Gazyva

Gazyva is used to treat active lupus nephritis, previously untreated or relapsed or refractory follicular lymphoma (FL), previously untreated chronic lymphocytic leukemia (CLL), and frequently relapsing or steroid-dependent childhood-onset idiopathic nephrotic syndrome in patients who are in complete remission. Gazyva is given as an IV infusion by a healthcare provider and is usually used in combination with other treatments.

Gazyva (obinutuzumab) gained FDA approval on November 1, 2013.

Gazyva (obinutuzumab) is approved for:

• Previously untreated chronic lymphocytic leukemia (CLL) adults in combination with chlorambucil
• Follicular lymphoma (FL) that has relapsed following, or is refractory to (r/r), a rituximab-containing regimen. Used in combination with bendamustine followed by Gazyva monotherapy
• Previously untreated stage II bulky, III, or IV Follicular lymphoma in adults. Used in combination with chemotherapy followed by Gazyva monotherapy in patients achieving at least a partial remission.
• Active Lupus Nephritis (LN) in adults who are receiving standard therapy.
• Frequently relapsing or steroid-dependent childhood-onset idiopathic nephrotic syndrome in adults and children 2 years of age and older. Used to reduce the risk of relapse in patients who are in complete remission.

Do not receive Gazyva infusion if you have had an allergic reaction (such as anaphylaxis or serum sickness) to obinutuzumab, Gazyva, or any of the ingredients in the infusion.

Before receiving Gazyva, tell your healthcare provider about all your medical conditions, including if you:

• Have had or have hepatitis B infection (HBV)
• Have any other infection
• Recently received or are scheduled to receive a vaccine. People who are treated with Gazyva should not receive live vaccines
• Are pregnant, think you might be pregnant, or planning to become pregnant
• Are breastfeeding or planning to breastfeed.

Pregnancy

Gazyva may harm your unborn baby. Speak to your doctor about using Gazyva while you are pregnant.

• Talk to your doctor or your child’s doctor about the safety and timing of live virus vaccinations for your infant if you received Gazyva during pregnancy.
• Women of childbearing potential should use effective contraception while taking Gazyva and for 6 months after their last dose.

Breastfeeding

Because of the potential risk of serious side effects in breastfed children, women should not breastfeed while taking Gazyva and for 6 months after their last dose.

Gazyva is administered as an intravenous infusion at a clinic or infusion center by a healthcare provider with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur.

• The first infusion usually takes several hours. Subsequent infusions will be shorter if well tolerated.
• Your doctor will premedicate you before each infusion with acetaminophen, antihistamines, and corticosteroids to reduce the risk of infusion-related reactions
• They will also provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome.
• Your doctor may slow or stop the infusion for reactions. The infusion time does not include premedications or observation.
• Speak with your provider if you miss an infusion appointment.

Lupus Nephritis

Significantly more patients in the Regency (NCT04221477) clinical trial achieved complete kidney recovery when Gazyva was added to standard treatment, compared with standard treatment alone.

• 46.4% of patients on Gazyva + standard treatment achieved complete recovery
• 33.1% of patients on standard treatment alone achieved complete recovery
• Treatment difference of 13.4% improvement (statistically significant, P=0.0232).

Previously Untreated Follicular Lymphoma (FL)

The Gazyva-based regimen significantly outperformed a rituximab-based regimen in preventing disease progression in previously untreated FL in the Gallium clinical trial (NCT01332968):

• 28% reduced risk of disease progression or death (HR=0.72; 95% CI, 0.56-0.93; P=0.0118)
• Median observation time: 38 months
• Neither treatment group reached median progression-free survival during the study period.

Relapsed/Refractory Follicular Lymphoma

Gazyva plus bendamustine more than doubled the median investigator-assessed progression-free survival compared with bendamustine alone in the Gadolin clinical trial (NCT01059630).

• 52% reduction in the risk of disease progression or death
• 29.2 months PFS with Gazyva + bendamustine followed by Gazyva monotherapy compared to 13.7 months with bendamustine alone (PFS HR 0.48; 95% CI, 0.34-0.67; p<0.0001; 21.1 months median follow-up).

Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Gazyva + chlorambucil (Clb) showed a significant improvement in PFS compared to rituximab + Clb after 6 cycles of therapy (NCT01010061):

• 26.7 months with Gazyva + Clb vs 14.9 months with rituximab + Clb
• This represented a 58% risk-reduction (HR=0.42, 95% CI, 0.33-0.54, p<0.0001).
• More patients achieved a complete response with Gazyva + Clb (26.1% vs 8.8% with rituximab + Clb).

