Pfizer announced that it is introducing three new biosimilars, ZIRABEV? (bevacizumab-bvzr), RUXIENCE? (rituximab-pvvr) and TRAZIMERA? (trastuzumab-qyyp) in the United States (U.S.). The medicines are expected to launch at the lowest Wholesale Acquisition Cost (WAC) among bevacizumab, rituximab or trastuzumab products currently on the market, becoming available at a substantially discounted price to the originator product. ?We?re proud to expand our leading biosimilars portfolio by launching these three treatments, which can potentially create significant savings for the U.S. healthcare system while increasing access to critical therapies,? said Angela Lukin, Regional President, North America Oncology at Pfizer. ?We look forward to working with payers and providers to deliver these important medicines to patients that are living with certain cancers and autoimmune conditions.?

Pfizer?s oncology mAb biosimilars which have and/or will soon launch include:

• ZIRABEV, which was introduced to the U.S. market on December 31, 2019 at a WAC of $61.34 per 10 mg. This represents a 23% discount to the WAC of Avastin?(bevacizumab).¹
  • ZIRABEV is available for the treatment of five types of cancer: metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer; recurrent glioblastoma; metastatic renal cell carcinoma; and persistent, recurrent or metastatic cervical cancer. Pfizer intends to seek expansion of the ZIRABEV label to include the treatment of epithelial ovarian, fallopian tube and primary peritoneal cancer as early as January 2021, pending regulatory approval.
• RUXIENCE, which was introduced to the U.S. market today at a WAC of $71.68 per 10 mg. This represents a 24% discount to the WAC of Rituxan?(rituximab).²
  • RUXIENCE is available for the treatment of adult patients with non-Hodgkin?s lymphoma, chronic lymphocyticleukemia, and granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is the first licensed biosimilar for the treatment of GPA and MPA.
• TRAZIMERA, which will be made available on February 15, 2020 at a WAC of $80.74 per 10 mg. This represents a 22% discount to the WAC of Herceptin?(trastuzumab).³
  • TRAZIMERA will become available for the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer and HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

The WAC of each treatment applies to all approved uses. WAC is not inclusive of discounts to payers, providers, distributors and other purchasing organizations.

Pass-through status is being pursued for each of the three biosimilars. Pass-through payment is a program which supports reimbursement and incentivizes access for Medicare patients for certain treatments. ?The introduction of three new biosimilars is significant, delivering additional treatment options for patients across nine cancer types,? said Dr. Mark Pegram, associate director for clinical research at the Stanford Comprehensive Cancer Institute, and director of the Breast Oncology Program at the Stanford Women?s Cancer Center. ?Biosimilars can play an important role in the care of people living with cancer, and I am encouraged by the possibility for improved access for providers to these medicines which are highly similar to their reference product.? Biosimilars have been a significant catalyst for change for the global healthcare industry over the last decade, with the potential to create a more sustainable healthcare system. Pfizer is proud to be at the forefront of this vital healthcare segment, bringing over 30 years of experience in manufacturing biologics paired with more than 10 years of global in-market experience in biosimilars and an industry-leading eight approved biosimilar products in the U.S. About ZIRABEV (bevacizumab-bvzr) ZIRABEV is a mAb biosimilar of the reference product, Avastin, which is believed to work by inhibiting the formation of new blood vessels (angiogenesis) by specifically recognizing and binding to vascular endothelial growth factor (VEGF) protein. As part of the REFLECTIONS clinical trial program, ZIRABEV has been studied in more than 350 patients to date.4,5,6,7 ZIRABEV INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS Metastatic colorectal cancer

ZIRABEV, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC). ZIRABEV, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen. Limitation of Use: ZIRABEV is not indicated for adjuvant treatment of colon cancer. First-line non-squamous non-small cell lung cancer ZIRABEV, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non?squamous non?small cell lung cancer (NSCLC).

Recurrent glioblastoma

ZIRABEV is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

Metastatic renal cell carcinoma

ZIRABEV, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).

