Bivigam Drug Information

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.

Preparation and Handling BIVIGAM is a clear or slightly opalescent, colorless to pale yellow solution. Inspect BIVIGAM visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or turbid, or contains particulate matter.

Allow refrigerated product to come to room temperature before use. Do not freeze or heat. Do not use any solution that has been frozen or heated.

DO NOT SHAKE. Do not mix BIVIGAM with other IGIV products or other intravenous medications. If large doses of BIVIGAM are to be administered, several vials may be pooled using aseptic technique into sterile infusion bags and infused.

Do not dilute BIVIGAM. BIVIGAM contains no preservatives. BIVIGAM vial is for single use only.

Any vial of BIVIGAM that has been entered should be used promptly and any unused portion should be discarded immediately. Do not reuse or save for future use. Maintain BIVIGAM at room temperature during administration.

Do not use after expiration date.

Recommended Dose

As there are significant differences in the half-life of IgG among patients with primary humoral immunodeficiency, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The dosage may be adjusted over time to achieve the desired trough levels and clinical response.

BIVIGAM dose adjustments may be required in patients who fail to maintain trough total IgG concentrations of at least 500 mg/dL with a target of 600 mg/dL. Starting with the second infusion, the dose will be adjusted proportionally, targeting a trough of ≥ 600 mg/dL, based on the previous trough and the associated dose.

Administration It has been reported that the frequency of adverse drug reactions to IGIV increases with the infusion rate. Initial infusion rates should be slow. If there are no adverse drug reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum rate.

For patients experiencing adverse drug reactions, it is advisable to reduce the infusion rate in subsequent infusions. Table 1: Recommended Infusion Rates for BIVIGAM Monitor patient vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur.

If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient. Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombotic events, administer BIVIGAM at the minimum infusion rate practicable, and consider discontinuation of administration if renal function deteriorates ( see Boxed Warning, Warnings and Precautions ).

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. 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. 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. 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). 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. In this study, four subjects (25.0%) experienced a total of 9 adverse reactions. 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 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.

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 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.

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 ).

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.