Obinutuzumab (Gazyva) is a humanized anti-CD20 cytolytic monoclonal antibody that is used in the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Obinutuzumab (Gazyva) Uses:

Chronic lymphocytic leukemia:

• Used for treatment of previously untreated chronic lymphocytic leukemia (CLL) in combination with chlorambucil.

Follicular lymphoma:

• Previously untreated:

  • Treatment of previously untreated stage II bulky, stage III, or stage IV follicular lymphoma in combination with chemotherapy and (in patients achieving at least a partial remission) followed by obinutuzumab monotherapy.

• Relapsed/refractory:

  • Treatment of follicular lymphoma (in combination with bendamustine followed by obinutuzumab monotherapy) in patients who relapsed after, or are refractory to, a rituximab-containing regimen.

Obinutuzumab (Gazyva) Dose in Adults 

Note:

• Premedication with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) 30 to 60 minutes prior to treatment may be necessary (see Administration).
• Anti-hyperuricemic prophylaxis and adequate hydration are recommended for patients at high risk for tumor lysis syndrome.
• In certain patients antimicrobial, antiviral, and antifungal prophylaxis may be considered

Dose in the treatment of previously untreated chronic lymphocytic leukemia (in combination with chlorambucil:

Cycle 1:

• 100 mg IV on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15).
• The treatment cycle is 28 days

Cycles 2 through 6:

• 1,000 mg IV on day 1 every 28 days for 5 doses

Missed doses:

• As soon as possible administer the missed dose.
• To maintain the time schedule between doses adjust the dosing schedule.
• In some cases, patients who do not complete the day 1 cycle 1 dose may proceed to the day 2 cycle 1 treatment (if appropriate).

Obinutuzumab Dose in the treatment of previously untreated chronic lymphocytic leukemia (as a single agent:

Cycle 1:

• 100 mg IV on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15).
• The treatment cycle is 21 days

Cycles 2 through 8:

• 1,000 mg IV on day 1 every 21 days for 7 doses

Obinutuzumab Dose in the treatment of previously untreated Chronic lymphocytic leukemia (in combination with ibrutinib:

Cycle 1:

• 100 mg IV on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15).
• The treatment cycle is 28 days

Cycles 2 through 6:

• 1,000 mg IV on day 1 every 28 days for 5 doses (continue ibrutinib until disease progression or unacceptable toxicity)

Obinutuzumab Dose in the treatment of previously untreated Follicular lymphoma:

Note:

• Patients with complete response or partial response to the initial 6 or 8 cycles of combination therapy (with either bendamustine or CHOP or CVP) should continue on obinutuzumab as monotherapy for up to 2 years.

Cycle 1 (either in combination with bendamustine or with CHOP or CVP chemotherapy):

• 1,000 mg IV weekly for 3 doses on day 1, day 8, and day 15; treatment cycle is either 21 or 28 days (depending on combination therapy)

Cycles 2 through 6 (in combination with bendamustine):

• 1,000 mg IV on day 1 every 28 days for 5 doses

Cycles 2 through 8 (in combination with CHOP):

• 1,000 mg IV on day 1 every 21 days for 5 combination therapy doses (in combination with CHOP in cycles 2 through 6), followed by 1,000 mg on day 1 every 21 days for 2 doses (as monotherapy) in cycles 7 and 8

Cycles 2 through 8 (in combination with CVP):

• 1,000 mg IV on day 1 every 21 days for 7 doses

Obinutuzumab monotherapy:

• 1,000 mg IV once every 2 months for up to 2 years beginning ~2 months after the last induction phase obinutuzumab dose.

Missed doses:

• As soon as possible administer the missed dose.
• Adjust the dosing schedule accordingly to maintain the time interval between chemotherapy cycles.
• During obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses.

Obinutuzumab Dose in the treatment of relapsed/ refractory Follicular lymphoma:

Note:

• Patients with stable disease, complete response, or partial response after 6 cycles of combination therapy (with bendamustine) should continue on obinutuzumab as monotherapy for up to 2 years.

Cycle 1 (in combination with bendamustine):

• 1,000 mg IV weekly for 3 doses on day 1, day 8, and day 15; treatment cycle is 28 days

Cycles 2 through 6 (in combination with bendamustine):

• 1,000 mg IV on day 1 every 28 days for 5 doses

Obinutuzumab monotherapy:

• 1,000 mg IV once every 2 months for up to 2 years beginning ~2 months after the last induction phase obinutuzumab dose.

