Rituxan Hycela

Name: Rituxan Hycela

What special precautions should I follow?

Before using rituximab,

  • tell your doctor and pharmacist if you are allergic to rituximab, any other medications, or any of the ingredients in rituximab injection or rituximab and hyaluronidase human injection . Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medication in the IMPORTANT WARNING section and either of the following: adalimumab (Humira); certolizumab (Cimzia); cisplatin (Platinol); etanercept (Enbrel); golimumab (Simponi); infliximab (Remicade); medications for high blood pressure; other medications for rheumatoid arthritis; and medications that suppress the immune system such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Prograf). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have any of the conditions mentioned in the IMPORTANT WARNING section and if you have or have ever had hepatitis C or other viruses such as chicken pox, herpes (a virus that may cause cold sores or outbreaks of blisters in the genital area), shingles, West Nile virus (a virus that is spread through mosquito bites and may cause serious symptoms), parvovirus B19 (fifth disease; a common virus in children that usually only causes serious problems in some adults), or cytomegalovirus (a common virus that usually only causes serious symptoms in people who have weakened immune systems or who are infected at birth), or kidney problems. Also tell your doctor if you have any type of infection now or if you have or have ever had an infection that would not go away or an infection that comes and goes.
  • tell your doctor if you are pregnant or if you plan to become pregnant. Rituximab may harm the fetus. You should use birth control to prevent pregnancy during your treatment with rituximab and for up to 12 months after your treatment. Talk to your doctor about types of birth control that will work for you. If you become pregnant while using rituximab, call your doctor.
  • tell your doctor if you are breastfeeding. You should not breastfeed during your treatment with rituximab and hyaluronidase human injection and for 6 month after your final dose.
  • ask your doctor whether you should receive any vaccinations before you begin your treatment with rituximab. Do not have any vaccinations during your treatment without talking to your doctor.

Rituxan Hycela Side Effects

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.

Commonly used brand name(s)

In the U.S.

  • Rituxan Hycela

Available Dosage Forms:

  • Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Monoclonal Antibody

Precautions While Using Rituxan Hycela

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

Serious skin reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills with this medicine.

This medicine may reactivate hepatitis B infection. Talk to your doctor if you have concerns about this.

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 infusion-related reactions, which can be life-threatening and require immediate medical attention. Tell your doctor right away if you start to have a fever, chills or shaking, dizziness, trouble breathing, itching or rash, lightheadedness or fainting after receiving this medicine.

This medicine may cause a serious allergic reaction, called anaphylaxis. This can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after receiving this medicine.

This medicine may cause a serious reaction, called tumor lysis syndrome (TLS). Call your doctor right away if you have a change in how much or how often you urinate, rapid weight gain, muscle or joint pain, swelling of the feet or lower legs, or unusual tiredness or weakness.

Call your doctor right away if you start to have a cough that won't go away, weight loss, night sweats, fever, chills, flu-like symptoms (such as a runny or stuffy nose, headache, blurred vision, or feeling generally ill), painful or difficult urination, or sores, ulcers, or white spots in the mouth or on the lips. These may be signs that you have an infection.

This medicine may worsen the condition of patients with heart disease or heart rhythm problems. Check with your doctor right away if you have chest pain or tightness, decreased urine output, dilated neck veins, extreme fatigue, irregular heartbeat, swelling of the face, fingers, feet, or lower legs, troubled breathing, or weight gain. You might also feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat.

Check with your doctor right away if you have bloody urine, a decrease in frequency or amount of urine, an increase in blood pressure, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, troubled breathing, unusual tiredness or weakness, vomiting, or weight gain. These could be symptoms of a serious kidney problem.

This medicine can cause bowel problems, including bowel blockage, tears, or holes. Check with your doctor right away if you have severe stomach pain or continuing vomiting.

Do not have any live vaccines (immunizations) while you are being treated with rituximab and hyaluronidase human, recombinant combination injection. Check with your doctor before having any vaccines.

If OVERDOSE is suspected

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.

Rituxan Hycela Dosage and Administration

Important Dosing Information

Rituxan Hycela is for subcutaneous use only. Rituxan Hycela should only be administered by a healthcare professional with appropriate medical support to manage severe reactions that can be fatal if they occur.

