1.1 Follicular Lymphoma (FL)

RITUXAN HYCELA is indicated for the treatment of adult patients with:

• Relapsed or refractory, follicular lymphoma 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.

1.2 Diffuse Large B-Cell Lymphoma (DLBCL)

RITUXAN HYCELA is indicated for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

1.3 Chronic Lymphocytic Leukemia (CLL)

RITUXAN HYCELA is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CLL.

1.4 Limitations of Use

• Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of a rituximab product by intravenous infusion [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)].
• RITUXAN HYCELA is not indicated for the treatment of non-malignant conditions.

2.1 Important Dosing Information

RITUXAN HYCELA is for subcutaneous use only. RITUXAN HYCELA should only be administered by a healthcare professional with appropriate medical support to manage severe reactions that can be fatal if they occur.

All patients must first receive at least one full dose of a rituximab product by intravenous infusion without experiencing severe adverse reactions before starting treatment with RITUXAN HYCELA. If patients are not able to receive one full dose by intravenous infusion, they should continue subsequent cycles with a rituximab product by intravenous infusion and not switch to RITUXAN HYCELA until a full intravenous dose is successfully administered [see Warnings and Precautions (5.4)].

Refer to the prescribing information for a rituximab product for intravenous infusion for additional information.

Premedicate before each dose of RITUXAN HYCELA [see Dosage and Administration (2.5)].

Dose reductions of RITUXAN HYCELA are not recommended. When RITUXAN HYCELA is given in combination with chemotherapy dose, reduce the chemotherapeutic drugs to manage adverse reactions.

2.2 Recommended Dosage for Follicular Lymphoma (FL)

All patients must receive at least one full dose of a rituximab product by intravenous infusion before starting treatment with RITUXAN HYCELA [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)]. Premedicate before each dose [see Dosage and Administration (2.5)].

The recommended dose is RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously at a fixed dose irrespective of patient's body surface area according to the following schedules:

• Relapsed or Refractory, Follicular Lymphoma
  Administer once weekly for 3 or 7 weeks following a full dose of a rituximab product by intravenous infusion at week 1 (i.e., 4 or 8 weeks in total).
• Retreatment for Relapsed or Refractory, Follicular Lymphoma
  Administer once weekly for 3 weeks following a full dose of a rituximab product by intravenous infusion at week 1 (i.e., 4 weeks in total).
• Previously Untreated, Follicular Lymphoma
  Administer on Day 1 of Cycles 2–8 of chemotherapy (every 21 days), for up to 7 cycles following a full dose of a rituximab product by intravenous infusion on Day 1 of Cycle 1 of chemotherapy (i.e., up to 8 cycles in total). In patients with complete or partial response, initiate RITUXAN HYCELA maintenance treatment 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, Follicular Lymphoma after first line CVP chemotherapy
  Following completion of 6–8 cycles of CVP chemotherapy and a full dose of a rituximab product by intravenous infusion at week 1, administer once weekly for 3 weeks (i.e., 4 weeks in total) at 6 month intervals to a maximum of 16 doses.

2.3 Recommended Dosage for Diffuse Large B-Cell Lymphoma (DLBCL)

All patients must receive at least one full dose of a rituximab product by intravenous infusion in combination with CHOP chemotherapy before starting treatment with RITUXAN HYCELA [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)]. Premedicate before each dose [see Dosage and Administration (2.5)].

The recommended dose for DLBCL is RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) at a fixed dose irrespective of patient's body surface area in combination with CHOP chemotherapy. Administer RITUXAN HYCELA 1,400 mg/23,400 Units on Day 1 of Cycles 2–8 of CHOP chemotherapy for up to 7 cycles following a full dose of a rituximab product by intravenous infusion at Day 1, Cycle 1 of CHOP chemotherapy (i.e., up to 6–8 cycles in total).

2.4 Recommended Dosage for Chronic Lymphocytic Leukemia (CLL)

All patients must receive at least one full dose of a rituximab product by intravenous infusion in combination with FC chemotherapy before starting treatment with RITUXAN HYCELA [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)]. Premedicate before each dose [see Dosage and Administration (2.5)].

The recommended dose for CLL is RITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) in combination with FC chemotherapy, at a fixed dose, irrespective of patient's body surface area. Administer RITUXAN HYCELA 1,600 mg/26,800 Units on Day 1 of Cycles 2–6 (every 28 days) for a total of 5 cycles following a full intravenous dose at Day 1, Cycle 1 (i.e., 6 cycles in total).

