2.1 Dosage

Treatment of Primary Immunodeficiency (PI)

If a patient has been exposed to measles, it may be prudent 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, 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.

As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. Adjust the dose according to the clinical response.

Adjust the dosage over time to achieve the desired trough IgG levels and clinical responses. No randomized controlled trial data are available to determine an optimum target trough serum IgG level.

2.2 Preparation and Handling

• Inspect Flebogamma 5% DIF visually for particulate matter and color prior to administration. Do not use the vial if particles are detected. Do not use if turbid.
• Several vials of Flebogamma 5% DIF may be pooled into an empty sterile solution container by using aseptic technique, if large doses are to be administered.
• Do not dilute with intravenous fluids. Do not inject other medications into intravenous tubing being used for Flebogamma 5% DIF.
• Infuse Flebogamma 5% DIF through a separate intravenous line. Do not add any medications or intravenous fluids to the Flebogamma 5% DIF infusion container. Do not mix IGIV products of different formulations or from different manufacturers.
• Discard unused contents and administration devices after use.
• Use promptly any vial that has been entered.
• Discard partially used vials. Do not save for future use because the solution contains no preservative.
• Do not use solution that has been frozen.

2.3 Administration

The recommended initial infusion rate of Flebogamma 5% DIF is 0.01 mL per kg body weight per minute (0.5 mg per kg per min). If the infusion is well-tolerated during the first 30 minutes, the rate may be gradually increased to a maximum of 0.10 mL per kg per minute (5 mg per kg per min).

Monitor patient vital signs throughout the infusion. Slow or stop infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.

5.1 Hypersensitivity

Severe hypersensitivity reactions and anaphylactic reactions with a fall in blood pressure may occur, even in patients who had tolerated previous treatment with IGIV. (see Contraindications [4]) If hypersensitivity reaction develops, discontinue Flebogamma 5% DIF infusion immediately and institute appropriate treatment.

Flebogamma 5% DIF contains trace amounts of IgA (less than 50 μg/mL). (see Description [11]) Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Flebogamma 5% DIF is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction. (see Contraindications [4])

5.2 Renal Dysfunction/Failure

Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death have been reported in patients receiving IGIV, particularly those products containing sucrose2. Flebogamma 5% DIF does not contain sucrose.

Ensure that patients are not volume-depleted before administering Flebogamma 5% DIF. For patients judged to be at risk for developing renal dysfunction, including patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, administer Flebogamma 5% DIF at the minimum dose and rate of infusion practicable3. (see Boxed Warning, Dosing and Administration [2.3])

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure1. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Flebogamma 5% DIF and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of the product.

5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Flebogamma 5% DIF therapy. It is clinically critical to distinguish true hyponatremia from a pseudohyponatremia that is temporally or causally related to hyperproteinemia with concomitant decreased calculated serum osmolarity 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 higher risk of thrombosis.

5.4 Thrombosis

Thrombosis may occur following treatment with immune globulin products, including Flebogamma 5% DIF. 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. (see Warnings and Precautions [5.10]) For patients at risk of thrombosis, administer Flebogamma 5% DIF 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 [2.3], and Patient Counseling Information [17])

5.5 Aseptic Meningitis Syndrome (AMS)

AMS has been reported to occur following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae4-7. The symptoms of AMS usually begin within several hours to 2 days following IGIV treatment.

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 to patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.

AMS may occur more frequently following high-dose (e.g. over 1.0 g per kg body weight) or rapid infusion of IGIV.

5.6 Hemolysis

Flebogamma 5% DIF may contain blood group antibodies that may 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 hemolysis8-11. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, consistent with intravascular hemolysis, has been reported12. 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., at least 2 g per kg), 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. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP and PI11. 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 prior to infusion and within 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, 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. (see Patient Counseling Information [17])

5.7 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema has been reported in patients following IGIV treatment15. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours after transfusion.

Monitor patients for pulmonary adverse reactions. (see Patient Counseling Information [17]) If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed by using oxygen therapy with adequate ventilatory support.

5.8 Infusion Reactions

Individuals receiving Flebogamma 5% DIF for the first time, or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at a higher risk for the development of fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations regarding dosage and administration may reduce the risk of these types of events. (see Dosage and Administration [2.3])

5.9 Transmissible Infectious Agents

Because Flebogamma 5% DIF is made from human plasma, 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. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or CJD have been associated with the use of Flebogamma 5% DIF. 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 Grifols Biologicals at 1-888-474-3657.

Before prescribing or administering Flebogamma 5% DIF, the physician should discuss the risks and benefits of its use with the patient. (see Patient Counseling Information [17])

5.10 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 BUN and serum creatinine, before the initial infusion of Flebogamma 5% DIF and at appropriate intervals thereafter.
• 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 because of the potentially increased risk of thrombosis.
• If signs and/or symptoms of hemolysis are present after an infusion of Flebogamma 5% DIF, perform appropriate laboratory testing for confirmation.
• If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient serum.