Missed doses:

• As soon as possible administer the missed dose.
• To maintain the time interval between chemotherapy cycles adjust the dosing schedule accordingly.
• During obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses.

Use in Children:

Not indicated

Obinutuzumab Pregnancy Risk Category: C

• Obinutuzumab (IgG) is a humanized monoclonal anti-bodies.
• The potential placental transfer human IgG depends on the IgG subclass and gestational ages. This generally increases as the pregnancy progresses.
• During the period of organogenesis, the lowest possible exposure is to be expected.
• Based on animal data and the mechanism of action, exposure during pregnancy may cause a decrease in B-cell count and may affect the newborn's immunologic function.
• Live vaccines should not be administered to infants or neonates who have been exposed in utero.
• Effective contraception should be used by females with reproductive potential during treatment and for up to 18 months following the last treatment (Gazyva Canadian product Labeling).

Use of Obinutuzumab during lactation:

• Obinutuzumab may be present in breast milk, but it is unknown. Endogenous human immunoglobulin may be found in breast milk.
• While antibodies found in breastmilk may not be detected in large quantities in infants breastfed, the manufacturer suggests that breastfeeding during therapy is done in order to minimize the risk to the infant as well as the benefits to the mother.
• Alternative options include ceasing breastfeeding during therapy, and continuing to breastfeed for up to 18 months following the last treatment (Gazyva Canadian product labels).

Obinutuzumab Dose in Kidney Disease:

• There are no dosage adjustments provided in the manufacturer's labeling.
• However, dosage adjustment is not likely necessary because pharmacokinetics are not affected.

Obinutuzumab Dose in Liver Disease:

• In the manufacturer's labeling there are no dosage adjustments provided (has not been studied)

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• Adverse reactions reported in combination with chlorambucil or bendamustine in addition to reaction incidence during the monotherapy phase.

Common Side Effects of Obinutuzumab (Gazyva):

• Endocrine & Metabolic:

  • Hypophosphatemia
  • Hypocalcemia
  • Hyperkalemia
  • Hyponatremia
  • Hypoalbuminemia
  • Hypokalemia

• Gastrointestinal:

  • Constipation
  • Vomiting

• Hematologic & Oncologic:

  • Lymphocytopenia
  • Leukopenia
  • Neutropenia
  • Decreased Hemoglobin
  • Thrombocytopenia
  • Anemia
  • Hemorrhage

• Hepatic:

  • Increased Serum AST
  • Increased Serum ALT
  • Increased Serum Alkaline Phosphatase

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Musculoskeletal Signs And Symptoms
  • Back Pain
  • Arthralgia
  • Weakness

• Renal:

  • Decreased Creatinine Clearance
  • Increased Serum Creatinine

• Respiratory:

  • Cough
  • Upper Respiratory Tract Infection
  • Sinusitis

Less Common Side Effects of Obinutuzumab (Gazyva):

• Central Nervous System:

  • Fatigue

• Dermatologic:

  • Pruritus

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Dyspepsia

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Tumor Lysis Syndrome
  • Febrile Neutropenia

• Hepatic:

  • Increased Liver Enzymes

• Immunologic:

  • Antibody Development

• Infection:

  • Sepsis

• Neuromuscular & Skeletal:

  • Limb Pain
  • Back Pain

• Respiratory:

  • Nasopharyngitis
  • Bronchitis
  • Nasal Congestion

• Miscellaneous:

  • Infusion Related Reaction
  • Fever

Side effects of Obinutuzumab (Frequency not defined):

• Cardiovascular:

  • Exacerbation Of Cardiac Disease

• Central Nervous System:

  • Progressive Multifocal Leukoencephalopathy

• Infection:

  • JCV (John Cunningham Virus) Infection
  • Reactivation Of HBV
  • Viral Infection (New Or Reactivation)

Contraindications to Obinutuzumab (Gazyva):

• There are known hypersensitivity reactions (eg anaphylaxis) that have been reported to obinutuzumab and any component of this formulation.
• Serum sickness after prior obinutuzumab treatment

