2.1 Dosage

Treatment of Primary Immunodeficiency (PI)

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. Dosing should be adjusted according to the clinical response.

The dosage may be adjusted 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.
• Dilution with intravenous fluids is not recommended. Injection of other medications into intravenous tubing being used for Flebogamma 5% DIF is not recommended.
• 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.
• Any vial that has been entered should be used promptly
• 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/kg body weight/minute (0.5 mg/kg/minute). If the infusion is well-tolerated, during the first 30 minutes, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute).

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 sucrose (2). 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 rate of infusion practicable (3). (See Boxed Warning) (See 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 failure (1). 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 sequelae (7-10). 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 with 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. > 1.0 g/kg body weight) and/or rapid-infusion of IGIV.

5.6 Hemolysis

Hemolytic anemia can develop subsequent to IGIV therapy, including Flebogamma 5% DIF. Flebogamma 5% DIF contains blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and hemolysis (11-13). Acute intravascular hemolysis has been reported, and delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration (14).

Monitor patients for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after Flebogamma 5% DIF infusion, perform appropriate confirmatory laboratory testing. (See Patient Counseling Information [17])

5.7 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema has been reported in patients following IGIV treatment (15). 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, 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 anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient's 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.

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 to 600 mg/kg body weight. Thirty-one subjects (67.4%) had at least an 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 ≥ 5% on a per subject basis are summarized in Table 1.

The most common other 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 107. There were a total of 709 infusions, resulting in a rate of 0.15 temporally associated adverse reactions per infusion (the upper bound of the 1-sided 95% confidence interval = 0.18). There were 70 infusions (9.7%, 1-sided 95% upper bound CI = 12.4%) associated with 1 or more adverse reaction that began within 72 hours after the completion of an infusion.

In 58 infusions the patients reported mild adverse reactions; 25 infusions were recorded with moderate adverse reactions and in 1 infusion the patient reported a severe adverse reaction. The percentages of infusions with a mild, moderate or severe adverse reaction were 8.2% (upper bound 95% CI=10.5%), 3.5 % (upper bound 95% CI=5.2%) and 0.1% (upper bound 95% CI=0.8%), respectively.

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.

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 products (16-17), including Flebogamma 5% DIF.

8.1 Pregnancy

Pregnancy Category C. 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.

8.3 Nursing Mothers

Use of Flebogamma 5% DIF has not been evaluated in nursing mothers.

8.4 Pediatric Use

Clinical studies of Flebogamma 5% DIF for the treatment of PI did not include sufficient numbers of subjects aged 16 and younger to determine whether they respond differently from adults. Efficacy and safety in pediatric patients have not been established (see Clinical Studies [14]).

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 infusion rate practicable and less than 0.06 mL/kg/min (3 mg/kg/minute). (See Boxed Warning, Warning and Precautions [5.2, 5.4]; Dosage and Administration [2.3]).

12.1 Mechanism of Action

Immune Globulin Intravenous (Human), Flebogamma 5% DIF 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 to 600 mg/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 (≤ 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 Carcinogenity, 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/kg body weight with infusion rates 6 to 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 out of the 25 rats treated with the highest dose at 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 macro 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.