5.11 Interference with Laboratory Tests

After infusion of IgG, 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.

5.12 Hereditary Fructose Intolerance

Flebogamma 5% DIF contains sorbitol. The presence of sorbitol presents a risk to those with hereditary fructose intolerance (HFI). The incidence of HFI is estimated at 1 in 20,000 births and is usually diagnosed at the time of weaning when fructose or sucrose is introduced into the diet. Clinical symptoms include recurrent vomiting, abdominal pain and hypoglycemia. Flebogamma 5% DIF must not be administered to subjects with HFI.

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 clinical practice.

Adverse reactions were reported in a study of 46 individuals with PI receiving infusions every 3 to 4 weeks of 300-600 mg per kg body weight. Thirty-one subjects (67.4%) had at least one adverse reaction at some time during the study that was considered product-related. None of the 46 subjects who participated in this study discontinued the study prematurely due to an adverse drug reaction.

Adverse reactions that occurred with an incidence of at least 5% on a per-subject basis are summarized in Table 1.

Other common adverse drug reactions reported in fewer than 5% of the subjects included hypertension, sinusitis, nausea/vomiting, positive Coombs test, arthralgia, myalgia, dizziness, bronchitis, and hypotension.

The total number of adverse reactions reported whose onset were within 72 hours after the end of an infusion of Flebogamma 5% DIF was 94. There were a total of 709 infusions, resulting in a ratio of 0.13 temporally associated adverse reactions per infusion (the upper bound of the 1-sided 95% confidence interval = 0.18). Of the 709 total infusions, 70 (9.7%, 1-sided 95% upper bound CI = 12.4%) were associated with at least one adverse reaction that began within 72 hours after the completion of an infusion. In this analysis, each infusion is only counted once, regardless of the number of adverse reactions that occurred during the infusion, when during the 72-hour period after the infusion the adverse reaction started, or the intensity of those adverse reactions.

Factoring adverse reaction intensity into the analysis of the 709 infusions shows that there were 58 infusions with at least one mild adverse reaction (8.2% [upper bound 95% CI=10.5%]), 25 infusions with at least one moderate adverse reaction (3.5% [upper bound 95% CI=5.2%]), and 1 infusion with a severe adverse reaction (0.1% [upper bound 95% CI=0.8%]). In this analysis, if a subject reported multiple events with different intensities during the same infusion (e.g., mild headache and moderate pyrexia), that infusion would be counted in all relevant categories. Therefore, the number of infusions counted is 84.

Three subjects (6.5%) experienced a treatment-emergent rise in AST (> 3x the upper-limit of normal), and 1 subject (2.2%) experienced a treatment-emergent rise in ALT (> 3x the upper-limit of normal). None of these abnormal lab values were long-lasting (i.e. they occurred at 1 or 2 infusions), and none of these subjects had a concomitant treatment-emergent rise in total bilirubin.

A clinical study with Flebogamma 5% DIF for the treatment of PI was conducted in 24 pediatric subjects aged 2-16 years to determine whether they respond differently from adult subjects. Pediatric subjects received intravenous infusions of 262-625 mg per kg body weight every 3-4 weeks. Twenty subjects (83.3%) had at least one adverse reaction at some time during the study that was considered product-related. There were no deaths or serious adverse reactions.

In 317 infusions, 20 pediatric subjects reported 159 treatment-related adverse drug reactions (ADR). Treatment-related adverse reactions that occurred with an incidence of at least 5% on a per-subject basis included headache (42%), pyrexia (29%), hypotension (25%), tachycardia (25%), diastolic hypotension (21%), nausea (8%), abdominal pain (8%), diarrhea (8%), pain (8%), and vomiting (8%). Of these, 99 ADRs were mild, 54 were moderate, and 6 were severe in intensity. The most common severe ADR was headache. Tachycardia was defined as mild, moderate, or severe by ratio of heart rate over baseline of 1.2-1.4, 1.41-1.6, or >1.6, respectively. Two episodes of tachycardia were moderate and 14 were mild, 1 mild case had the infusion interrupted and the rest had no action taken, and all resolved. Hypotension was defined as mild, moderate, or severe by the decrease in pressure below baseline of 10-15%, 16-25%, and >25%, respectively. Ten episodes of hypotension/diastolic hypotension were moderate and 29 were mild, one moderate case had the infusion interrupted and the rest had no action taken, and all resolved. None of the ADRs related to fluctuation in vital signs were severe, all resolved without sequelae, and none were considered clinically significant.

