Literature Scan
Higher Childhood Leukemia Risk in Offspring Raises
Questions About Hormonal Contraceptive Safety
Children born to women who were
using hormonal contraception within
three months of pregnancy and during
pregnancy have a higher risk of devel-
oping myeloid leukemia than those born
to mothers who were not using
hormonal contraception, according
to a nationwide cohort study pub-
lished in Lancet Oncology. Results
of the study suggest that exposure
to hormonal contraception in utero
is a potential predictor for child-
hood leukemia – a disease with few
established risk factors, given the
known association between expo-
sure to exogenous sex hormones
and tumor development.
“The strength of the associa-
tions and the biologic plausibility
of hormones causing cancer in
children show that these results are
strong enough to cause concern,”
study author Marie Hargreave,
PhD, from the Danish Cancer So-
ciety Research Center in Copenha-
gen, told ASH Clinical News. “Our
results can have direct implications
for clinical guidelines on how we
use hormonal contraception up to
pregnancy in the near future and
will potentially protect future gen-
erations of children from potential
harmful exposures before birth.”
Using data from the Danish
Cancer Registry and the Danish
Medical Birth Registry, investiga-
tors identified 1,185,157 children
born between 1996 and 2014. The
researchers then used the Danish
National Prescription Registry to
determine children’s exposure to
hormonal contraceptives, using the
following definitions:
• no use: mothers who never
used contraception prior to
birth (n=270,291)
• previous use (defined as
prescriptions filled):
mothers who used hormonal
contraceptives >3 months
prior to the start of pregnancy
(n=778,844)
• recent use: mothers who used
hormonal contraceptives ≤3
months prior to and during
pregnancy (n=136,022)
During a median of 9.3 years (range
= 4.6-14.2 years) from birth, 606
children were diagnosed with either
lymphoid leukemia (n=465) or
myeloid leukemia (n=141).
42
ASH Clinical News
Compared with children of women
who reported never using hormonal
contraception, children born to women
with recent use had a significantly higher
risk for any leukemia (primary endpoint;
hazard ratio [HR] = 1.46; 95% CI 1.09-
1.96; p=0.011). Among children who
were exposed to hormonal contraception
in utero, the HR rose non-significantly to
1.78 (95% CI 0.95-3.31; p=0.070).
JIVI ® [antihemophilic factor (recombinant), PEGylated-aucl]
lyophilized powder for solution, for intravenous use
Initial U.S. Approval: 2018
BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Jivi, antihemophilic factor (recombinant), PEGylated-aucl, is a
recombinant DNA-derived, Factor VIII concentrate indicated for
use in previously treated adults and adolescents (12 years of age
and older) with hemophilia A (congenital Factor VIII deficiency) for:
• On-demand treatment and control of bleeding episodes
• Perioperative management of bleeding
• Routine prophylaxis to reduce the frequency of bleeding episodes
Limitations of Use
Jivi is not indicated for use in children < 12 years of age due to
greater risk for hypersensitivity reactions [see Use in Specific
Populations (8.4)]. Jivi is not indicated for use in previously
untreated patients (PUPs).
Jivi is not indicated for the treatment of von Willebrand disease.
4
CONTRAINDICATIONS
Jivi is contraindicated in patients who have a history of
hypersensitivity reactions to the active substance, polyethylene
glycol (PEG), mouse or hamster proteins, or other constituents of
the product [see Description (11)].
There was no statistically signifi-
cant association between previous use
and lymphoid leukemia risk (HR=1.23;
95% CI 0.97-1.57; p=0.089) or between
recent use and lymphoid leukemia risk
5.4 Monitoring Laboratory Tests
• If monitoring of Factor VIII activity is performed, use a validated
chromogenic assay or a selected validated one-stage clotting
assay [see Dosage and Administration (2.1)].
• Laboratories intending to measure the Factor VIII activity of
Jivi should check their procedures for accuracy. For Jivi, select
silica-based one-stage assays may underestimate the Factor
VIII activity of Jivi in plasma samples; some reagents, e.g., with
kaolin-based activators, have the potential for overestimation 1 .
Therefore, the suitability of the assay must be ascertained. If a
validated one-stage clotting or chromogenic assay is not available
locally, then use of a reference laboratory is recommended.