All patients must first receive at least one full dose of a rituximab product by intravenous infusion without experiencing severe adverse reactions before starting treatment with Rituxan Hycela. If patients are not able to receive one full dose by intravenous infusion, they should continue subsequent cycles with a rituximab product by intravenous infusion and not switch to Rituxan Hycela until a full intravenous dose is successfully administered [see Warnings and Precautions (5.4)].

Refer to the prescribing information for a rituximab product for intravenous infusion for additional information.

Premedicate before each dose of Rituxan Hycela [see Dosage and Administration (2.5)].

Dose reductions of Rituxan Hycela are not recommended. When Rituxan Hycela is given in combination with chemotherapy dose, reduce the chemotherapeutic drugs to manage adverse reactions.

Recommended Dose for Follicular Lymphoma (FL)

All patients must receive at least one full dose of a rituximab product by intravenous infusion before starting treatment with Rituxan Hycela [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)]. Premedicate before each dose [see Dosage and Administration (2.5)].

The recommended dose is Rituxan Hycela 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously at a fixed dose irrespective of patient's body surface area according to the following schedules:

  • Relapsed or Refractory, Follicular Lymphoma
    Administer once weekly for 3 or 7 weeks following a full dose of a rituximab product by intravenous infusion at week 1 (i.e., 4 or 8 weeks in total).
  • Retreatment for Relapsed or Refractory, Follicular Lymphoma
    Administer once weekly for 3 weeks following a full dose of a rituximab product by intravenous infusion at week 1 (i.e., 4 weeks in total).
  • Previously Untreated, Follicular Lymphoma
    Administer on Day 1 of Cycles 2–8 of chemotherapy (every 21 days), for up to 7 cycles following a full dose of a rituximab product by intravenous infusion on Day 1 of Cycle 1 of chemotherapy (i.e., up to 8 cycles in total). In patients with complete or partial response, initiate Rituxan Hycela maintenance treatment 8 weeks following completion of Rituxan Hycela in combination with chemotherapy. Administer Rituxan Hycela as a single-agent every 8 weeks for 12 doses.
  • Non-progressing, Follicular Lymphoma after first line CVP chemotherapy
    Following completion of 6–8 cycles of CVP chemotherapy and a full dose of a rituximab product by intravenous infusion at week 1, administer once weekly for 3 weeks (i.e., 4 weeks in total) at 6 month intervals to a maximum of 16 doses.

Recommended Dose for Diffuse Large B-Cell Lymphoma (DLBCL)

All patients must receive at least one full dose of a rituximab product by intravenous infusion in combination with CHOP chemotherapy before starting treatment with Rituxan Hycela [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)]. Premedicate before each dose [see Dosage and Administration (2.5)].

The recommended dose for DLBCL is Rituxan Hycela 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) at a fixed dose irrespective of patient's body surface area in combination with CHOP chemotherapy. Administer Rituxan Hycela 1,400 mg/23,400 Units on Day 1 of Cycles 2–8 of CHOP chemotherapy for up to 7 cycles following a full dose of a rituximab product by intravenous infusion at Day 1, Cycle 1 of CHOP chemotherapy (i.e., up to 6–8 cycles in total).

Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

All patients must receive at least one full dose of a rituximab product by intravenous infusion in combination with FC chemotherapy before starting treatment with Rituxan Hycela [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)]. Premedicate before each dose [see Dosage and Administration (2.5)].

The recommended dose for CLL is Rituxan Hycela 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) in combination with FC chemotherapy, at a fixed dose, irrespective of patient's body surface area. Administer Rituxan Hycela 1,600 mg/26,800 Units on Day 1 of Cycles 2–6 (every 28 days) for a total of 5 cycles following a full intravenous dose at Day 1, Cycle 1 (i.e., 6 cycles in total).

Recommended Premedication and Prophylactic Medications

Premedicate with acetaminophen and an antihistamine before each dose of Rituxan Hycela. Premedication with a glucocorticoid should also be considered [see Dosage and Administration (2.2, 2.3, 2.4)].

Provide prophylaxis for Pneumocystis jiroveci pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate [see Warnings and Precautions (5.6)].

Administration and Storage

Rituxan Hycela is ready to use. To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration. Rituxan Hycela is compatible with polypropylene and polycarbonate syringe material and stainless steel transfer and injection needles. Use the product immediately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Rituxan Hycela should be a clear to opalescent and colorless to yellowish liquid. Do not use vial if particulates or discoloration is present.

