Included as part of the "PRECAUTIONS" Section
Severe hypersensitivity reactions may occur, even in patients who have
tolerated previous treatment with IgG. In case of hypersensitivity, discontinue
the HYQVIA infusion immediately and institute appropriate treatment.
Immune Globulin Infusion 10% (Human) of HYQVIA contains trace amount
of IgA (average concentration of 37 Âµg/mL). Patients with antibodies to IgA
potentially are at greater risk of developing potentially severe hypersensitivity
and anaphylactic reactions.
Thrombosis may occur following treatment with immune globulin products,
including HYQVIA. Risk factors may include advanced age, prolonged
immobilization, hypercoagulable conditions, history of venous or arterial
thrombosis, use of estrogens, indwelling central vascular catheters,
hyperviscosity, and cardiovascular risk factors. Thrombosis may occur
in the absence of known risk factors.
Consider baseline assessment of blood viscosity in patients at risk for
hyperviscosity, such as those with cryoglobulins, fasting chylomicronemia/
markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.
For patients at risk of thrombosis, administer HYQVIA at the minimum dose
and infusion rate practicable. Ensure adequate hydration in patients before
administration. Monitor for signs and symptoms of thrombosis and assess
blood viscosity in patients at risk for hyperviscosity. [see BOX WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION].
Immunogenicity Of Recombinant Human Hyaluronidase (PH20)
Eighteen percent (15 of 83) of subjects receiving HYQVIA in clinical
studies developed non-neutralizing antibodies to the Recombinant Human
Hyaluronidase component. The potential exists for such antibodies to crossreact
with endogenous PH20, which is known to be expressed in the adult
male testes, epididymis, and sperm. It is unknown whether these antibodies
can interfere with fertilization in humans. The clinical significance of these
antibodies is not known.
Aseptic Meningitis Syndrome (AMS)
AMS has been reported to occur with IgG products, including Immune
Globulin Infusion 10% (Human) administered intravenously and
subcutaneously. AMS may occur more frequently in female patients.
Discontinuation of IgG treatment has resulted in remission of AMS within
several days without sequelae. The syndrome usually begins within several
hours to two days following intravenously administered IgG.
AMS is characterized by the following signs and symptoms: severe headache,
nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea
and vomiting [see PATIENT INFORMATION]. Cerebrospinal fluid
(CSF) studies frequently reveal pleocytosis up to several thousand cells per
mm3, predominantly from the granulocytic series, and elevated protein levels
up to several hundred mg/dL, but negative culture results. Conduct a thorough
neurological examination on patients exhibiting such symptoms and signs,
including CSF studies, to rule out other causes of meningitis.
IgG products, including HYQVIA, contain blood group antibodies which may
act as hemolysins and induce in vivo coating of red blood cells (RBC) with
IgG. These antibodies may cause a positive direct antiglobulin reaction and
hemolysis6. Acute intravascular hemolysis has been reported following
intravenously administered IgG, including Immune Globulin Infusion 10%
(Human) administered intravenously, and delayed hemolytic anemia can
develop due to enhanced RBC sequestration [see ADVERSE REACTIONS].
Monitor patients for clinical signs and symptoms of hemolysis. If signs and/or
symptoms of hemolysis are present after HYQVIA infusion, perform appropriate
confirmatory laboratory testing [see PATIENT INFORMATION].
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular
nephropathy, osmotic nephrosis and death may occur upon use of IgG
products administered intravenously, especially those containing sucrose4.
HYQVIA does not contain sucrose. Acute renal dysfunction/failure has
been reported in association with Immune Globulin Infusion 10% (Human)
administered intravenously. Ensure that patients are not volume depleted
prior to the initiation of infusion of HYQVIA. In patients who are at risk of
developing renal dysfunction because of pre-existing renal insufficiency or
predisposition to acute renal failure (such as diabetes mellitus, age greater
than 65, volume depletion, sepsis, paraproteinemia, or patients receiving
known nephrotoxic drugs), monitor renal function and consider lower, more
Periodic monitoring of renal function and urine output is particularly
important in patients judged to be at increased risk for developing acute
renal failure. Assess renal function, including measurement of blood urea
nitrogen (BUN) and serum creatinine, before the initial infusion of HYQVIA
and again at appropriate intervals thereafter. If renal function deteriorates,
consider discontinuation of HYQVIA.
