Obinutuzumab, also known under the brand name Gazyva, is a type of medication that is classified as a monoclonal antibody. This drug was created to treat certain types of cancer, specifically chronic lymphocytic leukemia (CLL) and follicular lymphoma, which are both types of non-Hodgkin lymphoma.

Obinutuzumab works by binding to the CD20 protein on the surface of B cells, a type of white blood cell. By doing this, it helps your body's immune system destroy these cells. B cells are a vital part of the immune system, but in certain diseases like CLL and follicular lymphoma, they can become cancerous.

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:

• Before receiving obinutuzumab treatment, you might need to take some medications to help prevent certain side effects.
• These medications include acetaminophen (like Tylenol), an antihistamine (for allergies), and a glucocorticoid (like dexamethasone or methylprednisolone).
• You'll need to take these medications 30 to 60 minutes before getting the actual treatment.
• If you are at high risk of developing tumor lysis syndrome (a condition where cancer cells break down quickly), it is recommended to take medication to lower uric acid levels and to stay well-hydrated.
• In certain cases, your doctor may also consider giving you medications to prevent infections caused by bacteria, viruses, or fungi.

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

Obinutuzumab is used as part of a treatment plan for patients with chronic lymphocytic leukemia (CLL) who have not received previous treatments. It is typically used in combination with another medication called chlorambucil.

For the first cycle (28 days), the medication is given through an IV (intravenous infusion) as follows:

• On day 1, you get a dose of 100 mg.
• On day 2, you get a dose of 900 mg.
• After that, you get a dose of 1,000 mg once a week for 2 weeks (days 8 and 15).

For the next 5 cycles (each lasting 28 days), the medication is given like this:

• On the first day of each cycle, you get a dose of 1,000 mg.

Missed doses:

• If you miss a dose for any reason, you should get it as soon as you can.
• The rest of the dosing schedule should be adjusted so that there's the right amount of time between doses.
• For some patients who don't complete the first day of the first cycle, they might still be able to move on to the second day of treatment if it's suitable for them.

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

In an off-label use, obinutuzumab can be used alone (as a single agent) to treat patients with chronic lymphocytic leukemia (CLL) who have not been previously treated.

During the first cycle (which lasts 21 days), you'll receive the medication via an IV (intravenous infusion) like this:

• On day 1, you get a dose of 100 mg.
• On day 2, you get a dose of 900 mg.
• After that, you get a dose of 1,000 mg once a week for 2 weeks (on days 8 and 15).

For the next 7 cycles (each lasting 21 days), the medication is given like this:

• On the first day of each cycle, you get a dose of 1,000 mg.

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

In an off-label combination treatment, obinutuzumab is used together with ibrutinib to treat patients with chronic lymphocytic leukemia (CLL) who have not been previously treated.

For the first cycle (28 days), the medication is given through an IV (intravenous infusion) as follows:

• On day 1, you get a dose of 100 mg.
• On day 2, you get a dose of 900 mg.
• Then, you get a dose of 1,000 mg once a week for 2 weeks (days 8 and 15).

For the next 5 cycles (each lasting 28 days), the medication is given like this:

• On the first day of each cycle, you get a dose of 1,000 mg.

During this treatment, you should continue taking ibrutinib until the disease progresses (gets worse) or if the side effects become unacceptable (too difficult to manage).

Obinutuzumab Dose in the treatment of previously untreated Follicular lymphoma: 

Obinutuzumab is used as part of a treatment plan for patients with follicular lymphoma who have not received previous treatments. It can be used in combination with different chemotherapy regimens (like bendamustine, CHOP, or CVP) or as a single agent (monotherapy).

Note:

• If you are responding well to the initial 6 or 8 cycles of treatment (which includes obinutuzumab combined with either bendamustine, CHOP, or CVP), then your doctor might suggest continuing with obinutuzumab alone. This is called monotherapy.
• If you're in "complete response," it means that the treatment has gotten rid of all signs of your cancer. If you're in "partial response," it means that the treatment has reduced the size of your cancer or slowed down its growth.
• In either case, the goal is to continue the treatment that's working. You'll take obinutuzumab by itself for up to 2 years to keep fighting the cancer.

