RUXIENCE

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

The antibody is an

IgG1 kappa immunoglobulin containing murine light and heavy-chain variable region sequences and human constant region sequences 6, Label.

It was originally approved by the

U.S. FDA in as a single agent to treat patients with B-cell Non-Hodgkin's Lymphoma (NHL) 10, however, has now been approved for a variety of conditions Label.

On November 28, 2018, the US FDA approved Truxima, the first biosimilar to Rituxan (Rituximab) 9.

Rituximab is indicated for the treatment of adult patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's Lymphoma (NHL) as a single agent.

Also, it is indicated for the treatment of adult patients with 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. 12, 13, 14, 15, 16 Additionally, rituximab is indicated for the treatment of adult patients with non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; and previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. 12, 13, 14, 15, 16 Rituximab, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL). 12, 13, 14, 15, 16 In combination with methotrexate, rituximab is indicated for the treatment of adult patients with moderately-to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. 12, 13, 14, 15 Additionally, rituximab, in combination with glucocorticoids, is indicated for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA). 12, 13, 14, 15 RITUXAN (rituximab injection for intravenous use) is indicated for the treatment of pediatric patients aged 6 months and older with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy; as well as the treatment of adult patients with moderate to severe pemphigus vulgaris.

These indications for

RITUXAN are not included in the labels of rituximab biosimilar products (rituximab-arrx, rituximab-abbs, rituximab-pvvr). 13, 14, 15 The RITUXAN HYCELA (rituximab and hyaluronidase human injection, for subcutaneous use) is not indicated for the treatment of non-malignant conditions.

Rituximab is a chimeric murine/human monoclonal antibody that binds to the CD20 antigen.

CD20 is predominantly expressed on the surface of pre-B and mature B-lymphocytes, allowing rituximab to target and promote lysis in this specific type of cells. 6, 7, 12.

In Non-Hodgkin's Lymphoma patients, rituximab treatment depleted circulating and tissue-based B-cells.

In a study that included 166 patients, CD19-positive B-cells were depleted within three weeks, and in 83% of patients, cell depletion lasted up to 6-9 months.

B-cell levels started to recover at approximately 6 months and returned to normal 12 months after treatment was completed.

Approximately 14% of Non-Hodgkin's Lymphoma patients had IgM or IgG serum levels below the normal range 12.

Most rheumatoid arthritis (RA) patients treated with rituximab showed a near-complete depletion of peripheral B lymphocytes within 2 weeks after the first dose.

B-cell depletion was sustained for at least 6 months, and in approximately 4% of RA patients, peripheral B-cell depletion was sustained for more than 3 years after a single course of rituximab treatment.

IgG, IgA, and, more specifically, IgM levels were lower 24 weeks after the first cycle of rituximab treatment (2.8%, 0.8% and 10% below the lower limit of normal, respectively).

However, the clinical consequences of this decrease in immunoglobulin levels in RA patients are not clear at this time.

Treatment with rituximab in patients with

RA was also associated with a decreased level of inflammation markers.

In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) treated with rituximab, CD19 B-cells in peripheral blood were depleted to less than 10 cells/μl after the first two infusions.

By month 6, approximately 84% of patients had the same level of peripheral blood CD19 B-cells, and by month 12, 81% of patients demonstrated signs of B-cell return with counts >10 cells/μL. By Month 18, the majority of patients (87%) had counts >10 cells/μL 12.

Rituximab follows a linear pharmacokinetic model.

In patients with non-Hodgkin's lymphoma (NHL) administered 4 doses of 375 mg/m of rituximab (Intravenous) weekly, detectable levels were observed 3-6 months after treatment completion.

The pharmacokinetic profile of rituximab administered in combination with 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy was similar to the one observed when administered alone.

In patients with rheumatoid arthritis (RA) administered 2 doses of 500 mg of rituximab, the C max of the first and second infusions were 157 (SD ± 46) and 183 (SD ± 55) mcg/mL.

In patients administered 2 doses of 1,000 mg of rituximab, the C max of the first and second infusions were 318 (SD ± 86) and 381 (SD ± 98) mcg/mL.