Persistent, recurrent, or metastatic cervical cancer

ZIRABEV, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

• Gastrointestinal (GI) perforation ranged from 0.3% to 3% across clinical studies. Discontinue ZIRABEV in patients with GI perforation

• Surgery and wound healing complications. Discontinue in patients with wound healing complications requiring medical intervention
• Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-fold more frequently in patients receiving bevacizumab. In clinical studies, the incidence of grade =3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 7%. Do not administer ZIRABEV to patients with serious hemorrhage or a recent history of hemoptysis (=1/2 tsp of red blood). Discontinue ZIRABEV in patients who develop grade 3-4 hemorrhage
• Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
• Arterial thromboembolic events (grade =3, 5%, highest inpatients with GBM)
• Renal injury and proteinuria
  • Grade 3?4 proteinuria ranged from 0.7% to 7% in clinical studies
  • Nephrotic syndrome (<1%)
• Additional serious adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:
  • Venous thromboembolism (grade =3, 11% seen in GOG-0240)
  • Hypertension (grade 3?4, 5%?18%)
  • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • Congestive heart failure (CHF) (1%)
• Infusion-related reactions with the first dose of bevacizumab occurred in <3% of patients, and severe reactions occurred in 0.2% of patients
• Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with ZIRABEV

Pregnancy warning

• Based on the mechanism of action and animal studies, bevacizumab products may cause fetal harm
• Advise female patients that bevacizumab products may cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy
• Advise females of reproductive potential to use effective contraception during treatment with ZIRABEV and for 6 months after the last dose of ZIRABEV
• Advise nursing women that breastfeeding is not recommended during treatment with ZIRABEV and for 6 months following their last dose of treatment
• Bevacizumab products may impair fertility

Most common adverse events

• Across studies, the most common adverse reactions observed in bevacizumab patients at a rate >10% were:
  • Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
• Across all studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions

Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) in single-dose vials

Indication-specific adverse events

• In CC, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (=2%) in 218 patients receiving Avastin plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
• In mRCC, the most common grade 3?5 adverse events in AVOREN, occurring at a =2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
• In rGBM Study EORTC 26101, 22% of patients discontinued treatment in the Avastin with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications
• In first-line MCRC, the most common grade 3?4 events in Study 2107, which occurred at a =2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
• In second-line MCRC, the most common grade 3?5 (nonhematologic) and 4?5 (hematologic) events in Study E3200, which occurred at a higher incidence (=2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
• When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC5
• In NSCLC, grade 3?5 (nonhematologic) and grade 4?5 (hematologic) adverse events in Study E4599 occurring at a =2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thromboembolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
• In mRCC, the most common grade 3?5 adverse events in AVOREN, occurring at a =2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
• In CC, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (=2%) in 218 patients receiving Avastin plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)

Please see full Prescribing Information?here?for ZIRABEV (bevacizumab-bvzr).

About RUXIENCE (rituximab-pvvr)

RUXIENCE is a mAb biosimilar to Rituxan which works by targeting a protein called CD20, which is present on the surface of B lymphocytes, also known as B cells. When it attaches to CD20, rituximab helps destroy these B cells.8

RUXIENCE INDICATIONS AND IMPORTANT SAFETY INFORMATION

RUXIENCE? (rituximab-pvvr) is indicated for the treatment of adult?patients with:

• Non-Hodgkin?s Lymphoma (NHL)
  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B- cell NHL in combination with first-line chemotherapy, and in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low- grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy
  • Previously untreated diffuse large B-cell, CD20- positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
• Chronic Lymphocytic Leukemia (CLL)
  • Previously untreated and previously treated CD20- positive CLL in combination with fludarabine and cyclophosphamide
• Granulomatosis with Polyangiitis (GPA) (Wegener?s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult patients in combination with glucocorticoids

BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION

(A)?FATAL?INFUSION-RELATED?REACTIONS,?(B)?SEVERE?MUCOCUTANEOUS?REACTIONS,?(C)?HEPATITIS?B VIRUS REACTIVATION, (D) PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

1. Infusion-Related?Reactions:?Rituximab?product?administration?can?result?in?serious,?including?fatal,?infusion-related?reactions.?Deaths?within?24?hours?of?rituximab?infusion?have?occurred.?Approximately?80%?of?fatal?infusion-related?reactions?occurred?in?association?with?the?first?infusion.?Monitor?patients?closely.?Discontinue?RUXIENCE?infusion?for?severe?reactions?and?provide?medical?treatment?for?Grade?3 or 4 infusion-related reactions
2. Severe?Mucocutaneous?Reactions:?Severe,?including?fatal,?mucocutaneous?reactions?can?occur?in?patients?receiving?rituximab?products.?Discontinue?RUXIENCE?in?patients?who?experience?a severe mucocutaneous reaction. The safety of readministration of RUXIENCE to patients with severe mucocutaneous reactions has not been determined
3. Hepatitis?B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab products, 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 RUXIENCE. Discontinue RUXIENCE and concomitant medications in the event of HBV reactivation
4. Progressive?Multifocal?Leukoencephalopathy?(PML),?including?fatal?PML,?can?occur?in?patients?receiving?rituximab?products.?Discontinue?RUXIENCE?and?consider?discontinuation?or?reduction?of?any?concomitant?chemotherapy?or?immunosuppressive?therapy?in?patients?who?develop?PML