For the first cycle (which is either 21 or 28 days, depending on the combination therapy), you get a dose of 1,000 mg once a week for 3 weeks (on days 1, 8, and 15).

After the first cycle, the following applies:

• If you are on bendamustine, you get a dose of 1,000 mg on the first day of each 28-day cycle for the next 5 cycles.
• If you are on CHOP, you get a dose of 1,000 mg on the first day of each 21-day cycle for the next 5 cycles. After that, you get a dose of 1,000 mg on the first day of each 21-day cycle for the next 2 cycles (as monotherapy).
• If you are on CVP, you get a dose of 1,000 mg on the first day of each 21-day cycle for the next 7 cycles.

After completing the combination therapy, you might continue with obinutuzumab alone (monotherapy). You'll get a dose of 1,000 mg once every 2 months for up to 2 years, starting about 2 months after the last induction dose.

Missed doses:

• If you miss a dose for any reason, you should get it as soon as you can.
• The rest of the dosing schedule should be adjusted so that there's the right amount of time between doses.
• During the monotherapy phase, you should stick to the original dosing schedule for the following doses.

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

Obinutuzumab is used as part of a treatment plan for patients with follicular lymphoma who have not responded to previous treatments or whose cancer has come back. This is called relapsed or refractory follicular lymphoma. It is used in combination with bendamustine or by itself.

Note:

• After 6 cycles of treatment using both obinutuzumab and bendamustine, your doctor will check how your cancer is responding.
• If your cancer is "stable" (not getting worse), or if you're in "complete response" (all signs of your cancer are gone), or "partial response" (your cancer has become smaller or is growing slower), then you'll continue taking just obinutuzumab. This is called monotherapy.
• You'll take obinutuzumab alone for up to 2 years. This is done to keep fighting the cancer, since the treatment is working.

For the first cycle (28 days), you get obinutuzumab through an IV (intravenous infusion) like this:

• On day 1, day 8, and day 15, you get a dose of 1,000 mg each time. This means you get it once a week for 3 weeks.

For the next 5 cycles (each lasting 28 days), you get a dose of 1,000 mg on the first day of each cycle.

After completing these cycles, you might continue with obinutuzumab alone. This is called monotherapy. You'll get a dose of 1,000 mg once every 2 months for up to 2 years, starting about 2 months after the last dose from the previous cycles.

Missed doses:

• If you miss a dose for any reason, you should get it as soon as you can.
• The rest of the dosing schedule should be adjusted to keep the right amount of time between doses.
• When you're on monotherapy, you should stick to the original schedule for the following doses.

Use in Children:

Not indicated

Obinutuzumab Pregnancy Risk Category: C

• Obinutuzumab is a type of medicine that sticks to cancer cells to help the body's immune system destroy them
• This medicine can potentially cross over to the baby if a woman is pregnant, especially as the pregnancy goes on
• The chance of this happening is lowest during the time when the baby's organs are developing
• However, if the medicine does reach the baby, it could reduce the number of a certain type of immune cell (B-cells) in the baby and affect its immune function after birth
• Because of this, it's not recommended to give the baby any live vaccines until its B-cell levels have recovered
• To prevent any risks to the baby, it's suggested that women who can become pregnant should use effective birth control during treatment and for 18 months after the last dose.

Use of Obinutuzumab during lactation:

• It's not clear if Obinutuzumab can pass into breast milk
• However, similar substances naturally found in the body can be detected in milk
• Although these substances in breast milk may not significantly enter the baby's bloodstream, the drug manufacturer suggests weighing the risk of the baby being exposed to the medicine against the benefits of the mother receiving the treatment
• Another suggestion is to stop breastfeeding during the treatment and for 18 months after the last dose
• This helps to ensure that the baby is not exposed to any potential risk from the medication
• Remember, it's always best to discuss these issues with your healthcare provider to make the best decision for both you and your baby.

