2.1       Dose

Significant differences in the half-life of IgG among patients with PI may necessitate the dose and frequency of immunoglobulin therapy to vary from patient to patient. Determine the proper dose and frequency by monitoring clinical response.

Measles Exposure

If a patient has been exposed to measles, consult with physician to administer an extra dose of IGIV as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks.

If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3 - 4 weeks, then the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion.

2.2       Preparation and Handling

• ALYGLO (immune globulin intravenous, human-stwk) is a clear or slightly opalescent, colorless or pale yellow solution. Inspect parenteral products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use ALYGLO if the solution is cloudy or turbid, or if it contains particulate matter.
  
• Do not freeze, and do not use any ALYGLO that has been frozen.
  
• Do not shake.
  
• Do not mix ALYGLO with other IGIV products or other intravenous medications.
  
• Do not dilute.
  
• ALYGLO should be at room temperature at the time of administration. Allow refrigerated product to come to room temperature before use.
  
• Do not use beyond the expiration date on the product label.
  
• ALYGLO vial is for single use only. Due to the absence of anti-microbial preservatives, promptly administer ALYGLO after piercing the cap. Dispose of partially used or unused product.
  
• Infuse ALYGLO using a separate infusion line.
  
• An infusion pump may be used to control the rate of administration.
  
• ALYGLO may be pooled under aseptic conditions into sterile infusion bags. Infuse within 24 hours after pooling.

2.3       Administration

• Monitor vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside, 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 at increased risk of renal dysfunction or thrombotic events, administer ALYGLO at the minimum infusion rate practicable, and consider discontinuation of administration if renal function deteriorates [see Boxed Warning, Warnings and Precautions (5.2, 5.3)].
  
• After administration, the infusion line may be flushed with either normal saline or 5% dextrose in water.

5.1       Hypersensitivity

Severe hypersensitivity reactions may occur1. In case of hypersensitivity, discontinue ALYGLO infusion immediately and institute appropriate treatment. Have epinephrine available for immediate treatment of severe acute hypersensitivity reactions.

ALYGLO contains trace amounts of IgA (≤ 100 mcg/mL) [see Description (11)]. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. ALYGLO is contraindicated in IgA-deficient patients with antibodies against IgA or a history of hypersensitivity reaction [see Contraindications (4)].

5.2       Thrombotic Events

Thrombosis may occur following treatment with ALYGLO2,3,4. 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 patients with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer ALYGLO 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 (2), Patient Counseling Information (17)].

5.3       Renal Failure

Renal dysfunction, acute renal failure, osmotic nephropathy, and death5 may occur upon use of ALYGLO. Ensure that patients are not volume-depleted before administering ALYGLO. Monitor renal function and urine output periodically, especially in patients who are at higher risk of renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine before the initial infusion of ALYGLO and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing ALYGLO [see Patient Counseling Information (17)]. 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 > 65 years), administer ALYGLO at the minimum infusion rate practicable [see Boxed Warning, Dosage and Administration (2)].

5.4       Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving ALYGLO. 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. Such 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 events6.

5.5       Aseptic Meningitis Syndrome (AMS)

AMS may occur with ALYGLO. AMS usually begins within several hours to 2 days following ALYGLO treatment. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae7,8,9.

AMS may occur more frequently with high doses (2 g/kg) and/or rapid infusion of ALYGLO. 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 (17)]. 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.

5.6       Hemolysis

ALYGLO 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 test (DAT) (Coombs test) result and hemolysis10,11,12. Delayed hemolytic anemia due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, have been reported. Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV.

The following risk factors may be associated with the development of hemolysis following IGIV administration: High doses (e.g., 2 g/kg or more), given either as a single administration or divided over several days, and non-O blood group13. Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration of IGIV14, but their role is uncertain.

Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit.

If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform confirmatory laboratory testing, including direct antiglobulin test. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving ALYGLO, perform adequate cross-matching to avoid exacerbating ongoing hemolysis.

5.7       Transfusion-Related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] may occur in patients administered ALYGLO15. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Signs and symptoms typically appear within 1 to 6 hours following treatment. Patients with TRALI may be managed using oxygen therapy with adequate ventilator support.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and the patient's serum.

5.8       Transmissible Infectious Agents

Because ALYGLO is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors and by including virus inactivation/removal steps in the manufacturing process of ALYGLO.