Infusion-Related Reactions (IRR)

• Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30? 120 minutes
• Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death
• Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RUXIENCE. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved
• Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (=25,000/mm3)

Severe Mucocutaneous Reactions

• Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis
• The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue RUXIENCE in patients who experience a severe mucocutaneous reaction. The safety of readministration of rituximab products to patients with severe mucocutaneous reactions has not been determined

Hepatitis B Virus Reactivation (HBV)

• HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti- HBs] positive)
• HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level 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 RUXIENCE. 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 RUXIENCE treatment
• 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 RUXIENCE therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy
• In patients who develop reactivation of HBV while on RUXIENCE, immediately discontinue RUXIENCE and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming rituximab product treatment in patients who develop HBV reactivation. Resumption of RUXIENCE treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HPV.

Progressive Multifocal Leukoencephalopathy (PML)

• John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in rituximab product-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab
• 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 RUXIENCE and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Tumor Lysis Syndrome (TLS)

• Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12?24 hours after the first infusion of RUXIENCE in patients with non-Hodgkin?s lymphoma (NHL). 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 rituximab product-based therapy. 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 RUXIENCE for serious infections and institute appropriate anti-infective therapy
• RUXIENCE is not recommended for use in patients with severe, active infections

Cardiovascular Adverse Reactions

• Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock, may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RUXIENCE 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 rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RUXIENCE is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RUXIENCE 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 products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1?77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Immunization

• The safety of immunization with live viral vaccines following rituximab product therapy 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 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 RUXIENCE and for 12 months following the last dose of RUXIENCE

Concomitant Use With Biologic Agents and DMARDs Other Than Methotrexate

• Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in granulomatosis with polyangiitis (GPA) (wegener?s granulomatosis) or microscopic polyangiitis (MPA) patients exhibiting peripheral B-cell depletion following treatment with RUXIENCE

Adverse Reactions

• The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and chronic lymphocytic leukemia (CLL) were infusion-related reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections. Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials
• The most common adverse reactions (incidence =25%) in clinical trials of NHL and CLL were infusion-related reactions. Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials

Nursing Mothers

• There are no data on the presence of rituximab products in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs, including antibodies, are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of RUXIENCE, due to the potential for serious adverse reactions in breastfed infants

Clinical Trials Experience in GPA and MPA

• Adverse reactions reported in =15% of rituximab-treated patients were infections, nausea, diarrhea, headache, muscle spasms, anemia, and peripheral edema (other important adverse reactions include infusion-related reactions)

Induction Treatment of Patients With Active GPA/MPA (GPA/MPA Study 1)

Infusion-Related Reactions

• In GPA/MPA Study 1, 12% vs 11% (rituximab-treated vs cyclophosphamide-treated, respectively) of patients experienced at least one infusion-related reaction. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the rituximab group, the proportion of patients experiencing an infusion reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were premedicated with antihistamine and acetaminophen before each rituximab infusion and were on background oral corticosteroids, which may have mitigated or masked an infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion-related reactions

Infections

• In GPA/MPA Study 1, 62% vs 47% (rituximab-treated vs cyclophosphamide-treated, respectively) of patients experienced an infection by Month 6. The most common infections in the rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% vs 10% (rituximab-treated vs cyclophosphamide-treated, respectively), with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia

Hypogammaglobulinemia

• Hypogammaglobulinemia (IgA, IgG, or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with rituximab in GPA/MPA Study 1. At 6 months, in the rituximab group, 27%, 58%, and 51% of patients with normal immunoglobulin levels at baseline had low IgA, IgG, and IgM levels, respectively, compared to 25%, 50%, and 46% in the cyclophosphamide group

Immunogenicity

• A total of 23/99 (23%) rituximab-treated patients with GPA or MPA tested positive for anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti- rituximab antibody formation in RUXIENCE-treated patients is unclear

Treatment of Patients With GPA/MPA Who Have Achieved Disease Control With Induction Treatment (GPA/MPA Study 2)

• In GPA/MPA Study 2, the safety profile was consistent with the known safety profile of rituximab in immunologic indications

Infusion-Related Reactions

• In GPA/MPA Study 2, 7/57 (12%) patients in the non-US- licensed approved rituximab arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). One patient had two serious IRRs; two IRRs led to a dose modification; and no IRRs were severe, fatal