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)

• 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):

• If you're allergic to obinutuzumab or any part of the medication, you should not take it
• Allergic reactions can be serious and include conditions like anaphylaxis, which is a severe and life-threatening allergic reaction
• Also, if you've experienced something called serum sickness with previous use of obinutuzumab, you should not use it
• Serum sickness is a reaction that can happen after taking certain medications and can cause symptoms like rash, joint pain, and fever.

Warnings and precautions

Suppression of bone marrow

• Obinutuzumab can lower the number of certain cells in your blood, like neutrophils (a type of white blood cell that fights infections), and this can be severe or life-threatening
• This condition is called neutropenia
• If it happens, you might need another medicine called a granulocyte colony-stimulating factor to help your body make more neutrophils
• If neutropenia becomes severe and lasts more than a week, you may need preventive (prophylactic) treatment for infections.
• Obinutuzumab can also lower the number of platelets in your blood (thrombocytopenia), which are cells that help your blood to clot
• This can make you more likely to bleed, and it can be severe or even life-threatening, especially during the first cycle of treatment
• You might need platelet transfusions, and you may need to delay or reduce your doses of obinutuzumab and other chemotherapy drugs
• You might also need to stop taking medicines that can increase your risk of bleeding.
• Other blood cells, like white blood cells and red blood cells, can also be lowered by obinutuzumab
• It's important to have your blood counts checked often during your treatment
• If you notice any unusual bleeding or signs of infection (like fever), tell your healthcare provider right away.

Hepatitis B virus activation: [US-Boxed Warning]

• Obinutuzumab, a medicine used to treat certain cancers, can reactivate the hepatitis B virus (HBV) in people who are infected
• This can lead to severe liver problems and even death
• Before starting treatment with obinutuzumab, everyone should be tested for HBV
• This involves measuring two things in your blood: hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc)
• If you start to show signs of hepatitis or HBV during or after treatment, obinutuzumab and any other chemotherapy should be stopped and appropriate antiviral therapy should be started.
• Even if you had HBV in the past and it seemed to have gone away, it can still be reactivated by obinutuzumab
• It's important to use caution if you test positive for either HBsAg or anti-HBc
• You may need to be monitored and considered for antiviral therapy before and during obinutuzumab treatment
• If HBV is reactivated and then resolved, it's not known if it's safe to restart obinutuzumab treatment.
• According to the American Society of Clinical Oncology (ASCO), people receiving treatments like obinutuzumab are at high risk for HBV reactivation
• Those who have risk factors for HBV, like being born in a country where HBV is common, close contact with someone with HBV, certain high-risk behaviors, or having HIV, should also be screened before starting treatment
• If you test positive for HBsAg and anti-HBc, you should start preventative antiviral therapy right away and continue it for about 6 to 12 months after completing treatment
• If you test negative for HBsAg but positive for anti-HBc, you should be checked for HBV reactivation every 3 months during treatment, and antiviral therapy can be started at the first sign of reactivation.
•  

Serum sickness and hypersensitivity:

• Obinutuzumab, a drug used for certain types of cancer, can sometimes cause serious allergic reactions in people who take it
• These reactions can happen right away or can develop later
• Immediate symptoms can include trouble breathing, wheezing, low blood pressure, hives, and fast heart rate
• Later symptoms, which are due to a condition called serum sickness, can include chest pain, joint pain all over the body, and fever.
• It can be hard to tell the difference between these allergic reactions and reactions related to the infusion of the drug
• However, allergic reactions usually don't happen with the first infusion and typically occur after a patient has already been exposed to the drug.
• If you have an allergic reaction during or after an infusion, the infusion should be stopped right away and obinutuzumab should be discontinued permanently
• Patients who have had allergic reactions to obinutuzumab, including serum sickness, should not be treated with the drug again
• If you notice any signs of an allergic reaction, make sure to seek medical attention immediately.