One subject (6.5%) experienced a treatment-emergent rise in ALT (over 2.5x the upper-limit of normal). This was considered a mild treatment-related AE and resolved without sequelae. All other lab values were within normal limits. One subject experienced one positive Coombs' test result after baseline (experienced 14 days after the final infusion). No subjects experienced clinically significant abnormal lab values for LDH, bilirubin, serum creatinine. In addition, no subjects experienced positive test results for HBsAg, HCV, or HIV.

6.2 Post-marketing Experience

Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse reactions have been identified during the post-approval use of IGIV products16, 17, including Flebogamma 5% DIF.

8.1 Pregnancy

Risk Summary
There are no studies of Flebogamma 5% DIF use in pregnant women. Animal reproduction studies have not been performed with Flebogamma 5% DIF. It is also not known whether Flebogamma 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. Flebogamma 5% DIF should be given to a pregnant woman only if clearly needed.

8.2 Lactation

Risk Summary
There is no information regarding the presence of Flebogamma 5% DIF in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Flebogamma 5% DIF and any potential adverse effects on the breastfed infant from Flebogamma 5% DIF or from the underlying maternal condition.

8.4 Pediatric Use

Flebogamma 5% DIF was studied in a multicenter clinical trial for the treatment of PI in 24 subjects aged 2-16 years (seven were 2-5 years of age, seven were 6-11 years, and ten were 12-16 years), and found to be efficacious for the prevention of acute serious bacterial infections. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. Twenty subjects (83.3%) had at least one adverse reaction at some time during the study that was considered product-related. There were no deaths or serious adverse reactions. Treatment-related adverse reactions that occurred with an incidence of at least 5% on a per-subject basis included headache (42%), pyrexia (29%), hypotension (25%), tachycardia (25%), diastolic hypotension (21%), nausea (8%), abdominal pain (8%), diarrhea (8%), pain (8%), and vomiting (8%).

Safety and efficacy of Flebogamma 5% DIF in pediatric patients below the age of 2 years have not been established.

8.5 Geriatric Use

Limited information is available for the geriatric use of Flebogamma 5% DIF. Clinical studies of Flebogamma 5% DIF did not include sufficient numbers of subjects over the age of 65 to determine whether they respond differently from younger subjects. Use caution when administering Flebogamma 5% DIF to patients age 65 and over who are judged to be at increased risk for developing thrombosis or renal insufficiency. Do not exceed recommended dose, and administer Flebogamma 5% DIF at the minimum dose and infusion rate practicable, and at less than 0.06 mL per kg per minute (3 mg per kg per min). (see Boxed Warning, Warning and Precautions [5.2, 5.4], and Dosage and Administration [2.3])

12.1 Mechanism of Action

Flebogamma 5% DIF, immune globulin intravenous (human), is a replacement therapy for PI. It supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. Flebogamma 5% DIF also contains a spectrum of antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanisms of action of IgG in Flebogamma 5% DIF have not been fully elucidated.

12.3 Pharmacokinetics

In the clinical study assessing safety and efficacy in PI, Flebogamma 5% DIF was administered as an IV infusion (300-600 mg per kg) to subjects every 3 (n = 8) or 4 (n = 12) weeks for 12 months. The pharmacokinetics of total IgG was determined after the 7th infusion for the 3-week dosing interval and after the 5th infusion for the 4-week dosing interval (Table 3).

There were 3 adolescent (up to 16 years of age) subjects who underwent pharmacokinetic testing, all of whom were on the 3-week infusion schedule. There were no clinically relevant differences among the adults and adolescents that were tested.

13.1 Carcinogenicity, Mutagenesis, Impairment of Fertility

No animal studies were conducted to evaluate the carcinogenic or mutagenic effect of Flebogamma 5% DIF or its effects on fertility.

13.2 Animal Toxicology and/or Pharmacology

Acute toxicity studies were performed in mice and rats at doses up to 2.5 g per kg body weight with infusion rates 6-37 times higher than the maximum rates recommended for humans. The most common clinical observations in mice studies were piloerection, ptosis, ataxia, and increase in respiration all lasting 90 minutes or less. No relevant adverse effects could be confirmed affecting respiratory, circulatory, renal, autonomic and central nervous systems, somatomotor activity, and behavior of the treated mice and rats.

Five of the 25 rats treated with the highest dose, approximately 8 times the maximum infusion rate recommended for humans, showed a transient “reddish urine” sign which was not confirmed as a relevant toxicity-causing phenomenon after renal macroscopic and microscopic analysis. This phenomenon was ascribed to hemolysis when serum was analyzed, suggesting a possible relation to cross reactivity of rodent red cells with human antibodies. No “reddish urine” was detected in any mouse, a much smaller animal where the rate of infusion was comparatively much higher than in rats. The macroscopic inspection of all treated mice did not show any renal alteration.