Spread Of Localized Infection
Infusion into or around an infected area can spread a localized infection.
Do not infuse HYQVIA into these areas due to potential risk of spreading a
Transfusion-Related Acute Lung Injury (TRALI)
Non-cardiogenic pulmonary edema (TRALI) may occur with intravenously
administered IgG and has been reported to occur with Immune Globulin
Infusion 10% (Human) administered intravenously. TRALI is characterized
by severe respiratory distress, pulmonary edema, hypoxemia, normal left
ventricular function, and fever. Symptoms typically occur within 1 to 6 hours
Monitor patients for pulmonary adverse reactions [see PATIENT INFORMATION]. If TRALI is suspected, conduct an evaluation, including
appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies
in both the product and patient serum. TRALI may be managed using oxygen
therapy with adequate ventilatory support.
Transmittable Infectious Agents
Because Immune Globulin Infusion 10% (Human) of HYQVIA is made from
human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses,
the variant CJD (vCJD) agent, and theoretically, the classic Creutzfeldt-Jakob
disease agent. This also applies to unknown or emerging viruses and other
pathogens. No cases of transmission of viral diseases or vCJD have been
associated with HYQVIA.
Report all infections thought to be possibly transmitted by HYQVIA to
Baxalta US Inc., at 1-800-423-2090 (in the U.S.).
Interference With Laboratory Tests
- After infusion of IgG, the transitory rise of the various passively transferred
antibodies in the patient’s blood may yield false positive serological testing
results, with the potential for misleading interpretation. Passive transmission
of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive
direct or indirect antiglobulin (Coombs’) test.
- Infusions of immune globulin products can lead to false positive readings
in assays that depend on detection of Ã-D-glucans for diagnosis of fungal
infections; this may persist during the weeks following infusion of the product.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
Inform patients to immediately report the following signs and symptoms to
their healthcare professional:
- Acute respiratory distress, wheezing, swelling of the airway or severe hives
or itching. [see WARNINGS AND PRECAUTIONS]
- Instruct patients to immediately report symptoms of thrombosis. These
symptoms may include pain and/or swelling of an arm or leg with warmth
over the affected area, discoloration of an arm or leg, unexplained shortness
of breath, chest pain or discomfort that worsens on deep breathing,
unexplained rapid pulse, numbness or weakness on one side of the body.
[see WARNINGS AND PRECAUTIONS]
- Advise patients that PH20 antibodies can develop. The potential exists for
such antibodies to cross-react with endogenous PH20, which is known to
be expressed in the adult male reproductive tract. The clinical significance
of these antibodies is unknown. [see WARNINGS AND PRECAUTIONS]
- Severe headache, neck stiffness, drowsiness, fever, sensitivity to light,
painful eye movements, nausea, and vomiting. [see WARNINGS AND PRECAUTIONS)]
- Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored
urine. [see WARNINGS AND PRECAUTIONS]
- Decreased urine output, sudden weight gain, fluid retention/edema, and/or
shortness of breath. [see WARNINGS AND PRECAUTIONS]
- Trouble breathing, chest pain, blue lips or extremities, or fever that
can occur 1 to 6 hours after an infusion of HYQVIA. [see WARNINGS AND PRECAUTIONS]
- Inform patients that HYQVIA is made from human plasma and may contain
infectious agents that can cause disease (e.g., viruses and, theoretically, the
vCJD agent). Patients should report any symptoms that concern them which
might be caused by virus infections. [see WARNINGS AND PRECAUTIONS]
- Inform the female patient of the possibility of participating in the pregnancy
registry. [see Use In Specific Populations]
- Inform patients that HYQVIA can interfere with their immune response to live
viral vaccines such as measles, mumps, rubella, and varicella, and instruct
patients to notify their healthcare professional of this potential interaction
when they are receiving vaccinations [see DRUG INTERACTIONS].
If self-administration is deemed appropriate by the
physician, give clear instructions and training on how to administer HYQVIA.
