靶向CD20的抗体新药rituximab and hyaluronidase human（ 商品名  Rituxan Hycela)联合疗法获FDA批准利用于治疗某些血液恶性肿瘤

2017年6月22日，美国食品和药物管理局正式批准利妥昔单抗和人类透明质酸酶(商品名：Rituxan Hycela)联合疗法用于治疗患有滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤和慢性淋巴细胞性白血病的成人患者。
这项批准使患者能够皮下注射(Rituxan)利妥昔单抗，与给药时间需数小时的静脉内输注相比，给药时间可缩至5-7分钟。为新产品还提供平滑剂量选择。
这项批准规定这种新产品的适应证与利妥昔已批准的适应证类似，
·包括作为单药治疗复发性或难治性滤泡性淋巴瘤。
·与一线化疗联用于初次接受治疗的滤泡性淋巴瘤患者，与化疗相结合的情况下，作为单药维持疗法对利妥昔单抗完全或部分有效的患者。
·该药物可作为单药治疗继使用一线疗法环磷酰胺、长春新碱和泼尼松(CVP)化疗后无进展(包括病情稳定)的滤泡性淋巴瘤。
·与环磷酰胺、多柔比星、长春新碱，泼尼松(CHOP)或其他基于蒽环霉素的化疗方案联用于初次接受治疗的弥漫性大B细胞淋巴瘤(DLBCL)。
·与氟达拉滨和环磷酰胺(FC)联用治疗CLL(包括既往有过治疗和初次接受治疗)。
利妥昔单抗与人类透明质酸酶联用疗法不适用于非恶性疾病。
临床试验
这项批准是基于多项随机临床试验的结果：
(1) 给药 1400mg/23400 单位的利妥昔单抗/人类透明质酸酶的利妥昔单抗谷浓度水平不低于静脉注射利妥昔单抗 375mg/m2时谷浓度;
(2) 1600mg/26800单位利妥昔单抗/人类透明质酸酶的谷浓度水平不低于静脉注射利妥昔单抗500mg/m2时谷浓度;
(3) 两种产品的疗效和安全性相当。药物处方信息中提供试验结果。
滤泡性淋巴瘤患者的最常见不良事件(≥ 20%) 包括感染、嗜中性白细胞减少症、恶心、便秘、咳嗽和疲劳。
DLBCL患者的最常见不良事件(≥ 20%) 包括感染、嗜中性白细胞减少症、脱发、恶心和贫血。
CLL 患者的最常见不良事件(≥ 20%) 包括感染、嗜中性白细胞减少症、恶心、血小板减少症、发热、呕吐和注射部位红斑。
滤泡性淋巴瘤和DLBCL的推荐剂量为1400mg利妥昔单抗+23400单位人类透明质酸酶，CLL的推荐剂量为 1600mg利妥昔单抗+26800单位人类透明质酸酶。具体给药方案参照处方信息。
患者通过静脉输注至少一次全剂量的利妥昔单抗产品后，方能启动利妥昔单抗加人类透明质酸酶联合疗法.

Rituxan Hycela(rituximab and hyaluronidase human)
RITUXAN HYCELA
Leukemias, lymphomas, and other hematologic cancers  Only 4 drugs may be compared at once
Generic Name and Formulations:
Rituximab, hyaluronidase human 1400mg/23400 Units, 1600mg/26800 Units; soln for SC inj; preservative-free.
Company:
Genentech and Biogen
Select therapeutic use: Leukemias, lymphomas, and other hematologic cancers
Indications for RITUXAN HYCELA:
Relapsed or refractory, follicular lymphoma (FL) as a single agent. Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease) FL as a single agent after first-line CVP chemotherapy. Previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. Chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide.
Limitations Of use:
Start treatment only after receiving at least 1 full dose of a rituximab product by IV infusion. Not for treating non-malignant conditions.
Adult:
Give by SC inj into abdomen. Premedicate with an antihistamine and acetaminophen prior to each dose; may consider glucocorticoids. Monitor for at least 15mins after each dose. Relapsed or refractory FL: 1400mg/23400 Units over 5mins once weekly for 3 or 7 weeks following a full dose of IV rituximab at Week 1. May give retreatment once weekly for 3 weeks following a full dose of IV rituximab at Week 1. Previously untreated FL: 1400mg/23400 Units over 5mins on Day 1 of Cycles 2–8 of chemotherapy (every 21 days) for up to 7 cycles following a full dose of IV rituximab on Day 1 of Cycle 1; if complete or partial response, initiate Rituxan Hycela maintenance 8 weeks following completion of Rituxan Hycela in combination with chemotherapy. Administer Rituxan Hycela as a single-agent every 8 weeks for 12 doses. Non-progressing FL after first-line CVP chemotherapy: 1400mg/23400 Units over 5mins once weekly for 3 weeks at 6-month intervals following completion of 6–8 cycles of CVP and a full dose of IV rituximab at Week 1; max 16 doses. DLBCL: 1400mg/23400 Units over 5mins on Day 1 of Cycles 2–8 of CHOP chemotherapy for up to 7 cycles following a full dose of IV rituximab on Day 1 of Cycle 1. CLL: 1600mg/26800 Units over 7mins on Day 1 of Cycles 2–6 (every 28 days) for 5 cycles following a full dose of IV rituximab on Day 1 of Cycle 1. Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy.
