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  • CLASSES

    Antineoplastic Monoclonal Antibodies Targeting CD20

    BOXED WARNING

    Serious rash

    Mucocutaneous reactions including serious rash such as paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported in patients who received rituximab-containing products; some cases were fatal. Discontinue rituximab/hyaluronidase in patients who develop a severe mucocutaneous reaction; the safety of restarting rituximab/hyaluronidase in these patients has not been evaluated.

    Hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, including rituximab/hyaluronidase. Screen all patients for HBV (e.g., HBsAg and anti-HBc titers) prior to starting rituximab or rituximab/hyaluronidase therapy. In patients who have evidence of HBV, consult with an expert in hepatitis management for monitoring and treatment recommendations. Additionally, monitor all patients with current or prior HBV for signs of hepatitis or HBV reactivation during and for several months after therapy. In patients who develop HBV reactivation, discontinue rituximab/hyaluronidase and any concomitant chemotherapy and initiate appropriate treatment. The safety of restarting rituximab/hyaluronidase in these patients has not been evaluated.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML), caused by the JC virus, has been reported in patients who received rituximab/hyaluronidase; some cases were fatal. Evaluate patients who develop new neurologic symptoms; consider consulting a neurologist and obtaining a brain MRI and lumbar puncture. Discontinue rituximab/hyaluronidase in patients who develop PML; additionally, consider discontinuing or reducing concomitant chemotherapy or immunosuppressive therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    A combination of rituximab, a CD20-directed monoclonal antibody, and hyaluronidase human, an endoglycosidase that increases the dispersion and absorption of rituximab
    Used for certain types of follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia
    Severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy may occur

    COMMON BRAND NAMES

    Rituxan Hycela

    HOW SUPPLIED

    Rituxan Hycela Subcutaneous Inj Sol: 1mL, 120-2000U

    DOSAGE & INDICATIONS

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: Rituximab/hyaluronidase has been designated as an orphan drug by the FDA for the treatment of follicular lymphoma and diffuse large B-cell lymphoma.
    For the treatment of relapsed or refractory follicular lymphoma.
    Subcutaneous dosage
    Adults

    1,400 mg rituximab and 23,400 units hyaluronidase (11.7 mL) subcutaneously into the abdomen over about 5 minutes once weekly for 3 or 7 weeks following a full dose of an IV infusion rituximab product at week 1 for a total of 4 or 8 total rituximab doses. In patients who require retreatment, inject 1,400 mg rituximab and 23,400 units of hyaluronidase (11.7 mL) subcutaneously into the abdomen over about 5 minutes once weekly for 3 weeks following a full dose of an IV infusion rituximab product at week 1 for a total of 4 rituximab doses. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase dose; consider adding a glucocorticoid to the premedication regimen. Rituximab/hyaluronidase dose reductions are not recommended.

    For the treatment of follicular lymphoma, in combination with first-line chemotherapy.
    Subcutaneous dosage
    Adults

    1,400 mg rituximab and 23,400 units hyaluronidase (11.7 mL) subcutaneously into the abdomen over about 5 minutes on day 1 in combination with chemotherapy repeated every 21 days on cycles 2 to 8 following a full dose of an IV infusion rituximab product on day 1 of cycle 1 for a total of 8 rituximab doses. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase dose; consider adding a glucocorticoid to the premedication regimen. Rituximab/hyaluronidase dose reductions are not recommended; if appropriate, chemotherapy may be reduced to manage adverse reactions.

    As single-agent maintenance therapy in patients with follicular lymphoma who achieve a complete or partial response following first-line treatment with rituximab in combination with chemotherapy.
    Subcutaneous dosage
    Adults

    1,400 mg rituximab and 23,400 units hyaluronidase (11.7 mL) subcutaneously into the abdomen over about 5 minutes every 8 weeks for 12 doses; begin 8 weeks after the completion of rituximab/hyaluronidase in combination with chemotherapy. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase dose; consider adding a glucocorticoid to the premedication regimen. Rituximab/hyaluronidase dose reductions are not recommended.

    As single-agent maintenance therapy in patients with follicular lymphoma with nonprogressing disease (stable disease or better) following first-line treatment with cyclophosphamide, vincristine, and prednisone (CVP).
    Subcutaneous dosage
    Adults

    1,400 mg rituximab and 23,400 units hyaluronidase (11.7 mL) subcutaneously into the abdomen over about 5 minutes once weekly for 3 weeks following a full dose of an IV infusion rituximab product at week 1 (4 weekly rituximab doses); begin after the completion of 6 to 8 cycles of CVP chemotherapy. Repeat every 6 months up to a maximum of 16 rituximab doses. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase dose; consider adding a glucocorticoid to the premedication regimen. Rituximab/hyaluronidase dose reductions are not recommended.

