rituximab-hyaluronidase (Rx)

Percentages are for all grades of toxicity unless otherwise noted

>10% (FL)

Neutropenia (32%)

Nausea (31%)

Constipation (25%)

Cough (23%)

Fatigue (20%)

Diarrhea (18%)

Asthenia (17%)

Pyrexia (15%)

Anemia (15%)

Abdominal pain (14%)

Vomiting (14%)

Alopecia (14%)

Paresthesia (16%)

Injection site erythema (13%)

Arthralgia (13%)

Peripheral neuropathy (12%)

Dyspnea (11%)

Pneumonia (11%)

>10% (DLBCL)

Neutropenia (31%)

lopecia (24%)

Anemia (23%)

Nausea (22%)

Fatigue (19%)

Constipation (15%)

Diarrhea (14%)

Febrile neutropenia (14%)

Decreased neutrophil count (14%)

Pyrexia (13%)

Peripheral neuropathy (12%)

Cough (11%)

Asthenia (11%)

Vomiting (11%)

>10% (CLL)

Neutropenia (65%)

Nausea (38%)

Pyrexia (32%)

Injection site erythema (26%)

Thrombocytopenia (24%)

Vomiting (21%)

Leukopenia (19%)

Injection site pain (16%)

Erythema (15%)

Anemia (13%)

Chills (13%)

Cough (13%)

Upper respiratory tract infection (13%)

Rash (12%)

Diarrhea (12%)

Fatigue (11%)

Febrile neutropenia (11%)

1-10% (FL)

Bone pain (10%)

Extremity pain (10%)

Pruritus (10%)

Rash (10%)

Erythema (9%)

Back pain (9%)

Oropharyngeal pain (9%)

Insomnia (9%)

Dyspepsia (8%)

Chills (8%)

Injection site pain (8%)

Chills (8%)

Bronchitis (8%)

Urinary tract infection (8%)

Muscle spasms (8%)

Myalgia (8%)

Sinusitis (7%)

Dizziness (7%)

Insomnia (7%)

Stomatitis (6%)

Hypertension (6%)

Conjunctivitis (5%)

Upper abdominal pain (5%)

Peripheral edema (5%)

Mucosal inflammation (5%)

Influenza (4%)

Influenza-like illness (3%)

Peripheral neuropathy, Grade 3-4 (2%)

Diarrhea, Grade 3-4 (2%)

Asthenia, Grade 3-4 (1%)

Chest pain, Grade 3-4 (1%)

Dyspnea, Grade 3-4 (1%)

Hypertension, Grade 3-4 (1%)

1-10% (DLBCL)

Paresthesia (9%)

Mucosal inflammation (8%)

Peripheral edema (8%)

Decreased weight (8%)

Decreased appetite (8%)

Abdominal pain (7%)

Pneumonia (7%)

Leukopenia (7%)

Decreased WBC count (7%)

Insomnia (7%)

Stomatitis (6%)

Headache (6%)

Dyspnea (6%)

Dyspepsia (5%)

Lymphopenia (5%)

Decreased lymphocyte count (5%)

1-10% (CLL)

Abdominal pain (9%)

Arthralgia (9%)

Constipation (8%)

Asthenia (8%)

Respiratory tract infection (8%)

Pruritus (8%)

Bronchitis (7%)

Extremity pain (7%)

Headache (7%)

Bone pain (6%)

Oropharyngeal pain (6%)

Dyspnea (4%)

Urinary tract infection (2%)

Pneumonia (2%)

Insomnia (1%)

Hypotension (1%)

Postmarketing Reports

Skin: Severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation)

Contraindications

None

Cautions

Tumor lysis syndrome (TLS) can occur within 12-24 hr after administration; administer aggressive IV hydration and antihyperuricemic therapy in patients at high risk for TLS; correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated

Cardiac adverse reactions (eg, ventricular fibrillation, myocardial infarction, cardiogenic shock) may occur; discontinue treatment for serious or life-threatening cardiac arrhythmias; perform cardiac monitoring during and after all administrations for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Severe, including fatal, renal toxicity can occur after administration; closely monitor for signs of renal failure and discontinue treatment in patients with a rising serum creatinine or oliguria

Abdominal pain, bowel obstruction, and bowel perforation can occur in patients receiving rituximab-containing products, in combination with chemotherapy; in postmarketing reports, the mean time to documented gastrointestinal perforation was 6 days; evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Safety of immunization with live viral vaccines following rituximab-containing chemotherapy has not been studied, and vaccination with live virus vaccines is not recommended before or during treatment

Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in utero (see Pregnancy)

Infections

• Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab
• Infections reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure)
• New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella-zoster virus, West Nile virus, and hepatitis B and C viruses
• Discontinue treatment for serious infections and institute appropriate anti-infective therapy

Hypersensitivity

• Rituximab-containing products are associated with hypersensitivity and other administration reactions (eg, cytokine release syndrome, TLS, anaphylactic reactions)
• Severe infusion-related reactions (eg, pulmonary events, fever, chills, rigors, hypotension, urticaria, angioedema) with fatal outcome reported with IV use of rituximab, with an onset ranging within 30-120 minutes after starting the first IV infusion
• Cytokine release syndrome may occur within 1-2 hr of initiating infusion; severe cytokine release syndrome is characterized by severe dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema
• Local cutaneous reactions may occur more than 24 hr after administration
• During administration, interrupt treatment immediately when observing signs of a severe reaction, and initiate aggressive symptomatic treatment; closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm³ )
• Premedicate patients with an antihistamine and acetaminophen prior to each administration; also consider glucocorticoids

Pregnancy

Based on human data, rituximab can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to rituximab in utero

There are no available data on use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage

Verify pregnancy status in females of reproductive potential prior to initiating therapy

Animal data

• In animal reproduction studies, IV administration of a rituximab to pregnant cynomolgus monkeys during organogenesis caused lymphoid B-cell depletion in newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 g in humans
• Reduced fetal weight and increased fetal lethality were observed following SC administration of hyaluronidase human in mice at a dose >2700 times higher than the human dose

Contraception

• Females of childbearing potential should use effective contraception during treatment and for 12 months following treatment

Lactation

There are no data on the presence of rituximab or hyaluronidase human in human milk, the effect on the breastfed infant, or the effect on milk production

However, rituximab is detected in the milk of lactating cynomolgus monkeys, and IgG is present in human milk

Advise a lactating woman not to breastfeed during treatment and for at least 6 months after last dose

Pregnancy Categories

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

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

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

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

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

NA: Information not available.

Mechanism of Action

Monoclonal antibody targets CD20 antigen expressed on pre-B and mature B-lymphocytes’ surfaces

Upon binding to CD20, mediates B-cell lysis

Hyaluronidase human increases permeability of SC tissue by temporarily depolymerizing hyaluronan

In doses administered, hyaluronidase human acts locally; effects of hyaluronidase human are reversible and permeability of SC tissue is restored within 24-48 hr

Absorption

Bioavailability: 0.646 (FL); 0.634 (CLL)

Peak plasma concentration

• FL: 237 mcg/mL (cycle 7); 156 mcg/mL (cycle 18)
• CLL: 202 mcg/mL (cycle 6)

Peak trough concentration

• FL: 122.2 mcg/mL (cycle 7); 45.5 mcg/mL (cycle 18)
• CLL: 97.5 mcg/mL (cycle 6)

AUC

• FL: 3,779 mcg·d/mL (cycle 7); 5,000 mcg·d/mL (cycle 18)
• CLL: 4088 mcg·d/mL (cycle 5)

Distribution

Vd (steady-state): 8.09 L (FL); 8.52 (CLL)

Elimination

Half-life: 34.1 days (FL); 32 days (CLL)

Clearance: 0.18 L/day (FL); 0.204 (CLL)

SC Preparation

Solution for SC is ready to use

Visually inspect solution for particulates; solution should appear as a clear-to-opalescent and colorless-to-yellowish liquid

SC Administration

Consider premedication (ie, acetaminophen, diphenhydramine, and/or glucocorticoids)

Premedication with acetaminophen and diphenhydramine may attenuate infusion-related reactions

Observe patients for 15 minutes after SC administration

If administration is interrupted, administer at the same site or at a different site along the abdomen

Avoid coadministering other SC medications at the same site

Avoid injections into areas where skin appears red, bruised, tender, or hard

Avoid injections in areas where there are moles or scars No data available on other injection sites

SC injection rate

• Inject SC in abdomen
• 1,400 mg/23,400 IU/vial (1,400 mg rituximab and 23,400 Units hyaluronidase human): SC over ~5 minutes
• 1,600 mg/26,800 IU/vial (1,600 mg rituximab and 26,800 Units hyaluronidase human): SC over ~7 minutes

Storage

Unused vials: Refrigerate at 2-8°C (36-46°F)

Solution for SC injection: Refrigerate at 2-8°C (36-46°F) up to 48 hr and subsequently for 8 hr at room temperature up to 30°C (86°F)

Protect vials and solution from light