Children:
Not established.
Warnings/Precautions:
Discontinue if severe injection or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory failure, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Tumor lysis syndrome (esp. with high tumor burden); monitor renal function, fluid balance, electrolyte abnormalities (correct if occurs); discontinue if SCr rises or oliguria occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiac or pulmonary conditions, prior cardiopulmonary adverse events, high malignant cell count; monitor during and after treatment. Elderly. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for at least 12 months after last dose. Pregnancy (monitor newborns/infants for infection). Nursing mothers: not recommended (during and for at least 6 months after last dose).
Interactions:
Live virus vaccines: not recommended. Renal toxicity with concomitant cisplatin.
Pharmacological Class:
CD20-directed cytolytic monoclonal antibody + endoglycosidase.
Adverse Reactions:
Infections, neutropenia, nausea, constipation, cough, fatigue, alopecia, anemia, thrombocytopenia, pyrexia, vomiting, injection site erythema, mucocutaneous reactions (may be fatal), hypersensitivity, PML, tumor lysis syndrome, renal toxicity, bowel obstruction/perforation (when concomitant chemotherapy), HBV reactivation, arrhythmias (discontinue if serious).
Generic Availability:
NO
How Supplied:
Single-dose vial—1
FDA Approves Genentech's RITUXAN HYCELA, A Subcutaneous Rituximab Coformulated With Halozyme ENHANZE Technology
U.S. Food and Drug Administration (FDA) has approved Genentech's RITUXAN HYCELATM, a combination of rituximab and Halozyme's hyaluronidase human ENHANZE® technology, for subcutaneous injection in multiple blood cancer indications.
"We are pleased that RITUXAN HYCELA will now provide another treatment option for U.S. patients," said Dr. Helen Torley, president and chief executive officer. "RITUXAN HYCELA has the potential to reduce the treatment burden and administration time, and is an option preferred by many patients."
IMPORTANT SAFETY INFORMATION
BOXED WARNINGS: SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA
Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab-containing products, including RITUXAN HYCELA, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN HYCELA. Discontinue RITUXAN HYCELA and concomitant medications in the event of HBV reactivation
Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA
WARNINGS AND PRECAUTIONS
Severe Mucocutaneous Reactions
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab-containing products, including RITUXAN HYCELA. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis
Discontinue RITUXAN HYCELA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of a rituximab-containing product, including RITUXAN HYCELA, to patients with severe mucocutaneous reactions has not been determined
Hepatitis B Virus Reactivation
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with CD20-directed cytolytic antibodies, including rituximab-containing products
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases, increase in bilirubin levels, liver failure, and death can occur
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with a rituximab-containing product. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during treatment with a rituximab-containing product. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RITUXAN HYCELA. HBV reactivation has been reported up to 24 months following completion of therapy containing rituximab
In patients who develop reactivation of HBV while on RITUXAN HYCELA, immediately discontinue treatment and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RITUXAN HYCELA treatment in patients who develop HBV reactivation. Resumption of RITUXAN HYCELA treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV
Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death has been observed in patients receiving rituximab-containing products, including RITUXAN HYCELA
Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture
Discontinue RITUXAN HYCELA and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML
Hypersensitivity and Other Administration Reactions
Systemic Reactions
Patients must receive at least one full dose of RITUXAN before receiving RITUXAN HYCELA due to the higher risk of hypersensitivity and other acute reactions during the first infusion. Beginning therapy with RITUXAN allows management of hypersensitivity and other administration reactions by slowing or stopping the intravenous infusion
Rituximab-containing products, including RITUXAN HYCELA, are associated with hypersensitivity and other administration reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions. This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome, and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the route of administration of a rituximab-containing product
 Severe infusion-related reactions with fatal outcome have been reported with the use of RITUXAN, with an onset ranging within 30 minutes to 2 hours after starting the first intravenous infusion. They were characterized by pulmonary events in addition to fever, chills, rigors, hypotension, urticaria, angioedema, and other symptoms. Anaphylactic and other hypersensitivity reactions can also occur. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion
Severe cytokine release syndrome is characterized by severe dyspnea, often associated by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with acute respiratory failure and death. Cytokine release syndrome may occur within 1-2 hours of initiating the infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumor infiltration may be at a greater risk of poor outcome. Rituximab product administration should be interrupted immediately and aggressive symptomatic treatment initiated