    For first-line treatment of diffuse large B-cell lymphoma (DLBCL), in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimen.
    Subcutaneous dosage
    Adults

    1,400 mg rituximab and 23,400 units hyaluronidase (11.7 mL) subcutaneously into the abdomen over about 5 minutes on day 1 in combination with CHOP chemotherapy on cycles 2 to 8 following a full dose of an IV infusion rituximab product on day 1 of cycle 1 for a total of 8 rituximab doses. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase dose; consider adding a glucocorticoid to the premedication regimen. Rituximab/hyaluronidase dose reductions are not recommended; if appropriate, chemotherapy may be reduced to manage adverse reactions.

    For the treatment of chronic lymphocytic leukemia (CLL).
    NOTE: Rituximab/hyaluronidase has been designated as an orphan drug by the FDA for the treatment of CLL
    For the treatment of CLL, in combination with cyclophosphamide and fludarabine.
    Subcutaneous dosage
    Adults

    1,600 mg rituximab and 26,800 units hyaluronidase (13.4 mL) subcutaneously into the abdomen over about 7 minutes on day 1 in combination with cyclophosphamide and fludarabine repeated every 28 days on cycles 2 to 6 following a full dose of an IV infusion rituximab product on day 1 of cycle 1 for a total of 6 rituximab doses. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase dose; consider adding a glucocorticoid to the premedication regimen. Rituximab/hyaluronidase dose reductions are not recommended; if appropriate, chemotherapy may be reduced to manage adverse reactions. Pneumocystis jiroveci pneumonia and herpes virus infections prophylaxis is recommended in patients with CLL; give prophylactic medications during treatment and for up to 12 months following treatment as appropriate.

    MAXIMUM DOSAGE

    Adults

    NHL:1,400 mg rituximab and 23,400 units of hyaluronidase (11.7 mL) subcutaneously; frequency varies based on type of lymphoma.
    CLL: 1,600 mg rituximab and 26,800 units of hyaluronidase (13.4 mL) subcutaneously once every 28 days.

    Geriatric

    NHL:1,400 mg rituximab and 23,400 units of hyaluronidase (11.7 mL) subcutaneously; frequency varies based on type of lymphoma.
    CLL: 1,600 mg rituximab and 26,800 units of hyaluronidase (13.4 mL) subcutaneously once every 28 days.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    The rituximab; hyaluronidase solution is colorless to yellow. The solution may appear clear to opalescent; do not use if particles or discoloration if are present.

    Subcutaneous Administration

    Rituximab; hyaluronidase is for subcutaneous administration only; do not administer intravenously.
    Rituximab; hyaluronidase is a ready-to-use solution and does not need to be diluted.
    Prior to administering rituximab/hyaluronidase, all patients must have received at least 1 full dose of an IV infusion rituximab product without experiencing a severe adverse reaction.
    Premedicate with acetaminophen and an antihistamine prior to each dose; consider adding a glucocorticoid to the premedication regimen.
    Only health care professions with appropriate medical support and training to manage severe reactions should administer rituximab; hyaluronidase.
    Preparation:
    Using a narrow gauge (e.g., 25 to 30 gauge) stainless-steel transfer needle of any length, withdraw the appropriate amount (11.7 mL or 13.4 mL) from the single-use rituximab; hyaluronidase vial into a polypropylene and polycarbonate syringe.
    Label the syringe with the provided peel off label.
    Storage: If the prepared syringe solution is not used immediately, it may be stored for up to 48 hours refrigerated (2 to 8 degrees C; 36 to 46 degrees F) or up to 8 hours at room temperature (up to 30 degrees C; up to 86 degrees F).
    Subcutaneous Injection:
    Immediately prior to injection, change the needle to a half inch to 5/8th inch long, narrow gauge (e.g., 25 to 30 gauge) stainless-steel needle to avoid needle clogging.
    Inject subcutaneously in the abdomen; do not inject into skin that is red, bruised, tender, or hard or into moles or scars.
    Administer 11.7 mL injections over approximately 5 minutes; give 13.4 mL injections over approximately 7 minutes.
    If administration is interrupted, continue giving the injection at the same site or at a different site in the abdomen.
    Observe patients for signs or symptoms of a severe reaction for at least 15 minutes following the subcutaneous injection.
    Do not administer other subcutaneous medications at the same site.