Warnings and precautions

Suppression of bone marrow

• Clinical trials have shown severe and life-threatening neutropenia (including fever) in grades 3 and 4.
• Neutropenia can be delayed (>28 days) or prolonged (duration >28).
• You might consider granulocyte colony stimulating factors for patients with grade 3 or 4 neutropenia.
• Be on the lookout for symptoms and signs of infection.
• Patients with severe neutropenia lasting more than a week are advised to take antimicrobial prophylaxis. Continue prophylaxis until neutropenia improves.
• It is also worth considering antiviral and/or fungal prophylaxis.
• Combining chemotherapy with thrombocytopenia can lead to severe and potentially life-threatening thrombocytopenia.
• A small number of patients experienced acute thrombocytopenia (within 24 hours) following obinutuzumab treatment.
• Transfusions of platelets may be required.
• There have been reports of fatal hemorhagic events.
• Be on the lookout for bleeding episodes and thrombocytopenia, especially during the first cycle.
• For patients with thrombocytopenia, it may be necessary to delay the dose of obinutuzumab or chemotherapy and/or reduce the dose of chemotherapy.
• You may want to avoid taking anticoagulants or platelet inhibitors (especially in the first cycle) and other medications that can increase bleeding risk.
• Anemia, lymphopenia and leukopenia are common.
• During therapy, monitor blood counts regularly.

Hepatitis B virus activation: [US-Boxed Warning]

• Reactivation of the Hepatitis B virus, (HBV), may occur through the use CD20-directed Cytolytic Antibodies (obinutuzumab). This can lead to fulminant Hepatitis and hepatic Failure, as well as death.
• Before starting therapy, screen all patients for HBV infection.
• Monitor patients for signs and symptoms of hepatitis and HBV for several months following treatment.
• If viral hepatitis is detected, discontinue obinutuzumab and concomitant chemotherapy.
• Patients who have HBsAg positivity as well as those with HBsAg negativity but are anti-HBc have seen reactivation.
• Patients with HBV reactivation have also been seen in those who had previously treated the infection.
• HBV reactivation was reported in other CD20-directed antibodies after treatment discontinuation.
• Hepatitis is often the next step after HBV replication has been reactivated.
• Patients with evidence of HBV infection, such as HBsAg positive (regardless of antibody status) or HBsAg-negative but anti-HBc positive, should be treated cautiously.
• Discuss with your doctor the possibility of receiving antiviral therapy prior to or during obinutuzumab.
• Obinutuzumab is safe to resume treatment after HBV reactivation. Discuss reinitiation with HBV specialists who are experienced in HBV management.

American Society of Clinical Oncology (ASCO), provisional clinical opinion update regarding hepatitis B virus screening guidelines (Hwang 2015).

• Patients with antiCD20 antibodies for HBV reactivation are at high risk.
• Before starting treatment, screen for HBV infection using HBsAg or anti-HBc tests. A total anti-HBc test (with immunoglobulin IgG [IgG] and immunoglobulin [IgM]) should be performed to check for chronic or resolved HBV infections. Anti-HBc IgG testing should not be used as it can only confirm acute HBV infection.
• Patients with risk factors for HBV infection, such as birthplace in a country with >=2% HBV prevalence, sexual contact with HBV patients at home, high-risk behavior [eg intravenous drug abuse] and HIV infection, should be screened before starting therapy.
• Start prophylactic antiviral treatment (using antivirals that have low viral resistance rates) for HBsAgpositive/anti HBc-positive patients. Do not delay cancer therapy. Continue the antivirals for 6 to 12 months.
• Patients with HBsAg-negative or anti-HBc-positive should be tested for HBV reactivation by HBV DNA and ALT testing every three months.
• You can either start antiviral therapy prophylactically, or immediately at the first sign that HBV reactivation is apparent.

Serum sickness and hypersensitivity:

• Patients who received obinutuzumab have reported hypersensitivity reactions.
• Dyspnea and bronchospasm were signs of hypersensitivity.
• Obinutuzumab has been used to treat late-onset hypersensitivity, also known as serum sickness. Symptoms include chest pain, diffuse arthritis, fever, and chest pain.
• It may be difficult to distinguish hypersensitivity reactions from infusion-related reactions.
• Hypersensitivity is rare and usually occurs after the first infusion.
• If you suspect that there is a hypersensitivity reaction during or after the infusion, stop it immediately and discontinue treatment.
• Obinutuzumab should not be used in patients suffering from known hypersensitivity reactions.

Infection

• Therapy may be interrupted by fungal or bacterial infections, as well as new or reactivated viruses.
• There have been reports of fatal and serious infections.
• When obinutuzumab was combined with chemotherapy and obinutuzumab monotherapy, Grade 3 and higher infections were observed.
• Obinutuzumab administered with bendamustine in combination with CHOP or CVP has shown a higher incidence of grade 3 and 5 infections, even after monotherapy.
• Patients with active infections should not be treated.
• Patients who have had recurrent or ongoing infections in the past may be at higher risk. Keep an eye out for signs and symptoms of infection.

