1.1 Primary Humoral Immunodeficiency (PI)

GAMMAKED is indicated for treatment of primary humoral immunodeficiency in patients 2 years of age and older. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.(1-4)

1.2 Idiopathic Thrombocytopenic Purpura (ITP)

GAMMAKED is indicated for the treatment of adults and children with Idiopathic Thrombocytopenic Purpura to raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery.(5,6)

1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

GAMMAKED is indicated for the treatment of CIDP in adults to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse.

2.1 Preparation and Handling

• Visually inspect GAMMAKED for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid.
• Do not freeze. Do not use solutions that have been frozen.
• Prior to use, allow the solution to reach ambient room temperature.
• If the packaging shows any signs of tampering, do not use the product and notify Grifols Therapeutics LLC immediately [1-800-520-2807].
• The GAMMAKED vial is for single use only. GAMMAKED contains no preservative. Use any vial that has been entered promptly.  Discard partially used vials. Do not store after entry into vial.
• Infuse GAMMAKED using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving. The GAMMAKED infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.
• If dilution is required, GAMMAKED may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline.
• Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.
• Avoid simultaneous administration of GAMMAKED and Heparin through a single lumen delivery device due to GAMMAKED, Heparin incompatibilities. Flush Heparin Lock (Hep-Lock) through which GAMMAKED was administered with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection, and do not flush with Heparin. See table below.                           

• Do not mix with immune globulin intravenous (IGIV) products from other manufacturers.
• Do not use after expiration date.

2.2 PI

As there are significant differences in the half-life of IgG among patients with primary humoral immunodeficiencies, the ideal frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.

Intravenous (IV)

The dose of GAMMAKED for patients with PI is 300 mg/kg to 600 mg/kg body weight (3 mL/kg to 6 mL/kg) administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses.

The recommended initial infusion rate is 1 mg/kg/min (0.01 mL/kg/min). If the infusion is well-tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min (0.08 mL/kg/min). For patients judged to be at risk for renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable. [see Warnings and Precautions (5.2,5.4)]

If a patient routinely receives a dose of less than 400 mg/kg of GAMMAKED every 3 to 4 weeks (less than 4 mL/kg), and is at risk of measles exposure (i.e., traveling to a measles endemic area), administer a dose of at least 400 mg/kg (4 mL/kg) just prior to the expected measles exposure. If a patient has been exposed to measles, a dose of 400 mg/kg (4 mL/kg) should be administered as soon as possible after exposure.

Subcutaneous (SC)

The dose should be individualized based on the patient’s clinical response to GAMMAKED therapy and serum IgG trough levels. Begin treatment with GAMMAKED one week after the patient’s last IGIV infusion. See below under "Initial Weekly Dose". Prior to switching treatment from IGIV to GAMMAKED, obtain the patient’s serum IgG trough level to guide subsequent dose adjustments. See below under "Dose Adjustment".

Establish the initial weekly dose of GAMMAKED by converting the monthly IGIV dose into a weekly equivalent and increasing it using a dose adjustment factor. The goal is to achieve a systemic serum IgG exposure (Area Under the Concentration-Time Curve [AUC]) not inferior to that of the previous IGIV treatment. If the patient has not been previously treated with IV GAMMAKED, convert the monthly IGIV dose (in grams) by multiplying by 1.37, then dividing this dose into weekly doses based on the patient’s previous IGIV treatment interval. Monitor the patient’s clinical response, and adjust dose accordingly.

Initial Weekly Dose
To calculate the initial weekly dose of subcutaneous administration of GAMMAKED, multiply the previous IGIV dose in grams by the dose adjustment factor of 1.37; then divide this by the number of weeks between doses during the patient’s IGIV treatment (i.e., 3 or 4).

          Initial SC dose (in grams) = 1.37 × previous IGIV dose (in grams) 
                                                       Number of weeks between IGIV doses

To convert the GAMMAKED dose (in grams) to milliliters (mL), multiply the calculated Initial SC dose (in grams) by 10.

Dose Adjustment 
Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level. To determine if a dose adjustment may be considered, measure the patient’s serum IgG trough level on IGIV and as early as 5 weeks after switching from IGIV to subcutaneous. The target serum IgG trough level on weekly SC treatment is projected to be the last IGIV trough level plus 340 mg/dL. To determine if further dose adjustments are necessary, monitor the patient’s IgG trough level every 2 to 3 months.