    STORAGE

    Rituxan Hycela:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Serious rash

    Mucocutaneous reactions including serious rash such as paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported in patients who received rituximab-containing products; some cases were fatal. Discontinue rituximab/hyaluronidase in patients who develop a severe mucocutaneous reaction; the safety of restarting rituximab/hyaluronidase in these patients has not been evaluated.

    Hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, including rituximab/hyaluronidase. Screen all patients for HBV (e.g., HBsAg and anti-HBc titers) prior to starting rituximab or rituximab/hyaluronidase therapy. In patients who have evidence of HBV, consult with an expert in hepatitis management for monitoring and treatment recommendations. Additionally, monitor all patients with current or prior HBV for signs of hepatitis or HBV reactivation during and for several months after therapy. In patients who develop HBV reactivation, discontinue rituximab/hyaluronidase and any concomitant chemotherapy and initiate appropriate treatment. The safety of restarting rituximab/hyaluronidase in these patients has not been evaluated.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML), caused by the JC virus, has been reported in patients who received rituximab/hyaluronidase; some cases were fatal. Evaluate patients who develop new neurologic symptoms; consider consulting a neurologist and obtaining a brain MRI and lumbar puncture. Discontinue rituximab/hyaluronidase in patients who develop PML; additionally, consider discontinuing or reducing concomitant chemotherapy or immunosuppressive therapy.

    Angina, cardiac arrhythmias, cardiac disease

    Cardiac toxicity may occur with rituximab/hyaluronidase therapy; therefore, use caution in patients with cardiac disease. Perform cardiac monitoring (e.g., electrocardiograms) during and following each rituximab/hyaluronidase injection in patients with a history of cardiac arrhythmias or angina and in patients who develop clinically significant arrhythmias.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) may occur with rituximab/hyaluronidase use. Administer aggressive hydration and anti-hyperuricemic therapy as prophylaxis in patients at high-risk for developing TLS; correct electrolyte abnormalities prior to starting therapy. Monitor renal function and fluid balance during therapy in all patients and administer supportive care including dialysis if necessary if TLS occurs. Patients with a high number of circulating malignant cells (i.e., 25,000 cells/mm3 or higher) or high tumor burden are at increased risk for developing TLS. The time to onset of TLS is typically within 12 to 24 hours of rituximab administration.

    Fungal infection, infection, viral infection

    Serious infection has been reported during and following the completion of rituximab/hyaluronidase therapy, including bacterial and fungal infection and new or reactivated viral infection; some cases were fatal. Discontinue rituximab/hyaluronidase in patients who develop serious infections; start appropriate anti-infective therapy.

    Renal disease, renal impairment

    Severe and life-threatening renal toxicity may occur following treatment with rituximab/hyaluronidase; therefore, use caution in patients with renal impairment or renal disease. Monitor renal function in all patients; discontinue rituximab/hyaluronidase in patients who develop increased serum creatinine levels or oliguria. Renal toxicity has been reported in patients experiencing tumor lysis syndrome and in patients who received concomitant cisplatin therapy (unapproved use).

    GI obstruction, GI perforation

    GI perforation and GI obstruction have occurred in patients who received rituximab in combination with chemotherapy; some cases were fatal. Promptly evaluate patients who develop symptoms of obstruction such as abdominal pain or vomiting. The mean time to GI perforation was 6 days (range, 1 to 77 days).

    Anemia, neutropenia, thrombocytopenia

    Hematologic toxicity (e.g., anemia, neutropenia, and thrombocytopenia) has been reported with rituximab/hyaluronidase therapy. Although the manufacturer does not recommend specific monitoring for rituximab/hyaluronidase, the following monitoring recommendations for the rituximab IV infusion product are as follows: obtain complete blood counts (CBC) including platelet counts prior to each course of single-agent rituximab therapy and obtain CBC and platelet counts at weekly to monthly intervals (or more often if cytopenias develop) in patients receiving rituximab plus chemotherapy.

    Vaccination

    Vaccination with live or attenuated viral vaccines following rituximab/hyaluronidase therapy has not been studied and is not recommended before or during treatment with rituximab/hyaluronidase.

