Dosage & Administration
Ruxience Prescribing Information
Infusion-Related Reactions
Administration of rituximab products can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RUXIENCE infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
Severe Mucocutaneous Reactions
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products [see Warnings and Precautions (5.2)].
Hepatitis B Virus (HBV) Reactivation
HBV reactivation can occur in patients treated with rituximab products, 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 RUXIENCE. Discontinue RUXIENCE and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.3)].
Progressive Multifocal Leukoencephalopathy (PML)
Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products [see Warnings and Precautions (5.4), Adverse Reactions (6.3)].
Non-Hodgkin's Lymphoma (NHL)
RUXIENCE is indicated for the treatment of adult patients with:
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- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
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- Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
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- Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
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- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
Chronic Lymphocytic Leukemia (CLL)
RUXIENCE, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.
Rheumatoid Arthritis (RA)
RUXIENCE, in combination with methotrexate, is indicated for the treatment of adult patients with moderately-to severely-active rheumatoid arthritis who have had an inadequate response to one or more Tumor Necrosis Factor (TNF) antagonist therapies.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
RUXIENCE, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).
Important Dosing Information
Administer only as an intravenous infusion [see Dosage and Administration (2.8)]. Do not administer as an intravenous push or bolus.
RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur [see Warnings and Precautions (5.1)].
Premedicate before each infusion [see Dosage and Administration (2.7)].
Prior to First Infusion
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE [see Warnings and Precautions (5.3)]. Obtain complete blood counts (CBC) including platelets prior to the first dose.
During RUXIENCE Therapy
In patients with lymphoid malignancies, during treatment with RUXIENCE monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RUXIENCE course. During treatment with RUXIENCE and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias [see Adverse Reactions (6.1)]. In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RUXIENCE therapy. Continue to monitor for cytopenias after final dose and until resolution.
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- First Infusion
Standard Infusion: Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
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- Subsequent Infusions
Standard Infusion: Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.
For Previously Untreated Follicular NHL and DLBCL Adult Patients: If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen.
Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8).
Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm3 before Cycle 2 should not be administered the 90-minute infusion [see Clinical Studies (14.4)]. - •
- Interrupt the infusion or slow the infusion rate for infusion-related reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Continue the infusion at one-half the previous rate upon improvement of symptoms.
Recommended Dose for Non-Hodgkin's Lymphoma (NHL)
The recommended dose is 375 mg/m2 as an intravenous infusion according to the following schedules:
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- Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
Administer once weekly for 4 or 8 doses. - •
- Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
Administer once weekly for 4 doses. - •
- Previously Untreated, Follicular, CD20-Positive, B-Cell NHL
Administer on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate RUXIENCE maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer RUXIENCE as a single agent every 8 weeks for 12 doses. - •
- Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy
Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. - •
- Diffuse Large B-Cell NHL
Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.
Recommended Dose for Chronic Lymphocytic Leukemia (CLL)
The recommended dose is 375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of Cycles 2–6 (every 28 days).
Recommended Dose as a Component of Zevalin® for Treatment of NHL
When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m2 in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
Recommended Dose for Rheumatoid Arthritis (RA)
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- Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks.
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- Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions.
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- Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.
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- RUXIENCE is given in combination with methotrexate.
Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
Induction Treatment of Adult Patients with Active GPA/MPA
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- Administer RUXIENCE as a 375 mg/m2 intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA.
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- Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone as per clinical practice. This regimen should begin within 14 days prior to or with the initiation of RUXIENCE and may continue during and after the 4 week induction course of RUXIENCE treatment.
Follow up Treatment of Adult Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment
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- Administer RUXIENCE as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation.
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- If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RUXIENCE within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product.
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- If induction treatment of active disease was with other standard of care immunosuppressants, initiate RUXIENCE follow up treatment within the 4 week period that follows achievement of disease control.
Recommended Dose for Premedication and Prophylactic Medications
Premedicate with acetaminophen and an antihistamine before each infusion of RUXIENCE. For adult patients administered RUXIENCE according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion [see Clinical Studies (14.4)].
