Obinutuzumab

Obinutuzumab is part of the drug class:

• Monoclonal antibodies

Obinutuzumab is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Obinutuzumab is used in combination with another cancer medicine called chlorambucil to treat chronic lymphocytic leukemia.

Obinutuzumab is also used in combination with a cancer medicine called bendamustine to treat follicular lymphoma (a type of non-Hodgkin lymphoma).

Obinutuzumab may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Obinutuzumab may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy or nauseated, or have chest pain, trouble breathing, vomiting, or diarrhea.

Tell your caregiver right away if you have:

• fever, swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough, trouble breathing;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• dizziness, confusion, vision problems, loss of balance or coordination, problems with speech or walking;

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urinating; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse, feeling short of breath; confusion, fainting.

Common side effects may include:

• fever;

• cough; or

• muscle or joint pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Antineoplastic agent; a recombinant humanized anti-CD20 monoclonal antibody.1 4

Storage

Parenteral

2–8°C.1 Do not freeze.1 Protect vials from light.1

Following dilution, use immediately or store at 2–8°C; discard after 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities observed with PVC or polyolefin bags and administration sets.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• Other drugs may be given before obinutuzumab to help avoid side effects.
• You will need to be sure that you are not dehydrated before getting this medicine. Check with your doctor to see if you need to drink extra fluids before getting obinutuzumab.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• GA101
• R05072759
• R7159

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 (Sehn 2012).

Distribution

Vd: ~4.1 to 4.3 L

Half-Life Elimination

~26.4 to 36.8 days

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

Canadian labeling: Known hypersensitivity (IgE mediated) to obinutuzumab or any component of the formulation.

For IV infusion only. Do not administer IV push or as a bolus. Administer through a dedicated IV line; do not mix with or infuse with other medications. May use PVC or non-PVC administration sets. Premedication with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) may be required to prevent infusion reactions (see below). In patients with severe (grade 3 or 4) neutropenia lasting more than 1 week, antimicrobial prophylaxis is strongly recommended (continue until neutropenia resolves to grade 1 or 2); antiviral and antifungal prophylaxis should be considered.

Premedication to prevent infusion reactions:

Chronic lymphocytic leukemia (CLL) (cycle 1 [days 1 and 2]) and follicular lymphoma (FL) (day 1): All patients should receive acetaminophen (650 to 1,000 mg) and an antihistamine (eg, diphenhydramine 50 mg) at least 30 minutes prior to infusion. In addition, an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) should be administered at least 1 hour prior to infusion.

All subsequent infusions: All patients should receive acetaminophen 650 to 1,000 mg at least 30 minutes prior to infusion.

If patients experienced grade 1 or 2 infusion-related reaction with previous infusion: Administer an antihistamine (eg, diphenhydramine 50 mg) in addition to acetaminophen at least 30 minutes prior to infusion.

If patients experienced a grade 3 infusion-related reaction with previous infusion or have a lymphocyte count >25,000 cells/mm3 prior to next treatment: Administer an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) at least 1 hour prior to infusion, in addition to acetaminophen and an antihistamine at least 30 minutes prior to infusion.

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 previous infusion, initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/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/hour or faster, initiate infusion at 100 mg/hour for 30 minutes; if tolerated, may escalate infusion rate in increments of 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

FL:

Cycle 1 (day 1): Initiate infusion at 50 mg/hour; if tolerated, may escalate rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

All subsequent infusions: If no reaction to previous infusion and the final infusion rate was 100 mg/hour or faster, initiate infusion at 100 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

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

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

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

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

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. 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

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. Avoid combination

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. 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

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

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. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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

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. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. 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

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

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

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

Adverse effects were observed in animal reproduction studies. Monoclonal antibodies are known to cross the placenta. Based on the mechanism of action and on animal data, if exposure occurs during pregnancy, B-cell counts may be depleted and immunologic function may be affected in the neonate after birth. Administration of live vaccines to neonates and infants exposed in utero should be avoided until after B-cell recovery. It has been recommended that women of childbearing potential use effective contraception during therapy and for 18 months after the last treatment (Gazyva Canadian product labeling 2016).

ADMINISTRATION ADVICE:
Day 1: Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate.
Day 2: Administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
All subsequent infusions: Start at a rate of 100 mg/hr. May increase by 100 mg/hr every 30 minutes to a maximum rate of 400 mg/ hr.

PREMEDICATION GUIDELINES:
Premedications:
-Acetaminophen: 650 mg to 1000 mg at least 30 minutes before the infusion.
and/or
-Antihistamine (e.g. diphenhydramine 50 mg) at least 30 minutes before the infusion.
and/or
-IV glucocorticoid (dexamethasone 20 mg IV or methylprednisolone 80 mg IV) at least one hour prior to the infusion.

Premeds should be given as follows:

-Initial cycle, Day 1 and Day 2: Acetaminophen, antihistamine, and IV glucocorticoid
Subsequent cycles:
-Acetaminophen should be given prior to each infusion for all patients.
-Patients with a Grade 1 or greater infusion related reaction (IRR) with the previous infusion: Acetaminophen and antihistamine
-Patients with a Grade 3 IRR with the previous infusion, or with a lymphocyte count greater than 25 x 10(9)/L: Acetaminophen, antihistamine and IV glucocorticoid

STORAGE REQUIREMENTS:
-Refrigerate at 36F to 46F (2C to 8C)
-Protect from light
-Do not freeze
-Do not shake

RECONSTITUTION/PREPARATION:
-Refer to the manufacturer product information for complete preparation instructions.

IV COMPATIBILITY:
-Refer to the manufacturer product information for complete IV compatibility information.

GENERAL:
-If a planned dose is missed, administer the missed dose as soon as possible and adjust dosing schedule accordingly.
-Patients with neutropenia are recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.