To adjust the dose based on trough levels, calculate the difference (in mg/dL) of the patient’s serum IgG trough level from the target IgG trough level (the last IGIV trough level + 340 mg/dL). Then find this difference in Table 1 and the corresponding amount (in mL) by which to increase or decrease the weekly dose based on the patient’s body weight. However, the patient’s clinical response should be the primary consideration in dose adjustment.

For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target level is 1,000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of subcutaneous dose by 12 mL.

Monitor the patient’s clinical response, and repeat the dose adjustment as needed.

Dosage requirements for patients switching to GAMMAKED from another Immune Globulin Subcutaneous (IGSC) product have not been studied. If a patient on GAMMAKED does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of the previous IGSC treatment, adjust the dose accordingly. For such patients, Table 1 also provides guidance for dose adjustment to achieve a desired IGSC trough level.

2.3 ITP

       DO NOT ADMINISTER SUBCUTANEOUSLY [see Warnings and Precautions (5.10)]

GAMMAKED may be administered at a total dose of 2 g/kg, divided in two doses of 1 g/kg (10 mL/kg) given on two consecutive days or into five doses of 0.4 g/kg (4 mL/kg) given on five consecutive days. If after administration of the first of two daily 1 g/kg (10 mL/kg) doses, an adequate increase in the platelet count is observed at 24 hours, the second dose of 1 g/kg (10 mL/kg) body weight may be withheld.

The high dose regimen (1 g/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern. [see Warnings and Precautions (5.8), Clinical Studies (14)]

The recommended initial infusion rate is 1 mg/kg/min (0.01 mL/kg/min). If the infusion is well-tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min (0.08 mL/kg/min). For patients judged to be at risk for renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable. [see Warnings and Precautions (5.2, 5.4)] 

2.4 CIDP

GAMMAKED may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to four consecutive days. GAMMAKED may be administered as a maintenance infusion of 1 g/kg (10 mL/kg) administered over 1 day or divided into two doses of 0.5 g/kg (5 mL/kg) given on two consecutive days, every 3 weeks. Not all patients may require continued maintenance therapy beyond the initial 6 months of therapy in order to maintain their therapeutic response.

The recommended initial infusion rate is 2 mg/kg/min (0.02 mL/kg/min). If the infusion is well tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min (0.08 mL/kg/min). For patients judged to be at risk for renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable. [see Warnings and Precautions (5.2, 5.4)]

2.5 Administration

Administer intravenously for PI, ITP and CIDP.

GAMMAKED may also be administered subcutaneously for the treatment of PI.

• Administer GAMMAKED at room temperature.
• Inspect GAMMAKED visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
• Do not use if turbid and/or if discoloration is observed.

Intravenous

• Use only 18 gauge needles to penetrate the stopper for dispensing product from the 10 mL vial.
• Use 16 gauge needles or dispensing pins only with 25 mL vial sizes and larger.
• Insert needles or dispensing pins only once and be within the stopper area delineated by the raised ring.
• Penetrate the stopper perpendicular to the plane of the stopper within the ring.

• Use promptly any vial that has been opened.
• Discard partially used vials.
• If dilution is required, GAMMAKED may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. Infuse GAMMAKED using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving.  The GAMMAKED infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.

Subcutaneous for PI Only

Instructions for Administration

• Prior to use, allow the solution to reach ambient room temperature.
• DO NOT SHAKE.
• Do not use if the solution is cloudy or has particulates.
• Check the product expiration date on the vial. Do not use beyond the expiration date.