For RA, GPA and MPA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.
Provide prophylaxis treatment for Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate [see Warnings and Precautions (5.6)].
PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last RUXIENCE infusion.
Administration and Storage
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. RUXIENCE should be a clear to slightly opalescent, colorless to pale brownish-yellow liquid. Do not use vial if particulates or discoloration is present.
Administration
Use a sterile needle and syringe to prepare RUXIENCE. Withdraw the necessary amount of RUXIENCE and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.
Storage
If not used immediately, store diluted RUXIENCE solutions as shown in the table below.
Diluted RUXIENCE Solution Storage Conditions
Diluent Used to Prepare Solution for Infusion | Diluted RUXIENCE Solution Storage Conditions |
0.9% Sodium Chloride Injection, USP | Store RUXIENCE solution diluted in 0.9% Sodium Chloride Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 16 days after preparation. |
5% Dextrose Injection, USP | Store RUXIENCE solution diluted in 5% Dextrose Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours after preparation. |
No incompatibilities between RUXIENCE and polyvinylchloride bags have been observed.
Injection: RUXIENCE is a clear to slightly opalescent, colorless to pale brownish-yellow solution for intravenous infusion:
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- 100 mg/10 mL (10 mg/mL) in a single-dose vial
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- 500 mg/50 mL (10 mg/mL) in a single-dose vial
Pregnancy
Risk Summary
Based on human data, rituximab products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero (see Clinical Considerations). In animal reproduction studies, intravenous administration of rituximab to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B-cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Advise pregnant women of the risk to a fetus.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Observe newborns and infants for signs of infection and manage accordingly.
Data
Human Data
Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero.
Animal Data
An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum Days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21, and 22, at 15, 37.5, or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43, and 50, at 20, 50, or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells.
A subsequent pre- and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in-utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.
Lactation
There are limited data on the presence of rituximab in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. Rituximab is detected in the milk of lactating cynomolgus monkeys, and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RUXIENCE and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.
Females and Males of Reproductive Potential
Rituximab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating RUXIENCE.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with RUXIENCE and for 12 months after the last dose.
Pediatric Use
The safety and effectiveness of RUXIENCE have not been established in pediatric patients with NHL, CLL or RA.
Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system.
Geriatric Use
Diffuse Large B-Cell NHL
Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received rituximab in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis.
Low-Grade or Follicular Non-Hodgkin's Lymphoma
Patients with previously untreated follicular NHL evaluated in NHL Study 5 were randomized to rituximab as single-agent maintenance therapy (n=505) or observation (n=513) after achieving a response to rituximab in combination with chemotherapy. Of these, 123 (24%) patients in the rituximab arm were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other clinical studies of rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
Chronic Lymphocytic Leukemia
Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older; of these, 100 rituximab-treated patients (15%) were 70 years of age or older.
In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2 [see Clinical Studies (14.5)]. Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of rituximab. In CLL Study 1, the dose intensity of rituximab was similar in older and younger patients, however in CLL Study 2 older patients received a lower dose intensity of rituximab.
The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (CLL Study 1); 56% vs. 39% (CLL Study 2)], febrile neutropenia [16% vs. 6% (NHL Study 10 (NCT00719472))], anemia [5% vs. 2% (CLL Study 1); 21% vs. 10% (CLL Study 2)], thrombocytopenia [19% vs. 8% (CLL Study 2)], pancytopenia [7% vs. 2% (CLL Study 1); 7% vs. 2% (CLL Study 2)], and infections [30% vs. 14% (CLL Study 2)].
Rheumatoid Arthritis
Among the 2,578 patients in global RA studies completed to date, 12% were 65–75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and younger patients. The rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events were higher in older patients.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis
Of the 99 rituximab-treated GPA and MPA patients in GPA/MPA Study 1, 36 (36%) were 65 years old and over, while 8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
In GPA/MPA Study 2, 30 (26%) of the enrolled patients were at least 65 years old, of which 12 patients were exposed to non-U.S.-licensed rituximab and 18 were exposed to azathioprine. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
None.