Infection

• Obinutuzumab, a drug used for certain cancers, can increase the risk of infections, including bacterial, fungal, and viral ones
• These infections can happen during and after treatment and can sometimes be severe or even fatal
• Infections are more likely to occur when obinutuzumab is given with other cancer drugs and then used alone afterwards.
• More serious infections have been reported when obinutuzumab is used with a drug called bendamustine compared to when it's used with other chemotherapy combinations like CHOP or CVP.
• Obinutuzumab should not be given to patients who currently have an infection
• Patients who have a history of frequent or long-term infections may be at greater risk of getting an infection while using obinutuzumab
• These patients should be watched closely for signs of infection
• If you have any symptoms of an infection, such as fever, cough, or feeling generally unwell, seek medical attention right away.

Infusion reaction

• Obinutuzumab, a medicine used to treat certain cancers, can cause serious reactions during or after the infusion
• These reactions can include symptoms like difficulty breathing, chest discomfort, fast heartbeat, irritation in the throat, redness of the skin, high or low blood pressure, fever, dizziness, nausea, vomiting, diarrhea, headache, fatigue, and chills.
• These reactions happen more often with the first large dose or on the first day of the infusion
• But they can also happen up to 24 hours later or with later infusions
• To help prevent these reactions, you'll be given medicines like acetaminophen, an antihistamine, and a steroid (dexamethasone or methylprednisolone) before the infusion.
• If a reaction happens, the rate of the infusion might be slowed down, the infusion might be stopped, or the treatment might be stopped completely
• You'll be monitored during the whole infusion, and especially closely if you have heart or lung conditions
• You might need to temporarily stop taking any blood pressure medicines for 12 hours before, during, and 1 hour after the infusion.
• Obinutuzumab should be given in a place that has immediate access to emergency equipment and medicines, like steroids, epinephrine, bronchodilators, and oxygen, in case a serious reaction happens
• If you notice any symptoms of a reaction, make sure to seek medical attention right away.

Progressive multifocal Leukoencephalopathy: [US-Bound Warning]

• Progressive multifocal leukoencephalopathy (PML) is a rare and very serious brain infection that can happen in people who take obinutuzumab
• PML is caused by the JC virus and can lead to death
• If you start having new or worsening neurological symptoms (like changes in thinking, strength, vision, or balance), your healthcare provider should consider PML as a possible cause
• If PML is suspected, obinutuzumab should be stopped right away
• Any other chemotherapy or medicines that suppress the immune system that you're taking might also need to be stopped or reduced
• PML is a medical emergency, so any changes in neurological symptoms should be evaluated by a healthcare provider immediately.

Tumor lysis syndrome

• Tumor lysis syndrome (TLS) is a serious complication that can occur in people treated with obinutuzumab
• This happens when cancer cells break down very quickly after treatment, releasing large amounts of substances into the blood
• This can cause problems like kidney failure, high potassium levels, low calcium levels, high uric acid levels, and/or high phosphate levels
• Some cases of TLS have been fatal.
• Before starting obinutuzumab, patients at high risk of TLS should receive preventive treatment
• This includes those with a lot of cancer cells in their blood (more than 25,000 per mm^3), a high tumor burden, or impaired kidney function
• Preventive treatment can include medicines to reduce uric acid levels (like allopurinol or rasburicase) and plenty of fluids to keep hydrated.
• During the first few days of treatment, patients at risk for TLS should be monitored closely
• This involves blood tests to check for changes in electrolyte levels and kidney function
• Any electrolyte imbalances should be corrected, and the patient's fluid levels and kidney function should be closely watched
• Supportive care, including dialysis if needed, should be provided as necessary.

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

Monitoring Parameters:

Blood tests:

• Regular complete blood counts (CBC) with differential to look at different types of blood cells
• Also checks on kidney function, electrolytes, and uric acid, especially if you're at risk for something called tumor lysis syndrome, which is a rapid breakdown of cancer cells.

