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Medizinisch geprüft von Oliinyk Elizabeth Ivanovna, Apotheke Zuletzt aktualisiert am 27.05.2022
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Important Dosing Information
Administer only as an intravenous infusion .
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 .
Premedicate before each infusion .
Prior To First Infusion
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE . Obtain complete blood counts including platelets (CBC) 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 . In patients with 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.
- First 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.
- 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 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 ≥5,000/mm³ before Cycle 2 should not be administered the 90-minute infusion . - Interrupt the infusion or slow the infusion rate for infusion-related reactions . 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:
- 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
- Infuse RUXIENCE 250 mg/m² within 4 hours prior to the administration of Indium-111-(In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin.
- Administer RUXIENCE and In-111-Zevalin 7-9 days prior to RUXIENCE and Y-90- Zevalin.
- Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
Recommended Dose For Granulomatosis With Polyangiitis (GPA) (Wegener"s Granulomatosis) And Microscopic Polyangiitis (MPA)
Induction Treatment Of Patients With Active GPA/MPA
- Administer RUXIENCE as a 375 mg/m² intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA.
- Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. 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 Patients With GPA/MPA Who Have Achieved Disease Control With Induction Treatment
- 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.
- Patients should receive 100 mg intravenous methylprednisolone to be completed 30 minutes prior to each RUXIENCE infusion.
- If induction treatment of active disease was with a rituximab product, follow up treatment with RUXIENCE should be initiated 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.
- If induction treatment of active disease was with other standard of care immunosuppressants, RUXIENCE follow up treatment should be initiated 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 patients administered RUXIENCE according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion .
For GPA and MPA patients, glucocorticoids are given in combination with RUXIENCE (Wegener"s Granulomatosis) and Microscopic Polyangiitis (MPA)). 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 .
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
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, USP, or 5% Dextrose Injection, USP. 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
Diluted RUXIENCE solutions for infusion may be stored at 2°C to 8°C (36°F to 46°F) for 24 hours. Complete administration within 8 hours from removal from refrigeration. No incompatibilities between RUXIENCE and polyvinylchloride bags have been observed.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Infusion-Related Reactions
Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.
Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RUXIENCE. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm³ ) .
Severe Mucocutaneous Reactions
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue RUXIENCE in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined.
Hepatitis B Virus (HBV) Reactivation
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody (anti-HBs) positive).
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur.
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE. For patients who show evidence of prior hepatitis B infection (HBsAg positive (regardless of antibody status) or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RUXIENCE treatment.
Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RUXIENCE therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy.
In patients who develop reactivation of HBV while on RUXIENCE, immediately discontinue RUXIENCE and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RUXIENCE treatment in patients who develop HBV reactivation. Resumption of RUXIENCE treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.
Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab.
Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.
Discontinue RUXIENCE and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Tumor Lysis Syndrome (TLS)
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of rituximab products in patients with NHL. A high number of circulating malignant cells (≥25,000/mm³ ) or high tumor burden, confers a greater risk of TLS.
Administer aggressive intravenous hydration and anti-hyperuricemic 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 .
Infections
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been 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. Discontinue RUXIENCE for serious infections and institute appropriate anti-infective therapy . RUXIENCE is not recommended for use in patients with severe, active infections.
Cardiovascular Adverse Reactions
Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RUXIENCE for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina .
Renal Toxicity
Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RUXIENCE is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RUXIENCE in patients with a rising serum creatinine or oliguria ).
Bowel Obstruction And Perforation
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.
Immunization
The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.
Embryo-Fetal Toxicity
Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving RUXIENCE and for 12 months following the last dose of RUXIENCE.
Concomitant Use With Other Biologic Agents And DMARDS In GPA And MPA
Limited data are available on the safety of the use of biologic agents or disease modifying antirheumatic drugs (DMARDs). Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with rituximab products.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Infusion-Related Reactions
Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions including urticaria, hypotension, angioedema, sudden cough, breathing problems, weakness, dizziness, palpitations, or chest pain .
Severe Mucocutaneous Reactions
Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules .
Hepatitis B Virus Reactivation
Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes .
Progressive Multifocal Leukoencephalopathy (PML)
Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems .
Tumor Lysis Syndrome (TLS)
Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy .
Infections
Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, oral herpes simplex infection, and painful wounds with erythema and advise patients of the increased risk of infections during and after treatment with RUXIENCE .
Cardiovascular Adverse Reactions
Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats .
Renal Toxicity
Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor kidney function .
Bowel Obstruction And Perforation
Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting .
Embryo-Fetal Toxicity
Advise a pregnant woman of the potential risk to a fetus. Advise female patients that rituximab products can cause fetal harm if taken during pregnancy and to use effective contraception during treatment with RUXIENCE and for at least 12 months after the last dose of RUXIENCE. Advise patients to inform their healthcare provider of a known or suspected pregnancy .
Lactation
Advise women not to breastfeed during treatment with RUXIENCE and for 6 months after the last dose .
This product"s label may have been updated. For current full prescribing information, please visit www.pfizer.com.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab products or to determine potential effects on fertility in males or females.
Use In Specific Populations
Pregnancy
Risk Summary
Based on human data, rituximab products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero . 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
Risk Summary
There are no data on the presence of rituximab products in human milk, the effect on the breastfed child, or the effect on milk production. However, rituximab is detected in the milk of lactating cynomolgus monkeys, and IgG is present in human milk. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of RUXIENCE due to the potential for serious adverse reactions in breastfed infants.
Females And Males Of Reproductive Potential
Rituximab products can cause fetal harm .
Contraception
Females
Females of childbearing potential should use effective contraception while receiving RUXIENCE and for 12 months following treatment.
Pediatric Use
The safety and effectiveness of rituximab products in pediatric patients have not been established.
Hypogammaglobulinemia has been observed in pediatric patients treated with rituximab.
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 11 or in CLL Study 12; 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 12 . 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 11, the dose intensity of rituximab was similar in older and younger patients, however in CLL Study 12 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 11); 56% vs. 39% (CLL Study 12)), febrile neutropenia (16% vs. 6% (CLL Study 10 (NCT00719472)), anemia (5% vs. 2% (CLL Study 11); 21% vs. 10% (CLL Study 12)), thrombocytopenia (19% vs. 8% (CLL Study 12)), pancytopenia (7% vs. 2% (CLL Study 11); 7% vs. 2% (CLL Study 12)), and infections (30% vs. 14% (CLL Study 12)).
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.