HepaGam B: Package Insert and Label Information

HEPAGAM B- human hepatitis b virus immune globulin injection
Saol Therapeutics Inc.

1 INDICATIONS AND USAGE

HepaGam B [Hepatitis B immune globulin intravenous (Human)] is an intravenous or intramuscular immune globulin indicated for the following:

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 DOSAGE AND ADMINISTRATION

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).

Table 1 — HepaGam B Dosing Regimen for HBV-Related Liver Transplant Patients

* Each dose should contain 20,000 international units calculated from the measured potency as stamped on the vial label [see Dosage Forms and Strengths (3) ].
Anhepatic Phase	Week 1 Post-Operative	Weeks 2-12 Post-Operative	Month 4 onwards
First dose	Daily from Day 1-7	Every two weeks from Day 14	Monthly

Table 2 – HepaGam B Intravenous Infusion Rate

Route of Administration	Dosage	Infusion Rate
Intravenous	20,000 international units per dose	2 milliliters per minute. Decrease to 1 milliliter per minute or slower if the patient develops discomfort or infusion-related adverse reactions.

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.

Table 3 – HepaGam B Dosing Regimen for Postexposure Prophylaxis (Intramuscular)

Indication	Dosage	Instructions
Acute Exposure to Blood Containing HBsAg	0.06 milliliter per kilogram	Administer HepaGam B as soon as possible after exposure. The value after seven days following exposure is unclear2, 3.For persons who refuse Hepatitis B vaccine or who are known non-responders to vaccine, give a second dose of HepaGam B one month after the first dose2.
Perinatal exposure of Infants Born to HBsAg-positive mothers	0.5 milliliter	Administer after physiologic stabilization of the infant and preferably within twelve hours of birth. Administer concurrently with Hepatitis B vaccine.
Sexual Exposure to HBsAg-Positive Persons	0.06 milliliter per kilogram	Administer HepaGam B and Hepatitis B Vaccine series within 14 days of sexual contact or if sexual contact with the infected person will continue.
Household Exposure to Person with Acute HBV Infection	0.5 milliliter	For infants less than twelve months of age administered concurrently with Hepatitis B Vaccine. Prophylaxis of other household contacts of persons with acute HBV infection is not indicated unless there is an identifiable blood exposure to the index patient, such as by sharing toothbrushes or razors. Treat such exposures like sexual exposures.

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 vaccine^2,3.

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.

3 DOSAGE FORMS AND STRENGTHS

• HepaGam B is a sterile solution of purified gamma globulin (5% or 50 milligrams per milliliter) that contains greater than 312 international units per milliliter of anti-HBs.
• The measured potency of each lot is stamped on the vial label.
• To ensure that the label claim of greater than 312 international units per milliliter is maintained over the product shelf life, a higher potency of 550 international units per milliliter is targeted at the time of manufacture.
  • This higher target potency is a manufacturing requirement to account for variability in the potency assay and changes in potency over time.
  • The potency assay has a relative standard deviation (RSD) of approximately 10%.
  • The actual potency test result may vary from approximately 400 to 700 international units per milliliter (3x RSD) based on statistical assessment of manufactured lots with a target potency of 550 international units per milliliter.
• Calculate the dosing for the prevention of hepatitis B recurrence following liver transplantation from the measured potency of the particular lot of HepaGam B as stamped on the vial label.

4 CONTRAINDICATIONS

• Individuals known to have anaphylactic or severe systemic reactions to the parenteral administration of human globulin preparations should not receive HepaGam B.
• Individuals who are deficient in IgA may have the potential to develop anti-IgA antibodies and have an anaphylactoid reaction.
  • HepaGam B contains less than 40 micrograms per milliliter of IgA.
• 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 WARNINGS AND PRECAUTIONS

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 1-877-443-0224.

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 products^{4, 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 ADVERSE REACTIONS

The only adverse reactions observed in clinical trial subjects were hypotension and nausea (2% of clinical trial subjects).

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 StudiesSeventy 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:

Cardiac disorders:	Sinus tachycardia
Gastrointestinal disorders:	Abdominal pain upper Nausea
General disorders and administration site conditions:	Chills Feeling cold Influenza like illness Pyrexia
Immune system disorders:	Anaphylactoid reaction Hypersensitivity
Investigations:	Lipase increased Transaminases increased
Musculoskeletal and connective tissue disorders:	Back pain
Nervous system disorders:	Dizziness Headache
Respiratory, thoracic and mediastinal disorders:	Dyspnoea
Skin and subcutaneous tissue disorders:	Cold sweat

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 DRUG INTERACTIONS

7.1 Live Attenuated Virus Vaccines

Immune globulin administration may impair the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella^2,3,7. 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 produced^2,3.

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