Obinutuzumab

Mechanism of effect

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.

Pharmacodynamic

Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. The CD20 antigen is expressed on the surface of pre B- and mature B-lymphocytes; upon binding to CD20, obinutuzumab activates complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, resulting in cell death

Pharmacokinetics

Absorption

Obinutuzumab is administered intravenously, so its absorption is 100%.

Volume of distribution

Obinutuzumab has a volume of distribution of about 3.8 L.

Protein binding

Obinutuzumab does not bind to plasma proteins.

Metabolism

Obinutuzumab is not metabolized by the liver.

Route of elimination

The route of elimination of obinutuzumab was not indicated (FDA label).

Half-life

The half life of obinutuzumab is 28.4 days.

Clearance

The clearance of obinutuzumab is 0.09L/day.

Drug indications

Chronic Lymphocytic Leukemia
Follicular Lymphoma

Dosage

Dosage Forms & Strengths

IV solution

25mg/mL (1000mg/40mL single-use vial)

Chronic Lymphocytic Leukemia

Indicated for previously untreated chronic lymphocytic leukemia in combination with chlorambucil

Administer for 6 treatment cycles (28-day cycles)

Cycle 1

Day 1: 100 mg IV infused at 25 mg/hr over 4 hr; do not increase infusion rate
Day 2
- 900 mg IV
- No infusion reaction with previous infusion: Infuse at 50 mg/hr; may increase rate of infusion in 50 mg/hr increments q30min, not to exceed 400 mg/hr
- Infusion reaction with previous infusion: Infuse at 25 mg/hr; may increase rate in 50 mg/hr increments q30min, not to exceed 400 mg/hr
Days 8 and 15
- 1000 mg IV
- No infusion reaction with previous infusion: Infuse at 100 mg/hr or faster; may increase rate of infusion in 100 mg/hr increments q30min, not to exceed 400 mg/hr
- Infusion reaction with previous infusion: Infuse at 50 mg/hr; may increase rate in 50 mg/hr increments q30min, not to exceed 400 mg/hr

Cycles 2-6

Day 1: 1000 mg IV
No infusion reaction with previous infusion: Infuse at 100 mg/hr or faster; may increase rate of infusion in 100 mg/hr increments q30min, not to exceed 400 mg/hr
Infusion reaction with previous infusion: Infuse at 50 mg/hr; may increase rate in 50 mg/hr increments q30min, not to exceed 400 mg/hr

Follicular Lymphoma

Indications

For patients with follicular lymphoma (FL) who relapsed after, or are refractory to a rituximab-containing regimen; administer in combination with bendamustine (six 28-day cycles) followed by obinutuzumab monotherapy for up to 2 years
In addition, for patients with untreated stage II bulky, III or IV follicular lymphoma; administer in combination with chemotherapy followed by obinutuzumab monotherapy
Previously untreated FL chemotherapy regimens
- Six 28-day cycles in combination with bendamustine
- Six 21-day cycles in combination with CHOP, followed by 2 additional 21-day cycles of obinutuzumab alone
- Eight 21-day cycles in combination with CVP
- Patients with previously untreated FL who achieve a complete response or partial response to initial 6 or 8 cycles should continue on obinutuzumab 1000 mg as monotherapy for up to 2 years

Cycle 1

Day 1: 1000 mg IV infuse at 50 mg/hr; may increase rate of infusion in 50 mg/hr increments q30 min, not to exceed 400 mg/hr
Day 8 and 15
- 1000 mg IV
- No infusion reaction or Grade 1 infusion reaction with previous infusion and final infusion rate was ≥100 mg/hr: Infuse at 100 mg/hr and may increase by 100 mg/hr increments q30min, not to exceed 400 mg/hr
- Infusion reaction of ≥Grade 2 occurred with previous infusion: Infuse at 50 mg/hr; may increase rate in 50 mg/hr increments q30min, not to exceed 400 mg/hr