During RITUXAN HYCELA administration, the injection should be interrupted immediately when observing signs of a severe reaction and aggressive symptomatic treatment should be initiated. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥ 25,000/mm3)
Premedicate patients with an antihistamine and acetaminophen prior to each administration of RITUXAN HYCELA. Premedication with glucocorticoids should also be considered. Observe patients for at least 15 minutes following RITUXAN HYCELA. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions
Local Cutaneous Reactions
Local cutaneous reactions, including injection site reactions, have been reported in patients receiving RITUXAN HYCELA. Symptoms included pain, swelling, induration, hemorrhage, erythema, pruritus, and rash. Some local cutaneous reactions occurred more than 24 hours after RITUXAN HYCELA administration. The incidence of local cutaneous reactions following administration of RITUXAN HYCELA was 16%. Reactions were mild or moderate and resolved without any specific treatment. Local cutaneous reactions of any Grade were most common during the first RITUXAN HYCELA cycle (Cycle 2: 5%), with the incidence decreasing with subsequent injections
Tumor Lysis Syndrome (TLS)
TLS can occur within 12-24 hours after administration of a rituximab-containing product, including RITUXAN HYCELA
A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated
Infections
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of therapy with rituximab-containing products, including RITUXAN HYCELA. The incidence of infections with RITUXAN HYCELA vs. RITUXAN was 56% and 49% respectively in patients with CLL, and 46% and 41% respectively in patients with FL/DLBCL in combination with chemotherapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure)
New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RITUXAN HYCELA for serious infections and institute appropriate anti-infective therapy
Cardiovascular Adverse Reactions
Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock, may occur with rituximab-containing products, including RITUXAN HYCELA
Discontinue RITUXAN HYCELA for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all administrations of RITUXAN HYCELA for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina
Renal Toxicity
Severe, including fatal, renal toxicity can occur after administration of rituximab-containing products, including RITUXAN HYCELA. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN HYCELA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN HYCELA in patients with a rising serum creatinine or oliguria
Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA, in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur
Immunization
The safety of immunization with live viral vaccines following rituximab-containing products, including RITUXAN HYCELA, has not been studied and vaccination with live virus vaccines is not recommended before or during treatment
Embryo-Fetal Toxicity
Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving RITUXAN HYCELA and for 12 months following the last dose of rituximab-containing products, including RITUXAN HYCELA
ADVERSE REACTIONS
The most common adverse reactions (≥20%) of RITUXAN HYCELA observed in patients with FL in SABRINA were: infections, neutropenia, nausea, constipation, cough, and fatigue
The most common adverse reactions (≥20%) of RITUXAN HYCELA observed in patients with DLBCL in MabEASE were: infections, neutropenia, alopecia, nausea, and anemia
The most common adverse reactions (≥20%) of RITUXAN HYCELA observed in patients with CLL in part 2 of SAWYER were: infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema
With the exception of local cutaneous reactions, the incidence and profile of adverse reactions reported for RITUXAN HYCELA were comparable with those for RITUXAN. The overall incidence of adverse reactions for RITUXAN plus chemotherapy vs. RITUXAN HYCELA plus chemotherapy for FL/DLBCL was 93% vs. 95% (BSA ≤ 1.73 m2), 89% vs. 93% (1.73 < BSA ≤ 1.92 m2), and 94% vs. 94% (BSA > 1.92 m2). The overall incidence of adverse reactions for RITUXAN vs. RITUXAN HYCELA in CLL was 89% vs. 100% (BSA ≤ 1.81 m2), 97% vs. 88% (1.82 < BSA ≤ 1.99 m2), and 88% vs. 93% (BSA > 2.00 m2)
PREGNANCY AND LACTATION
Based on human data, rituximab-containing products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to rituximab in-utero. There are no available data on RITUXAN HYCELA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the risk to a fetus
 There are no data on the presence of rituximab or hyaluronidase human in human milk, the effect on the breastfed infant, or the effect on milk production. Advise lactating women not to breastfeed during treatment and for at least 6 months after the last dose of RITUXAN HYCELA due to the potential for serious adverse reactions in breastfed infants
Please see the full Prescribing Information, including BOXED WARNINGS and Medication Guide, for additional Important Safety Information.
Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN HYCELA treatment.
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.
INDICATIONS
RITUXAN HYCELA™ (rituximab/hyaluronidase human) is indicated for the treatment of adult patients with:
Relapsed or refractory, follicular lymphoma (FL) as a single agent
Previously untreated follicular lymphoma in combination with first-line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
Non-progressing (including stable disease) follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy
Previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens
Previously untreated and previously treated chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide (FC)