Rituximab and Hyaluronidase

• It is used to treat a type of leukemia.
• It is used to treat a type of lymphoma.
• It may be given to you for other reasons. Talk with the doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• Very bad and sometimes deadly allergic reactions have rarely happened with other forms of rituximab and hyaluronidase as well as drugs like this one. Talk with the doctor.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• Skin reactions have happened where the shot is given or close to the area. This includes pain, swelling, hardness, redness, bleeding, itching, and rash. These skin reactions have also happened more than 24 hours after the injection. Talk with the doctor.
• People who took rituximab and hyaluronidase with some cancer drugs have had bowel block or tears in the bowel. Sometimes this has been deadly. Call your doctor right away if you have very bad belly pain; very hard stools (constipation); throwing up, throwing up blood, or throw up that looks like coffee grounds; or black, tarry, or bloody stools.
• Patients with cancer who take this medicine may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• A very bad and sometimes deadly health problem called cytokine release syndrome (CRS) has happened in people getting rituximab and hyaluronidase. Call your doctor right away if you have chills, dizziness, feeling tired or weak, fever, headache, passing out, rash, swelling of the face, trouble breathing, upset stomach or throwing up, or wheezing.
• Heart failure has rarely happened in people taking this medicine. Sometimes, this has been deadly. Call your doctor right away if you have shortness of breath, a big weight gain, or swelling in the arms or legs.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking rituximab and hyaluronidase and for up to 12 months after this medicine.
• If you get pregnant while taking rituximab and hyaluronidase or within 12 months after your last dose, call your doctor right away.

• Anti-CD20 Monoclonal Antibody
• Hyaluronidase and Rituximab
• Rituximab Subcutaneous

CLL: B-cells begin to deplete following the first cycle of rituximab, with 28% of patients B-cell depleted prior to the dose in cycle 2; by cycle 6, 96% of patients were B-cell depleted.

FL: Peripheral B-cell counts decrease to levels below normal following the first cycle of rituximab and are maintained during treatment with rituximab/hyaluronidase.

Withdraw dose from the vial and transfer to a syringe; label with the peel-off sticker. To avoid clogging the needle, attach the injection needle to the syringe immediately prior to administration; rituximab/hyaluronidase is compatible with polypropylene and polycarbonate syringes and stainless steel transfer and injection needles.

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store in original packaging to protect from light. Following transfer from vial to syringe, the manufacturer recommends immediate use. If not used immediately, syringes may be stored for 48 hours at 2°C to 8°C (36°F to 46°F) and subsequently for 8 hours at 30°C (86°F) in diffused daylight.

Abatacept: RiTUXimab may enhance the adverse/toxic effect of Abatacept. Avoid combination

Alpha-/Beta-Agonists: Hyaluronidase may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of alpha-/beta-agonists. Use of hyaluronidase for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated. Exceptions: Dipivefrin; EPINEPHrine (Nasal); EPINEPHrine (Oral Inhalation); Isometheptene; Pseudoephedrine. Consider therapy modification

Antihistamines: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Certolizumab Pegol: RiTUXimab may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Corticosteroids: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Exceptions: Beclomethasone (Nasal); Budesonide (Nasal); Ciclesonide (Nasal); Desonide; Dexamethasone (Ophthalmic); Difluprednate; Flunisolide (Nasal); Fluocinolone (Ophthalmic); Fluticasone (Nasal); Hydrocortisone (Ophthalmic); Loteprednol; Mometasone (Nasal); PrednisoLONE (Ophthalmic); Triamcinolone (Nasal); Triamcinolone (Ophthalmic). Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DOPamine: Hyaluronidase may enhance the adverse/toxic effect of DOPamine. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of dopamine. Use of hyaluronidase for other purposes in patients receiving dopamine may be considered as clinically indicated. Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Estrogen Derivatives: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Local Anesthetics: Hyaluronidase may enhance the adverse/toxic effect of Local Anesthetics. Exceptions: Benzocaine; Benzydamine; Cocaine; Dibucaine; Dyclonine; Ethyl Chloride; Hexylresorcinol; Lidocaine (Ophthalmic); Lidocaine (Topical); Pramoxine; Proparacaine; Tetracaine (Ophthalmic); Tetracaine (Topical). Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Phenylephrine (Systemic): Hyaluronidase may enhance the vasoconstricting effect of Phenylephrine (Systemic). Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of phenylephrine. Use of hyaluronidase for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Salicylates: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving salicylates (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: RiTUXimab may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase.

Hepatitis B virus (HBV) reactivation can occur in patients treated with rituximab-containing products, including rituximab/hyaluronidase, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab/hyaluronidase. Discontinue rituximab/hyaluronidase and concomitant medications in the event of HBV reactivation.

Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase.

Concerns related to adverse effects:

• Bowel obstruction/perforation: Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal) in patients receiving rituximab-containing products, with an average onset of symptoms of ~6 days (range: 1 to 77 days); evaluate abdominal pain or repeated vomiting.

• Cardiovascular effects: Cardiac events (eg, ventricular fibrillation, myocardial infarction, and cardiogenic shock) may occur with rituximab-containing products. Discontinue rituximab/hyaluronidase for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after administration in patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.

• Cytopenias: Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment. Monitor blood counts.

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur with rituximab-containing products, including rituximab/hyaluronidase, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab/hyaluronidase. Discontinue rituximab/hyaluronidase and concomitant medications in the event of HBV reactivation. Screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc); monitor patients for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment. If viral hepatitis develops, initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported up to 24 months after rituximab discontinuation. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during rituximab treatment. The safety of resuming rituximab-containing treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with physicians experienced in HBV management.

- American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for hepatitis B virus (HBV) reactivation. Screen for HBV infection with HBsAG and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV infected patients, high-risk behaviors [eg, intravenous drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg positive/anti-HBc positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

• Hypersensitivity: Rituximab-containing products are associated with hypersensitivity reactions (may be related to cytokine release and/or other chemical mediators). Due to the higher risk of hypersensitivity and other acute reactions, patients must receive at least one full dose of intravenous rituximab prior to receiving subcutaneous rituximab/hyaluronidase. Infusion-related reactions (with the use of intravenous rituximab formulations) usually occur within 30 to 120 minutes and may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and in more severe cases pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or anaphylactoid events. Anaphylactic and other hypersensitivity reactions may occur (typically occur within minutes of infusion initiation); severe cytokine release syndrome may occur within 1 to 2 hours of starting infusion. Patients with a history of pulmonary insufficiency or with pulmonary tumor infiltration may have a poorer outcome. Closely monitor patients with a history of prior cardiopulmonary reactions or with preexisting cardiac or pulmonary conditions and patients with high numbers of circulating malignant cells (>25,000/mm3). Prior to administration, premedicate patients with acetaminophen and an antihistamine (and consider glucocorticoids). Observe patients for at least 15 minutes following subcutaneous administration; increase observation time in patients at higher risk of hypersensitivity reactions. Interrupt rituximab/hyaluronidase administration immediately for signs of a severe reaction; initiate aggressive symptomatic treatment. Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, antihistamines, corticosteroids) should be available for immediate use.

• Infections: Serious and potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur during treatment and after completing therapy with rituximab-containing products. Infections have been observed in patients with prolonged hypogammaglobulinemia, defined as hypogammaglobulinemia >11 months after rituximab exposure. Associated new or reactivated viral infections have included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue rituximab/hyaluronidase in patients who develop serious infections and initiate appropriate anti-infective treatment.

• Mucocutaneous and cutaneous reactions: [US Boxed Warning]: Severe, including fatal, mucocutaneous reactions may occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase. Paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported. Discontinue in patients experiencing severe mucocutaneous skin reactions; the safety of reexposure following mucocutaneous reactions has not been evaluated. Subcutaneous rituximab has been associated with localized cutaneous (and injection site) reactions (eg, pain, erythema, swelling, induration, rash, pruritus, hemorrhage); may occur >24 hours after administration. Reactions have been mostly mild to moderate and have resolved without intervention. Local reactions were most common during the first rituximab/hyaluronidase cycle (incidence decreases with subsequent injections).

• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) (including fatalities) may occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase. Promptly evaluate any patient presenting with neurological changes; consider neurology consultation, brain MRI and lumbar puncture for suspected PML. Discontinue rituximab/hyaluronidase in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.

• Renal toxicity: Rituximab-containing products may cause severe or fatal renal toxicity. Patients who received combination therapy with cisplatin and rituximab for NHL experienced renal toxicity (associated with tumor lysis syndrome) during clinical trials; this combination is not an approved treatment regimen. Renal toxicity also occurred due to tumor lysis syndrome. Monitor for signs of renal failure; discontinue rituximab-containing products with increasing serum creatinine or oliguria.

• Tumor lysis syndrome: Tumor lysis syndrome may occur within 12 to 24 hours after administration of a rituximab-containing product. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy, hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities; monitor renal function and hydration status, and administer supportive care as indicated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: Live vaccines should not be given concurrently with rituximab; there is no data available concerning secondary transmission of live vaccines with or following rituximab-containing treatment.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.