1. Use aseptic technique when preparing and administering GAMMAKED for injection.
2. Remove the protective cap from the vial to expose the central portion of the stopper. If the packaging shows any sign of tampering, do not use the product and notify Grifols Therapeutics LLC immediately [1-800-520-2807].
3. Wipe the stopper with alcohol and allow to dry.
4. Using a sterile syringe and needle, prepare to withdraw GAMMAKED by first injecting air into the vial that is equivalent to the amount of GAMMAKED to be withdrawn. Then withdraw the desired volume of GAMMAKED. If multiple vials are required to achieve the desired dose, repeat this step. (Figure 1) 
5. Follow the manufacturer’s instructions for filling the pump reservoir and preparing the pump, administration tubing and Y-site connection tubing, if needed. Be sure to prime the administration tubing to ensure that no air is left in the tubing or needle by filling the tubing/needle with GAMMAKED.
6. Select the number and location of injection sites. (Figure 2)
7. Cleanse the injection site(s) with antiseptic solution using a circular motion working from the center of the site and moving to the outside. Sites should be clean, dry, and at least two inches apart. (Figure 3) 
8. Grasp the skin between two fingers and insert the needle into the subcutaneous tissue. (Figure 4) 
9. After inserting each needle, make sure that a blood vessel has not been accidentally entered. Attach a sterile syringe to the end of the primed administration tubing, pull back on the plunger, and if you see blood, remove and discard the needle and administration tubing. (Figure 5)
10. Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site. Secure the needle in place by applying sterile gauze or transparent dressing over the site.
11. If using multiple, simultaneous injection sites, use Y-site connection tubing and secure to the administration tubing.
12. Infuse GAMMAKED following the manufacturer’s instructions for the pump. (Figure 6)

Rate of Administration

Intravenous

Following initial infusion (see table below), the infusion rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute) as tolerated.

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.

Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thrombosis, administer GAMMAKED at the minimum infusion rate practicable and discontinue GAMMAKED if renal function deteriorates.

Subcutaneous for PI Only

For PI, it is recommended that GAMMAKED is infused at a rate of 20 mL per hour per infusion site for adults, and up to 8 infusion sites may be used (most patients used 4 infusion sites). Children and adolescents weighing ≥ 25 kg should start out at a slower infusion rate of 15 mL/hour/infusion site and increase their infusion rate up to 20 mL/hour/infusion site. For children and adolescents weighing < 25 kg, a rate of 10 mL/hour/infusion site is recommended. In children up to 6 infusion sites simultaneously may be used. For patients of all ages ensure that the infusion sites are at least 2 inches (5 cm) apart.

4.1 Hypersensitivity Reactions to Immune Globulins

GAMMAKED is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

4.2 IgA Sensitive Patients with History of Hypersensitivity Reaction

GAMMAKED is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity.

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur with IGIV products, including GAMMAKED. In case of hypersensitivity, discontinue GAMMAKED infusion immediately and institute appropriate treatment. Have medications such as epinephrine available for immediate treatment of acute hypersensitivity reaction.

GAMMAKED contains trace amounts of IgA (average 46 micrograms/mL). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reaction. [see Contraindications (4)]

5.2 Renal Failure

Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur upon use of IGIV products, especially those containing sucrose.(7,8) GAMMAKED does not contain sucrose. Ensure that patients are not volume depleted prior to the initiation of the infusion of GAMMAKED. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, prior to the initial infusion of GAMMAKED and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMMAKED. [see Patient Counseling Information (17)]  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 GAMMAKED at the minimum infusion rate practicable [less than 8 mg/kg/min (0.08 mL/kg/min)]. [see Dosage and Administration (2.5)]

5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV treatment, including GAMMAKED. It is clinically critical to distinguish true hyponatremia from a pseudohyponatremia that is associated with concomitant decreased calculated serum osmolality 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 possible predisposition to thrombosis.(9)

5.4 Thrombosis

Thrombosis may occur following treatment with immune globulin products, including GAMMAKED.(10-12) 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. For patients at risk of thrombosis, administer GAMMAKED 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 (2.5), Patient Counseling Information (17)]

5.5 Aseptic Meningitis Syndrome (AMS)

AMS may occur infrequently with IGIV treatment, including GAMMAKED. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.  The syndrome usually begins within several hours to two days following IGIV treatment. AMS is characterized by the following symptoms and signs:  severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cu mm, 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 on patients exhibiting such symptoms and signs including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.

5.6 Hemolysis

GAMMAKED may contain 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.(13-16) Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration, and acute hemolysis consistent with intravascular hemolysis, has been reported. [see Adverse Reactions (6)]

The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥ 2 grams/kg, single administration or divided over several days) and non-O blood group.(17) Underlying inflammatory state in an individual patient may increase the risk of hemolysis, but its role is uncertain.(18)

Closely monitor patients for clinical signs and symptoms of hemolysis [see Warnings and Precautions (5.11)], particularly patients with risk factors noted above and those with pre-existing anemia and/or cardiovascular or pulmonary compromise. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform additional 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.

5.7 Transfusion-related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV products, including GAMMAKED.(19) TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.

