Hyaluronidase and rituximab

Follicular Lymphoma (FL)

Hyaluronidase and rituximab 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 (Hyaluronidase and 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)

Hyaluronidase and rituximab 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.

Chronic Lymphocytic Leukemia (CLL)

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

Limitations of Use

• Initiate treatment with Hyaluronidase and rituximab only after patients have received at least one full dose of a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion.
• Hyaluronidase and rituximab is not indicated for the treatment of non-malignant conditions.

Hyaluronidase and rituximab is a prescription medicine used to treat adults with:

• Follicular Lymphoma (FL): alone or with certain chemotherapy medicines.
• Diffuse Large B-Cell Lymphoma (DLBCL): with certain other chemotherapy medicines in people who have not had previous treatment for their DLBCL.
• Chronic Lymphocytic Leukemia (CLL): with the chemotherapy medicines fludarabine and cyclophosphamide.

You can only receive Hyaluronidase and rituximab after you receive at least one full dose of a Rituximab (Hyaluronidase and rituximab) product by IV infusion. Rituximab (Hyaluronidase and rituximab) given via intravenous infusion may cause severe infusion reactions, which usually happen during the first dose. Read the Medication Guide for Rituxan for more information about infusion reactions.

infusion reactions is not for use to treat medical conditions other than cancers.

It is not known if infusion reactions is safe and effective in children.

Before you receive treatment, tell your healthcare provider about all of your medical conditions, including if you:

• have had a severe reaction to a Rituximab (Hyaluronidase and rituximab) product
• have a history of heart problems, irregular heart beat or chest pain
• have lung or kidney problems
• have an infection or weakened immune system
• have or have had any severe infections including:
  • Hepatitis B virus (HBV)
  • Hepatitis C virus (HCV)
  • Cytomegalovirus (CMV)
  • Herpes simplex virus (HSV)
  • Parvovirus B19
  • Varicella zoster virus (chickenpox or shingles)
  • West Nile Virus
• have had a recent vaccination or are scheduled to receive vaccinations. You should not receive certain vaccines before or during treatment.
• are pregnant or plan to become pregnant. Talk to your healthcare provider about the risks to your unborn baby if you receive Hyaluronidase and rituximab during pregnancy.
• Females who are able to become pregnant should use effective birth control (contraception) during treatment, and for 12 months after the last dose. Talk to your healthcare provider about effective birth control.
• are breastfeeding or plan to breastfeed. It is not known if Hyaluronidase and rituximab passes into your breast milk. Do not breastfeed during treatment and for at least six months after your last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Important Dosing Information

Hyaluronidase and rituximab is for subcutaneous use only. Hyaluronidase and rituximab 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 (Hyaluronidase and rituximab) product by intravenous infusion without experiencing severe adverse reactions before starting treatment with Hyaluronidase and rituximab. If patients are not able to receive one full dose by intravenous infusion, they should continue subsequent cycles with a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion and not switch to Hyaluronidase and rituximab until a full intravenous dose is successfully administered.

Refer to the prescribing information for a Rituximab (Hyaluronidase and rituximab) product for intravenous infusion for additional information.

Premedicate before each dose of Hyaluronidase and rituximab.

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

Recommended Dose for Follicular Lymphoma (FL)

All patients must receive at least one full dose of a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion before starting treatment with Hyaluronidase and rituximab. Premedicate before each dose.

The recommended dose is Hyaluronidase and rituximab 1,400 mg/23,400 Units (1,400 mg Rituximab (Hyaluronidase and rituximab) and 23,400 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) 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 (Hyaluronidase and 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 (Hyaluronidase and 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 (Hyaluronidase and 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 Hyaluronidase and rituximab maintenance treatment 8 weeks following completion of Hyaluronidase and rituximab in combination with chemotherapy. Administer Hyaluronidase and rituximab 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 (Hyaluronidase and 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.

Recommended Dose for Diffuse Large B-Cell Lymphoma (DLBCL)

All patients must receive at least one full dose of a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion in combination with CHOP chemotherapy before starting treatment with Hyaluronidase and rituximab. Premedicate before each dose.

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

Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

All patients must receive at least one full dose of a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion in combination with FC chemotherapy before starting treatment with Hyaluronidase and rituximab. Premedicate before each dose.