2.5 Recommended Premedication and Prophylactic Medications

Premedicate with acetaminophen and an antihistamine before each dose of RITUXAN HYCELA. Premedication with a glucocorticoid should also be considered [see Dosage and Administration (2.2, 2.3, 2.4)].

Provide prophylaxis for Pneumocystis jiroveci pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate [see Warnings and Precautions (5.6)].

2.6 Preparation and Administration

To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is RITUXAN HYCELA for subcutaneous use. Do not administer RITUXAN HYCELA intravenously.

RITUXAN HYCELA is ready to use.

5.1 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.

5.2 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 drugs classified as 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.

5.3 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 [see Adverse Reactions (6.1)].

5.4 Hypersensitivity and other Administration Reactions

5.5 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 [see Warnings and Precautions (5.8)].

5.6 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 rituximab 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 [see Adverse Reactions (6.1)].

5.7 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 [see Adverse Reactions (6.1)].

5.8 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 [see Warnings and Precautions (5.5)].

5.9 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.

5.10 Immunization

The safety of immunization with live viral vaccines following rituximab-containing products, including RITUXAN HYCELA, therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

5.11 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 potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to RITUXAN HYCELA in 892 patients in four controlled trials with exposures ranging from a single injection up to 27 months of treatment.

The population included 382 patients with follicular lymphoma (FL), 369 patients with diffuse large B-cell lymphoma (DLBCL), and 141 patients with chronic lymphocytic leukemia (CLL). The median age was 60 years (range: 18–85 years, 53% were male, and 84% were White. In the SABRINA study patients with FL received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human), in combination with chemotherapy for up to 7 doses (i.e., total of 8 doses in combination with chemotherapy), or as monotherapy for up to 12 doses (maintenance treatment). In the MabEase study patients with DLBCL received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human), given in combination with chemotherapy for up to 7 doses (i.e., up to a total of 8 doses). In the SAWYER study patients with CLL on part 2 received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,600 mg rituximab/26,800 Units hyaluronidase human) for up to 5 doses, in combination with fludarabine and cyclophosphamide (i.e., total of 6 doses).

The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with FL on the SABRINA study were: infections, neutropenia, nausea, constipation, cough, and fatigue.

The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with DLBCL on the MabEase study were: infections, neutropenia, alopecia, nausea, and anemia.

The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with CLL on part 2 of the SAWYER study were: infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RITUXAN HYCELA and rituximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In the SABRINA study, where previously untreated patients with follicular lymphoma were treated with RITUXAN HYCELA or rituximab in combination with CVP or CHOP, the incidence of treatment-induced/enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was similar to that observed in the rituximab group (2.0% RITUXAN HYCELA vs. 1.9% rituximab). The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 15% in the RITUXAN HYCELA group compared with 8% in the rituximab group, and the overall proportion of patients found to have anti-recombinant human hyaluronidase antibodies remained generally constant over the follow-up period in both cohorts. All patients who tested positive for anti-recombinant human hyaluronidase antibodies at any point during the study were negative for neutralizing antibodies.

In the SAWYER study, where previously untreated patients with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC, the incidence of treatment-induced/enhanced anti-rituximab antibodies was 12% in the RITUXAN HYCELA group and 15% in the rituximab group. The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 11% in the RITUXAN HYCELA treatment arm. None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies.

The clinical relevance of the development of anti-rituximab or anti-recombinant human hyaluronidase antibodies after treatment with RITUXAN HYCELA is not known.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rituximab-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3–4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia
• Cardiac: fatal cardiac failure
• Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash.
• Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections
• Neoplasia: disease progression of Kaposi's sarcoma.
• Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).
• Gastrointestinal: bowel obstruction and perforation.
• Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.

8.1 Pregnancy

8.2 Lactation

There are no data on the presence of hyaluronidase human in human milk or the effect of rituximab on milk production, and there is limited data on the effect of rituximab on the breastfed child. However, rituximab is detected in the milk of lactating cynomolgus monkeys and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RITUXAN HYCELA and for 6 months after the last dose due to the potential for serious adverse reactions in breastfed children.

8.3 Females and Males of Reproductive Potential

Rituximab-containing products can cause fetal harm [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action

Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase human in RITUXAN HYCELA acts locally.

The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Hyaluronidase human has been shown to increase the absorption rate of a rituximab product into the systemic circulation when given in the subcutis of Göttingen Minipigs.

12.2 Pharmacodynamics

Peripheral B-cell counts declined to levels below normal following a dose of rituximab by intravenous infusion. In patients treated with rituximab for hematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer.