    Cytokine release syndrome, pulmonary disease

    Systemic hypersensitivity reactions including cytokine release syndrome (CRS) and anaphylaxis may occur with rituximab/hyaluronidase use. Premedicate with acetaminophen and an antihistamine prior to each rituximab/hyaluronidase injection; consider adding a glucocorticoid to the premedication regimen. Observe patients for at least 15 minutes following the rituximab/hyaluronidase injection. Immediately interrupt the injection if a patient develops a severe reaction and administer aggressive symptomatic treatment. Closely monitor patients with pre-existing cardiac disease or pulmonary disease, patients with a prior history of cardiopulmonary adverse reactions, and patients with high numbers of circulating malignant cells (i.e., 25,000 cells/mm3 or higher) for CRS. Signs and symptoms of CRS include bronchospasm, hypoxia, severe dyspnea, fever, chills, rigors, urticaria, and/or angioedema; acute respiratory failure and death may occur. Patients with a history of pulmonary insufficiency or pulmonary tumor infiltration may have poor outcomes. The time to onset of CRS is usually within 1 to 2 hours; anaphylaxis and other hypersensitivity reactions typically occur within minutes.

    Pregnancy

    Rituximab-containing products may cause fetal harm when administered to a pregnant woman: therefore, avoid the use of rituximab/hyaluronidase during pregnancy. If rituximab/hyaluronidase is used during pregnancy, advise the patient of the risk to the fetus and monitor newborns and infants for signs of infection. In postmarketing surveillance, B-cell lymphocytopenia usually lasting less than 6 months has been reported in infants exposed to rituximab in-utero. Additionally, rituximab has been detected in the serum of infants who were exposed to rituximab in-utero.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during rituximab/hyaluronidase treatment. Pregnancy testing should be performed prior to starting rituximab/hyaluronidase in female patients of reproductive potential. These patients should avoid pregnancy and use effective contraception during and for 12 months after treatment with rituximab/hyaluronidase.
     

    Breast-feeding

    It is not known if hyaluronidase is secreted in human milk or the effects of rituximab on the breast-fed infant or on milk production. Maternal IgG is secreted into human milk. Rituximab has been reported to be excreted at low concentrations in human breast milk, although the clinical significance for breast-fed children is unknown. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during rituximab/hyaluronidase therapy and for at least 6 months after the last dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 25.0-56.0
    leukopenia / Delayed / 3.0-14.0
    thrombocytopenia / Delayed / 0-6.0
    infection / Delayed / 0-5.0
    anemia / Delayed / 5.0-5.0
    fever / Early / 0-5.0
    vomiting / Early / 0-2.0
    diarrhea / Early / 0-2.0
    injection site reaction / Rapid / 0-2.0
    GI perforation / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    nausea / Early / 0-1.0
    constipation / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    sinusitis / Delayed / 0-1.0
    pancytopenia / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    pemphigus / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    bone pain / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    bronchiolitis obliterans / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    insomnia / Early / 0-1.0
    heart failure / Delayed / 0-1.0
    cardiac arrest / Early / 0-1.0
    hypertension / Early / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    fatigue / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    serum sickness / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    lupus-like symptoms / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    cytokine release syndrome / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    erythema / Early / 0-15.0
    antibody formation / Delayed / 2.0-15.0
    conjunctivitis / Delayed / 0-5.0
    hypotension / Rapid / 0-1.0
    hepatitis / Delayed / Incidence not known
    hypoxia / Early / Incidence not known