The recommended dose for CLL is Hyaluronidase and rituximab 1,600 mg/26,800 Units (1,600 mg Rituximab (Hyaluronidase and rituximab) and 26,800 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) human) in combination with FC chemotherapy, at a fixed dose, irrespective of patient's body surface area. Administer Hyaluronidase and rituximab 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).

Recommended Premedication and Prophylactic Medications

Premedicate with acetaminophen and an antihistamine before each dose of Hyaluronidase and rituximab. 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.

Administration and Storage

Hyaluronidase and rituximab is ready to use. To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration. Hyaluronidase and rituximab is compatible with polypropylene and polycarbonate syringe material and stainless steel transfer and injection needles. Use the product immediately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Hyaluronidase and rituximab should be a clear to opalescent and colorless to yellowish liquid. Do not use vial if particulates or discoloration is present.

Administration

• Inject Hyaluronidase and rituximab into the subcutaneous tissue of the abdomen over approximately 5–7 minutes and 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 Hyaluronidase and rituximab 1,400 mg/23,400 Units vial (1,400 mg Rituximab (Hyaluronidase and rituximab) and 23,400 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) human) subcutaneously into the abdomen over approximately 5 minutes.
• Inject 13.4 mL of Hyaluronidase and rituximab 1,600 mg/26,800 Units vial (1,600 mg Rituximab (Hyaluronidase and rituximab) and 26,800 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) human) subcutaneously into the abdomen over approximately 7 minutes.

If administration of Hyaluronidase and rituximab 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 Hyaluronidase and rituximab administration.

During treatment with Hyaluronidase and rituximab, do not administer other medications for subcutaneous use at the same sites as Hyaluronidase and rituximab.

Storage

After the solution of Hyaluronidase and rituximab is withdrawn from the vial, it should be labeled with the peel-off sticker and used immediately. If not used immediately, prepare in controlled and validated aseptic conditions. Once transferred from the vial into the syringe, store the solution of Hyaluronidase and rituximab in the refrigerator at 2°C–8°C (36°F–46°F) up to 48 hours and subsequently for 8 hours at room temperature up to 30°C (86°F) in diffuse light.

See also:
What is the most important information I should know about Hyaluronidase and rituximab?

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Known type 1 hypersensitivity or anaphylactic reaction to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation; patients who have or have had progressive multifocal leukoencephalopathy (PML); patients with severe, active infections

Use: Labeled Indications

Chronic lymphocytic leukemia: Treatment of adult patients with previously untreated and previously treated chronic lymphocytic leukemia (CLL) (in combination with fludarabine and cyclophosphamide)

Diffuse large B-cell lymphoma: Treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens

Follicular lymphoma: Treatment of adult patients with:

Relapsed or refractory follicular lymphoma (FL) as a single agent;

Previously untreated FL (in combination with first-line chemotherapy) and, in patients achieving a complete or partial response to Rituximab (Hyaluronidase and rituximab) in combination with chemotherapy (as single-agent maintenance therapy);

Non-progressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy

Limitations of use: Initiate treatment with Rituximab (Hyaluronidase and rituximab)/Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) only after patients have received at least 1 full dose of a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion; Rituximab (Hyaluronidase and rituximab)/Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) is not indicated for the treatment of non-malignant conditions.

See also:
What other drugs will affect Hyaluronidase and rituximab?

Alpha-/Beta-Agonists: Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Avoid the use of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) to enhance dispersion or absorption of alpha-/beta-agonists. Use of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated. Exceptions: EPINEPHrine (Nasal); EPINEPHrine (Oral Inhalation); Isometheptene; Pseudoephedrine. Consider therapy modification