12.3 Pharmacokinetics

The geometric mean rituximab exposures are provided in Table 4. The pharmacokinetic properties of rituximab following the administration of RITUXAN HYCELA in the approved indications are provided in Table 5. The elimination of rituximab was characterized by a time-dependent process that occurred early in therapy and a time-independent process.

In the SABRINA study, the geometric mean Ctrough in the RITUXAN HYCELA arm was higher than in the rituximab arm with a geometric mean ratio (Ctrough, RITUXAN HYCELA/Ctrough, rituximab) of 1.52 (90% CI: 1.36, 1.70) at Cycle 7 [see Clinical Studies (14.1)].

In the SAWYER study, the geometric mean Ctrough in the RITUXAN HYCELA arm was higher than in the rituximab arm with an adjusted geometric mean ratio of 1.53 (90% CI: 1.27–1.85) at Cycle 5 [see Clinical Studies (14.3)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN HYCELA or rituximab, or to determine potential effects on fertility in males or females.

RITUXAN HYCELA contains hyaluronidase human. Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase human. In addition, when hyaluronidase human was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is > 90 times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

14.1 Follicular Lymphoma

The SABRINA study [NCT01200758] was a randomized, two-stage, open-label, multicenter study that enrolled a total of 410 patients with previously untreated, CD20-positive follicular lymphoma of Grade 1, 2 or 3a requiring therapy. The study design is identical in stage 1 and 2. Patients were randomized (1:1) to receive either a rituximab product by intravenous infusion 375 mg/m2 for 8 cycles or 1 cycle of a rituximab product by intravenous infusion 375 mg/m2 followed by 7 cycles of RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) both every 3 weeks in combination with a total of 6–8 cycles of CHOP or 8 cycles of CVP chemotherapy. Patients underwent interim staging after 4 cycles. Patients who received R-CHOP and achieved a CR, CRu, PR or SD at the interim assessment could receive either 4 more cycles of R-CHOP or 2 cycles of R-CHOP followed by 2 cycles of monotherapy with rituximab product or RITUXAN HYCELA depending on randomization arm (i.e., a total of 8 cycles of rituximab product or RITUXAN HYCELA). Patients with at least a PR after combination treatment with chemotherapy continued with single agent maintenance treatment administered every 8 weeks for 24 months with rituximab product or RITUXAN HYCELA as per their randomization (i.e., total of 12 cycles of maintenance treatment).

Randomization was stratified by: underlying chemotherapy backbone (CHOP vs CVP), Follicular Lymphoma International Prognostic Index (FLIPI) (low-risk vs. intermediate-risk vs. high-risk), and region (Europe and North America vs. South and Central America vs Asia).

The main outcome measure for Stage 1 was the estimated ratio of observed rituximab serum Ctrough SC/Ctrough IV at Cycle 7 of combination treatment with chemotherapy every 3 weeks. The main outcome measure for Stage 2 was the investigator-assessed ORR consisting of CR, CRu, and PR at the completion of combination treatment with chemotherapy. Additional outcome measures were CRR (CR and CRu) at the end of completion of combination treatment with chemotherapy, ORR and CRR at the end of completion of maintenance treatment, and time-to-event endpoints (progression-free survival (PFS), and overall survival (OS)).

Of all randomized patients, the median age was 57 years (range: 28 to 86), 53% were female, and 86% were White. The median BSA was 1.83 m2. 45% had high risk or 34% had intermediate risk FLIPI score, and 54% had Ann Arbor Stage IV disease. Ninety percent of patients completed all 8 cycles of combination treatment with chemotherapy, and 70% of patients completed 20 cycles of both combination and maintenance treatment. Median treatment duration was 27.1 months in both groups. The median number of cycles received was 20 in both groups.

The pharmacokinetic results for the primary endpoint in Stage 1, rituximab Ctrough at Cycle 7 (i.e., 21 days after Cycle 7 rituximab administration), demonstrated that RITUXAN HYCELA 1,400 mg/23,400 Units was non-inferior compared with rituximab at 375 mg/m2 in patients receiving combination treatment with chemotherapy [see Clinical Pharmacology (12.3)]. The efficacy results are presented in Table 6.

14.2 Diffuse Large B-Cell Lymphoma (DLBCL)

The MabEase study [NCT01649856] enrolled a total of 576 patients with previously untreated CD20-positive DLBCL. Patients were randomized (2:1) to receive either a rituximab product by intravenous infusion, 375 mg/m2 for 8 cycles or 1 cycle of a rituximab product by intravenous infusion 375 mg/m2 followed by 7 cycles of RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human), both in combination with up to 6–8 cycles of CHOP chemotherapy, every 14 (CHOP-14) or 21 days (CHOP-21). Randomization was stratified by: age (< 60 years, ≥ 60 years), International Prognostic Index (IPI) risk category (low, low-intermediate, high-intermediate, high), and chemotherapy regimen (CHOP-21 or CHOP-14). The main outcome measure was investigator-assessed complete response rate (CR/CRu) at the end of combination treatment with chemotherapy. Additional outcome measures were time-to-event endpoints (PFS and OS).