Childhood-Onset Idiopathic Nephrotic Syndrome (INS)

In the INSHORE clinical trial (NCT05627557), significantly more children and young people with frequently relapsing or steroid-dependent nephrotic syndrome stayed relapse-free and in complete remission at one year on Gazyva than on mycophenolate mofetil (MMF).

• 95% of patients on Gazyva had no relapse after Week 8 and were in complete remission at Week 52
• 73% of patients on MMF had no relapse after Week 8 and were in complete remission at Week 52
• Treatment difference of 22% (95% CI, 6-38; P=0.004)

Warnings

Gazyva carries a boxed warning for hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML).

Hepatitis B Reactivation

Gazyva can reactivate a dormant hepatitis B virus, which may cause liver failure or death. You should not receive Gazyva if you have active hepatitis B liver disease.

Your doctor or healthcare team will need to screen you for hepatitis B before, and monitor you during and after, your treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Seek immediate medical attention if symptoms of hepatitis occur, such as:

• Fatigue
• Yellowing of the skin or eyes
• Pain in the upper right abdomen
• Abdominal swelling
• Nausea and vomiting
• Confusion.

Progressive Multifocal Leukoencephalopathy (PML)

Progressive Multifocal Leukoencephalopathy (PML) is a rare and serious brain infection caused by a virus. PML can be fatal. Your weakened immune system could put you at risk. Your doctor will watch for symptoms. Symptoms of PML include confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems

Common Side Effects

The most common side effects of Gazyva in previously untreated CLL are:

• Infusion-related reactions
• Low white blood cell count (neutropenia).

The most common side effects of Gazyva in r/r NHL*:

• Infusion-related reactions
• Fatigue
• Low white blood cell count (neutropenia)
• Upper respiratory tract infections
• Cough
• Musculoskeletal pain

The most common side effects of Gazyva in previously untreated NHL*:

• Infusion-related reactions
• Neutropenia
• Upper respiratory tract infections
• Cough
• Constipation
• Diarrhea.

The most common side effects of Gazyva in lupus nephritis:

• Upper respiratory tract infections
• COVID-19
• Urinary tract infections
• Bronchitis
• Pneumonia
• Infusion-related reactions
• Neutropenia.

The most common side effects of Gazyva in childhood-onset idiopathic nephrotic syndrome:

• Upper respiratory tract infection
• Infusion-related reactions
• Ear infection
• Pneumonia
• Influenza
• Neutropenia
• Bronchitis
• COVID-19
• Conjunctivitis
• Urinary tract infection.

* NHL = non-Hodgkin Lymphoma. Follicular lymphoma (FL) is a slow-growing or indolent form of NHL.

Serious side effects and warnings

Gazyva can cause the following other serious side effects.

Infusion-Related Reactions (IRRs)

Infusion-related reactions may occur during or within 24 hours of any Gazyva infusion. Some IRRs can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening IRRs.

• If you have a reaction, the infusion is either slowed or stopped until your symptoms are resolved.
• Most patients are able to complete infusions and receive medication again.
• However, if the IRR is life-threatening, the infusion of Gazyva will be permanently stopped.
• Your healthcare team will take steps to help lessen any side effects you may have to the infusion process.
• You may be given medicines to take before each Gazyva treatment.

Tell your healthcare provider immediately if you develop symptoms of an IRR, such as a fast heartbeat, tiredness, dizziness, headache, redness of the face, nausea, chills, fever, vomiting, diarrhea, rash, high blood pressure, low blood pressure, difficulty breathing, and chest discomfort

Hypersensitivity Reactions, Including Serum Sickness

Some people receiving Gazyva may have severe or life-threatening allergic reactions. This reaction may be severe, may happen during or after an infusion, and may affect many areas of the body. If an allergic reaction occurs, your doctor will stop the infusion and permanently discontinue Gazyva. Symptoms may include: skin rash, hives, itching, swelling of face/lips/throat, difficulty breathing, wheezing, rapid heartbeat, dizziness, nausea, vomiting, or in severe cases, anaphylaxis requiring emergency care.

Tumor Lysis Syndrome (TLS)

Tumor lysis syndrome, including fatal cases, has been reported in CLL and NHL patients receiving Gazyva.

• Gazyva works to break down cancer cells quickly.
• As cancer cells break apart, their contents are released into the blood.
• These contents may cause damage to organs and the heart and may lead to kidney failure, requiring the need for dialysis treatment.

Your doctor may prescribe medication to help prevent TLS. Your doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness. TLS is not identified as a risk in LN.