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

5.8 Volume Overload

The high dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

5.9 Transmission of Infectious Agents

Because GAMMAKED 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. No cases of transmission of viral diseases, vCJD or CJD have ever been identified for GAMMAKED. 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 Therapeutics LLC [1-800-520-2807].

5.10 Hematoma Formation

Do not administer GAMMAKED subcutaneously in patients with ITP because of the risk of hematoma formation.

5.11 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 GAMMAKED 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 GAMMAKED, 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.

5.12 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 studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in clinical practice.

PI: Intravenous Administration

The most serious adverse event observed in clinical study subjects receiving GAMMAKED IV for PI was an exacerbation of autoimmune pure red cell aplasia in one subject.

In four different clinical trials to study PI, out of 157 subjects treated with GAMMAKED, 4 subjects discontinued due to the following adverse events: Coombs negative hypochromic anemia, autoimmune pure red cell aplasia, arthralgia/hyperhidrosis/fatigue/myalgia/nausea and migraine.

In a study of 87 subjects, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion, such as diphenhydramine and acetaminophen.

Table 2 lists the adverse reactions reported by at least 5% of subjects during the 9-month treatment.

Table 3 lists the frequency of adverse reactions (as defined for Table 2), which were reported by at least 5% of subjects.

The mean number of adverse reactions per infusion that occurred during or within 72 hours of the end of product infusion was 0.33 for the GAMMAKED and 0.39 for the GAMIMUNE® N, 10% [Immune Globulin Intravenous (Human), 10%] treatment group.

In all three trials in primary humoral immunodeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The infusion rate was reduced for 11 of 222 exposed subjects (7 GAMMAKED, 4 GAMIMUNE N, 10%) at 17 occasions. In most instances, mild to moderate hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills. There were no anaphylactic or anaphylactoid reactions to GAMMAKED or GAMIMUNE N, 10% in clinical trials.

In the IV efficacy and safety study, serum samples were drawn to monitor the virus safety at baseline and one week after the first infusion of IGIV (for parvovirus B19), eight weeks after first and fifth infusion of IGIV (for hepatitis C, hepatitis B, and HIV-1), 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study (for hepatitis C, hepatitis B, HIV-1, and parvovirus B19). Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, Polymerase Chain Reaction [PCR]) and serological testing.  There were no treatment related emergent findings of virus transmission for either GAMMAKED or GAMIMUNE N, 10%.

PI: Subcutaneous Administration (PK and Safety Studies)

Adverse reactions were divided into 2 types: 1) Local infusion site reactions, and 2) Non-infusion site adverse reactions. Table 4 lists those adverse reactions (as defined for Table 2) occurring in ≥ 2% of infusions during the SC phase of two pharmacokinetic (PK) crossover and safety trials, one in adults and adolescents and the other in children and adolescents. [see Clinical Pharmacology (12.3)]

Table 5 lists the adverse reactions occurring in ≥ 5% of subjects and the frequency of adverse reactions (as defined for Table 2) per infusion.

There were no serious bacterial infections in the SC phase of the PK and safety trials.

Local Infusion Site Reactions

Local infusion site reactions with SC GAMMAKED consisted of erythema, pain and swelling. One child discontinued due to infusion site pain. The majority of local infusion site reactions resolved within 3 days. The number of subjects experiencing an infusion site reaction and the number of infusion site reactions decreased over time as subjects received continued weekly SC infusions. At the beginning of the SC phase (week 1) in the adult and adolescent trial, a rate of approximately 1 infusion site reaction per infusion was reported, whereas at the end of the study (week 24) this rate was reduced to 0.5 infusion site reactions per infusion, a reduction of 50%. In the children and adolescent trial, the rate of local infusion site reactions decreased from week 1 for all age groups by the end of the study.

ITP

In two different clinical trials to study ITP, out of 76 subjects treated with GAMMAKED, 2 subjects discontinued due to the following adverse reactions: Hives and Headache/Fever/Vomiting.

One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMMAKED. The death was judged to be unrelated to GAMMAKED.

No pre-medication with corticosteroids was permitted by the protocol. Twelve ITP subjects treated in each treatment group were pretreated with medication prior to infusion. Generally, diphenhydramine and/or acetaminophen were used. More than 90% of the observed drug related adverse events were of mild to moderate severity and of transient nature.