    Mild

    headache / Early / 6.0-13.0
    chills / Rapid / 8.0-13.0
    rash / Early / 0-12.0
    pharyngitis / Delayed / 0-10.0
    pruritus / Rapid / 0-10.0
    dyspepsia / Early / 5.0-8.0
    myalgia / Early / 0-8.0
    muscle cramps / Delayed / 0-8.0
    dizziness / Early / 0-7.0
    influenza / Delayed / 0-4.0
    throat irritation / Early / 0-2.0
    flushing / Rapid / 0-2.0
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Major) Avoid the concomitant use of rituximab and abatacept; coadministration may result in additive immunosuppression and an increased risk of infection. There is insufficient experience to assess the safety and efficacy of abatacept administered concurrently with other biologic therapy, such as rituximab, and therefore such use is not recommended.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Adalimumab: (Major) Avoid the concomitant use of rituximab with adalimumab, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor.
    Amide local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Aminosalicylate sodium, Aminosalicylic acid: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Anakinra: (Major) Utilize caution with concomitant use of rituximab with other biologic agents, such as anakinra; coadministration may result in additive immunosuppression and an increased risk of infection. Limited data are available on the safety of the use of biologic agents in rheumatoid arthritis patients exhibiting peripheral B-cell depletion following treatment with rituximab. Monitor patients closely for signs or symptoms of infection.
    Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as rituximab. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Articaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Aspirin, ASA: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Carisoprodol: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Dipyridamole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Omeprazole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Oxycodone: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Aspirin, ASA; Pravastatin: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Azathioprine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as azathioprine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Azelastine; Fluticasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Beclomethasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including rituximab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Betamethasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Bismuth Subsalicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Budesonide: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Budesonide; Formoterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Bupivacaine Liposomal: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine; Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Bupivacaine; Meloxicam: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Certolizumab pegol: (Major) Avoid the concomitant use of rituximab with certolizumab pegol, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients who received rituximab in combination with a TNF blocker.
    Chloroprocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Choline Salicylate; Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ciclesonide: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Cisplatin: (Moderate) Closely monitor renal function for signs of renal failure if concomitant use with cisplatin and rituximab is necessary; discontinue rituximab in patients with a rising serum creatinine or oliguria. The combination of cisplatin and rituximab is not an approved treatment regimen. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with non-Hodgkin's Lymphoma administered concomitant cisplatin therapy during clinical trials.
    Cocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Conjugated Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Corticosteroids: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Corticotropin, ACTH: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Cortisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy. (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Deflazacort: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Desogestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Dexamethasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Dienogest; Estradiol valerate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Diethylstilbestrol, DES: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Estetrol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like rituximab. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Elagolix; Estradiol; Norethindrone acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ester local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Esterified Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Levonorgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Norgestimate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estradiol; Progesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Estropipate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Etanercept: (Major) The concomitant use of rituximab with etanercept, a tumor necrosis factor inhibitor, may result in additive immunosuppression and an increased risk of infection. Combination therapy has been reported in published open-label trials for patients refractory to rituximab alone, but further study is needed to establish an increased clinical benefit and impact on side effects, including immunosuppression and infection rates. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor in controlled clinical trials. Monitor patients receiving this combination closely for signs or symptoms of infection.
    Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Etonogestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Fludrocortisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Flunisolide: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone; Salmeterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone; Vilanterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Formoterol; Mometasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Gold: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), including gold compounds, may result in additive immunosuppression and an increased risk of infection. According to treatment guidelines, thare no data that adequately address the safety and efficacy of gold compounds in combination with biologic therapies. Monitor patients closely for signs or symptoms of infection.
    Golimumab: (Major) Avoid the concomitant use of rituximab with golimumab, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor.
    Hydrocortisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Hydroxychloroquine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as hydroxychloroquine, may result in an increased risk of infection. Hydroxychloroquine itself does not increase immunosuppression or infection risk, but, is often used in DMARD regimens where infection risk is increased. Monitor patients closely for signs or symptoms of infection.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Infliximab: (Major) Avoid the concomitant use of rituximab and infliximab if they are used to treat the same condition due to additive immunosuppression and an increased risk of infection. If coadministration is necessary for separate conditions, monitor patients closely for signs or symptoms of infection.
    Leflunomide: (Moderate) Coadministration may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection.
    Levobupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Levonorgestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Lidocaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Lidocaine; Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to rituximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving rituximab. At least 4 weeks before initiation of rituximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Rituximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Mepivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Mepivacaine; Levonordefrin: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Mestranol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Methotrexate: (Moderate) These drugs are commonly used together. However, coadministration of rituximab with immunosuppressive DMARDs, like methotrexate, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of methotrexate did not alter the pharmacokinetics of rituximab.
    Methylprednisolone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Mometasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Natalizumab: (Major) Natalizumab should not be used in combination with rituximab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norethindrone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Norgestimate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ocrelizumab: (Major) Avoid the use of ocrelizumab and rituximab together. Both drugs are monoclonal antibodies directed against CD20-expressing B-cells. There are no data on the safety and efficacy of using these drugs at the same time. The concomitant use of rituximab and ocrelizumab may result in additive immunosuppression and an increased risk of infection. Additionally, additive immunosuppression may occur if ocrelizumab is administered before or after rituximab therapy. When switching from drugs with prolonged immune effects, such as rituximab, consider the duration and mode of action of rituximab when initiating ocrelizumab. Monitor patients closely for signs or symptoms of infection.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Prednisolone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Prednisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Prilocaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Procaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Relugolix; Estradiol; Norethindrone acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Ropivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Salicylates: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Salsalate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Sarilumab: (Major) Avoid using sarilumab with other biological agents, including anti-CD20 monoclonal antibodies such as rituximab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sedating H1-blockers: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Sipuleucel-T: (Moderate) Use rituximab and sipuleucel-T together with caution. If appropriate, consider reducing or discontinuing immunosuppressive agents prior to treatment with sipuleucel-T. Sipuleucel-T works by stimulating the immune system; therefore, concurrent use with immunosuppressive agents, such as rituximab, may alter its efficacy or safety.
    Sulfasalazine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine, may result in an increased risk of infection. Monitor patients closely for signs or symptoms of infection. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.
    Tetracaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
    Tocilizumab: (Major) Avoid the concomitant use of rituximab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
    Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Triamcinolone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

