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DRUG INTERACTIONS

Formal drug interaction studies have not been performed with rituximab products . In patients with CLL , rituximab did not alter systemic exposure to fludarabine or cyclophosphamide . In clinical trials of patients with another indication , concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab .

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 . Because of the potential of serious adverse reactions in the breastfed child , advise women not to breastfeed during treatment with RUXIENCE and for at least 6 months after the last dose .

Females and Males of Reproductive Potential Contraception Rituximab products can cause fetal harm when administered to a pregnant woman .

Females Advise females of reproductive potential to use effective contraception during treatment with RUXIENCE and for at least 12 months after the last dose .

Pediatric Use The safety and effectiveness of rituximab products have not been established in pediatric patients with NHL or CLL .

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 . 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 )].

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 pregnant women of the potential risk to a fetus . Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy .

Advise females of reproductive potential to use effective contraception during treatment with RUXIENCE and for at least 12 months after the last dose .

Lactation Advise women not to breastfeed during treatment with RUXIENCE and for at least 6 months after the last dose . This product ' s label may have been updated . For current full prescribing information , please visit www . RuxienceHCP . com .

This Brief Summary is based on : LAB-1273-2.0 PP-RIT-USA-0176