Rituxan Hycela

WARNING: SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Severe mucocutaneous reactions, some with fatal outcomes (

  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

  .

  ).
• Hepatitis B virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death

  (

  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.

  ).
• Progressive multifocal leukoencephalopathy resulting in death (

  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)]

  .

  ).

RITUXAN HYCELA is a combination of rituximab, a CD20-directed cytolytic antibody, and hyaluronidase human, an endoglycosidase, indicated for the treatment of adult patients with:

• Follicular Lymphoma (FL) (
  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.
  )
  • 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
• Diffuse Large B-cell Lymphoma (DLBCL) (
  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.
  )
  • Previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens
• Chronic Lymphocytic Leukemia (CLL) (
  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.
  )
  • Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC)

• Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of a rituximab product by intravenous infusion. (
  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.
  ,
  5.4 Hypersensitivity and other Administration Reactions

  Systemic Reactions

  Patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA due to the higher risk of hypersensitivity and other acute reactions during the first infusion

  [see Dosage and Administration (2.1)].

  Beginning therapy with a rituximab product by intravenous infusion 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 intravenous formulations of rituximab products, 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

  [see Warnings and Precautions (5.5)]

  . 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)

  [see Warnings and Precautions (5.5, 5.7)].

  Premedicate patients with an antihistamine and acetaminophen prior to each administration of RITUXAN HYCELA

  [see Dosage and Administration (2.5)].

  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

  [see Adverse Reactions (6.1)]

  . 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.
  ).
• RITUXAN HYCELA is not indicated for the treatment of non-malignant conditions. (
  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.
  )

• For subcutaneous use only
  (
  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.
  )
• All patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA by subcutaneous injection (
  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.
  ).
• FL/DLBCL: Administer 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously according to recommended schedule (
  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).
  ).
• CLL: Administer 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously according to recommended schedule (
  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).
  ).
• Premedicate with acetaminophen and antihistamine before each dose; in addition, consider premedication with glucocorticoids (
  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)].
  ,
  5.4 Hypersensitivity and other Administration Reactions

  Systemic Reactions

  Patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA due to the higher risk of hypersensitivity and other acute reactions during the first infusion

  [see Dosage and Administration (2.1)].

  Beginning therapy with a rituximab product by intravenous infusion 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 intravenous formulations of rituximab products, 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

  [see Warnings and Precautions (5.5)]

  . 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)

  [see Warnings and Precautions (5.5, 5.7)].

  Premedicate patients with an antihistamine and acetaminophen prior to each administration of RITUXAN HYCELA

  [see Dosage and Administration (2.5)].

  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

  [see Adverse Reactions (6.1)]

  . 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.
  )
• Administer specified volume into subcutaneous tissue of abdomen: (
  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.

  Preparation

  Use a sterile needle and syringe to prepare RITUXAN HYCELA. RITUXAN 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. RITUXAN HYCELA should be a clear to opalescent and colorless to yellowish liquid. Do not use if particulates or discoloration is present.

  Administration

  • Inject RITUXAN 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

  [see Warnings and Precautions (5.4)].

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

  Storage

  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.
  )
  • 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

RITUXAN HYCELA is a colorless to yellowish, clear to opalescent solution for subcutaneous injection:

• Injection: 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL (120 mg/2,000 Units per mL) in a single-dose vial.
• Injection: 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL (120 mg/2,000 Units per mL) in a single-dose vial.

• Lactation: Advise not to breastfeed. (
  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.
  )