Infusion reaction

• Infusion reactions can be life-threatening and severe.
• Some reactions include chest discomfort, bronchospasm and dyspnea.
• Infusion reactions are more common when the first 1,000 mg is infused or the first day of the infusion.
• Reactions with subsequent infusions can cause delayed reactions that may last up to 24 hours.
• Premedicate with acetaminophen and an antihistamine before infusion.
• Hydrocortisone is not effective in reducing the rate at which infusion reactions occur and should not be used.
• Infusion reactions can require rate reduction, interruption or discontinuation of therapy.
• Observe the infusion throughout.
• Patients with preexisting cardiac and pulmonary conditions should be closely monitored.
• Temporarily withhold antihypertensive treatments for 12 hours before, during, or for 1 hour after administration.
• Administer the medication in a place that has immediate access to resuscitative medications (eg, glucocorticoids , epinephrine and bronchodilators and/or oxygen).

Progressive multifocal Leukoencephalopathy: [US-Bound Warning]

• Treatment may result in progressive multifocal leukoencephalopathy, which can lead to death.
• PML is caused by JC virus infection.
• PML should be considered in patients with neurological symptoms that are new or worsening. If PML is suspected, stop obinutuzumab (or reduce the dose of any chemotherapy or immunosuppressive therapy), and have your patient evaluated promptly.

Tumor lysis syndrome

• Obinutuzumab has been used in cases of tumor lysis syndrome (TLS), some of which were fatal.
• Hyperkalemia, hypocalcemia and hyperphosphatemia can all occur.
• If necessary, administer prophylaxis (antihyperuricemic treatment [eg, allopurinol and rasburicase]) to patients at high risk (high levels of circulating lymphocyte count [>25,000/mm3], high burden of tumors, renal impairment, or high toxicity) before initiating obinutuzumab (administer before each subsequent cycle).
• Patients at high risk of TLS should monitor their lab results during the initial treatment.
• Correct electrolyte anomalies
• Monitoring renal function and hydration is important. If necessary, supportive care may be provided, such as dialysis.

Obinutuzumab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.)	May enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
Alfuzosin	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Anticoagulants	May enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
Antipsychotic Agents (Second Generation [Atypical])	Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]).
Barbiturates	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Benperidol	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Brimonidine (Topical)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Diazoxide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
DULoxetine	Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.
Herbs (Hypotensive Properties)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Lormetazepam	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Molsidomine	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Naftopidil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicergoline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicorandil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Pentoxifylline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Pholcodine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.
Phosphodiesterase 5 Inhibitors	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Prostacyclin Analogues	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Quinagolide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Amifostine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered.
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
Blood Pressure Lowering Agents	Obinutuzumab may enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion.
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.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
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).
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.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
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.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
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.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Bromperidol	Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
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.

Monitoring Parameters:

• CBC with differential (at regular intervals).
• Renal function
• Electrolytes
• If you are at high risk of developing tumor lysis syndrome, take uric acid.
• Before therapy is initiated, all patients must be screened for hepatitis B (HBsAg or anti-HBc tests).

• Hepatitis B virus (HBV), screening recommendations (American Society of Clinical Oncology provisional Clinical Opinion Update [Hwang 2015]).

  • HBV infection can be detected by hepatitis B antigen (HBsAg), and hepatitis B core antibodies (anti-HBc), before treatment initiation. A total anti-HBc test (with immunoglobulin IgG [IgG] or immunoglobulin [IgM] should be performed to check for chronic or resolved HBV infections. Anti-HBc IgG tests should not be used as they may only confirm acute HBV infection.
  • Patients with HBsAg-negative/anti HBc-positive status should be tested for HBV reactivation by HBV DNA and ALT testing every three months.
  • Monitor for symptoms of active hepatitis B infection during and up to 12 months following treatment.
• Watch out for signs and symptoms such as infusion reaction, signs of infection, fluid status, signs/symptoms progressive multifocal encephalopathy (PML), focal neurologic deficits. These may include hemiparesis or visual field deficits cognitive impairment, aphasia and/or cranial nervous deficits.
• Assess for PML using brain MRI, lumbar puncture and neurologist consultation.

How to administer Obinutuzumab (Gazyva)?