Of all randomized patients, the median age was 64 years (range: 18 to 80 years); 54% were male; and 79% were White. The median BSA was 1.83 m2. 31% low risk or 30% low intermediate risk IPI score, 24% high intermediate risk, or 15% high risk IPI score and 42% of patients had Ann Arbor Stage IV disease. A total of 470 patients (82%) received 8 cycles of treatment. Median duration of exposure to treatment was 4.9 months in both treatment groups. The median number of administrations/cycles (RITUXAN HYCELA or rituximab) was 8 in both groups.

The efficacy results for are presented in Table 7. The median observation time was approximately 28 months.

14.3 Chronic Lymphocytic Leukemia (CLL)

The SAWYER study [NCT01292603] was a randomized, two-part, open-label, multicenter study that enrolled a total of 176 patients with previously untreated CLL. Patients were randomized (1:1) to receive either a rituximab product by intravenous infusion, 375 mg/m2, in Cycle 1 followed by up to 5 cycles of rituximab, 500 mg/m2, or rituximab, 375 mg/m2, in Cycle 1 followed by subsequent cycles (2–6) of RITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human), both in combination with fludarabine and cyclophosphamide (FC) chemotherapy. The main outcome measure was the non-inferiority of the pharmacokinetic profile of RITUXAN HYCELA compared to rituximab. An additional outcome measure in Part 2 was investigator-assessed response rate.

The median age was 60 years (range: 25 to 78); 65% were males and 96% were White. The median BSA was 1.9 m2, 62% had Binet Stage B disease and 93% had typical CLL characterization.

The pharmacokinetic results demonstrated that RITUXAN HYCELA 1,600 mg/26,800 Units serum rituximab Ctrough level was non-inferior compared with rituximab at 500 mg/m2 in patients receiving combination treatment with chemotherapy [see Clinical Pharmacology (12.3)].

The efficacy results for Part 2 are presented in Table 8.

14.4 Patient Experience

Previously untreated adult patients outside of the United States with CD20+ diffuse large B-cell lymphoma (DLBCL) or CD20+ follicular non-Hodgkin's lymphoma (FL) Grades 1, 2, or 3a were randomized to receive a standard chemotherapy regimen (CHOP, CVP, or bendamustine) and either RITUXAN HYCELA 1,400 mg/23,400 Units at Cycles 2–4 (after the first cycle with intravenous rituximab) or a rituximab product by intravenous infusion at Cycles 1–4. After the fourth cycle, patients were crossed over to the alternative route of administration for the remaining 4 cycles. After Cycle 8, 477 of 620 patients (77%) reported preferring subcutaneous administration of RITUXAN HYCELA over intravenous rituximab and the most common reason was that administration required less time in the clinic. After Cycle 8, 66 of 620 patients (11%) preferred rituximab intravenous administration and the most common reason was that it felt more comfortable during administration. Forty eight of 620 patients (7.7%) had no preference for the route of administration. Twenty nine subjects of 620 (4.7%) received Cycle 8 but did not complete the preference questionnaire.

Storage

Store RITUXAN HYCELA vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze.

Severe Mucocutaneous Reactions

Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the lips or mouth, blisters, peeling skin, rash, and pustules [see Warnings and Precautions (5.1)].

Hepatitis B Virus Reactivation

Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2)].

Progressive Multifocal Leukoencephalopathy (PML)

Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems [see Warnings and Precautions (5.3)].

Hypersensitivity and Other Administration Reactions

Inform patients about the signs and symptoms of hypersensitivity and administration-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of administration-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.4)].

Tumor Lysis Syndrome (TLS)

Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.5)].

Infections

Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, cold sores, and painful wounds with erythema [see Warnings and Precautions (5.6)]

Cardiovascular Adverse Reactions

Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats. [see Warnings and Precautions (5.7)]

Renal Toxicity

Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor kidney function [see Warnings and Precautions (5.8)].

Bowel Obstruction and Perforation

Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting [see Warnings and Precautions (5.9)].

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise femalesof reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of of rituximab-containing products, including RITUXAN HYCELA [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with RITUXAN HYCELA and for 6 months after the last dose [see Use in Specific Populations (8.2)].