Document their ability to independently administer HYQVIA.
- Ensure the patient understands the importance of following regularly
scheduled infusions to maintain appropriate steady IgG levels.
- Instruct the patient to keep a treatment infusion log. This infusion log
should include information about each infusion such as, the lot number(s),
infusion site location, the time, date, dose, and any reactions.
- Inform the patient that due to the volume that can be infused, swelling
is common with HYQVIA. Mild to moderate local infusion-site reactions
(e.g., swelling and redness) are common side effects of facilitated
subcutaneous treatment with HYQVIA. Instruct the patient to contact their
healthcare professional if a local reaction increases in severity or persists
for more than a few days.
- Instruct the patient on the importance of following the directions for the
pump for infusion of the Immune Globulin Infusion 10% (Human) of HYQVIA.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Immune Globulin Infusion 10% (Human)
Long-term animal studies have not been conducted to evaluate the
carcinogenic potential of Immune Globulin Infusion 10% (Human) or its effect
An in vitro mutagenicity test was performed for Immune Globulin Infusion
10% (Human). No evidence of mutagenicity was observed.
Recombinant Human Hyaluronidase
Hyaluronidases are found in most tissues of the body. Long-term animal
studies to evaluate the carcinogenic or mutagenic potential of Recombinant
Human Hyaluronidase have not been conducted.
No adverse effects on fertility were observed in mice, rabbits and
cynomolgus monkeys exposed to antibodies that bind to Recombinant
Human Hyaluronidase and species-specific hyaluronidase. Reversible
infertility has been observed in male and female guinea pigs immunized to
produce antibodies to hyaluronidase. However, antibodies to hyaluronidase
did not influence reproduction following immunization of mice, rabbits,
sheep, or cynomolgus monkeys. The effects of antibodies that bind to
Recombinant Human Hyaluronidase on human fertility are unknown.
Use In Specific Populations
No human data are available to indicate the presence or absence of drugassociated
risk. Animal reproduction studies have not been conducted with
Immune Globulin Infusion 10% (Human) component of HYQVIA. It is not known
whether HYQVIA can cause fetal harm when administered to a pregnant woman
or can affect reproduction capacity. Immune globulins cross the placenta from
maternal circulation increasingly after 30 weeks of gestation.
Development and reproductive toxicology studies have been conducted
with Recombinant Human Hyaluronidase in mice and rabbits [see Animal Pharmacology]. No adverse effects on pregnancy were
associated with anti-rHuPH20 antibodies. In these studies, maternal antibodies
to Recombinant Human Hyaluronidase were transferred to offspring in utero.
The effects of antibodies to the Recombinant Human Hyaluronidase component
of HYQVIA on the human embryo or on human fetal development are unknown.
HYQVIA should be given to a pregnant woman only if clearly indicated.
Women who become pregnant during HYQVIA treatment are encouraged to
enroll in the HYQVIA Pregnancy Registry by calling 1-866-424-6724.
No human data are available to indicate the presence or absence of drugassociated
risk. In animal studies, maternal antibodies binding to Recombinant
Human Hyaluronidase were transferred to offspring during lactation. No adverse
effects on pregnancy or offspring development were associated with antirHuPH20
antibodies. The effects of antibodies that bind to Recombinant Human
Hyaluronidase of HYQVIA transferred during human lactation are unknown. The
developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for HYQVIA and any potential adverse effects on
the breastfed infant from HYQVIA or from the underlying maternal condition.
Females And Males Of Reproductive Potential
Animal studies do not indicate direct or indirect harmful effects of Recombinant
Human Hyaluronidase with respect to reproductive potential at the doses used
for facilitating administration of IG 10%. [See Carcinogenesis, Mutagenesis,
Impairment Of Fertility]
Safety has not been established in children.
HYQVIA was evaluated in 7 subjects over age 65 in the clinical trial. The
available data are too limited to draw safety conclusions.
4. Pierce LR, Jain N. Risks associated with the use of intravenous
Transfusion Med Rev. 2003;17:241-251.
6. Daw Z, Padmore R, Neurath D, Cober N, Tokessy M, Desjardins D, et al.
Hemolytic transfusion reactions after administration of intravenous immune