Serious, Including Fatal, Infections

While you’re taking Gazyva, you may develop infections. Some of these infections may be fatal and severe, so be sure to talk to your doctor if you think you have an infection. Patients:

• Administered Gazyva in combination with chemotherapy, followed by Gazyva alone, are at a high risk of infections during and after treatment.
• With a history of recurring or chronic infections may be at an increased risk of infection.
• With an active infection should not be treated with Gazyva.
• Taking Gazyva plus standard therapy for LN may be at higher risk for fatal or severe infections compared to patients taking standard therapy plus placebo.
• Taking Gazyva plus bendamustine may be at higher risk for fatal or severe infections compared to patients taking Gazyva plus CHOP or CVP.

If you develop a serious infection, your doctor will immediately discontinue Gazyva and begin treatment for the infection. Call your healthcare provider immediately or seek emergency attention if you develop any signs of an infection, which may include:

• Fever or chills
• Confusion
• Rapid heartbeat
• Difficulty breathing
• Persistent vomiting
• Severe pain
• Painful or burning urination
• Frequent urge to urinate.

Low White Blood Cell Counts

When you have an abnormally low count of infection-fighting white blood cells, it is called neutropenia.

While you are taking Gazyva, your doctor will do blood work to check your white blood cell count. Severe and life-threatening neutropenia can develop during or after treatment with Gazyva.

Some cases of neutropenia can last for more than one month. If your white blood cell count is low, your doctor may prescribe medication to help prevent infections

Low Platelet Counts

Platelets help stop bleeding or blood loss. Gazyva with chemotherapy may reduce the number of platelets you have in your blood; having a low platelet count is called thrombocytopenia.

This may affect the clotting process. While you are taking Gazyva, your doctor will do blood work to check your platelet count. Severe and life-threatening thrombocytopenia can develop during treatment with Gazyva.

Fatal bleeding events have occurred in patients treated with Gazyva. If your platelet count gets too low, your treatment may be delayed or reduced.

Disseminated Intravascular Coagulation (DIC)

Fatal and severe DIC has been reported in people receiving Gazyva for CLL and NHL. DIC is a rare and serious abnormal blood clotting condition that should be monitored and managed by your doctor, as it can lead to uncontrollable bleeding

Notes:

These are not all the possible side effects of Gazyva. For more information, ask your doctor or pharmacist. Tell your doctor right away about any side effects you experience. You may report side effects to the FDA at (800) FDA-1088, or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Gazyva is a CD20-directed antibody that targets a specific protein (CD20) found on certain white blood cells called B-lymphocytes. By binding to this protein, Gazyva:

• Helps your immune system identify and destroy marked cells
• Directly attacks cancer cells
• Preserves stem cells in bone marrow, allowing your body to keep producing healthy blood cells.

Gazyva belongs to the drug class called CD20 monoclonal antibodies.

Dose of Gazyva for Previously Untreated CLL

• Cycle 1 (28 days): 100 mg (Day 1), 900 mg (Day 2), 1000 mg (Day 8), 1000 mg (Day 15)
• Cycles 2-6: 1000 mg (Day 1 only)

Administer in combination with chlorambucil as per the prescribing information.

Dose of Gazyva for R/R FL or Previously Untreated FL

• Cycle 1 (28 days): 1000 mg (Days 1, 8, 15)
• Cycles 2-6 or 2-8: 1000 mg (Day 1 only)
• Maintenance: 1000 mg every 2 months for up to 2 years.

Administer in combination with bendamustine or other medications as per the prescribing information.

Dose of Gazyva for Active LN

• Initial infusion: 1000 mg
• Week 2: 1000 mg
• Week 24: 1000 mg
• Week 26: 1000 mg
• Every 6 months thereafter: 1000 mg.

Dose of Gazyva for childhood-onset idiopathic nephrotic syndrome

Patients weighing 45 kg or more:

• 1,000 mg at the initial infusion, on Week 2, 24 and 26.

For patients weighing less than 45 kg

• the recommended dose is 20 mg/kg, at the initial infusion, on Week 2, 24, and 26.

For patients receiving concomitant oral corticosteroids, the corticosteroids should be tapered off after initiating Gazyva at the discretion of the healthcare provider.

If a planned dose of Gazyva is missed, it should be administered as soon as possible – do not wait until the next planned dose. The schedule of administration should be adjusted to maintain the appropriate interval between doses.

Do not receive live vaccines, such as BCG (tuberculosis), MMR (measles, mumps, rubella), MMRV (measles, mumps, rubella, varicella), rotavirus, or varicella (chickenpox) while receiving Gazyva.

Active ingredient: Obinutuzumab.

Inactive ingredients: L-histidine, L-histidine hydrochloride, trehalose, poloxamer 188 (pH 6.0).

Supplied as 1,000 mg/40 mL (25 mg/mL) in single-dose vials.

Gazyva is manufactured by Genentech, Inc., a member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990, U.S. License No. 1048.