Antihistamines: May diminish the therapeutic effect of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Larger doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may be required. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Corticosteroids: May diminish the therapeutic effect of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Larger doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may be required. Exceptions: Beclomethasone (Nasal); Budesonide (Nasal); Ciclesonide (Nasal); Desonide; DexAMETHasone (Ophthalmic); Difluprednate; Flunisolide (Nasal); Fluocinolone (Ophthalmic); Fluticasone (Nasal); Hydrocortisone (Ophthalmic); Loteprednol; Mometasone (Nasal); PrednisoLONE (Ophthalmic); Triamcinolone (Nasal); Triamcinolone (Ophthalmic). Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DOPamine: Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may enhance the adverse/toxic effect of DOPamine. Management: Avoid the use of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) to enhance dispersion or absorption of dopamine. Use of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) for other purposes in patients receiving dopamine may be considered as clinically indicated. Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Estrogen Derivatives: May diminish the therapeutic effect of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Larger doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may be required. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Local Anesthetics: Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may enhance the adverse/toxic effect of Local Anesthetics. Exceptions: Benzocaine; Benzydamine; Cocaine (Topical); Dibucaine; Dyclonine; Ethyl Chloride; Hexylresorcinol; Lidocaine (Ophthalmic); Lidocaine (Topical); Pramoxine; Proparacaine; Tetracaine (Ophthalmic); Tetracaine (Topical). Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Phenylephrine (Systemic): Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may enhance the vasoconstricting effect of Phenylephrine (Systemic). Management: Avoid the use of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) to enhance dispersion or absorption of phenylephrine. Use of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Avoid combination

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Salicylates: May diminish the therapeutic effect of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Management: Patients receiving salicylates (particularly at larger doses) may not experience the desired clinical response to standard doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)). Larger doses of Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) may be required. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

See also:
What are the possible side effects of Hyaluronidase and rituximab?

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Mucocutaneous reactions
• Hepatitis B reactivation including fulminant hepatitis
• Progressive multifocal leukoencephalopathy
• Hypersensitivity and other administration reactions
• Tumor lysis syndrome
• Infections
• Cardiac arrhythmias
• Renal toxicity
• Bowel obstruction and perforation

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 Hyaluronidase and rituximab 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 population was aged 18–85 years (with a median age of 60 years), 53% male and 47% female. Most of the patients were Caucasians (84%). In the SABRINA study patients with FL received a full dose of a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion, followed by Hyaluronidase and rituximab (1,400 mg Rituximab (Hyaluronidase and rituximab)/23,400 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) 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 (Hyaluronidase and rituximab) product by intravenous infusion, followed by Hyaluronidase and rituximab (1,400 mg Rituximab (Hyaluronidase and rituximab)/23,400 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) 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 (Hyaluronidase and rituximab) product by intravenous infusion, followed by Hyaluronidase and rituximab (1,600 mg Rituximab (Hyaluronidase and rituximab)/26,800 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) 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 Hyaluronidase and rituximab observed in patients with FL on the SABRINA study were: infections, neutropenia, nausea, constipation, cough, and fatigue.

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

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

Administration-related reactions (ARRs)

Administration-related reactions (ARRs) with Hyaluronidase and rituximab were defined as all the adverse reactions related to the administration of Hyaluronidase and rituximab within the 24 hours post injection.

The incidence of ARRs with Hyaluronidase and rituximab was 34% in FL/DLBCL in combination with chemotherapy with injection site erythema (5%), chills (3%), dyspnea, erythema, flushing, injection site pain, nausea, pruritus, pyrexia, rash, and throat irritation (2% each) being the most common ARRs. The incidence of ARRs in FL maintenance setting was 20%. The most common ARRs were injection site erythema (7%), erythema (4%), injection site pain/edema, myalgia, and rash (2% each).

The incidence of ARRs with Hyaluronidase and rituximab in CLL was 44%.

With the exception of Local Cutaneous Reactions, the incidence and profile of adverse reactions reported for Hyaluronidase and rituximab were comparable with those for Rituximab (Hyaluronidase and rituximab). The overall incidence of adverse reactions for intravenous Rituximab (Hyaluronidase and rituximab) versus Hyaluronidase and rituximab in combination with chemotherapy for FL/DLBCL was 93% versus 95% (BSA ≤ 1.73 m2), 89% versus 93% (1.73 < BSA ≤ 1.92 m2), and 94% versus 94% (BSA > 1.92 m2). The overall incidence of adverse reactions for Rituximab (Hyaluronidase and rituximab) versus Hyaluronidase and rituximab in CLL was 89% versus 100% (BSA ≤ 1.81 m2), 97% versus 88% (1.82 < BSA ≤ 1.99 m2), and 88% versus 93% (BSA > 2.00 m2).

