Included as part of the PRECAUTIONS section.
In the SUSTAIN clinical trial, infusion-related reactions
(defined as occurring within 24 hours of infusion) were observed in 2 (3%)
patients treated with ADAKVEO 5 mg/kg. Monitor patients for signs and symptoms
of infusion-related reactions, which may include fever, chills, nausea,
vomiting, fatigue, dizziness, pruritus, urticaria, sweating, shortness of
breath or wheezing. Discontinue ADAKVEO infusion for severe reactions and
institute appropriate medical care.
Laboratory Test Interference
Interference with automated platelet counts (platelet
clumping) has been observed following administration of ADAKVEO, in particular
when blood samples were collected in tubes containing
ethylenediaminetetraacetic acid (EDTA). Mitigation strategies are recommended [see
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Advise patients to contact their healthcare provider
immediately for signs or symptoms of infusion-related reactions [see WARNINGS
Interference With Automated Platelet Counts
Advise patients to inform their healthcare provider that
they are receiving ADAKVEO prior to any blood tests due to the potential
interference with laboratory tests used to measure platelet counts [see WARNINGS
Impairment Of Fertility
No carcinogenicity or
genotoxicity studies have been conducted with crizanlizumab-tmca.
In the 26-week repeat-dose
toxicity study, cynomolgus monkeys were administered crizanlizumab-tmca once
every 4 weeks at doses up to 50 mg/kg (at least 13.5 times the human clinical
exposure based on AUC in patients with sickle cell disease at 5 mg/kg once
every 4 weeks). There were no adverse effects of crizanlizumab-tmca on male or
female reproductive organs.
Use In Specific Populations
Based on data from animal studies, ADAKVEO has the
potential to cause fetal harm when administered to a pregnant woman. In an
animal reproduction study, intravenous administration of crizanlizumab-tmca to
pregnant cynomolgus monkeys from the onset of organogenesis through delivery
resulted in a non-dose related increased fetal loss (abortions/stillbirths) at
doses approximately 2.8 times the exposure at the recommended clinical dose at
5 mg/kg/dose once every 4 weeks (see Data).
There are insufficient human data on ADAKVEO use in
pregnant women to evaluate for a drug-associated risk of major birth defects,
miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of
the potential risk to a fetus. ADAKVEO should only be used during pregnancy if
the expected benefit to the patient justifies the potential risk to the fetus.
The estimated background risk of major birth defects and
miscarriage for the indicated population is approximately 14% and up to 43%,
respectively. All pregnancies have a background risk of birth defect, loss, or
other adverse outcomes.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Women with sickle cell disease have an increased risk of
adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at
greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality. For
the fetus, there is an increased risk for intrauterine growth restriction,
preterm delivery, low birth weight, and perinatal mortality.
In an enhanced pre-and postnatal development study in
cynomolgus monkeys, pregnant animals received intravenous doses of
crizanlizumab-tmca at 10 and 50 mg/kg once every 2 weeks during the period of
onset of organogenesis through delivery. No maternal toxicity was observed.
Maternal exposures at doses of 10 and 50 mg/kg were between 2.8 and 16 times,
respectively, the human clinical exposure based on area under the curve (AUC)
in patients with sickle cell disease at 5 mg/kg/dose once every 4 weeks. There
was an increase in fetal loss (abortions or still births) at both
crizanlizumabtmca doses which was higher in the third trimester.
There were no effects on infant growth and development
through 6-months postpartum that were attributable to crizanlizumab-tmca.
Measurable crizanlizumab-tmca serum concentrations were
observed in the infant monkeys at postnatal Day 28, confirming that
crizanlizumab crosses the placental barrier.
There is no data on the presence of crizanlizumab-tmca in
human or animal milk, the effects on the breastfed child, or the effects on
milk production. Maternal IgG is known to be present in human milk. The effects
of local gastrointestinal exposure and limited systemic exposure in the
breastfed child to crizanlizumab-tmca are unknown.
The developmental and health benefits of breast-feeding
should be considered along with the motherÃ¢â¬™s clinical need for ADAKVEO and any
potential adverse effects on the breastfed child from ADAKVEO or from the
underlying maternal condition.
The safety and effectiveness of ADAKVEO for sickle cell
disease have been established in pediatric patients aged 16 years and older.
Use of ADAKVEO for sickle cell disease is supported by evidence from adequate
and well-controlled studies in adults and pediatric patients (SUSTAIN Trial).
The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO 5 mg/kg
aged 16 years old [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical
The safety and efficacy of ADAKVEO in pediatric patients
below the age of 16 years have not been established.
Clinical studies of ADAKVEO did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects.