Bivigam Drug Information
Generic name: IMMUNE GLOBULIN INTRAVENOUS (HUMAN) 10%
Human Immunoglobulin G [EPC]
Uses of Bivigam
Primary Humoral Immunodeficiency
BIVIGAM is an Immune Globulin Intravenous (Human), 10% Liquid, indicated for the treatment of adults and pediatric patients 2 years of age and older with primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
Dosage & Administration of Bivigam
| PI | 300-800 mg/kg every 3-4 weeks |
|---|
Side Effects of Bivigam
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice. In a multicenter, open-label, non-randomized clinical trial, 63 subjects with PI, on regular IGIV replacement therapy, received doses of BIVIGAM ranging from 254 to 1029 mg/kg (median dose 462.8 mg/kg) every 3 weeks or 4 weeks for up to 12 months (mean 317.3 days; range 66 – 386 days) ( see Clinical Studies ). The use of pre-medication was discouraged; however, if subjects required pre-medication (antipyretic, antihistamine, or antiemetic agent) for recurrent reactions to immune globulins, they were allowed to continue those medications for this trial. Of the 746 infusions administered, 41 (65%) subjects received premedication prior to 415 (56%) infusions.
Fifty-nine subjects (94%) had an adverse reaction at some time during the study. The proportion of subjects who had at least one adverse reaction was the same for both the 3- and 4-week cycles. The most common adverse reactions observed in this clinical trial were headache (32 subjects, 51%), sinusitis (24 subjects, 38%), fatigue (18 subjects, 29%), upper respiratory tract infection (16 subjects, 25%), diarrhea (13 subjects, 21%), cough (14 subjects, 22%), bronchitis (12 subjects, 19%), pyrexia (12 subjects, 19%), and nausea (9 subjects, 14%). Adverse reactions (ARs) are those occurring during or within 72 hours after the end of an infusion.
In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of BIVIGAM infusions with one or more temporally associated adverse reactions was 31%. The total number of adverse reactions was 431 (a rate of 0.58 ARs per infusion). Table 2: Adverse Reactions (ARs) (within 72 hours after the end of a BIVIGAM infusion) in ≥5% of Subjects ARs No. Subjects Reporting ARs (% of Subjects) No. Infusions With ARs (% of Infusions) Headache 27 (43%) 115 (15.4%) Fatigue 15 (24%) 59 (7.9%) Infusion Site Reaction 5 (8%) 5 (0.7%) Nausea 5 (8%) 8 (1.1%) Sinusitis 5 (8%) 5 (0.7%) Blood Pressure Increased 4 (6%) 5 (0.7%) Diarrhea 4 (6%) 4 (0.5%) Dizziness 4 (6%) 4 (0.5%) Lethargy 4 (6%) 4 (0.5%) Back Pain 3 (5%) 3 (0.4%) Blood Pressure Diastolic Decreased 3 (5%) 5 (0.7%) Fibromyalgia a 3 (5%) 17 (2.3%) Migraine 3 (5%) 8 (1.1%) Myalgia 3 (5%) 4 (0.5%) Pharyngolaryngeal Pain 3 (5%) 3 (0.4%) a Symptoms occurring under pre-existing fibromyalgia Seven subjects (11.1%) experienced 11 serious ARs.
Two of these were related serious ARs (vomiting and dehydration) that occurred in one subject. One subject withdrew from the study due to ARs related to BIVIGAM (lethargy, headache, tachycardia and pruritus). All 63 subjects enrolled in this study had a negative direct antiglobulin (Coombs’) test at baseline. During the study, no subjects showed clinical evidence of hemolytic anemia.
No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. During the clinical trial no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). There was a single positive finding for parvovirus (B19 virus) during the study. This subject came in contact with acute B19 virus from working at a school, greeting children, where a child was reported to have symptomatic Fifth's disease. There was no cluster (no other cases in other subjects) of B19 virus transmission with the IGIV batch concerned.
Pediatric Only Study In a prospective, open-label, single-arm, multi-center study, 16 children and adolescents with PI received doses of BIVIGAM ranging from 300 to 800 mg/kg every 3-weeks (±7 days) days (actual doses ranged from 350 mg/kg to 1077 mg/kg) or 4-weeks (±7 days) (actual doses ranged from 312 mg/kg to 693 mg/kg), for up to 5 months. In this study, four subjects (25.0%) experienced a total of 9 adverse reactions. Adverse reactions (ARs) are those occurring during or within 72 hours after the end of an infusion.
All ARs were of mild (3 events) or moderate severity (6 events). No infusion site reactions occurred during the study. No deaths and no treatment-related SAEs occurred during the study. Seven of the 96 (7.3%) BIVIGAM infusions administered were temporally associated with an adverse reaction.
Two infusions were associated with more than one AR. Table 3: Adverse Reactions (ARs) within 72 hours after the end of a BIVIGAM Infusion Adverse Reaction (AR) Number of Subjects Reporting AR (n=16) % of Subjects Reporting AR (n=16) Number of Infusions with AR (n=96) % of Infusions with AR (n=96) Fatigue 1 6 2 2 Headache 3 19 5 5 Nausea 1 6 1 1 Rash 1 6 1 1
Postmarketing Experience
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. The following adverse reactions have been identified and reported during the post-approval use of IGIV products: Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Associated Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm. Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension.
Neurological: Coma, loss of consciousness, seizures, tremor. Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis. Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test.
General/Body as a Whole: Pyrexia, rigors. Musculoskeletal: Back pain. Gastrointestinal: Hepatic dysfunction, abdominal pain.
Warnings & Cautions for Bivigam
Thrombosis Thrombosis may occur following treatment with immune globulin products (IGIV), including
BIVIGAM. 4,5,6 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, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer BIVIGAM 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 Boxed Warning, Dosage and Administration , Patient Counseling Information ).
Hypersensitivity Severe hypersensitivity reactions may occur with
IGIV products, including BIVIGAM. In case of hypersensitivity, discontinue BIVIGAM infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. BIVIGAM contains trace amounts of IgA (≤ 200 micrograms per milliliter) ( see Description ). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions.
BIVIGAM is contraindicated in IgA deficient patients with antibodies against IgA and a history of hypersensitivity reaction ( see Contraindications ).
Acute Renal Dysfunction and Acute Renal Failure Acute renal dysfunction/failure, osmotic nephrosis
and death 1,2 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering BIVIGAM. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure 2. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing BIVIGAM ( see Patient Counseling Information ). 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, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer BIVIGAM at the minimum infusion rate practicable ( see Dosage and Administration ).
Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia Hyperproteinemia, increased serum viscosity, and hyponatremia
may occur in patients receiving IGIV therapy, including BIVIGAM. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events 3.
Aseptic Meningitis Syndrome (AMS)
AMS may occur infrequently with IGIV treatments including BIVIGAM. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 7,8,9 AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting ( see Patient Counseling Information ). Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, 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 signs and symptoms, including CSF studies, to rule out other causes of meningitis.
AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.
Hemolysis
IGIV products, including BIVIGAM, may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. 10,11,12 Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration, 13 and acute hemolysis, consistent with intravascular hemolysis, has been reported. Monitor patients for clinical signs and symptoms of hemolysis ( see Patient Counseling Information ). If these are present after BIVIGAM infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.
Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients
following IGIV treatment 14 including BIVIGAM. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions.
If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum ( see Patient Counseling Information ). TRALI may be managed using oxygen therapy with adequate ventilatory support.
Transmissible Infectious Agents
Because BIVIGAM is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to ADMA Biologics at 1-800-458-4244. Before prescribing BIVIGAM, the physician should discuss the risks and benefits of its use with the patient ( see Patient Counseling Information ).
Monitoring Laboratory Tests Periodic monitoring of renal function and urine output is
particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis with IGIV treatment, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.