Summary of Clinical Trial Experience in Follicular Lymphoma (FL)

The data in Table 1 were obtained in the SABRINA study, a two-stage randomized, controlled study in patients with previously untreated FL. The study compared patients receiving Hyaluronidase and rituximab (1,400 mg Rituximab (Hyaluronidase and rituximab)/23,400 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) human; n=197) with patients receiving a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion (375 mg/m2; n=210), both in combination with CHOP or CVP followed by maintenance treatment with Hyaluronidase and rituximab or a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion.

The majority of patients completed all 8 cycles of combination treatment with chemotherapy (91% Hyaluronidase and rituximab vs. 90% Rituximab (Hyaluronidase and rituximab)). In addition, 69% of patients in each of the treatment groups completed all 20 cycles of combination plus maintenance treatment. In both Hyaluronidase and rituximab and Rituximab (Hyaluronidase and rituximab) groups, patients experienced similar median duration of exposure (27.1 months for each arm).

Across the two stages, the overall demographics and baseline characteristics were balanced between the treatment groups. However, there were more female patients (53%) randomized in the study than male patients (47%) and a higher proportion of females were randomized to receive Hyaluronidase and rituximab (59% female) compared with the Rituximab (Hyaluronidase and rituximab) group (48%). The treatment groups in the combined Stage 1 and 2 population were otherwise balanced in regard to baseline demographics, characterized by a median age of 57 years (56.0 years [range 28–85 years] for Hyaluronidase and rituximab and 57 years [range 28–86 years] for Rituximab (Hyaluronidase and rituximab)) and median BSA of 1.83 m2 (1.80 and 1.84 m2 for Hyaluronidase and rituximab and Rituximab (Hyaluronidase and rituximab), respectively).

The incidence of all adverse reactions was 96% for Hyaluronidase and rituximab vs. 95% for Rituximab (Hyaluronidase and rituximab) (Table 1). Grade 3–4 adverse reactions were reported in 55% of patients receiving Hyaluronidase and rituximab vs. 53% in patients receiving Rituximab (Hyaluronidase and rituximab). Serious adverse reactions were reported in 37% of patients receiving Hyaluronidase and rituximab vs. 34% of patients receiving Rituximab (Hyaluronidase and rituximab). The most common adverse reactions (occurring in ≥ 20% of patients in any arm) were infections, neutropenia, nausea, constipation, cough, and fatigue.

A total of 36 patients died, including 14/197 patients (7%) who received Hyaluronidase and rituximab and 22/210 patients (10%) who received Rituximab (Hyaluronidase and rituximab). Of these 36 patients, 19 patients (7 patients Hyaluronidase and rituximab [4%] vs. 12 patients Rituximab (Hyaluronidase and rituximab) [6%]) died due to adverse reactions and 13 patients (6 patients Hyaluronidase and rituximab [3%] vs. 7 patients Rituximab (Hyaluronidase and rituximab) [3%]) died due to disease progression.

The incidence of administration-related reactions (ARRs) due to the subcutaneous route of administration associated with Hyaluronidase and rituximab was assessed in combination with chemotherapy and during maintenance. Thirty patients (15%) experienced an ARR during the first administration of Hyaluronidase and rituximab (Cycle 2). Incidence of ARRs generally decreased at subsequent cycles with 18 patients (9%) reporting ARR at Cycle 3, 13 patients (7%) at Cycle 4, 11 patients (6%) at Cycles 5 and 6, 12 patients (7%) at Cycle 7, and 8 patients (4%) at Cycle 8. During Hyaluronidase and rituximab monotherapy in the maintenance setting the incidence of ARRs at each cycle was ≤ 7% and was observed in 24 patients (14%) overall. Grade 1–2 ARRs constituted 96% of the overall ARRs. Grade 3 ARRs were reported during the first administration of Hyaluronidase and rituximab at Cycle 2 by 2 patients. Of the reported ARRs, local cutaneous reactions with Hyaluronidase and rituximab were reported in 32 patients. These events resolved within a median of 2 days from the onset (range 1 to 37 days). Majority of these reactions were Grade 1 and 2 and were observed in 31 patients (16%).

Summary of Clinical Trial Experience in Diffuse Large B-Cell Lymphoma (DLBCL)

The data in Table 2 were obtained in the MabEASE study, a comparative, randomized, parallel-group, multicenter study to investigate the efficacy of Hyaluronidase and rituximab (1,400 mg Rituximab (Hyaluronidase and rituximab) and 23,400 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) human; n=369) versus 375 mg/m2 a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion (n=203) both in combination with CHOP (R-CHOP) in previously untreated patients with CD20-positive DLBCL.