Report all infections thought by a physician possibly transmitted by ALYGLO to GC Biopharma USA, Inc. at 1-833-426-6426. Discuss the risks and benefits of its use with the patient before prescribing or administering this product [see Patient Counseling Information (17)].

5.9       Monitoring Laboratory Tests

• Periodic monitoring of renal function and urine output is particularly important in patients 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 ALYGLO and at appropriate intervals thereafter.
  
• Because of the potential for increased risk of thrombosis with ALYGLO, 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 ALYGLO, perform appropriate laboratory testing for confirmation. Measure hemoglobin and/ or hematocrit at baseline and approximately 36 to 96 hours post-infusion in patients at higher risk of hemolysis.
  
• 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.

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.

In an open-label, single-arm, multicenter, non-randomized clinical trial, 33 subjects with primary humoral immunodeficiency received doses of ALYGLO (immune globulin intravenous, human-stwk) ranging from 319 mg/kg to 817 mg/kg every 21 days or 28 days for up to 12 months.

Twenty-eight subjects (85%) experienced a total of 145 temporally associated adverse reactions (adverse events that occurred during or within 72 hours after the end of an infusion) during the study. The temporally associated ARs were headache (13 subjects, 39%), nausea/vomiting (11 subjects, 33%), fatigue (6 subjects, 18%), nasal/sinus congestion (5 subjects, 15%), rash (4 subjects, 12%), arthralgia, diarrhea (3 subjects, 9% each), muscle pain/aches, Infusion site pain/swelling, abdominal pain/discomfort, cough, dizziness (2 subjects, 6% each). These are presented in Table 2.

There were no deaths and no adverse reactions leading to withdrawal from the study.

* Adverse events that occurred during or within 72 hours after the end of an infusion

1 Total number of subjects

2 Total number of infusions

6.2       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 marketed IGIV products:

8.1       Pregnancy

Risk Summary

No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with ALYGLO (immune globulin intravenous, human-stwk). It is not known whether ALYGLO 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. 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%, respectively16,17. ALYGLO should be given to pregnant women only if clearly needed.

8.2       Lactation

Risk Summary

No human data are available to indicate the presence or absence of drug-associated risk during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ALYGLO and any potential adverse effects on the breastfed infant from ALYGLO or from the underlying maternal condition.

8.4       Pediatric Use

Safety and effectiveness in pediatric patients < 17 years has not been established.

8.5       Geriatric Use

Clinical studies of ALYGLO 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

ALYGLO (immune globulin intravenous, human-stwk) supplies a broad spectrum of neutralizing IgG antibodies to bacterial and viral pathogens, and their toxins. The mechanism of action has not been fully elucidated in PI.

12.2       Pharmacodynamics

ALYGLO contains mainly IgG with a broad spectrum of antibodies against various infectious agents reflecting the IgG activity found in the donor population. ALYGLO which is prepared from pooled material, has an IgG subclass distribution similar to that of native human plasma. An adequate dose of IGIV can restore abnormally low IgG level to the normal range. Standard pharmacodynamics studies were not performed.

12.3       Pharmacokinetics

Serum concentrations of total IgG were measured in 22 subjects (22 adults aged ≥ 17 to 70 years) following the 5th infusion of ALYGLO. The administered dose of ALYGLO during the PK assessment ranged from 313 mg/kg to 821 mg/kg. Blood samples for PK analyses were collected until Day 22 (±1 day) or Day 29 (±2 days) for subjects treated according to the 21 days and 28 days schedule, respectively.

Table 4 summarizes the PK parameters of ALYGLO based on serum concentration of total IgG.

AUC0-tau=area under the (time concentration) curve within a dosing interval; CL=clearance based on AUC0-tau; Cmax=maximum serum concentration; SD=standard deviation; Tmax=time to maximum serum concentration; T1/2=elimination half-life; Vss=(apparent) volume of distribution at steady state based on AUC0-tau

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies were conducted on carcinogenesis, mutagenesis, or impairment of fertility with ALYGLO (immune globulin intravenous, human-stwk).

13.2       Animal Toxicology and/or Pharmacology

A single-dose toxicity study was performed in rats at doses up to 3000 mg/kg body weight. No toxicologically significant changes attributable to the test article were observed at any dose.

In safety pharmacology studies, there were no test article related adverse effects on respiratory, cardiovascular or central nervous systems of the treated mice and rats.