If signs and/or symptoms of hemolysis are present after an infusion of BIVIGAM, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.10 Interference with Laboratory Tests After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield 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.
Drug Interactions with Bivigam
Live Virus Vaccines Immunoglobulin administration may transiently impair the efficacy of live
attenuated virus vaccines such as measles, mumps, rubella, and varicella because the continued presence of high levels of passively acquired antibody may interfere with an active antibody response. 15,16 The immunizing physician should be informed of recent therapy with BIVIGAM so that appropriate measures may be taken (see Patient Counseling Information ).
Pregnancy Safety for Bivigam
Pregnancy No human data are available to indicate the presence or absence of drug-associated risk. Animal reproductive studies have not been conducted with BIVIGAM. It is not known whether BIVIGAM 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.
BIVIGAM should be given to pregnant women only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Pediatric Use of Bivigam
Pediatric Use BIVIGAM was evaluated in 25 pediatric patients (3 children ages 2 to <6, 9 children ages 6 to <12, and 13 adolescents ages 12 to 16 years) with PI. The safety and effectiveness of BIVIGAM for the treatment of PI has been established in pediatric patients 2 years of age and older, based on data from 2 prospective, open-label, single-arm, multi-center studies, supported by evidence from a population PK analysis of adult and pediatric PK data ( see Adverse Reactions, Clinical Pharmacology, and Clinical Studies ). PK, safety and efficacy were similar to those in adults. No specific dose requirements were necessary to achieve the targeted serum IgG levels in the pediatric subjects. The safety and effectiveness of BIVIGAM has not been established in pediatric patients with PI who are under the age of 2 ( see Clinical Studies ).
Contraindications for Bivigam
is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. BIVIGAM is contraindicated in IgA deficiency patients with antibodies to IgA and a history of hypersensitivity. History of anaphylactic or severe systemic reactions to human immunoglobulin.
IgA deficient patients with antibodies to IgA and a history of hypersensitivity.
Clinical Studies of Bivigam
Infections Number of confirmed serious acute bacterial infections b 2 Rate of
SBIs (SBIs/total person-years) 0.037 Total infections 197 Infections per subject per year
Antibiotic use c Number of subjects (%) 50 (86%) Days per subject
per year
Days off school/work due to infections Number of persons with days off
of school or work due to infections (%) 21 (36%) Total days (%) 122 (0.6%) Days per subject per year
Hospitalization Number of subjects (%) 2 (3.4%) Number of Days 11 (0.06%)
Days per subject per year 0.21 Pediatric Only Study A prospective, open-label, single-arm, multi-center study evaluating the safety, efficacy, and PK of BIVIGAM was conducted in 16 pediatric subjects; 3 subjects ≥2 to <6, 5 subjects ≥6 to <12, and 8 subjects ≥12 to ≤16 years, with confirmed and documented clinical diagnosis of PID, including hypogammaglobulinemia or agammaglobulinemia. Of the 16 subjects enrolled, all (100%) were male, and the majority (80%) were white. Subjects received a BIVIGAM infusion administrated every 3 or 4 weeks (based on the dose and schedule depending on their prior treatment regimen) for approximately 5 months.
Average BIVIGAM doses administered (all infusions, both infusion regimens combined, values rounded) ranged from 368 to 1077 mg/kg in the 2 to <6 years age group, from 312 to 693 mg/kg in the 6 to <12 years age group and from 350 to 795 mg/kg in the 12 to 16 years age group. The efficacy analysis is based on the incidence of acute serious bacterial infections (SBIs). SBIs encompass bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, or visceral abscess. No acute SBIs occurred during the mean observation period of 152 days, yielding a mean number of acute SBI episodes per person-year of 0.0. No other serious infections, or hospitalizations due to infections occurred, and no subjects required IV antibiotics during the study.
Trough Total IgG levels were maintained above 500 mg/dL in all subjects throughout the study. There were no apparent differences in the Total IgG or subclass concentrations before the first and last infusions.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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