1.1 Prevention of Hepatitis B recurrence following liver transplant in HBsAg-positive liver transplant patients

1.2 Post-exposure prophylaxis

including

• acute exposure to HBsAg-positive blood, plasma, or serum (parenteral exposure, direct mucus membrane contact, oral ingestion, etc.),
• perinatal exposure of infants born to HBsAg-positive mothers,
• sexual exposure to HBsAg-positive persons, and
• household exposure to persons with acute HBV infection.

2.1 Prevention of Hepatitis B recurrence following liver transplantation

Administer the first dose of HepaGam B during the grafting of the transplanted liver (the anhepatic phase) with subsequent dosing as recommended in Table 1.

Calculate the dosing from the measured potency of the particular lot of HepaGam B as stamped on the vial label.

Administer by intravenous infusion (Table 2).

HepaGam B dose adjustments may be required in patients who fail to reach anti-HBs levels of 500 International Units per liter within the first week post-liver transplantation1. Patients who have surgical bleeding or abdominal fluid drainage (greater than 500 milliliters) or patients who undergo plasmapheresis are particularly susceptible to extensive loss of circulated anti-HBs. In these cases, the dosing regimen should be increased to a half-dose (10,000 International Units calculated from the measured potency as stamped on the vial label) intravenously every 6 hours until the target anti-HBs is reached.

2.2 Postexposure Prophylaxis

Administer HepaGam B intramuscularly as recommended in Table 3.

HepaGam B may be administered at the same time (but at a different site), or up to one month preceding Hepatitis B vaccination without impairing the active immune response to Hepatitis B vaccine2,3.

2.3 Preparation

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid.
• Do not shake vials during preparation to avoid foaming.
• The HepaGam B vial is for single use only. HepaGam B contains no preservatives.
• Promptly use any vial of HepaGam B that has been entered. Do not reuse or save for future use.
• For intravenous administration, administer HepaGam B through a separate intravenous line using an infusion pump.
• Use normal saline as the diluent if dilution of HepaGam B is preferred prior to intravenous administration. [see Clinical Trials in Liver Transplant Patients (14.1)]
• Do not use dextrose (5%) in water (D5W).
• Use a separate vial, sterile syringe, and needle for each individual patient, to prevent transmission of infectious agents from one person to another.

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur with HepaGam B. HepaGam B should be administered in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, anaphylaxis and shock. In case of hypersensitivity, discontinue HepaGam B infusion immediately and begin appropriate emergency treatment. Medications such as epinephrine and antihistamines should be available for immediate treatment of acute hypersensitivity reactions.

HepaGam B contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA may have a greater risk of severe hypersensitivity and anaphylactic reactions. HepaGam B is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reaction. (see CONTRAINDICATIONS [4])

5.2 Interference with Blood Glucose Testing

The maltose contained in HepaGam B can interfere with some types of blood glucose monitoring systems, i.e., those based on the glucose dehydrogenase pyrroloquine quinone (GDH-PQQ) method. This can result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated results.

5.3 Monitoring: Serum Anti-HBs Antibody Levels

Liver transplant patients should be monitored regularly for serum anti-HBs antibody levels using a quantitative assay to ensure that adequate protective levels are maintained.

5.4 Infusion Reactions

Certain adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under Dosage and Administration (2.1) must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period and immediately following an infusion.

5.5 Transmissible Infectious Agents

Because HepaGam B is made from human plasma, 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 HepaGam B. 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 Saol Therapeutics at 1-833-644-4216.

5.6 Coagulation Disorders

For postexposure prophylaxis indications, HepaGam B must be administered intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, HepaGam B should be given only if the expected benefits outweigh the potential risks.

5.7 Thrombotic Events

Thrombotic events may occur during or following treatment with IGIV products4, 5. Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity.

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 who are at risk of developing thrombotic events, administer HepaGam B at the minimum rate of infusion practicable.

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 the clinical trials of another drug and may not reflect the rates observed in practice.

Hepatitis B-Related Liver Transplantation
In a clinical trial with 27 liver transplant patients, one adverse drug reaction was reported following the 578 (less than 1%) HepaGam B infusions. This study utilized the recommended dosing regimen outlined in Table 1 [see Dosage and Administration (2.1)]. The attributed adverse drug reaction of hypotension was reported in one patient. The reaction was associated with a single HepaGam B infusion during the first day post-transplant. The reaction resolved on the same day and did not recur with subsequent HepaGam B infusions.

Healthy Volunteer Studies
Seventy healthy male and female volunteers received a single dose of HepaGam B intramuscularly in clinical trials6. Only one adverse drug reaction, an episode of nausea, was reported.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of HepaGam B. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postexposure Prophylaxis:

Dizziness has been reported in the postmarketing surveillance of HepaGam B for the postexposure prophylaxis indication.

Hepatitis B-Related Liver Transplantation:

The system organ classification of reported adverse reactions is provided below:

Healthcare professionals should report adverse reactions following the administration of HepaGam B to Saol Therapeutics at 1-833-644-4216 or FDA’s MedWatch reporting system at 1-800-FDA-1088 or www.fda.gov/medwatch.

7.1 Live Attenuated Virus Vaccines

Immune globulin administration may impair the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella2,3,7. Vaccination with live virus vaccines should be deferred until approximately three months after administration of HepaGam B, Hepatitis B Immune Globulin Intravenous (Human). Persons who received HepaGam B less than 14 days after live virus vaccination should be revaccinated 3 months after the administration of the immune globulin, unless serologic test results indicate that antibodies were produced2,3.