Eighty two percent of patients receiving Hyaluronidase and rituximab or Rituximab (Hyaluronidase and rituximab) completed all 8 cycles of study treatment. In both Hyaluronidase and rituximab and Rituximab (Hyaluronidase and rituximab) treatment groups, patients experienced 4.9 months median duration of Rituximab (Hyaluronidase and rituximab) exposure in each arm.

The demographic characteristics were balanced between the two treatment groups. Most patients were Caucasian (79%) and more than half (54%) were male. The study population had a median age of 64 years (61% of patients aged ≥ 60 years) with median BSA of 1.83 m2 (1.83 and 1.84 m2 for Hyaluronidase and rituximab and Rituximab (Hyaluronidase and rituximab) groups, respectively).

The incidences of adverse reactions of any grade (Hyaluronidase and rituximab [94%] vs. Rituximab (Hyaluronidase and rituximab) [92%]) (Table 2), Grade 3–4 adverse reactions (Hyaluronidase and rituximab [63%] vs. Rituximab (Hyaluronidase and rituximab) [57%]), and serious adverse reactions (Hyaluronidase and rituximab [42%] vs. Rituximab (Hyaluronidase and rituximab) [37%]) were generally comparable between the two treatment groups. The common adverse reactions (occurring in ≥ 20% of patients in any treatment group) were neutropenia, alopecia, nausea, and anemia.

A total of 91 patients (16%) died, including 58/369 patients (16%) in Hyaluronidase and rituximab and 33/203 patients (16%) in Rituximab (Hyaluronidase and rituximab). Of these patients, 44 patients (29 patients Hyaluronidase and rituximab [8%] vs. 15 patients Rituximab (Hyaluronidase and rituximab) [7%]) died due to adverse reactions and 35 patients (22 patients Hyaluronidase and rituximab [6%] vs. 13 patients Rituximab (Hyaluronidase and rituximab) [6%]) died due to disease progression. Pneumonia (4 patients Hyaluronidase and rituximab vs. 1 patient Rituximab (Hyaluronidase and rituximab)), septic shock (2 patients Hyaluronidase and rituximab vs. 3 patients Rituximab (Hyaluronidase and rituximab)), and cardiac arrest (1 patient Hyaluronidase and rituximab vs. 3 patients Rituximab (Hyaluronidase and rituximab)) were the most common adverse reactions leading to death.

The incidence of administration-related reactions was balanced between the Hyaluronidase and rituximab and Rituximab (Hyaluronidase and rituximab) groups (28% vs. 29%). Grade 1–2 ARRs constituted 97% of the overall ARRs for the Hyaluronidase and rituximab arm and 80% for the Rituximab (Hyaluronidase and rituximab) arm. Of the reported ARRs, local cutaneous reactions with Hyaluronidase and rituximab were reported in 17 patients. These events resolved within a median of 2 days from the onset (range 1 to 32 days). Majority of these reactions were Grade 1 and 2 and were observed in 16 patients (4%).

Summary of Clinical Trial Experience in Chronic Lymphocytic Leukemia

The data in Table 3 were obtained in part 2 of the SAWYER study, a two-part, comparative, randomized, parallel-group, multicenter study of Hyaluronidase and rituximab versus a Rituximab (Hyaluronidase and rituximab) product by intravenous infusion both in combination with fludarabine and cyclophosphamide (FC) chemotherapy in patients with previously untreated CLL.

The safety analysis population in part 2 of the study included 85 patients receiving Hyaluronidase and rituximab (1,600 mg Rituximab (Hyaluronidase and rituximab)/26,800 Units Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) human) and 89 patients receiving 500 mg/m2 Rituximab (Hyaluronidase and rituximab). In both Hyaluronidase and rituximab and Rituximab (Hyaluronidase and rituximab) groups, patients had similar median duration of Rituximab (Hyaluronidase and rituximab) exposure (4.9 vs. 4.7 months). The majority of patients received all 6 cycles of study treatment (86% Hyaluronidase and rituximab vs. 81% Rituximab (Hyaluronidase and rituximab)).

