Rituxan Hycela

Hyaluronidase is a genetically designed protein.

Rituximab is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Hyaluronidase and rituximab is a combination medicine used to treat follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia.

Hyaluronidase and rituximab is sometimes used together with other cancer medicines.

Hyaluronidase and rituximab may also be used for purposes not listed in this medication guide.

Rituximab may cause a serious brain infection that can lead to disability or death. Call your doctor right away if you have changes in your mental state, vision changes, weakness on one side of your body, or problems with speech or walking.

Tell your doctor if you have ever had hepatitis B. Rituximab can cause this condition to come back or get worse.

Severe skin problems can also occur during treatment with rituximab. Call your doctor if you have painful skin or mouth sores, or a severe skin rash with blistering, peeling, or pus.

Some side effects may occur during the injection or within 24 hours afterward. Tell your caregiver right away if you feel itchy, dizzy, weak, light-headed, short of breath, chilled, feverish, or if you have chest pain, wheezing, a sudden cough, or pounding heartbeats or fluttering in your chest.

You should not use hyaluronidase and rituximab if you are pregnant. Avoid getting pregnant for at least 12 months after you stop using this medicine.

You should not be treated with this medicine if you are allergic to hyaluronidase or rituximab.

To make sure hyaluronidase and rituximab is safe for you, tell your doctor if you have ever had:

• kidney disease;
• lung disease;
• a weak immune system (caused by disease or by using certain medicines);
• an infection such as herpes, shingles, cytomegalovirus, chickenpox, parvovirus, West Nile virus, or hepatitis B or C;
• heart disease, angina (chest pain), or heart rhythm disorder; or
• if you recently received any vaccine, or you are are scheduled to receive a vaccine.

Using hyaluronidase and rituximab during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or if you become pregnant. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 12 months after your last dose.

It is not known whether hyaluronidase and rituximab passes into breast milk or if it could harm a nursing baby. Do not breast-feed while using hyaluronidase and rituximab, and for at least 6 months after your last dose.

Hyaluronidase is a genetically designed protein.

Rituximab is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Hyaluronidase and rituximab is a combination medicine used to treat follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia.

Hyaluronidase and rituximab is sometimes used together with other cancer medicines.

Hyaluronidase and rituximab may also be used for purposes not listed in this medication guide.

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

Some side effects may occur during the injection (or within 24 hours afterward). Tell your caregiver right away if you feel itchy, dizzy, weak, light-headed, short of breath, chilled, feverish, or if you have chest pain, wheezing, a sudden cough, or pounding heartbeats or fluttering in your chest.

Serious and sometimes fatal infections may occur during treatment with hyaluronidase and rituximab. Call your doctor right away if you have signs of infection such as:

• fever, sore throat, cold or flu symptoms;

• sores or white patches in your mouth or throat;

• pain or burning when you urinate;

• earaches, headaches; or

• painful skin sores with redness, warmth, or swelling.

Rituximab may cause a serious viral infection of the brain or spinal cord that can lead to disability or death. Call your doctor right away if you have any of the following symptoms (which may start gradually and get worse quickly):

• confusion, memory problems, or other changes in your mental state;

• weakness on one side of your body;

• vision changes; or

• problems with speech or walking.

Call your doctor at once if you have any of these other side effects, even if they occur several months after you are treated with hyaluronidase and rituximab, or after your treatment ends.

• skin or mouth sores, or a severe skin rash with blistering, peeling, or pus;

• severe stomach pain, severe vomiting;

• chest pain, irregular heartbeats;

• little or no urination;

• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, easy bruising, unusual bleeding, feeling light-headed; or

• signs of tumor cell breakdown--vomiting, diarrhea; little or no urination; numbness or tingly feeling; muscle weakness or twitching; fast or slow heart rate; confusion, hallucinations, seizure, feeling restless or irritable.

Common side effects may include:

• low blood cell counts;

• nausea, vomiting, constipation;

• hair loss;

• feeling tired;

• cough; or

• redness where the injection was given.

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.

Other drugs may interact with hyaluronidase and rituximab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Rituximab and hyaluronidase human, recombinant combination injection is used alone or together with other cancer medicines to treat follicular lymphoma and chronic lymphocytic leukemia (CLL). It is also used together with other medicines to treat diffuse large B-cell lymphoma (DLBCL) in people who have not received previous treatment.

Rituximab and hyaluronidase human, recombinant combination injection is an antineoplastic agent (cancer medicine). It interferes with the growth of cancer cells, which are eventually destroyed by the body.

This medicine is to be given only by or under the direct supervision of your doctor.

• 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.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Rituxan Hycela is refilled. If you have any questions about this medicine, please talk with the doctor, 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 Rituxan Hycela (rituximab and hyaluronidase) 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 Rituxan Hycela. 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

Mechanism of Action

Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase human in Rituxan Hycela acts locally.