Intravenous

• Only for intravenous infusion.
• You should not give intravenous pushes or boluses.
• Use an intravenous line to administer the medication; don't mix or infuse it with any other medications.
• You can use non-PVC or PVC administration sets.
• To prevent infusion reactions, you may need to take acetaminophen, a antihistamine and a glucocorticoid (dexamethasone, methylprednisolone), as well as medication with acetaminophen.
• Antimicrobial prophylaxis for severe neutropenia (grade 3-4) that lasts more than a week is strongly advised. Continue this treatment until neutropenia improves to grade 1 or 2.
• It is important to consider antiviral and/or antifungal prophylaxis.

Premedication to avoid infusion reactions

CLL (cycle 1 [days 1, 2]) and FL (day 1):

• All patients should be given acetaminophen (650-1000 mg) and antihistamines (eg, diphenhydramine 50mg) prior to infusion.
• Additionally, an intravenous glucosecorticoid (dexamethasone 20mg or methylprednisolone80mg) should be administered at the least one hour before infusion.
• An IV glucocorticoid will not be required if obinutuzumab is given on the same day that a chemotherapy regimen containing glucocorticoid has been administered.

All subsequent infusions

• Patients should be given acetaminophen 650-1000 mg at least 30 min before infusion.
• Patients who experienced infusion-related reactions of grade 1 or 2 with their previous infusions:
• Take acetaminophen and diphenhydramine 50mg at least 30 minutes before infusion.
• Patients who have experienced an infusion-related reaction of grade 3 or more with their previous infusion, or have a lymphocyte count greater than 25,000 cells/mm3 before the next treatment are eligible for this program.
• Infusions should be completed at least one hour before the administration of intravenous glucocorticoid (methylprednisolone 80mg or dexamethasone 20mg).
• You should also take acetaminophen 30 minutes before you infuse.

Infusion rate:

CLL:

Cycle 1 (day 1):

• Infuse at 25 mg/hour over 4 hours; do not increase the infusion rate.

Cycle 1 (day 2):

• If no reaction to the previous infusion, initiate infusion at 50 mg per hour for 30 minutes.
• if tolerated, may escalate rate in increments of 50 mg per hour every 30 minutes to a maximum rate of 400 mg per hour.
• If an infusion reaction occurred during the previous infusion, initiate infusion at 25 mg per hour for 30 minutes.
• If tolerated, may escalate the rate in increments of up to 50 mg/hour every 30 minutes to a maximum rate of 400 mg per hour.

Cycle 1 (days 8 and 15), and cycles 2 through 6:

• If no reaction to previous infusion and the final infusion rate was 100 mg per hour or faster, initiate infusion at 100 mg per hour for 30 minutes.
• If tolerated, may escalate the infusion rate in increments of 100 mg per hour every 30 minutes to a maximum rate of 400 mg per hour.
• If an infusion reaction occurred during the previous infusion, initiate infusion at 50 mg per hour for 30 minutes.
• If tolerated, may escalate the rate in increments of 50 mg per hour every 30 minutes to a maximum rate of 400 mg per hour.

FL (previously untreated or relapsed/refractory):

Cycle 1 (day 1):

• Initiate infusion at 50 mg per hour for 30 minutes.
• If tolerated, may escalate the rate in increments of 50 mg per hour every 30 minutes to a maximum rate of 400 mg per hour.

All subsequent infusions:

• If no reaction or grade 1 reaction to previous infusion and the final infusion rate was 100 mg per hour or faster, initiate infusion at 100 mg per hour for 30 minutes.
• If tolerated, may escalate the rate in increments of 100 mg per hour every 30 minutes to a maximum rate of 400 mg per hour.
• If a grade 2 or higher infusion reaction occurred during the previous infusion, initiate infusion at 50 mg per hour for 30 minutes.
• If tolerated, may escalate the rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg per hour.

Mechanism of action of Obinutuzumab (Gazyva):

• Obinutuzumab, a monoclonal anti-CD20 glycoengineered type II antibody is available.
• The CD20 antigen can be found on the surface pre-B- and mature B lymphocytes.
• Obinutuzumab activates complement dependent cytotoxicity, anti-body-dependent cell cytotoxicity and anti-body-dependent intracellular phagocytosis upon binding to CD20 (Sehn 2012).
• Pharmacodynamics and Pharmacokinetics

Distribution:

• V : ~4.1 to 4.3 L

Half-life elimination:

• 25.5 to 35.3 days

International Brands of Obinutuzumab:

• Gazyva
• Gazyvaro

Obinutuzumab Brand Names in Pakistan:

• No Brands Available in Pakistan.