There are no available data on drug interactions of HepaGam B with other medications.

7.2 Drug-Laboratory Interactions: Serological Testing

Antibodies present in HepaGam B may interfere with some serological tests. After administration of immune globulins like HepaGam B, a transitory increase of passively transferred antibodies in the patient’s blood may result in misleading positive results in serological testing (e.g. Coombs' test).

7.3 Drug-Laboratory Interactions: Blood Glucose Testing

HepaGam B contains maltose which can interfere with certain types of blood glucose monitoring systems. [See Warnings and Precautions (5.2).] Only testing systems that are glucose-specific should be used in patients receiving HepaGam B. This interference can result in falsely elevated glucose readings that can lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

8.1 Pregnancy

Animal reproduction studies have not been conducted with HepaGam B. It is also not known whether HepaGam B can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. HepaGam B should be given to a pregnant woman only if clearly indicated.

8.2 Lactation

It is not known whether HepaGam B is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HepaGam B is administered to a nursing mother.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients. However, for postexposure prophylaxis, the safety and effectiveness of similar hepatitis B immune globulins have been demonstrated in infants and children8.

8.5 Geriatric Use

Clinical studies of HepaGam B did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

HepaGam B provides passive immunization for individuals exposed to the hepatitis B virus, by binding to the surface antigen and reducing the rate of hepatitis B infection13-16.

12.2 Pharmacokinetics

The pharmacokinetic profile of HepaGam B has been evaluated in two 84-day clinical trials in which 70 healthy subjects received an intramuscular injection of 0.06 milliliter per kilogram of HepaGam B. The mean peak concentrations (Cmax) in both studies were comparable and occurred within 4-5 days of administration. Both studies demonstrated mean elimination half-lives (t½) following IM administration of 22 to 25 days. The mean clearance rate was 0.21 to 0.24 liter per day and the volume of distribution was approximately 7.5 liter. Thus, HepaGam B demonstrates pharmacokinetic parameters similar to those reported by Scheiermann and Kuwert17.

The maximum concentration of anti-HBs achieved by HepaGam B was consistent with that of two other licensed comparator Hepatitis B Immune Globulin (Human) products 6. Comparability of pharmacokinetics between HepaGam B and a commercially available hepatitis B immune globulin product administered IM indicates that comparable efficacy of HepaGam B should be inferred.

14.1 Clinical Trials in Liver Transplant Patients

A clinical trial examined the effectiveness of HepaGam B in the prevention of hepatitis B recurrence following liver transplantation. The study was a multi-center, open-labeled, superiority study involving HBsAg-positive/HBeAg-negative liver transplant patients. The study included two arms, an active treatment group of patients enrolled to receive the described dosing regimen of HepaGam B starting during transplant and continuing over the course of a year, and a retrospective untreated control group of historical patients with data gathered by chart review.

There were 27 liver transplant patients who received HepaGam B and 14 retrospective untreated control patients. The patients in both groups were HBsAg-positive/HBeAg-negative liver transplant patients who met similar entry criteria, had similar medical history and had similar status at transplant based on MELD and/or ChildPugh-Turcotte scores.

In the active treatment group, HepaGam B intravenous doses of 35 milliliters were initiated during transplant according to the regimen identified in Table 1 [see Dosage and Administration (2.1)]. As a result of the targeted potency of 550 international units per milliliter at the time of manufacture [see Dosage Forms and Strengths (3.)], the 35 milliliter doses of HepaGam B used in this study actually contained between 17,000 and 23,000 international units anti-HBs. These 35 milliliter doses consistently yielded anti-HBs trough levels greater than 500 international units per liter (99% of all anti-HBs levels were greater than 500 international units per liter; see Figure 1). Patients received HepaGam B doses diluted with 50 mL of saline.

Figure 1: Frequency Histogram of Trough anti-HBs Levels more than 30 days after Transplant

Values below the target trough were only observed in the 2 patients with HBV recurrence who had anti-HBs levels less than 150 international units per liter at the time of seroconversion.

For the efficacy endpoint of the proportion of patients with HBV recurrence (HBsAg positive and/or HBeAg positive after 4 weeks post-OLT), a significant treatment effect was observed. As summarized in Table 5, HBV recurrence was seen in 2/24 or 8.3% of HepaGam B patients compared to 12/14 or 86% of retrospective untreated control patients (see Table 5). Two of the HepaGam B patients who died within 28 days post-transplant were excluded from all efficacy analyses, but included for safety analyses. The deaths were not HBV or study drug related.

The conclusion that HepaGam B monotherapy post-OLT is effective at preventing HBV recurrence post-OLT is further supported by the secondary endpoints of time to recurrence, survival, anti-HBs levels, biochemical markers of liver inflammation, and liver biopsy. Time to recurrence for the HepaGam B treatment group was 358 days for two HBV recurrent patients. In comparison, the retrospective untreated control patients had a median time to recurrence of 88 days with a 95% confidence interval of 47 to 125 days. Survival calculations showed that 96% (23/24) of patients in the active treatment group survived for at least 1 year post-OLT compared to 43% (6/14) retrospective control patients. The endpoints for HBV recurrence were supported by an observed drop in anti-HBs levels, elevated liver function tests, and abnormal liver biopsy result at the time of recurrence.

HepaGam B is recommended in patients who have no or low levels of viral replication at the time of liver transplantation. The clinical trial evaluating HepaGam B in liver transplant patients selected patients with no or low replication status only. HepaGam B therapy has not been evaluated in combination with antiviral therapy post-transplantation.