Cycles 2-6

Day 1: 1000 mg IV
No infusion reaction or Grade 1 infusion reaction with previous infusion and final infusion rate was ≥100 mg/hr: Infuse at 100 mg/hr and may increase by 100 mg/hr increments q30min, not to exceed 400 mg/hr
Infusion reaction of ≥Grade 2 occurred with previous infusion: Infuse at 50 mg/hr; may increase rate in 50 mg/hr increments q30min, not to exceed 400 mg/hr

Drug contraindications

GAZYVA 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

Side effects

Back pain
black, tarry stools
bleeding gums
blood in the urine or stools
chest tightness
chills
cough
fever
flushing
headache
hoarseness
lower back or side pain
nausea
painful or difficult urination
pale skin
pinpoint red spots on the skin
sore throat
trouble breathing
troubled breathing with exertion
ulcers, sores, or white spots in the mouth
unusual bleeding or bruising
unusual tiredness or weakness
vomiting

Less common

Joint pain, stiffness, or swelling
stomach pain
swelling of the feet or lower legs

Incidence not known

Blurred vision
confusion
dark urine
dizziness
drowsiness
general tiredness and weakness
light-colored stools
seizures
upper right abdominal or stomach pain
yellow eyes and skin

Interactions

Terazosin , Hydralazine , Ramipril , Rotigotine , Tolcapone , Sodium nitrite , Meningococcal conjugate vaccine , alirocumab

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. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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. Consider therapy modification

Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Anticoagulants: May enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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. 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

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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. Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. 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

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

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

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

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

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

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

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

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

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

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

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

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

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. 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

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. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Avoid combination

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

Alerts

Bone marrow suppression: Severe and life-threatening (grade 3 and 4) neutropenia (including neutropenic fever) has been observed in clinical trials. Neutropenia may have a late onset (>28 days after therapy completion) and/or be prolonged (duration >28 days). Consider administration of granulocyte colony-stimulating factors in patients who develop grade 3 or 4 neutropenia. Monitor for signs/symptoms of infection; antimicrobial prophylaxis is recommended in neutropenic patients with severe neutropenia that lasts more than 1 week (continue prophylaxis until neutropenia improves to ≤ grade 2). Antiviral and/or antifungal prophylaxis should also be considered. Severe and life-threatening thrombocytopenia has also been reported when used in combination with chemotherapy. In a small percentage of patients, thrombocytopenia occurred acutely (within 24 hours) after obinutuzumab administration; platelet transfusions may be necessary. Fatal hemorrhagic events have been reported; monitor frequently for thrombocytopenia and bleeding episodes, particularly during the initial cycle. Thrombocytopenia may require dose delays of obinutuzumab and chemotherapy and/or dose reductions of chemotherapy. Consider withholding platelet inhibitors, anticoagulants, or other medications which may increase bleeding risk (especially during the first cycle). Leukopenia, lymphopenia, and anemia commonly occur. Monitor blood counts frequently throughout therapy.

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur with use of CD20-directed cytolytic antibodies (including obinutuzumab) and may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to therapy initiation; monitor patients for clinical and laboratory signs of hepatitis or HBV during and for several months after treatment. Discontinue obinutuzumab (and concomitant medications) if viral hepatitis develops and initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported for other CD20-directed antibodies after therapy discontinuation. Reactivation of HBV replication is often followed by hepatitis. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during obinutuzumab treatment. The safety of resuming obinutuzumab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with health care providers experienced in HBV management.

American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for HBV reactivation. Screen for HBV infection with HBsAg and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both immunoglobulin G [IgG] and immunoglobulin M [IgM]) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM, as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV-infected patients, high-risk behaviors [eg, intravenous drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg-positive/anti-HBc-positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg-negative/anti-HBc-positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

• Hypersensitivity/serum sickness: Hypersensitivity reactions have been reported with obinutuzumab. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria, and tachycardia. Late-onset hypersensitivity (diagnosed as serum sickness) has also been reported with obinutuzumab; symptoms included chest pain, diffuse arthralgia, and fever. Hypersensitivity reactions may be difficult to clinically differentiate from infusion-related reactions. However, hypersensitivity very rarely occurs with the initial infusion and generally occurs after a prior exposure. If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. Obinutuzumab is contraindicated in patients with known hypersensitivity reactions (including serum sickness) with prior obinutuzumab use.

