Obinutuzumab – Uses, Dosage, Side Effects, Interaction

Obinutuzumab is an antineoplastic CD20 antibody used to treat untreated chronic lymphocytic leukemia in combination with chlorambucil. Obinutuzumab is a humanized monoclonal antibody used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. It was approved by the FDA in November 2013 and is marketed under the brand name Gazyva. There is a black box warning of fatal Hepatitis B Virus (HBV) reactivation and fatal Progressive Multifocal Leukoencephalopathy (PML).

Mechanism of action

In contrast to rituximab, which is a classic type I CD20 antibody, obinutuzumab binds to type II CD20 antibodies. This allows obinutuzumab to have a much higher induction of antibody-dependant cytotoxicity and a higher direct cytotoxic effect than the classic CD20 antibodies.

Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector
cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis. As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.
In patients with CLL, GAZYVA caused CD19 B-cell depletion (defined as CD19 B cell counts < 0.07 x 109 /L). Initial CD19 B cell recovery was observed in some patients approximately 9 months after the last GAZYVA dose. At 18 months of follow-up, some patients remain B cell-depleted. Although the depletion of B cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B cells in solid organs or in malignant deposits. B cell depletion has not been shown to be directly correlated to clinical response.

Indications

• Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia.
• Refractory Follicular Lymphoma
• Previously untreated Chronic lymphocytic leukemia
• It can be used as a first-line treatment for chronic lymphocytic leukemia in combination with chemotherapy or with venetoclax, as a first-line treatment for follicular lymphoma in combination with chemotherapy, and as a treatment for relapsed or refractory follicular lymphoma in combination with bendamustine chemotherapy.

Use in Cancer

Obinutuzumab is approved to be used with other drugs to treat:

• Chronic lymphocytic leukemia (CLL). It is used with chlorambucil in patients who have not yet been treated for CLL.
• Follicular lymphoma. It is used:
  • With bendamustine hydrochloride and then by itself to treat follicular lymphoma that relapsed after treatment with rituximab or did not respond to the treatment.
  • With chemotherapy as first-line treatment in adults with stage II bulky, stage III, or stage IV follicular lymphoma. Patients who have at least a partial remission are then treated with obinutuzumab by themselves.

Obinutuzumab is also being studied in the treatment of other types of cancer.

Contraindications

• It is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior obinutuzumab use.
• a bad infection
• anemia
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• pregnancy
• reactivation of hepatitis B infection
• progressive multifocal leukoencephalopathy, a type of brain infection

Dosage

STRENGTHS: 1000 mg/40 mL (25 mg/mL) single-dose vial.

Prepare the solution for infusion, using an aseptic technique, as follows:

• Inspect visually for any particulate matter and discoloration prior to administration.
• Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other diluents such as dextrose (5%).

Chronic Lymphocytic Leukemia

Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1:

• Withdraw 40 mL of GAZYVA solution from the vial.
• Dilute 4 mL (100 mg) of GAZYVA into a 100 mL 0.9% sodium chloride infusion bag for immediate administration.
• Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% sodium chloride infusion bag at the same time for use on day 2 and store at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use it immediately. Clearly label each infusion bag.

Preparation of solution for infusion on days 8 and 15 of Cycle 1 and day 1 of Cycles 2–6:

• Withdraw 40 mL of GAZYVA solution from the vial. Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag. Follicular Lymphoma

Chronic Lymphocytic Leukemia

THERAPY CONSISTS OF SIX 28-DAY TREATMENT CYCLES IN COMBINATION WITH CHLORAMBUCIL:

• Cycle 1, Day 1: 100 mg IV at 25 mg/hr over 4 hours; do not increase the infusion rate
• Cycle 1, Day 2: 900 mg IV at 50 mg/hr if no infusion reaction occurred during the previous infusion and the rate can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr; if an infusion reaction occurred during the previous infusion, administer at 25 mg/hr and the rate can be escalated in increments of up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr
• Cycle 1, Days 8 and 15 AND Cycles 2 through 6, Day 1: 1000 mg IV at 100 mg/hr if no infusion reaction occurred during the previous infusion and the final rate was 100 mg/hr or faster and the rate can be escalated in increments of 100 mg/hr every 30 minutes to a maximum rate of 400 mg/hr; if an infusion reaction occurred during the previous infusion, administer at 50 mg/hr and the rate can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr

NOTE: If a dose is missed, administer it as soon as possible and adjust dosing schedule to maintain the time interval between doses. If appropriate, patients who do not complete the Cycle 1 Day 1 dose may proceed to the Cycle 1 Day 2 dose.