The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Hyaluronidase human has been shown to increase the absorption rate of a rituximab product into the systemic circulation when given in the subcutis of Göttingen Minipigs.

Pharmacodynamics

Peripheral B-cell counts declined to levels below normal following a dose of rituximab by intravenous infusion. In patients treated with rituximab for hematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer.

Follicular Lymphoma (FL)

Peripheral B-cell counts decline to levels below normal following the first cycle of rituximab and are maintained during treatment with Rituxan Hycela. After stopping Rituxan Hycela treatment, B-cell repletion followed similar kinetics to that of rituximab with B-cell repletion beginning after 6 months of stopping treatment, although in some patients this may take longer.

Chronic Lymphocytic Leukemia (CLL)

Following the first cycle of treatment of rituximab, B-cells begin to deplete, with 28% of patients B-cell depleted at pre-dose Cycle 2 in the SAWYER study. An increase in the proportion of B-cell depleted patients was observed with subsequent cycles of Rituxan Hycela and by Cycle 6, 96% of patients were depleted. Patients remained B-cell depleted until the month 9 follow-up visit, where signs of repletion were seen.

Pharmacokinetics

The geometric mean rituximab exposures are provided in Table 4. The pharmacokinetic properties of rituximab following the administration of Rituxan Hycela in the approved indications are provided in Table 5. The elimination of rituximab was characterized by a time-dependent process that occurred early in therapy and a time-independent process.

In the SABRINA study, the geometric mean Ctrough in the Rituxan Hycela arm was higher than in the rituximab arm with a geometric mean ratio (Ctrough, Rituxan Hycela/Ctrough, rituximab) of 1.52 (90% CI: 1.36, 1.70) at Cycle 7 [see Clinical Studies (14.1)]. In the SAWYER study, the geometric mean Ctrough in the Rituxan Hycela arm was higher than in the rituximab arm with an adjusted geometric mean ratio of 1.53 (90% CI: 1.27–1.85) at Cycle 5 [see Clinical Studies (14.3)].

Specific Populations

The pharmacokinetics of rituximab and hyaluronidase human in children and adolescents is unknown. The effect of either renal or hepatic impairment on the pharmacokinetics of rituximab and hyaluronidase human is unknown.

Drug Interaction Studies

The drug interaction potential of rituximab and hyaluronidase human is unknown.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Severe Mucocutaneous Reactions

Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the lips or mouth, blisters, peeling skin, rash, and pustules [see Warnings and Precautions (5.1)].

Hepatitis B Virus Reactivation

Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2)].

Progressive Multifocal Leukoencephalopathy (PML)

Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems [see Warnings and Precautions (5.3)].

Hypersensitivity and Other Administration Reactions

Inform patients about the signs and symptoms of hypersensitivity and administration-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of administration-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.4)].

Tumor Lysis Syndrome (TLS)

Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.5)].

Infections

Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, cold sores, and painful wounds with erythema [see Warnings and Precautions (5.6)]

Cardiovascular Adverse Reactions

Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats. [see Warnings and Precautions (5.7)]

Renal Toxicity

Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor kidney function [see Warnings and Precautions (5.8)].

Bowel Obstruction and Perforation

Advise patients to contact their healthcare provider immediately for sign and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting [see Warnings and Precautions (5.9)].

Embryo-Fetal Toxicity

Advise a pregnant woman of the potential risk to a fetus. Advise female patients that rituximab containing products can cause fetal harm if taken during pregnancy and to use effective contraception during treatment with Rituxan Hycela and for at least 12 months after the last dose of Rituxan Hycela. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with Rituxan Hycela and for 6 months after the last dose [see Use in Specific Populations (8.2)].

Rituxan Hycela™ [rituximab and hyaluronidase human]

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
US License No.: 1048

Rituxan Hycela™ is a trademark of Biogen.
Jointly marketed by: Biogen and Genentech USA, Inc.
©2017 Biogen and Genentech USA, Inc.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

NDC 50242-109-01
Rituxan Hycela™
(rituximab and
hyaluronidase human)
Injection

1,600 mg and
26,800 Units/13.4 mL
(120 mg and 2,000 Units/mL)

For Subcutaneous Use Only.

Single-Dose Vial.
Discard Unused Portion.

Attention Pharmacist: Dispense the
accompanying Medication Guide to
each patient.

1 vial

Rx only

Genentech | Biogen®

10173775

Call your doctor for instructions if you miss a dose of Rituxan Hycela.

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 liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Chest pain or pressure or a fast heartbeat.
• A heartbeat that does not feel normal.
• Dizziness or passing out.
• Feeling very tired or weak.
• Any unexplained bruising or bleeding.
• A burning, numbness, or tingling feeling that is not normal.
• Very bad and sometimes deadly kidney problems have happened with this drug. Call your doctor right away if you are unable to pass urine or if you have blood in the urine or a change in the amount of urine passed.
• Very bad and sometimes deadly lung problems have happened with this drug. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.