    PREGNANCY AND LACTATION

    Pregnancy

    Rituximab-containing products may cause fetal harm when administered to a pregnant woman: therefore, avoid the use of rituximab/hyaluronidase during pregnancy. If rituximab/hyaluronidase is used during pregnancy, advise the patient of the risk to the fetus and monitor newborns and infants for signs of infection. In postmarketing surveillance, B-cell lymphocytopenia usually lasting less than 6 months has been reported in infants exposed to rituximab in-utero. Additionally, rituximab has been detected in the serum of infants who were exposed to rituximab in-utero.

    It is not known if hyaluronidase is secreted in human milk or the effects of rituximab on the breast-fed infant or on milk production. Maternal IgG is secreted into human milk. Rituximab has been reported to be excreted at low concentrations in human breast milk, although the clinical significance for breast-fed children is unknown. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during rituximab/hyaluronidase therapy and for at least 6 months after the last dose.

    MECHANISM OF ACTION

    Rituximab: Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody that binds to the antigen CD20 on the surface of B-cell precursors and mature B-lymphocytes.
    Hyaluronidase: Recombinant human hyaluronidase is an endoglycosidase that is used to increase the dispersion and absorption of other drugs when administered subcutaneously. It is produced by Chinese Hamster Ovary cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase.

    PHARMACOKINETICS

    Rituximab/hyaluronidase is administered subcutaneously. Following the subcutaneous administration of rituximab/hyaluronidase, the mean apparent volume of distribution (Vd) of rituximab was 8.09 L (coefficient of variance (CV), 19%), the mean terminal half-life of rituximab was 34.1 days (CV, 27%), and the mean clearance of rituximab was 0.18 L/day (CV, 34%) in patients with follicular lymphoma (FL); the mean apparent Vd was 8.52 L (CV, 13%), the mean terminal half-life was 32 days (CV, 24%), and the mean clearance was 0.204 L/day (CV, 31%) in patients with chronic lymphocytic leukemia (CLL).
     
    In patients with FL, peripheral B-cell counts decline to levels below normal following the first cycle of rituximab; these low levels are maintained during rituximab/hyaluronidase therapy. B-cell repletion may occur after 6 months of stopping rituximab/hyaluronidase treatment or longer. In patients with CLL, B-cell counts begin to decline before the cycle 2 rituximab/hyaluronidase dose and 96% of patients have B-cell depletion by cycle 6. Signs of B-cell repletion were observed in patients at the 9-month follow-up visit.

    Subcutaneous Route

    The absolute bioavailability was 0.646 (95% CI, 0.634 to 0.659) in patients with follicular lymphoma (FL) and 0.634 (95% CI, 0.602 to 0.665) in patients with chronic lymphocytic leukemia (CLL) following subcutaneous administration of rituximab/hyaluronidase compared with IV rituximab. Following the subcutaneous administration of rituximab 1,400 mg/hyaluronidase 23,400 units dosing in patients with FL, the Cmax and AUC values were 237 mcg/mL (coefficient of variance (CV), 29.4%) and 3,779 mcg x day/mL (CV, 33.7%), respectively, after cycle 7 of therapy and 156 mcg/mL (CV, 24.7%) and 5,000 mcg/mL (CV, 34.3%), respectively, after cycle 18 of therapy. The geometric mean Cmin ratio of subcutaneous rituximab/hyaluronidase to IV rituximab at cycle 7 was 1.52 (90% CI, 1.36 to 1.70). Following the subcutaneous administration of rituximab 1,600 mg/hyaluronidase 26,800 units dosing in patients with CLL, the Cmax (after cycle 6) and AUC (after cycle 5) values were 202 mcg/mL (CV, 36.1%) and 4,088 mcg x day/mL (CV, 34.2%), respectively. The adjusted geometric mean Cmin ratio of subcutaneous rituximab/hyaluronidase to IV rituximab at cycle 5 was 1.53 (90% CI, 1.27 to 1.85).