PREMEDICATION TO PREVENT INFUSION-RELATED REACTIONS (IRR):

• CLL Cycle 1, Day 1 and 2 AND FL Cycle 1, Day 1: All patients should receive dexamethasone 20 mg or methylprednisolone 80 mg at least 1 hour prior to the obinutuzumab infusion AND acetaminophen 650 to 1000 mg and an antihistamine (e.g., diphenhydramine 50 mg) at least 30 minutes before the obinutuzumab infusion.
• All Subsequent Infusions: All patients should receive acetaminophen 650 to 1000 mg at least 30 minutes prior to the obinutuzumab infusion.
• If patients experienced Grade 1 or 2 IRR with the previous infusion: Administer acetaminophen 650 to 1000 mg and an antihistamine (e.g., diphenhydramine 50 mg) at least 30 minutes prior to the obinutuzumab infusion.
• If patients experienced Grade 3 IRR with the previous infusion OR have a lymphocyte count greater than 25 X 10(9)/L prior to the next treatment: Administer an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) at least 1 hour prior to the obinutuzumab infusion AND acetaminophen 650 to 1000 mg and an antihistamine (e.g., diphenhydramine 50 mg) at least 30 minutes prior to the obinutuzumab infusion.
• The administration should be by a healthcare professional with medical support to manage severe infusion reactions.
• Premedicate before each infusion to reduce infusion-related reactions.
• Administer only as an IV infusion through a dedicated line; do not administer as an IV push or bolus.
• Patients at high risk of tumor lysis syndrome (e.g., high tumor burden, high circulating absolute lymphocyte counts [greater than 25 x 10(9)/L] or renal impairment) should be premedicated with antihyperuricemics (e.g., allopurinol, rasburicase) and be adequately hydrated prior to each infusion.
• Hypotension may occur during the IV infusion. The clinician may consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion and for the first hour after administration.
• Monitor blood counts at regular intervals.
• Patients with Grade 3 to 4 neutropenia lasting more than one week should receive antimicrobial prophylaxis until the resolution of neutropenia to Grade 1 or 2.
• Antiviral and antifungal prophylaxis should be considered.
• Consider therapy interruption if patients experience an infection, Grade 3 or 4 cytopenia, or Grade 2 or higher nonhematologic toxicity.
• The treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) in combination with chlorambucil

Follicular Lymphoma

THERAPY REGIMENS FOR FOLLICULAR LYMPHOMA (FL):

• For patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen, administer obinutuzumab in combination with bendamustine in six 28-day cycles. Patients who achieve stable disease, complete response, or partial response to the initial 6 cycles should continue obinutuzumab 1000 mg as monotherapy for up to 2 years.

For patients with previously untreated FL, administer obinutuzumab with one of the following chemotherapy regimens:

• Six 28-day cycles in combination with bendamustine.
• Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), followed by 2 additional 21-day cycles of obinutuzumab alone.
• Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone (CVP).
• Patients with previously untreated FL who achieve a complete response or partial response to the initial 6 or 8 cycles should continue obinutuzumab 1000 mg as monotherapy for up to 2 years.

DOSE TO BE ADMINISTERED DURING 6 TO 8 TREATMENT CYCLES, FOLLOWED BY OBINUTUZUMAB AS MONOTHERAPY FOR PATIENTS WITH FL:

• Cycle 1, Day 1: 1000 mg IV at 50 mg/hr; the rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr
• Cycle 1, Day 8, and Day 15 AND Cycles 2 through 6 on Day 1 OR 2 through 8 on Day 1 AND as monotherapy every 2 months for up to 2 years: 1000 mg IV at 100 mg/hr if no infusion reaction or a Grade 1 reaction occurred during the previous infusion and the final rate was 100 mg/hr or faster and the rate can be escalated in increments of 100 mg/hr every 30 minutes to a maximum rate of 400 mg/hr; if an infusion reaction of Grade 2 or higher occurred during the previous infusion, administered at 50 mg/hr and the rate can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr
• If a planned dose is missed, administer it as soon as possible. During obinutuzumab and chemotherapy treatment, adjust the dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During monotherapy, maintain the original dosing schedule for subsequent doses. Monotherapy should be initiated approximately 2 months after the last dose of obinutuzumab administered during the induction phase.

PREMEDICATION TO PREVENT INFUSION-RELATED REACTIONS (IRR):