Administration

  • Inject Rituxan Hycela into the subcutaneous tissue of the abdomen over approximately 5–7 minutes and never inject into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars. No data are available on performing the injection at other sites of the body.
  • Inject 11.7 mL of Rituxan Hycela 1,400 mg/23,400 Units vial (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously into the abdomen over approximately 5 minutes.
  • Inject 13.4 mL of Rituxan Hycela 1,600 mg/26,800 Units vial (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously into the abdomen over approximately 7 minutes.

If administration of Rituxan Hycela is interrupted, continue administering at the same site, or at a different site, but restricted to the abdomen.

Observe patients for at least 15 minutes following Rituxan Hycela administration [see Warnings and Precautions (5.4)].

During treatment with Rituxan Hycela, do not administer other medications for subcutaneous use at the same sites as Rituxan Hycela.

Storage

After the solution of Rituxan Hycela is withdrawn from the vial, it should be labeled with the peel-off sticker and used immediately. If not used immediately, prepare in controlled and validated aseptic conditions. Once transferred from the vial into the syringe, store the solution of Rituxan Hycela in the refrigerator at 2°C–8°C (36°F–46°F) up to 48 hours and subsequently for 8 hours at room temperature up to 30°C (86°F) in diffuse light.

Use in specific populations

Pregnancy

Risk Summary

Based on human data, rituximab-containing products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to rituximab in-utero (see Clinical Considerations). There are no available data on Rituxan Hycela use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, intravenous administration of a rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at a dose > 2700 times higher than the human dose. Comparable systemic exposure levels could occur in a pregnant patient following accidental intravenous administration of an entire vial of Rituxan Hycela (see Data). Advise pregnant women of the risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Observe newborns and infants for signs of infection and manage accordingly.

Data

Human Data

Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero.

Animal Data

Rituxan Hycela for subcutaneous injection contains rituximab and hyaluronidase human [see Description (11)].

Rituximab Product:

  • An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells.
  • A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.

Hyaluronidase Human:

  • In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U/kg, which is > 2700 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 450 times higher than the human dose.
  • In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1,300 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

Lactation

There are no data on the presence of rituximab or hyaluronidase human in human milk, the effect on the breastfed infant, or the effect on milk production. However, rituximab is detected in the milk of lactating cynomolgus monkeys, and IgG is present in human milk. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of Rituxan Hycela due to the potential for serious adverse reactions in breastfed infants.

Females and Males of Reproductive Potential

Rituximab-containing products can cause fetal harm [see Use in Specific Populations (8.1)].

Contraception

Females

Females of childbearing potential should use effective contraception while receiving Rituxan Hycela and for 12 months following treatment.

Pediatric Use

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

Geriatric Use

Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Rituxan Hycela Description

Rituxan Hycela is a combination of rituximab and hyaluronidase human. Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

Recombinant human hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is produced by mammalian (Chinese Hamster Ovary) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). It is a glycosylated single-chain protein with an approximate molecular weight of 61 kD.

Rituxan Hycela (rituximab and hyaluronidase human) Injection is a colorless to yellowish, clear to opalescent solution supplied in sterile, preservative-free, single-dose vials for subcutaneous administration.

Rituxan Hycela is supplied as 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL in single-dose vials or 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL in single-dose vials. Each mL of solution contains rituximab (120 mg), hyaluronidase human (2,000 Units), L-histidine (0.53 mg), L-histidine hydrochloride monohydrate (3.47 mg), L-methionine (1.49 mg), polysorbate 80 (0.6 mg), α,α-trehalose dihydrate (79.45 mg), and Water for Injection.

What is Rituxan Hycela?

Rituxan Hycela contains a combination of hyaluronidase and rituximab. Hyaluronidase is a genetically designed protein. Rituximab is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Rituxan Hycela is used to treat follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia.

Rituxan Hycela is sometimes used together with other cancer medicines.

What happens if I overdose?

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Irritation where the shot is given.
  • Feeling tired or weak.
  • Headache.
  • Upset stomach or throwing up.
  • Belly pain.
  • Not hungry.
  • Hard stools (constipation).
  • Loose stools (diarrhea).
  • Hair loss.
  • Signs of a common cold.
  • Nose or throat irritation.
  • Muscle spasm.
  • Muscle or joint pain.
  • Bone pain.
  • Back pain.
  • Not able to sleep.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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