Hepatitis B screening:

• All patients should be checked for hepatitis B before starting treatment
• This involves measuring two things in your blood: hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc)
• Patients who are negative for HBsAg but positive for anti-HBc should be checked for hepatitis B reactivation with HBV DNA and ALT testing about every 3 months during treatment.

Signs of hepatitis B:

• Keep an eye out for signs of active hepatitis B infection during and for up to 12 months after treatment is over.

Infusion reactions:

• Watch for signs or symptoms of a reaction to the infusion, like trouble breathing, chest discomfort, or skin redness.

Infections:

• Be aware of signs of infections, like fever, cough, or feeling generally unwell.

Fluid status:

• Your fluid levels will be checked to make sure you're not dehydrated or overloaded with fluid.

Signs of PML:

• Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection
• Look out for signs like weakness on one side of the body, vision problems, thinking problems, trouble speaking, problems with balance and coordination, and changes in face or eye movements
• If PML is suspected, you'll need more tests like a brain MRI, a lumbar puncture (spinal tap), and a consult with a neurologist.

How to administer Obinutuzumab (Gazyva)?

Obinutuzumab is given through an IV (a needle in your vein) but not as a quick injection. It should be given slowly over time through its own IV line and should not be mixed with other medications.

• Pre-Medications: Before you get the obinutuzumab infusion, you may need to take some medications to prevent reactions to the infusion. This can include acetaminophen (like Tylenol), an antihistamine (like Benadryl), and a steroid (like dexamethasone or methylprednisolone).
• If you have low neutrophil counts: If your neutrophil count is very low (a condition called severe neutropenia) for more than a week, you may need to take antibiotics to prevent infections. If your neutropenia lasts more than a week, you may also need to take antiviral and antifungal medicines.
• Infusion rate: The speed at which obinutuzumab is given can change depending on how you've reacted to previous infusions. If you've had reactions before, the infusion might need to be given more slowly.
• Chronic Lymphocytic Leukemia (CLL): On the first day of your first cycle, the infusion will be given slowly over 4 hours. On the second day and all future infusions, the speed can be increased gradually, as long as you're not having any reactions.
• Follicular Lymphoma (FL): For the first infusion, obinutuzumab will be given slowly and the speed can be gradually increased as long as you're not having any reactions. For all future infusions, the speed will depend on how you've reacted to previous infusions.

Mechanism of action of Obinutuzumab (Gazyva):

Obinutuzumab is a special type of medicine known as a glycoengineered type II anti-CD20 monoclonal antibody. This means that it's designed to target and stick to a protein called CD20, which is found on the surface of certain immune cells known as B-lymphocytes. These cells are part of your body's immune system, but in some conditions like certain types of cancer, they can grow out of control.

Once obinutuzumab binds to CD20, it triggers processes in the body that cause these cells to be destroyed. These processes include:

• Complement-dependent cytotoxicity: This involves proteins in your blood, called complement proteins, which can poke holes in the targeted cells, causing them to die.
• Antibody-dependent cellular cytotoxicity: This involves other cells of your immune system, which can recognize obinutuzumab on the targeted cells and destroy these cells.
• Antibody-dependent cellular phagocytosis: This involves cells of your immune system that can engulf and digest the targeted cells.

In all these ways, obinutuzumab can help to reduce the number of harmful B-lymphocytes in your body and help to control conditions like certain types of cancer.

Distribution:

• The volume of distribution is about 4.1 to 4.3 liters.
• This means the drug spreads into a volume of about 4.1 to 4.3 liters in the body.
• This volume isn't an actual space, but a way to describe how well the drug spreads through the body.

Half-life:

• The half-life is between 25.5 to 35.3 days.
• Half-life is how long it takes for half of the drug to be removed from your body.
• So, it takes about 25.5 to 35.3 days for half of obinutuzumab to be eliminated from your body.

International Brands of Obinutuzumab:

• Gazyva
• Gazyvaro

Obinutuzumab Brand Names in Pakistan:

Update soon.