You Make the Call : Readers ’ Response
until hemostasis is achieved . Are my dosing recommendations correct ?
For major surgery or patients with bleeding history with vWD , I usually use 50 IU / kg every 12 hours for three days and start 12 hours prior to a procedure .
William Caceres , MD San Juan VA Medical Center
Río Piedras , Puerto Rico
I might consider daily infusions at home to keep her level up , should she go into labor beforehand , and 2,400 units is close to what I might choose as a daily dose . I would probably induce earlier than week 39 if all indicators suggest child is matured . Giving Humate-P , which has less FVIII than vWF , seems appropriate . Also , she has had this product previously . I agree with the dose before epidural and keeping vWF : RCo above 50 percent by bolus every 12 hours . I would give an additional dose proximal to parturition if the prior dose was more than six hours earlier . Postpartum , I would maintain vWF above 50 percent for three days . Beyond that , dosing depends on the non-pregnant baseline vWF and FVIII levels , as well as bleeding symptoms . I would prefer FVIII above 30 percent for at least a week to 10 days and use Humate-P to maintain vWF near 30 percent until day five .
Ken D . Friedman , MD BloodCenter of Wisconsin
Milwaukee , WI remained generally constant over the follow-up period in both cohorts . All patients who tested positive for anti-recombinant human hyaluronidase antibodies at any point during the study were negative for neutralizing antibodies .
In the SAWYER study , where previously untreated patients with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC , the incidence of treatment-induced / enhanced anti-rituximab antibodies was 2.4 % in the RITUXAN HYCELA group vs . 6.7 % in rituximab group . The incidence of treatmentinduced / enhanced anti- recombinant human hyaluronidase antibodies was 10.6 % in the RITUXAN HYCELA treatment arm . None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies .
The clinical relevance of the development of anti-rituximab or anti-recombinant human hyaluronidase antibodies after treatment with RITUXAN HYCELA is not known .
6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rituximab-containing products . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
• Hematologic : prolonged pancytopenia , marrow hypoplasia , Grade 3 – 4 prolonged or lateonset neutropenia , hyperviscosity syndrome in Waldenstrom ’ s macroglobulinemia , prolonged hypogammaglobulinemia
• Cardiac : fatal cardiac failure
• Immune / Autoimmune Events : uveitis , optic neuritis , systemic vasculitis , pleuritis , lupus-like syndrome , serum sickness , polyarticular arthritis , and vasculitis with rash .
• Infection : viral infections , including progressive multifocal leukoencephalopathy ( PML ), increase in fatal infections in HIV-associated lymphoma , and a reported increased incidence of Grade 3 and 4 infections
• Neoplasia : disease progression of Kaposi ’ s sarcoma .
• Skin : severe mucocutaneous reactions .
• Gastrointestinal : bowel obstruction and perforation .
• Pulmonary : fatal bronchiolitis obliterans and fatal interstitial lung disease .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy
Risk Summary Based on human data , rituximab-containing products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to rituximab in-utero ( see Clinical Considerations ). There are no available data on RITUXAN HYCELA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage . In animal reproduction studies , intravenous administration of a rituximab product 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 . Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at a dose > 2700 times higher than the human dose . Comparable systemic exposure levels could occur in a pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA ( see Data ). 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 population 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 RITUXAN HYCELA for subcutaneous injection contains rituximab and hyaluronidase human [ see Description ( 11 )].
Rituximab Product :
• 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 .
Hyaluronidase Human :
• In an embryo-fetal study , mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U / kg , which is > 2700 times higher than the human dose . The study found no evidence of teratogenicity . Reduced fetal weight and increased numbers of fetal resorptions were observed , with no effects found at a daily dose of 360,000 U / kg , which is > 450 times higher than the human dose .
• In a peri-and post-natal reproduction study , mice have been dosed daily by subcutaneous injection , with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U / kg , which is > 1,300 times higher than the human dose . The study found no adverse effects on sexual maturation , learning and memory or fertility of the offspring .
8.2 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 . 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 RITUXAN HYCELA due to the potential for serious adverse reactions in breastfed infants .
8.3 Females and Males of Reproductive Potential Rituximab-containing products can cause fetal harm [ see Use in Specific Populations ( 8.1 )].
Contraception Females
Females of childbearing potential should use effective contraception while receiving RITUXAN HYCELA and for 12 months following treatment .
8.4 Pediatric Use The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established .
8.5 Geriatric Use Of the total number of subjects in the SABRINA , MabEase , and SAWYER studies , 37 % were 65 and over , while 10 % were 75 and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ).
Severe Mucocutaneous Reactions Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions , including painful sores or ulcers on the lips or mouth , blisters , peeling skin , rash , and pustules [ see Warnings and Precautions ( 5.1 )].
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 [ see Warnings and Precautions ( 5.2 )].
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 [ see Warnings and Precautions ( 5.3 )].
Hypersensitivity and Other Administration Reactions Inform patients about the signs and symptoms of hypersensitivity and administration-related reactions . Advise patients to contact their healthcare provider immediately to report symptoms of administrationrelated reactions including dizziness , nausea , chills , fever , vomiting , diarrhea , urticaria , angioedema , breathing problems , or chest pain [ see Warnings and Precautions ( 5.4 )].
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 [ see Warnings and Precautions ( 5.5 )].
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 , cold sores , and painful wounds with erythema [ see Warnings and Precautions ( 5.6 )].
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 [ see Warnings and Precautions ( 5.7 )].
Renal Toxicity Advise patients of the risk of renal toxicity . Inform patients of the need for healthcare providers to monitor kidney function [ see Warnings and Precautions ( 5.8 )].
Bowel Obstruction and Perforation Advise patients to contact their healthcare provider immediately for sign and symptoms of bowel obstruction and perforation , including severe abdominal pain or repeated vomiting [ see Warnings and Precautions ( 5.9 )].
Embryo-Fetal Toxicity Advise a pregnant woman of the potential risk to a fetus . Advise female patients that rituximab containing products can cause fetal harm if taken during pregnancy and to use effective contraception during treatment with RITUXAN HYCELA and for at least 12 months after the last dose of RITUXAN HYCELA . Advise patients to inform their healthcare provider of a known or suspected pregnancy [ see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.1 , 8.3 )].
Lactation Advise women not to breastfeed during treatment with RITUXAN HYCELA and for 6 months after the last dose [ see Use in Specific Populations ( 8.2 )].
RITUXAN HYCELA ™ [ rituximab and hyaluronidase human ]
Manufactured by : Genentech , Inc . A Member of the Roche Group 1 DNA Way South San Francisco , CA 94080-4990
U . S . License No .: 1048
RITUXAN HYCELA ™ is a trademark of Biogen .
Jointly marketed by : Biogen and Genentech USA , Inc .
© 2017 Biogen and Genentech USA , Inc .
RSC / 062017 / 0061 06 / 17
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