The infusion rate was reduced for 4 of the 97 exposed subjects (1 GAMMAKED™, 3 GAMIMUNE N, 10%) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons.

Table 6 lists the adverse reactions (as defined for Table 2) reported by at least 5% of subjects during the 3-month efficacy and safety study.

Serum samples were drawn to monitor the virus safety of the ITP subjects at baseline, nine days after the first infusion (for parvovirus B19), and 3 months after the first infusion of IGIV and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, PCR), and serological testing. There were no treatment related emergent findings of virus transmission for either GAMMAKED or GAMIMUNE N, 10%.

CIDP

In the CIDP efficacy and safety study, 113 subjects were exposed to GAMMAKED and 95 were exposed to Placebo. [see Clinical Studies (14)] As a result of the study design, the drug exposure with GAMMAKED was almost twice that of Placebo, with 1096 GAMMAKED infusions versus 575 Placebo infusions. Therefore, adverse reactions are reported per infusion (represented as frequency) to correct for differences in drug exposure between the 2 groups. The majority of loading-doses were administered over 2 days. The majority of maintenance-doses were administered over 1 day. Infusions were administered in the mean over 2.7 hours.

Table 7 shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events.

The most common adverse reactions with GAMMAKED were headache and pyrexia. Table 8 lists adverse reactions (as defined for Table 2) reported by at least 5% of subjects in any treatment group.

The most serious adverse reaction observed in clinical study subjects receiving GAMMAKED for CIDP was pulmonary embolism (PE) in one subject with a history of PE.

Laboratory Abnormalities

During the course of the clinical program, ALT and AST elevations were identified in some subjects.

• For ALT, in the IV PI study treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMMAKED group versus 5/88 (6%) of subjects in the GAMIMUNE N, 10% group (p = 0.026).
• In the SC PI study treatment emergent laboratory abnormalities during the SC phase occurred in several subjects. Four subjects (4/32, 13%) had elevated Alkaline Phosphatase. One subject (1/32, 3%) had an elevated ALT and three subjects (3/32, 9%) had an elevated AST. No elevations were > 1.6 times the upper limit of normal.
• In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding for elevation of ALT was observed among 3/44 (7%) of subjects in the GAMMAKED group versus 8/43 (19%) of subjects in the GAMIMUNE N, 10% group (p = 0.118).
• In the CIDP study, 15/113 (13%) of subjects in the GAMMAKED group and 7/95 (7%) in the Placebo group (p=0.168) had a treatment emergent transient elevation of ALT.

Elevations of ALT and AST were generally mild (< 3 times upper limit of normal), transient, and were not associated with obvious symptoms of liver dysfunction.

GAMMAKED may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 class.  Direct antiglobulin tests (DAT or direct Coombs tests), which are carried out in some centers as a safety check prior to red blood cell transfusions, may become positive temporarily.  There were 2 cases of hemolytic anemia across these clinical trials. One hemolytic event not associated with positive DAT findings was observed in the IV PI study in a woman with common variable immune deficiency and B12 deficiency (pernicious anemia) at a dose of (450 mg/kg).  The other hemolytic event occurred in the CIDP study in a subject with positive DAT at a dose of 1g/kg.

6.2 Postmarketing Experience

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

The following adverse reactions have been identified during post-approval use of IGIV products,(8,20) including GAMMAKED:

• Infusion Reactions:                  Hypersensitivity (e.g., anaphylaxis), tachycardia, malaise, flushing, or other skin reactions, chest discomfort, rigors, and 
                                                   changes in blood pressure
• Renal:                                       Acute renal dysfunction/failure, osmotic nephropathy
• Respiratory:                             Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, bronchospasm
• Cardiovascular:                       Cardiac arrest, thromboembolism, vascular collapse, hypotension
• Neurological:                           Coma, loss of consciousness, seizures/convulsions, tremor, aseptic meningitis
• Integumentary:                         Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
• Hematologic:                            Pancytopenia, leukopenia, hemolysis, hemolytic anemia, positive direct antiglobulin (Coombs test)
• General/Body as a Whole:       Rigors 
• Gastrointestinal:                      Hepatic dysfunction

8.1 Pregnancy

Risk Summary

There are no data with GAMMAKED use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with GAMMAKED. It is not known whether GAMMAKED can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMMAKED should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

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

8.4 Pediatric Use

PI: Intravenous

GAMMAKED was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects exposed to GAMMAKED were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that vomiting was more frequently reported in pediatrics (3 of 18 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels.