• CLL Cycle 1, Day 1 and 2 AND FL Cycle 1, Day 1: All patients should receive dexamethasone 20 mg or methylprednisolone 80 mg at least 1 hour prior to the obinutuzumab infusion AND acetaminophen 650 to 1000 mg and an antihistamine (e.g., diphenhydramine 50 mg) at least 30 minutes before the obinutuzumab infusion.
• All Subsequent Infusions: All patients should receive acetaminophen 650 to 1000 mg at least 30 minutes prior to the obinutuzumab infusion.
• If patients experienced Grade 1 or 2 IRR with the previous infusion: Administer acetaminophen 650 to 1000 mg and an antihistamine (e.g., diphenhydramine 50 mg) at least 30 minutes prior to the obinutuzumab infusion.
• If patients experienced Grade 3 IRR with the previous infusion OR have a lymphocyte count greater than 25 X 10(9)/L prior to the next treatment: Administer an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) for at least 1 hour prior to the obinutuzumab infusion AND acetaminophen 650 to 1000 mg and an antihistamine (e.g., diphenhydramine 50 mg) at least 30 minutes prior to the obinutuzumab infusion.
• The administration should be by a healthcare professional with medical support to manage severe infusion reactions.
• Premedicate before each infusion to reduce infusion-related reactions.
• Administer only as an IV infusion through a dedicated line; do not administer as an IV push or bolus.
• Patients at high risk of tumor lysis syndrome (e.g., high tumor burden, high circulating absolute lymphocyte counts [greater than 25 x 10(9)/L] or renal impairment) should be premedicated with antihyperuricemics (e.g., allopurinol, rasburicase) and be adequately hydrated prior to each infusion.
• Hypotension may occur during the IV infusion. The clinician may consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion and for the first hour after administration.
• Monitor blood counts at regular intervals.
• Patients with Grade 3 to 4 neutropenia lasting more than one week should receive antimicrobial prophylaxis until the resolution of neutropenia to Grade 1 or 2.
• Antiviral and antifungal prophylaxis should be considered.
• Consider therapy interruption if patients experience an infection, Grade 3 or 4 cytopenia, or Grade 2 or higher nonhematologic toxicity.
• In combination with bendamustine followed by obinutuzumab as monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen
• In combination with chemotherapy followed by obinutuzumab monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL)

Dose Adjustments

INFUSION REACTIONS IN CLL AND FL PATIENTS:
GRADE 1 to 2 (mild to moderate):

• Reduce infusion rate or interrupt the infusion and treat symptoms.
• Upon resolution of symptoms, continue or resume infusion.
• If no further infusion reaction symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose.
• For CLL patients only: The Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.

GRADE 3 (severe):

• Interrupt infusion and manage symptoms.
• Upon resolution of symptoms, consider restarting the infusion at no more than half the previous rate (the rate used at the time the infusion reaction occurred).
• If no further infusion reaction symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose.
• Permanently discontinue therapy if patients experience a Grade 3 infusion-related symptom at rechallenge.
• For CLL patients only: The Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.

GRADE 4 (life-threatening):

• Stop infusion immediately and permanently discontinue therapy.

Administration advice:

• If a planned dose is missed, administer the missed dose as soon as possible and adjust the dosing schedule accordingly.
• Administer as an IV infusion only.
• Do not administer as an IV push or bolus.
• Do not mix this drug with other drugs.

Preparation of solution for infusion:

• Withdraw 40 mL of GAZYVA solution from the vial.
• Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag.
• Mix diluted solution by gentle inversion. Do not shake or freeze.
• For microbiological stability, the diluted GAZYVA infusion solution should be used immediately. Dilute under appropriate aseptic conditions. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours
  prior to use. The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL. Administration for CLL and FL Patients
• Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus.
• Do not mix GAZYVA with other drugs.
• No incompatibilities between GAZYVA and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed [see How Supplied/Storage and Handling

Side Effects

The Most Common

Infusion-related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion.

• Neutropenia includes neutropenia, agranulocytosis, febrile neutropenia, granulocytopenia and neutrophil count decreased; febrile
• neutropenia includes febrile neutropenia, neutropenic infection, neutropenic sepsis, and febrile bone marrow aplasia.
• Thrombocytopenia includes thrombocytopenia and platelet count decreased.
• Upper respiratory tract infection includes upper respiratory tract congestion, upper respiratory tract inflammation, sinusitis bacterial, upper respiratory tract infection bacterial, pharyngitis streptococcal, sinusitis fungal, upper respiratory fungal infection,
• acute sinusitis, chronic sinusitis, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, rhinovirus infection, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection.
• Herpesvirus infection includes genital herpes, genital herpes zoster, herpes dermatitis, herpes ophthalmic, herpes simplex, herpes simplex pharyngitis, herpes virus infection, herpes zoster, herpes zoster disseminated, herpes zoster infection neurological, herpes zoster oticus, nasal herpes, ophthalmic herpes simplex, ophthalmic herpes zoster, oral herpes, varicella, varicella-zoster virus infection.
• Pneumonia includes pneumonia bacterial, pneumonia Haemophilus, pneumonia pneumococcal, pneumonia fungal, pneumocystis jirovecii infection, pneumocystis jirovecii pneumonia, atypical pneumonia, lung infection, pneumonia, pneumonia aspiration, lung infiltration.
• Cough includes cough, productive cough, and upper-airway cough syndrome.
• Diarrhea includes diarrhea, defecation urgency, frequent bowel movement, gastroenteritis, and gastroenteritis viral.
• Headache includes cluster headache, headache, sinus headache, tension headache, and migraine.
• Insomnia includes initial insomnia, insomnia, and sleep disorder.
• Pruritus includes pruritus and pruritus generalized.

