Gazyva

Pregnancy: Obinutuzumab is likely to cause fetal B-cell depletion; avoid administering live vaccines to neonates and infants exposed to obinutuzumab in utero until B-cell recovery occurs

Lactation: Unknown if distributed in human breast milk; excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk; consider developmental and health benefits along with the mother’s clinical need for therapy and any potential adverse effects on breastfed infant

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

CD20-directed cytolytic antibody; upon binding to CD20, obinutuzumab mediates B-cell lysis through 1) engagement of immune effector cells, 2) by directly activating intracellular death signaling pathways and/or, 3) activation of the complement cascade

CD20 antigen is expressed on the surface of pre B- and mature B-lymphocytes; the immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis

Distribution

Vd: 3.8 L

Elimination

Half-life: 28.4 days

Clearance: 0.09 L/day

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Gazyva falls into category C. There are no well-controlled studies of Gazyva in pregnant women. Women who can become pregnant should use effective contraception while receiving Gazyva and for 12 months after treatment. Gazyva should be used during pregnancy only if the potential benefit outweighs the potential risk to the unborn baby.

• Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including Gazyva. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with Gazyva. Discontinue Gazyva concomitant medications in the event of HBV reactivation.
• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving Gazyva.

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

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects. Blood tests may be needed to check for unwanted effects.

Check with your doctor right away if you have any symptoms of liver problems, such as yellow skin or eyes, dark brown-colored urine, right-sided stomach pain, fever, or severe tiredness.

This medicine may increase your risk of developing a serious and rare brain infection called progressive multifocal leukoencephalopathy (PML). Check with your doctor right away if you have vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, or weak legs.

This medicine may cause an infusion reaction within a few hours after you receive it. Check with your doctor right away if you have chest pain, itching, hives, a rash, flushing of the face, dizziness, fainting, lightheadedness, trouble breathing, swelling of the face, tongue, and throat, a fever, or chills.

This medicine may cause a serious type of reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount, joint pain, stiffness, or swelling, lower back, side, or stomach pain, a rapid weight gain, swelling of the feet or lower legs, or unusual tiredness or weakness.

Obinutuzumab can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

While you are being treated with obinutuzumab, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Obinutuzumab may lower your body's resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

• If you have an allergy to obinutuzumab or any other part of Gazyva.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have an infection.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Gazyva with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very bad headache.
• Feeling very tired or weak.
• Patients with cancer who take this medicine may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• Some people have side effects while getting Gazyva or within 24 hours after getting this medicine. Call your doctor right away if you have a fast heartbeat, fever, chills, muscle or joint pain, flushing or swelling of the face, upset stomach or throwing up, weakness, shortness of breath, dizziness or passing out, diarrhea, or chest pain or pressure.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Gazyva or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Gazyva. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

None.

Pregnancy

Risk Summary

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

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Gazyva is likely to cause fetal B-cell depletion [see Data]. Avoid administering live vaccines to neonates and infants exposed to Gazyva in utero until B-cell recovery occurs [see Warnings and Precautions (5.8)] and Clinical Pharmacology (12.2)].

Data

Animal Data

In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition, which includes the period of organogenesis. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. There were no embryo-toxic or teratogenic effects in animals. Secondary opportunistic infections, immune complex mediated hypersensitivity reactions, or a combination of both were observed in exposed dams. When first measured on day 28 postpartum, obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day, and B-cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition. Concentrations in milk were approximately 0.04% and 0.13% of concentrations in maternal serum in the 25 and 50 mg/kg groups, respectively.

Lactation

Risk Summary

There is no information regarding the presence of Gazyva in human milk, the effects on the breastfed infant, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Use in Specific Populations (8.1)]. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Gazyva and any potential adverse effects on the breastfed infant from Gazyva or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Gazyva in pediatric patients have not been established.

Geriatric Use

Chronic Lymphocytic Leukemia

Of 336 patients with previously untreated CLL who received Gazyva in combination with chlorambucil, 81% were 65 years and older, while 46% were 75 and older. Of the patients 75 years and older, 46% experienced serious adverse events and 7% experienced adverse events leading to death. Of the patients younger than 75, 33% experienced a serious adverse event and 2% an adverse event leading to death. No significant differences in efficacy were observed between younger and older patients [see Clinical Studies (14.1)].

Non-Hodgkin Lymphoma

Of 194 patients with iNHL treated with Gazyva plus bendamustine, 44% were 65 and over, while 14% were 75 and over. In patients 65 and over, 52% of patients experienced serious adverse events and 26% experienced adverse events leading to treatment withdrawal while in patients under 65, 28% and 12% experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. No clinically meaningful differences in efficacy were observed between these patients and younger patients.

There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of Gazyva and supportive therapy.

Gazyva (obinutuzumab) is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B cells. The molecular mass of the antibody is approximately 150 kDa.

Gazyva is produced by mammalian cell (CHO) suspension culture. Gazyva was engineered for reduced fucose content as compared to a typical IgG1 produced in CHO cells. Gazyva is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for intravenous administration. Gazyva is supplied at a concentration of 25 mg/mL in 1000 mg single-use vials. The product is formulated in 20 mM L-histidine/L-histidine hydrochloride, 240 mM trehalose, 0.02% poloxamer 188. The pH is 6.0.

NDC 50242-070-01

Gazyva®
(obinutuzumab)
Injection

1000 mg/40 mL
(25 mg/mL)

For Intravenous Infusion After Dilution.
Single-Dose Vial. Discard Unused Portion.
No preservative.

1 vial

Rx only

Genentech

10173393