• Infection: Bacterial, fungal, and new or reactivated viral infections may occur during and/or following obinutuzumab therapy; serious and/or fatal infections have been reported. Grade 3 and higher infections have been observed (during and after treatment) when obinutuzumab was administered in combination with chemotherapy followed by obinutuzumab monotherapy. A higher incidence of grade 3 to 5 infections (including during monotherapy and after treatment) have been observed when obinutuzumab was administered in combination with bendamustine (compared to cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] or cyclophosphamide, vincristine, and prednisone [CVP]). Do not administer to patients with an active infection. Patients with a history of recurrent or chronic infections may be at increased risk; monitor closely for signs/symptoms of infection.

• Infusion reaction: May cause severe and life-threatening infusion reactions; reactions may include bronchospasm, dyspnea, chest discomfort, tachycardia, larynx and throat irritation, wheezing, laryngeal edema, flushing, rash, hypertension, hypotension, fever, dizziness, nausea, vomiting, diarrhea, headache, fatigue, and/or chills. Infusion reactions occur more frequently with the first 1,000 mg infused or on day 1 of the infusion. Infusion reactions have occurred within 24 hours of receiving obinutuzumab; reactions with subsequent infusions have also occurred. Premedicate with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) prior to infusion. Hydrocortisone has not been effective in reducing the rate of infusion reactions and is not recommended. Based on the severity, infusion reactions may require interruption of therapy, rate reduction, and/or treatment discontinuation; appropriate medical management (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen) may also be necessary. Monitor closely during the entire infusion; patients with preexisting cardiac or pulmonary conditions may be at higher risk for infusion reactions and should be monitored more frequently during infusion and in the postinfusion period. Because infusion reaction may include hypotension, consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after administration (consider risks/benefits of withholding antihypertensive therapy in patients at risk for hypertensive crisis).

• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) resulting in death may occur with treatment. PML is due to John Cunningham virus infection. Consider PML in any patient with new onset or worsening neurological symptoms and if PML is suspected, discontinue obinutuzumab (consider discontinuation or dose reduction of any concomitant chemotherapy or immunosuppressive therapy) and evaluate promptly.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has been reported with obinutuzumab (some cases fatal). Patients with high tumor burden, high circulating lymphocyte counts (>25,000/mm³), or renal impairment are at higher risk for TLS. Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer appropriate TLS prophylaxis with antihyperuricemic therapy (eg, allopurinol, rasburicase) and adequate hydration in patients at high risk prior to initiating obinutuzumab therapy (and prior to subsequent cycles if needed). Monitor lab parameters during initial treatment days in patients at risk for TLS. Correct electrolyte abnormalities; monitor renal function and hydration status, and administer supportive care, including dialysis as indicated.

Points of recommendation

Safety and efficacy have not been established in patients younger than 18
Advise patients to seek immediate medical attention for signs of infusion reactions (e.g., dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, chest pain).
-Advise patients to seek immediate medical attention for signs of tumor lysis syndrome (TLS) (e.g., nausea, vomiting, diarrhea, lethargy).
-Advise patients to seek immediate medical attention for signs of infection (e.g., fever, cough).
-Advise patients to seek immediate medical attention for signs of hepatitis (e.g., worsening of fatigue, yellow discoloration of the skin or eyes).
-Advise patients to seek immediate medical attention for new or changes in neurological symptoms (e.g., confusion, dizziness, loss of balance, difficulty talking or walking, vision problems)..

Pregnancy level

Tell your doctor if you are pregnant, think that you might be pregnant, or plan to become pregnant. 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 to your infant if you received GAZYVA during pregnancy. Women of childbearing potential should use effective contraception while taking GAZYVA and for 6 months after your GAZYVA treatment

Breast feeding warning

Because of the potential risk of serious side reactions in breastfed children, women should not breastfeed while taking GAZYVA and for 6 months after your last dose

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GENERIC DRUG INFO

suppliment

Drug information of Obinutuzumab