
The Gazyvaro dose
You will be given 6 treatment cycles of Gazyvaro. Each cycle lasts 28 days. On Day 1 of your first cycle, you will be given 100 mg of Gazyvaro very slowly and your doctor will monitor you carefully. If you do not have an infusion reaction during the infusion, you may be given the rest of your first dose (900 mg) on the same day. However, if you do have an infusion reaction, you will be given the rest of the first dose on Day 2. A typical schedule is shown below.
Your first cycle:
•Day 1 – 100 mg
•Day 2 or Day 1 (continued) – 900 mg
•Day 8 – 1,000 mg
•Day 15 – 1,000 mg
Your next cycles 2, 3, 4, 5 and 6:
•Day 1 – 1,000 mg.
Medicines given before each infusion
Before each infusion of Gazyvaro, you will be given medicines which help to reduce possible infusion reactions or tumour lysis syndrome. These may include:
•fluids
•medicines to reduce an allergic reaction (anti-histamines)
•medicines to reduce inflammation (corticosteroids)
•painkillers (analgesics)
•medicines to reduce a fever
•medicine to prevent tumour lysis syndrome (such as allopurinol).
If you forget to have Gazyvaro
For anticancer treatment to be fully effective, it is very important to follow the dosing schedule. Therefore, if you miss your appointment, make another one as soon as possible.
If you have any further questions on the use of this medicine, ask your doctor or nurse.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. The following serious side effects have been reported with this medicine:
Infusion reactions (very common – these may affect more than 1 in 10 people): tell your doctor or nurse straight away if you get any of the following in the 24 hours following your infusion:
Most frequently reported:
•headache
•fever, flushing or chills
•feeling sick, vomiting
•shortness of breath
•low or high blood pressure
•your heart beating very fast
•diarrhoea
Less frequently reported:
•wheezing, difficulty breathing, tight chest or throat irritation
•throat and airway swelling
•irregular heartbeat
If you get any of the above, tell your doctor or nurse straight away.
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) is a very rare and life-threatening brain infection that has been reported with Gazyvaro.
Tell your doctor or nurse straight away if you have
•memory loss
•trouble communicating
•difficulty with walking
•loss of vision
If you had these symptoms prior to treatment with Gazyvaro, tell your doctor immediately about any changes in these symptoms. You may need medical treatment.
Infections
You might get infections more easily following Gazyvaro therapy. Often these are colds, but there have been cases of more severe infections. Return of hepatitis B, a liver disease, has also been reported in patients who have had hepatitis B in the past.
Tell your doctor after your Gazyvaro treatment if you get any symptoms of an infection, for example
•fever
•cough
•sore throat
•burning pain when passing urine
•feeling weak or generally unwell.
Other side effects include:
Very common (may affect more than 1 in 10 people)
•fever
•diarrhoea
•shown in blood tests:
•low levels of neutrophils (a type of white blood cell)
•low level of platelets (a type of blood cell that helps your blood to clot)
•anaemia (low levels of red blood cells)
Common (may affect up to 1 in 10 people)
•urinary tract infection
•cold sores
•runny nose
•nose and/or throat inflammation
•cough
•joint or back pain
•muscle and bone pain in your chest
•weight increase
•irregular heart rhythm (atrial fibrillation)
•hair loss
•skin cancer (squamous cell carcinoma)
•constipation
•shown in blood tests:
•low levels of lymphocytes (a type of white blood cells)
•low levels of all types of white blood cell (combined)
•increase in potassium, phosphate or uric acid - which can cause kidney problems (part of tumour lysis syndrome)
Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.