More Common

• muscle or joint pain
• constipation
• headache
• difficulty falling asleep or staying asleep
• decreased appetite
• itching
• fever, chills, cough, sore throat, or other signs of infection
• unusual bleeding or bruising
• unusual tiredness or weakness
• pain, tenderness, or redness in one leg
• shortness of breath, new or worsening cough, coughing up blood
• stomach area pain, nausea, vomiting, fever, or chills
• chest pain, joint pain, and fever
• decreased urination frequency or amount

Rare

• lower back or side pain
• nausea
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• sore throat
• trouble breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• Joint pain, stiffness, or swelling
• stomach pain
• swelling of the feet or lower legs
• Bruising
• confusion
• coughing or vomiting blood
• persistent bleeding or oozing from puncture sites, mouth, or nose
• rash
• Blurred vision
• dark urine
• dizziness
• drowsiness
• general tiredness and weakness
• light-colored stools
• seizures
• upper right abdominal or stomach pain
• yellow eyes and skin

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned.

Pregnancy

GAZYVA is likely to cause fetal B-cell depletion based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no data on GAZYVA use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1000 mg monthly produced opportunistic infections and immune complex-mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys (see Data). Consider the potential risk to the fetus when prescribing GAZYVA to a pregnant woman.

Lactation

There is no information regarding the presence of GAZYVA in human milk, the effects on the breastfed child, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Use in Specific Populations. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and child circulations in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GAZYVA and any potential adverse effects on the breastfed child from GAZYVA or from the underlying maternal
condition

WARNINGS

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 anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level 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., an increase in transaminase levels and, in severe cases, an increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. 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 treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following the completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with
expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

Progressive Multifocal Leukoencephalopathy

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated wit GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

Infusion Reactions

GAZYVA can cause severe and life-threatening infusion reactions. Sixty-five percent of patients with CLL experienced a reaction to the first 1000 mg of GAZYVA infused. Thirty-eight percent of patients with relapsed or refractory NHL and 60% of patients with previously untreated NHL experienced a reaction on Day 1 of GAZYVA infusion. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). The most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash,
hypertension, hypotension, flushing, headache, pyrexia, and chills. Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion
reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred. For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms. For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication as is suggested here.

Hypersensitivity Reactions Including Serum Sickness

Hypersensitivity reactions have been reported in patients treated with GAZYVA. Signs of immediate onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria, and tachycardia. Late-onset hypersensitivity diagnosed as serum sickness has also been reported, with symptoms that include chest pain, diffuse arthralgia, and fever. Hypersensitivity reactions may be difficult to clinically
distinguish from infusion-related reactions. However, hypersensitivity very rarely occurs with the first infusion and, when observed, often occurs after previous exposure. If a hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity reactions to GAZYVA, including serum sickness, must not be retreated.

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS), including fatal cases, has been reported in patients receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count (> 25 x 109 /L) or renal impairment are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemia (e.g., allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA
. During the initial days of GAZYVA treatment, monitor the laboratory parameters of patients considered at risk for TLS. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Infections

Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. When GAZYVA is administered with chemotherapy followed by GAZYVA monotherapy, Grade 3 to 5 infections have been reported in up to 8% of patients during combination therapy, up to 13% of patients during monotherapy, and up to 8% of patients after treatment. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. In GALLIUM, more Grade 3 to 5 infections were reported in the recipients of GAZYVA and bendamustine (117/410 patients, 29%), as compared to GAZYVA plus CHOP or CVP (43/281 patients, 15%). More fatal infections were reported in patients treated with GAZYVA and
bendamustine (3%), as compared to GAZYVA plus CHOP or CVP (< 1%), including during the monotherapy phase and after completion of treatment.

Neutropenia

Severe and life-threatening neutropenia, including febrile neutropenia, has been reported during treatment with GAZYVA. Monitor patients with Grade 3 to 4 neutropenia frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing an infection. Consider the administration of granulocyte colony-stimulating factors (GCSF) in patients with Grade 3 or 4 neutropenia. Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days). Consider dose delays in the case of Grade 3 or 4 neutropenia. Patients with severe and long-lasting (> 1 week) neutropenia are strongly recommended to receive antimicrobial prophylaxis until the resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis.

Thrombocytopenia

Severe and life-threatening thrombocytopenia has been reported during treatment with GAZYVA in combination with chemotherapy. Fatal hemorrhagic events have been reported in patients with NHL and CLL treated with GAZYVA in combination with chemotherapy, including during Cycle 1. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chemotherapy or dose reductions of chemotherapy. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications, which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

Immunization

The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy have not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.