• Monitor for development of Factor VIII inhibitors. Perform a
Bethesda inhibitor assay if expected Factor VIII plasma levels
are not attained or if bleeding is not controlled with the expected
dose of Jivi. Use Bethesda Units (BU) to report inhibitor titers.
6
ADVERSE REACTIONS
The most frequently (≥ 5%) reported adverse reactions in clinical
trials in previously treated patients (PTPs) ≥ 12 years of age were
headache, cough, nausea and fever (see Table 3).
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in clinical trials of another
drug and may not reflect the rates observed in clinical practice.
A total of 221 subjects constituted the safety population from three
studies. Subjects who received Jivi for perioperative management
(n=17) with treatment period of 2 to 3 weeks were excluded
from pooled safety analysis but included in analysis for inhibitor
development. The median EDs for adults and adolescents (≥ 12 years
of age) was 131 EDs (range: 1–309) per subject; and the median EDs
for subjects < 12 years of age was 53 EDs (range: 1–68) per subject.
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions, including severe allergic reactions, have
occurred with Jivi. Monitor patients for hypersensitivity symptoms.
Early signs of hypersensitivity reactions, which can progress
to anaphylaxis, may include chest or throat tightness, dizziness,
mild hypotension and nausea. If hypersensitivity reactions occur, Table 3: Adverse Reactions reported for Jivi
immediately discontinue administration and initiate appropriate
MedDRA Standard
All
Subjects ≥12
treatment.
System Organ Class
Subjects years of age
Jivi may contain trace amounts of mouse and hamster proteins
Preferred term
n (%)
n (%)
[see Description (11)]. Patients treated with this product may
n=221
n=148
develop hypersensitivity to these non-human mammalian proteins.
Gastrointestinal Disorders
Hypersensitivity reactions may also be related to antibodies against
Abdominal pain
9 (4%)
5 (3%)
polyethylene glycol (PEG) [see Warnings and Precautions (5.3)].
Nausea
9 (4%)
8 (5%)
5.2 Neutralizing Antibodies
Vomiting
10 (5%)
5 (3%)
Neutralizing antibody (inhibitor) formation can occur following
General Disorders and
administration of Jivi. Carefully monitor patients for the development
Administration Site Conditions
of Factor VIII inhibitors, using appropriate clinical observations and
a
4 (2%)
2 (1%)
laboratory tests. If expected plasma Factor VIII activity levels are not Injection site reactions
Pyrexia
(fever)
20
(9%)
8 (5%)
attained or if bleeding is not controlled as expected with administered
Immune
System
Disorders
dose, suspect the presence of an inhibitor (neutralizing antibody)
Hypersensitivity
8 (4%)
3 (2%)
[see Warnings and Precautions (5.4)].
Nervous System Disorders
5.3 Immune Response to PEG
3 (1%)
3 (2%)
A clinical immune response associated with IgM anti-PEG antibodies, Dizziness
Dysgeusia
(distorted
sense
of
taste)
1
(1%)
0
manifested as symptoms of acute hypersensitivity and/or loss of
Headache
29
(13%)
21
(14%)
drug effect, has been observed primarily in patients < 6 years of age
[see Warnings and Precautions (5.1) and Use in Specific Populations Psychiatric Disorders
(8.4)]. The symptoms of the clinical immune response were Insomnia
5 (2%)
4 (3%)
transient. Anti-PEG IgM titers decreased over time to undetectable Respiratory, Thoracic and
levels. No immunoglobulin class switching was observed.
Mediastinal Disorders
In case of clinical suspicion of loss of drug effect, conduct testing Cough
18 (8%)
10 (7%)
for Factor VIII inhibitors [see Warnings and Precautions (5.4) and Skin and Subcutaneous Tissue
Adverse Reactions (6.1)] and Factor VIII recovery.
Disorders
A low post-infusion Factor VIII level in the absence of detectable Erythema b (redness)
3 (1%)
2 (1%)
Factor VIII inhibitors indicates that loss of drug effect is likely due Pruritus (itching)
2 (1%)
1 (1%)
to anti-PEG antibodies. Discontinue Jivi and switch patients to a Rash c
9 (4%)
3 (2%)
previously effective Factor VIII product.
B:17
T:15
S:1