In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab Intravenous once a week, the AUC 0-180 was 9787 µg/mL⋅day (range from 4838-20446 µg/mL⋅day).

In adult patients given the same dose, the AUC 0-180 of rituximab was 10302 µg/mL⋅day (range from 3653-21874 µg/mL⋅day).

The bioavailability of rituximab administered

Intravenous is expected to be close to 100%.

Compared to rituximab administered

Intravenous, the bioavailability of RITUXAN HYCELA, a of rituximab and hyaluronidase (human recombinant), is 64.6% in patients with follicular lymphoma and 63.4% in patients with chronic lymphocytic leukemia (CLL).

Based on a pharmacokinetic analysis that included 2005 patients with rheumatoid arthritis (RA), the volume of distribution of rituximab is 3.1 L.

In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab Intravenous once a week, the volume of distribution was 2.28 L (range from 1.43-3.17 L).

In adult patients given the same dose, the volume of distribution was 3.12 L (range from 2.42-3.91 L).

In patients with pemphigus vulgaris given an intravenous infusion of 1000 mg of rituximab on days 1, 15, 168, and 182, the volume of distribution was 3.49 L (range from 2.48-5.22 L).

As a monoclonal antibody, rituximab is expected to be metabolized by proteases throughout the body.

Monoclonal antibodies (mAb) such as rituximab trigger the formation of antidrug antibodies (ADAs) that form ADA-mAb immune complexes.

The endogenous elimination of these immune complexes is mediated by the reticuloendothelial system, most likely via fragment crystallizable-gamma (Fcγ)-mediated endocytosis 5.

In patients with non-Hodgkin's lymphoma (NHL) treated with rituximab once a week or once every three weeks (n=298), the median terminal elimination half-life was 22 days (range of 6.1-52 days).

In patients with chronic lymphocytic leukemia (CLL) treated with rituximab (n=21), the estimated median terminal half-life was 32 days (range of 14-62 days).

Based on a pharmacokinetic analysis that included 2005 patients with rheumatoid arthritis (RA), the mean terminal elimination half-life of rituximab is 18.0 days.

In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab Intravenous once a week, the terminal half-life was 22 days (range from 11-42 days).

In adult patients given the same dose, the terminal half-life was 25 days (range from 11-52 days).

In patients with pemphigus vulgaris given an intravenous infusion of 1000 mg of rituximab, the terminal half-life was 21.1 days (range from 9.3-36.2 days) in the first infusion cycle (days and 15), and 26.2 days (range from 16.4-42.8 days) in the second infusion cycle (days and 182).

In patients with non-Hodgkin's lymphoma (NHL), those with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had higher rituximab clearance 12.

Based on a pharmacokinetic analysis that included 2005 patients with rheumatoid arthritis (RA), the clearance of rituximab is 0.335 L/day.

In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab Intravenous once a week, clearance was 0.222 L/day (range from 0.0996-0.381 L/day).

In adult patients given the same dose, clearance was 0.279 L/day (range from 0.113-0.653 L/day).

In patients with pemphigus vulgaris given an intravenous infusion of 1000 mg of rituximab, clearance was 0.30 L/day (range from 0.16-1.51 L/day) in the first infusion cycle (days and 15), and 0.24 L/day (range from 0.13-0.45 L/day) in the second infusion cycle (days and 182).

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

information regarding rituximab is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as fatal infusion-related reactions and severe mucocutaneous reactions.

Symptomatic and supportive measures are recommended.

No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab or to determine potential effects on fertility in males or females 12.

The maximum tolerated dose of rituximab in mice administered intraperitoneally is higher than 100 mg/kg.

For subcutaneous use only

All patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA by subcutaneous injection.

FL/DLBCL: Administer 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously according to recommended schedule.

Administer 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously according to recommended schedule.

Premedicate with acetaminophen and antihistamine before each dose; in addition, consider premedication with glucocorticoids Administer specified volume into subcutaneous tissue of abdomen: 11.7 mL from 1,400 mg/23,400 Units vial over approximately 5 minutes. 13.4 mL from 1,600 mg/26,800 Units vial over approximately 7 minutes.

Observe 15 minutes following administration 2.1 Important Dosing Information RITUXAN HYCELA is for subcutaneous use only.

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.

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

Premedicate before each dose of RITUXAN

Dose reductions of RITUXAN

HYCELA are not recommended.

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.

Premedicate before each dose.

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).

Untreated, Follicular Lymphoma Administer on Day 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 of Cycle 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.

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.

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.

HYCELA 1,400 mg/23,400 Units on Day 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 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.

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.

HYCELA 1,600 mg/26,800 Units on Day 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.

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. 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.

HYCELA is ready to use.

Preparation Use a sterile needle and syringe to prepare RITUXAN HYCELA.

HYCELA is compatible with polypropylene and polycarbonate syringe material and stainless steel transfer and injection needles.

Using a 20 mL syringe, withdraw the required volume from the vial with a narrow (e.g., 25–30 gauge) needle of any length.

Label the syringe with the provided peel-off label.

Change the needle to a 1/2" to 5/8" long, narrow gauge needle (e.g., 25–30 gauge) immediately prior to subcutaneous administration to avoid needle clogging.

Visually inspect for particulate matter and discoloration prior to administration.

HYCELA should be a clear to opalescent and colorless to yellowish liquid.

Do not use if particulates or discoloration is present.

HYCELA into the subcutaneous tissue of the abdomen over approximately 5–7 minutes.

Never inject into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.

No data are available on performing the injection at other sites of the body.

Inject 11.7 mL of RITUXAN HYCELA 1,400 mg/23,400 Units vial (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously into the abdomen over approximately 5 minutes.

Inject 13.4 mL of RITUXAN HYCELA 1,600 mg/26,800 Units vial (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously into the abdomen over approximately 7 minutes.

If administration of RITUXAN

HYCELA is interrupted, continue administering at the same site, or at a different site, but restricted to the abdomen.

Observe patients for at least 15 minutes following RITUXAN HYCELA administration.

During treatment with RITUXAN

HYCELA, do not administer other medications for subcutaneous use at the same sites as RITUXAN HYCELA.

Use immediately.

If not used immediately store refrigerated at 2°C to 8°C (36°F to 46°F) up to 48 hours and subsequently for 8 hours at room temperature up to 30°C (86°F) in diffuse light.

(rituximab and hyaluronidase human) injection, for subcutaneous use is supplied as a sterile preservative-free liquid solution in a single-dose vial.

The following configurations are available

Individually packaged single-dose vials: RITUXAN HYCELA 1,400 mg/23,400 Units (NDC 50242-108-01) providing 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL RITUXAN HYCELA 1,600 mg/26,800 Units (NDC 50242-109-01) providing 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL 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.

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.

Based on human data, rituximab-containing products can cause fetal harm due to 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.

In animal reproduction studies, intravenous administration of a rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans.

Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at a dose > 2700 times higher than the human dose.

Comparable systemic exposure levels could occur in a pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk in the

U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.

Fetal/Neonatal Adverse Reactions Observe newborns and infants for signs of infection and manage accordingly.

Data Human Data Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than 6 months can occur in infants exposed to rituximab in-utero.

Rituximab was detected postnatally in the serum of infants exposed in-utero.

HYCELA for subcutaneous injection contains rituximab and hyaluronidase human.

An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.

Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50).

Rituximab was administered as loading doses on post coitum (PC) Days and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days and 50, at 20, 50 or 100 mg/kg/week.

The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans.

Rituximab crosses the monkey placenta.

Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells.

A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero.

Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose.

Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28.

Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals.

B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.

In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U/kg, which is > 2700 times higher than the human dose.

The study found no evidence of teratogenicity.

Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 450 times higher than the human dose.

In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1,300 times higher than the human dose.

The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

The safety and effectiveness of RITUXAN

HYCELA in pediatric patients have not been established.

Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were and over, while 10% were 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.