PI: Subcutaneous

SC GAMMAKED was evaluated in three pediatric subjects (age range 13-15 years) with PI along with adults, and separately in a second trial in 11 children and adolescents (age range 2-16 years). Pharmacokinetics and safety were similar to those in adults. No pediatric-specific dose requirements were necessary to achieve circulating IgG levels. Efficacy and safety in pediatric patients under 2 years of age using the SC route of administration have not been established.

ITP

For treatment of ITP, GAMMAKED must be administered by the intravenous route.

GAMMAKED was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects exposed to GAMMAKED were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that fever was more frequently reported in pediatrics (6 of 12 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels. One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMMAKED. The death was judged to be unrelated to GAMMAKED.

CIDP

The safety and effectiveness of GAMMAKED have not been established in pediatric subjects with CIDP.

8.5 Geriatric Use

Use caution when administering GAMMAKED to patients age 65 and over who are at increased risk for thrombosis or renal insufficiency. [see Boxed Warning, Warnings and Precautions (5.2, 5.4)] Do not exceed recommended doses, and administer GAMMAKED at the minimum infusion rate practicable. Clinical studies of GAMMAKED did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

PI

GAMMAKED supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacterial, viral, parasitic, and mycoplasmal agents, and their toxins. The mechanism of action in PI has not been fully elucidated.

ITP

The mechanism of action of high doses of immunoglobulins in the treatment of ITP has not been fully elucidated.

CIDP

The precise mechanism of action in CIDP has not been fully elucidated.

12.3 Pharmacokinetics

Two pharmacokinetic crossover trials were carried out with GAMMAKED in 44 subjects with Primary Humoral Immunodeficiency to assess intravenous vs subcutaneous administration. In the first study, a single sequence, open-label, crossover trial in adults and adolescents, the pharmacokinetics, safety, and tolerability of SC administered GAMMAKED in subjects with PI were evaluated.(24) A total of 32 and 26 subjects received GAMMAKED as IV or SC for PK study, respectively, of whom 3 were adolescents.  Subjects received GAMMAKED 200-600 mg/kg IV every 3-4 weeks for at least 3 months, at which time they entered the IV phase of the study. Subjects were crossed over to weekly SC infusions. The weekly SC dose was determined by multiplying the total IV dose by 1.37 and dividing the resultant new total dose by 3 or 4 depending on the previous IV interval.

In the second study, a single sequence, open-label, crossover trial, the pharmacokinetics, safety, and tolerability of SC administered GAMMAKED were evaluated in children and adolescents.  The design of the study was essentially the same as above. A total of 11 subjects received GAMMAKED as IV and 10 received GAMMAKED as SC for PK analysis. Age groups were as follows: age 2 to 5 years, [N = 1 both phases]; 6 to 11 years, [N = 5 completing IV phase, N = 4 evaluated in SC phase]; 12-16 years: [N = 5 both phases].

Intravenous Administration

The pharmacokinetic parameters of GAMMAKED, measured as total IgG for intravenous administration are shown in Table 10.

PI: Subcutaneous Administration

The PK parameter (AUC of total IgG) following IV and SC administration is summarized in Table 11 for subcutaneous vs intravenous administration in the two pharmacokinetic trials. In the adult and adolescent trial, the lower bound of the 90% confidence interval for the geometric mean ratio of AUC (SC vs. IV) was 0.861, therefore, meeting the pre-specified non-inferiority margin between the two modes of administration. The PK analysis results in children and adolescents are consistent to those in the adult and adolescent trial, demonstrating the appropriateness of the conversion factor of 1.37 applied to calculating the SC dose from the IV dose of GAMMAKED in pediatric populations.

The mean trough concentrations (mean Ctrough) of total IgG following IV and SC administration are presented in Table 12 for both studies.

In contrast to plasma total IgG levels observed with monthly IV GAMMAKED treatment (rapid peaks followed by a slow decline), the plasma IgG levels in subjects receiving weekly SC GAMMAKED therapy were relatively stable (Figure 7, adult and adolescent trial).

Figure 7: Mean Steady-state Plasma Total IgG Concentration vs. Time Curves Following IV Administration or Weekly SC Administration in Adults and Adolescents