The patient population was predominantly Caucasian (96%), male (65%), with a median age of 60 years and median BSA of 1.9 m2 (1.97 and 1.86 m2 for the Hyaluronidase and rituximab and intravenous Rituximab (Hyaluronidase and rituximab) groups, respectively). Overall, the treatment groups were balanced with respect to demographic characteristics, with the exception of more males in the Hyaluronidase and rituximab arm (71% Hyaluronidase and rituximab vs. 60% Rituximab (Hyaluronidase and rituximab)). Baseline disease characteristics were similar between the two groups. Over half of the patients (62%) had Binet Stage B disease and the majority had typical CLL characterizations (93%), with median time from first CLL diagnosis to randomization being 18.5 months.

The incidences of adverse reactions were balanced between the two treatment groups (96% Hyaluronidase and rituximab vs. 91% Rituximab (Hyaluronidase and rituximab)), and the common adverse reactions (occurring in ≥ 20% of patients in any arm) were infections, neutropenia, nausea, thrombocytopenia, pyrexia, anemia, vomiting, and injection site erythema. The incidences of Grade 3–4 adverse reactions were also balanced between the two treatment groups (69% Hyaluronidase and rituximab vs. 71% Rituximab (Hyaluronidase and rituximab)). The incidence of serious adverse reactions was 29% for Hyaluronidase and rituximab and 33% for Rituximab (Hyaluronidase and rituximab). The incidence of administration-related reactions was 44% for Hyaluronidase and rituximab and 45% for Rituximab (Hyaluronidase and rituximab)). Of the reported ARRs, local cutaneous reactions with Hyaluronidase and rituximab were reported in 15 patients. These events resolved within a median of 6 days from the onset (range 3 to 29 days). Majority of these reactions were Grade 1 and 2 and were observed in 14 patients (16%).

A total of 9 patients (5%) died, including 5 patients in the Hyaluronidase and rituximab group and 4 patients in the Rituximab (Hyaluronidase and rituximab) group. In the Hyaluronidase and rituximab group, 1 patient died due to herpes zoster infection, 1 patient died as a result of progressive multifocal leukoencephalopathy (PML) (considered by the investigator as related to Rituximab (Hyaluronidase and rituximab)), and 3 patients died due to disease progression. In the Rituximab (Hyaluronidase and rituximab) group, 2 patients died due to diarrhea and listeriosis and 2 patients died due to disease progression.

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 Hyaluronidase and rituximab and Rituximab (Hyaluronidase 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 Hyaluronidase and rituximab or Rituximab (Hyaluronidase and rituximab) in combination with CVP or CHOP, the incidence of treatment-induced/enhanced anti-Rituximab (Hyaluronidase and rituximab) antibodies in the Hyaluronidase and rituximab group was similar to that observed in the Rituximab (Hyaluronidase and rituximab) group (2.0% Hyaluronidase and rituximab vs. 1.5% Rituximab (Hyaluronidase and rituximab)). The incidence of treatment-induced/enhanced anti-recombinant human Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) antibodies was 13% in the Hyaluronidase and rituximab group compared with 8% in the Rituximab (Hyaluronidase and rituximab) group, and the overall proportion of patients found to have anti-recombinant human Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) antibodies remained generally constant over the follow-up period in both cohorts. All patients who tested positive for anti-recombinant human Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) 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 Hyaluronidase and rituximab or Rituximab (Hyaluronidase and rituximab) in combination with FC, the incidence of treatment-induced/enhanced anti-Rituximab (Hyaluronidase and rituximab) antibodies was 2.4% in the Hyaluronidase and rituximab group vs. 6.7% in Rituximab (Hyaluronidase and rituximab) group. The incidence of treatment-induced/enhanced anti- recombinant human Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) antibodies was 10.6% in the Hyaluronidase and rituximab treatment arm. None of the patients who tested positive for anti-recombinant human Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) antibodies tested positive for neutralizing antibodies.

The clinical relevance of the development of anti-Rituximab (Hyaluronidase and rituximab) or anti-recombinant human Hyaluronidase (Hyaluronidase and Rituximab (Hyaluronidase and rituximab)) antibodies after treatment with Hyaluronidase and rituximab is not known.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Rituximab (Hyaluronidase and 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.
• Gastrointestinal: bowel obstruction and perforation.
• Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.